The Role of Estrogens in Rheumatoid Arthritis Physiopathology

*Maria Fernanda Romo-García, Martín Zapata-Zuñiga, José Antonio Enciso-Moreno and Julio Enrique Castañeda-Delgado*

### **Abstract**

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease that can lead to irreversible disability. It affects women in a higher proportion than men (3:1 cases). Several reports suggest a link between female sexual hormones (estrogens) and RA features. It's been described that biological processes where basal estrogen levels are altered like in menstruation, pregnancy, and menopause modifies RA onset, flare, disease severity, and inflammation. Estrogens have a direct action upon the immune system though ERα and ERβ receptors, which have distinct affinity to estrogen concentrations and modifications and have effects upon RA in a dose and receptor dependent manner. The studies focused on dose dependent response at experimental settings reveal a wide (from 25 pg/L to several μg/L) and even contradictory spectrum of effects in patients and cells. This chapter summarizes the contributions and effects of estrogens in RA physiopathology, clinical features, and discusses the possible contributions of estrogen administration and concentration of hormone replacement therapy (HRT) to improve the quality of life and reduce the symptoms of RA patients based on the knowledge of the biology of these hormones.

**Keywords:** rheumatoid arthritis, physiopathology, immune function, estrogen

### **1. The RA-gender-hormones link**

Rheumatoid arthritis (RA) is defined as a chronic, inflammatory joint disease that without effective and timely treatment can lead to irreversible disability by cumulative joint damage. This autoimmune disease is characterized in most cases by autoantibodies against immunoglobulin G (RF) and citrullinated proteins (ACPAs) [1–3]. The alterations in the immune response is only one face of the disease since it has been described as a heterogeneous disease [4, 5]. This is supported by the wide variation in responsiveness to different rheumatic treatments [6]. Research suggests this might be due to variations in the distribution/expression of estrogen receptors (ERs) in immune cells; ERs often bind to promoter regions in the DNA associated with transcription factors (e.g., NF-κB, SP1, AP-1, C/EBPb) that are important for immune cell function [7].


is 3 to 1 compared to men [20, 21]. Also, RA is much more severe in women compared to men (**Table 2**). For example, in a multiple logistic regression analysis for all point and period remissions, male gender seemed to be a strong predictor of remission; for women, the frequency of remission at 18, 24, and 60 months was 30.4, 32.1, and 30.8%, respectively; meanwhile for men, the remission rate was 41.7, 48.0, and 52.4% [22]. Additionally, in another study from a total of 1709 RA patients, (77% female) women had a longer disease duration (P < 0.001) despite the fact that at baseline, women had a lower frequency of anti-CCP positivity (P = 0.03) and lower CRP (P < 0.001), and at 12 months, men achieved remission

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

more frequently (18% vs. 12%, P = 0.045) compared to women [23].

associated with autoimmune diseases.

BARFOT [22]

QUEST RA n = 6400 [24]

AIR [23]

AIR n = 1709 [23]

**Table 2.**

**19**

*various studies.*

during pregnancy and postpartum in women with RA.

**Reference Year Features men Features women Main findings**

2014 Lower frequency

DAS28 5.37 CRP 18

DAS28 5.6 CRP 28 ERS 33 CCP positives 74.7%

DAS28 4.3 ESR 30 HAQ = 1.1

of anti-CCP (P = 0.03) Lower CRP (P < 0.001)

*Baseline and remission characteristics of RA in men vs. women: comparison of different clinical characteristics of female RA patients compared to male RA patients and the difference in remission rates documented on*

Women had a much lower remission rate than men, although their disease activity before treatment seemed similar

At 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045). In anti-TNF failure, remission rates were higher in

30% of men and 17% of women in QUEST-

men than in women

RA were in DAS28 remission

Female had longer disease duration At 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045)

2007 DAS28 = 5.09 CRP 27

2014 DAS28 = 5.6 CRP 32 ERS 34 CCP positives 80.7%

2009 DAS28 = 3.8 ESR 23 HAQ = 0.8

The estrogen dysregulation has been associated with disease severity and accel-

eration of lumbar facet joint damage in arthritis [25, 26]. Added to this, some disorders of the reproductive system seem to increase the risk to develop RA, for example, physician-diagnosed polycystic ovary syndrome (RR 2.58; 95% CI, 1.06– 6.30) and endometriosis (RR 1.72; 95% CI, 0.93–3.18) [27, 28]. Suggesting an important role of sex hormones and menstrual cycle regulation as risk factors

These differences could be attributed to the fact that women respond after immunization with a more exacerbated antibody production and an increase in cellmediated responses. Thus, female patients show higher CD4+ T-cell counts, higher levels of IgM, and T-helper 1 (Th1) cytokine production [29]. This suggests that differences in immune response could be mediated by the hormonal ratios observed

There is an increased risk of RA worsening or new onset of disease especially after the first trimester postpartum (**Table 3**), where several immune and hormonal changes are detected like: elevation of monocyte-related transcripts [30], decrease in corticosteroids, estrogen, progesterone, IL-4, IL-10, and humoral immunity, and increase of TNF-α and IFN-γ [31]. These postpartum flares occur within the first 4 months in most patients with chronic RA [32, 33], even a 62% had more affected joints at postpartum; these results were similar when the analysis was restricted to tender joints only [32]. Aggravation of disease activity (in 6 of 9 patients with RA)

#### **Table 1.**

*Average levels of estrogens on distinct phases of the reproductive cycle.*

The relation of immune response and estrogens in RA began with the observation of S. Hench in 1938, where he found pregnancy ameliorated RA, this was the basis for the formulation of his hypothesis sustaining that hormone deficiency could lead to the development of RA, but at that moment, he hypothesized adrenal insufficiency as the responsible of RA pathogenesis [8]. Furthermore, administration of corticosteroids was prescribed for RA patients and the results of the therapy were considered "a miracle cure for RA," but in the case of women, the regulation of adrenal glands seems to be only a part of the therapy. Other studies demonstrate that sexual hormones seem to have a very important role in RA pathogenesis. For example, in vitro studies demonstrated that the achieved concentrations of cortisol do not affect inflammatory cell function, as did the serum of pregnant women, which is rich in sexual hormones. Also the corticosteroid levels return to normality 3 days after delivery, which does not coincide with the pattern of rheumatoid arthritis relapse, common after the third month of delivery [9]. This antecedent opened a new field of study focused on hormones and RA. When concentrations of hormones were analyzed in synovial fluid, a correlation was found in this tissue including, dehydroepiandrosterone (DHEA) which levels are inversely correlated with disease severity and associated with autoimmunity [10, 11] and corticotrophin-releasing hormone (CRH) which levels remain constant in synovial fluids and tissues from RA patients despite the steroid treatment [12]. The dysregulated production of estrogen levels in RA is not exclusive of women; higher estradiol (E2) concentrations and decreased androgen levels have been found in women and men synovia [13]. These concentrations are correlated with those measured in serum in 66% of the patients (14 of 21 patients). The estradiol mean concentrations was 38.25–9.74 pg/ml in serum and 18.83–5.70 pg/ml in synovia; these concentrations showed a positive correlation (R = 0.79, P < 0.0003) [13–15].

Fluctuations in estrogen levels appear to remarkably impact immunologic profile. Estrogen concentration during lactation is slightly low compared to normal levels (35.9–54.4 pg/ml vs. 63.3–216 pg/ml) upon the normal higher levels (100– 400 pg/ml in the late follicular stage) (**Table 1**); together, prolactin and estrogen levels could lead to a change in immune response [16, 17].

#### **2. Prevalence, incidence, and severity of RA in women**

Autoimmune diseases affect approximately 8% of the population, out of this percentage 78% are women [18, 19] and for the specific case of RA, the proportion

#### *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

is 3 to 1 compared to men [20, 21]. Also, RA is much more severe in women compared to men (**Table 2**). For example, in a multiple logistic regression analysis for all point and period remissions, male gender seemed to be a strong predictor of remission; for women, the frequency of remission at 18, 24, and 60 months was 30.4, 32.1, and 30.8%, respectively; meanwhile for men, the remission rate was 41.7, 48.0, and 52.4% [22]. Additionally, in another study from a total of 1709 RA patients, (77% female) women had a longer disease duration (P < 0.001) despite the fact that at baseline, women had a lower frequency of anti-CCP positivity (P = 0.03) and lower CRP (P < 0.001), and at 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045) compared to women [23].

The estrogen dysregulation has been associated with disease severity and acceleration of lumbar facet joint damage in arthritis [25, 26]. Added to this, some disorders of the reproductive system seem to increase the risk to develop RA, for example, physician-diagnosed polycystic ovary syndrome (RR 2.58; 95% CI, 1.06– 6.30) and endometriosis (RR 1.72; 95% CI, 0.93–3.18) [27, 28]. Suggesting an important role of sex hormones and menstrual cycle regulation as risk factors associated with autoimmune diseases.

These differences could be attributed to the fact that women respond after immunization with a more exacerbated antibody production and an increase in cellmediated responses. Thus, female patients show higher CD4+ T-cell counts, higher levels of IgM, and T-helper 1 (Th1) cytokine production [29]. This suggests that differences in immune response could be mediated by the hormonal ratios observed during pregnancy and postpartum in women with RA.

There is an increased risk of RA worsening or new onset of disease especially after the first trimester postpartum (**Table 3**), where several immune and hormonal changes are detected like: elevation of monocyte-related transcripts [30], decrease in corticosteroids, estrogen, progesterone, IL-4, IL-10, and humoral immunity, and increase of TNF-α and IFN-γ [31]. These postpartum flares occur within the first 4 months in most patients with chronic RA [32, 33], even a 62% had more affected joints at postpartum; these results were similar when the analysis was restricted to tender joints only [32]. Aggravation of disease activity (in 6 of 9 patients with RA)


#### **Table 2.**

*Baseline and remission characteristics of RA in men vs. women: comparison of different clinical characteristics of female RA patients compared to male RA patients and the difference in remission rates documented on various studies.*

#### *Rheumatoid Arthritis - Other Perspectives towards a Better Practice*


could possibly be related to "premenstrual tension syndrome" and alteration in pain perception [44], but in a study where only objective measures of disease activity were measured, a significant cyclical change in finger joint size (FJS) was seen in 4 of 7 patients with RA, with all peaks occurring within 6 days of the start of menstruation [45] while on contrary, the morning stiffness was reduced during the post-ovulatory phase where estrogen and progesterone are high [46], indicating that this worsening of symptoms might be related to variations in hormone levels [47]. Based on this evidence, a relation between low levels of estrogen (at luteal phase) can correspond to enhancement of RA symptoms. Contrary to what occurs on pregnancy, where high estrogen levels seem to have a protective effect. Until now there is no follow up study available to display the effect of cyclical variations

As stated previously, the relationship of RA onset and sex hormones has been widely studied. This phenomena was described first 80 years ago [8] and was noticed that pregnant patients with RA usually go into remission [48] in a 20–40% by the third trimester and 50% had low disease activity [49]. Prospective studies have shown that only 48–66% of women with RA experience improvement in pregnancy, with 20% becoming quiescent by the third trimester and 16% in com-

plete remission (no joints with active disease without therapy) [32, 50].

scarce information about its possible function during pregnancy.

clinical improvement observed in RA during pregnancy.

**3.3 Menopause and arthritis**

**21**

It has been hypothesized that estradiol might be the principal regulator of immune response during pregnancy, nevertheless other estrogens might be implicated in this immune regulation, as an example we can cite estriol (E3) which is mainly produced during pregnancy [51, 52], and estetrol (E4) is synthesized exclusively by the fetal liver during pregnancy being able to reach the maternal circulation through the placenta [53]; thus, these two estrogens, specifically E4 could have an important role in the immune regulation during pregnancy; nevertheless, there is

A shift from a Th1/Th17 pro-inflammatory response to a Th2/Treg response has been observed in pregnancy [54, 55]. This could explain the decrease of IL-2 during pregnancy, while soluble TNF receptor, p55 and p75, increases [56]. The role of the immune system in pregnancy is very important. It has been observed that a depletion of immune cells can cause the termination of the pregnancy. Nevertheless, it is not very clear how such changes in T helper cell function could impact the implantation process. It has been suggested that the response could be induced by trophoblastic cells that can secrete IL-6, IL-8, MCP-1, and GRO-α, early in pregnancy [43]. During the first trimester, NK cells, dendritic cells, macrophages, and regulatory T cells (Treg) infiltrate the decidua and accumulate around the trophoblastic cells [57–59]. This regulation of the immune response could be the cause beneath the

RA onset is common in the peri-menopausal age, which is not the case with SLE [60] and while hormone replace therapy (HRT) is proposed as therapy for women with RA, OCP and postmenopausal hormones significantly increased the risk of SLE [61]. Also, there is an inverse trend for RA incidence when women reach menopause after 51 years compared to those who reach menopause before 45 years of age. This is consistent with a decline in the production of sex hormones and suggesting that changes in immune regulation due to the availability of estrogen receptors in

in estrogen levels and symptoms severity in RA patients.

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

**3.2 Arthritis and pregnancy**

#### **Table 3.**

*Percentage of healthy subjects who presented RA onset after delivery or post-partum.*

was detected at 6 and 12 weeks postpartum as a progressive decrease in leucocyte counts and increased CPR, whose levels where normal during pregnancy [34]. In the "Pregnancy induced Amelioration of Rheumatoid Arthritis" (PARA) study, 118 patients were followed up until 26 weeks postpartum and levels of autoantibodies anti-CCP, IgM-RF, IgG-RF, and IgA-RF were measured. The median levels of autoantibodies during pregnancy were stable and declined postpartum. When hemodilution was taken into account, an increase in the levels of antibodies explains the symptom onset as well as the start of symptoms due to inflammatory processes directly related to immunoglobulin actions [8]**.**

These dramatic postpartum changes can explain why there is a three to fivefold increased risk of onset during the first 3 months postpartum, with the highest risk being after a first pregnancy [38], in the cohort of Iijima composed by 2547 patients, and the same results were obtained [33]. The available studies on pregnancies in women with RA suggest that outcomes are worse than in the general population [39].

Such RA onset coincides with hormonal changes in the postpartum period, and only the changes during postpartum contribute to RA. During breastfeeding prolactin [40] by itself increases the antibody production and pro-inflammatory cytokines [41] and after the first pregnancy the risk of RA increases several times [42]. An additional link between sex-hormones and increased risk of RA come from data showing that the administration of drugs for lactation suppression which mainly are high-dose estrogens, increased risk of RA development [26]. Given that several cytokines are regulated by estrogens, so a decrease in this hormone could be responsible for flare and disease onset as it contributes to the activation of the immune system necessary for the delivery [43].

Estrogen seems to orchestrate several key features of the immune response and may be a critical factor in the incidence and severity of the disease in women. Small variations in estrogen concentration can have a very wide range of effects, even some of them could be opposite even when they are provoked by the same molecule.

#### **3. Influence of reproductive cycle hormones and their role in RA immune response**

#### **3.1 Arthritis and menstruation**

Since 1980, it was noted that young women with rheumatoid arthritis (RA) report an exacerbation of symptoms just before or at the time of menstruation, it *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

could possibly be related to "premenstrual tension syndrome" and alteration in pain perception [44], but in a study where only objective measures of disease activity were measured, a significant cyclical change in finger joint size (FJS) was seen in 4 of 7 patients with RA, with all peaks occurring within 6 days of the start of menstruation [45] while on contrary, the morning stiffness was reduced during the post-ovulatory phase where estrogen and progesterone are high [46], indicating that this worsening of symptoms might be related to variations in hormone levels [47]. Based on this evidence, a relation between low levels of estrogen (at luteal phase) can correspond to enhancement of RA symptoms. Contrary to what occurs on pregnancy, where high estrogen levels seem to have a protective effect. Until now there is no follow up study available to display the effect of cyclical variations in estrogen levels and symptoms severity in RA patients.

#### **3.2 Arthritis and pregnancy**

As stated previously, the relationship of RA onset and sex hormones has been widely studied. This phenomena was described first 80 years ago [8] and was noticed that pregnant patients with RA usually go into remission [48] in a 20–40% by the third trimester and 50% had low disease activity [49]. Prospective studies have shown that only 48–66% of women with RA experience improvement in pregnancy, with 20% becoming quiescent by the third trimester and 16% in complete remission (no joints with active disease without therapy) [32, 50].

It has been hypothesized that estradiol might be the principal regulator of immune response during pregnancy, nevertheless other estrogens might be implicated in this immune regulation, as an example we can cite estriol (E3) which is mainly produced during pregnancy [51, 52], and estetrol (E4) is synthesized exclusively by the fetal liver during pregnancy being able to reach the maternal circulation through the placenta [53]; thus, these two estrogens, specifically E4 could have an important role in the immune regulation during pregnancy; nevertheless, there is scarce information about its possible function during pregnancy.

A shift from a Th1/Th17 pro-inflammatory response to a Th2/Treg response has been observed in pregnancy [54, 55]. This could explain the decrease of IL-2 during pregnancy, while soluble TNF receptor, p55 and p75, increases [56]. The role of the immune system in pregnancy is very important. It has been observed that a depletion of immune cells can cause the termination of the pregnancy. Nevertheless, it is not very clear how such changes in T helper cell function could impact the implantation process. It has been suggested that the response could be induced by trophoblastic cells that can secrete IL-6, IL-8, MCP-1, and GRO-α, early in pregnancy [43].

During the first trimester, NK cells, dendritic cells, macrophages, and regulatory T cells (Treg) infiltrate the decidua and accumulate around the trophoblastic cells [57–59]. This regulation of the immune response could be the cause beneath the clinical improvement observed in RA during pregnancy.

#### **3.3 Menopause and arthritis**

RA onset is common in the peri-menopausal age, which is not the case with SLE [60] and while hormone replace therapy (HRT) is proposed as therapy for women with RA, OCP and postmenopausal hormones significantly increased the risk of SLE [61]. Also, there is an inverse trend for RA incidence when women reach menopause after 51 years compared to those who reach menopause before 45 years of age. This is consistent with a decline in the production of sex hormones and suggesting that changes in immune regulation due to the availability of estrogen receptors in

immune cells and circulating estrogens might also have an effect on RA onset on these late menopausal women [26].

RA, CD8+, lymphocytes were significantly diminished in the spleen of the estradiol-

Fibroblast-like synoviocytes: on FLS (**Figure 1**), estrogens induce an increase of MMP invasion of cartilage when these cells were transfected with ERα, thus estrogen levels can influence joint erosion degradation of extracellular matrix [80].

B cells: concentrations of E2 ranging 75 pg/ml or above activate ERs, leading to an upregulation of CD22, SHP-1, BCL-2, and V-CAM-1. This can alter the survival of immature B cells that would normally be deleted [82]. Also a decrease in transitional B cells and increased marginal zone B cells [83] has been observed. In the presence of estrogen, BAFF increased its expression by 5-fold, but this characteristic was more pronounced in cells isolated from women than in those from man [84]. An overexpression of BAFF in transgenic mice leads to manifestations of autoimmune disease [85], and similar BAFF increase has been reported in the serum of patients with RA, [86] even at early stages of RA and correlates with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (R = 0.76 and R = 0.49) [87]. It has been hypothesized that high levels of estrogens during pregnancy could prevent B cell apoptosis and therefore enhance survival of autoreactive cells [88]. Implications of estrogen signaling on auto reactive B cell expansion and autoantibodies production have not been evaluated in the clinical

*E2 cell receptors in different cell populations: different effects of estrogen concentrations upon estrogen receptors ER-α and ER-β present on each cell. Left: receptors and cells were they are present. Horizontal red arrow: gradient of estrogen concentrations. Blue arrows: decrease of an effect by estrogen concentration. Red arrows: increase of an effect by estrogen concentrations. This is an original image made explicitly for this publication*

Regarding this antecedent, an increase in hormonal levels at synovia could influence cytokine levels but it is not clear if the effects of estrogen upon certain cytokines like TNF-α, IL-10, and IL-6 are unidirectional or could be an initial trigger of aromatase activity. For example, TNF-α, IL-1, and IL-6 stimulate fibroblast aromatase activity in a dose-dependent manner; the aromatase enzyme complex

is involved in the peripheral conversion of androgens (testosterone and androstenedione) to estrogens (estrone and estradiol, respectively) [81].

treated animals and were suppressed in the thymus [79].

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

setting.

**Figure 1.**

**23**

*and not subject to copyright.*

### **4. Molecular aspects of estrogen effects in immune response**

#### **4.1 Regulation by estrogen receptors**

ERα (NR3A1) and ERβ (NR3A2) that are encoded by ESR-1 and ESR-2 genes expressed on human chromosomes 6 and 14, respectively [62]. It is estimated that both receptors regulate 40% of the genes in cell line U2OS [63], but despite both are estrogen receptors (ERs), ERα and ERβ microarray analysis had demonstrated that they regulate different genes [7, 64, 65]. The activation of one or other of these ERs has specific effects in distinct, non-overlapping or even antagonist effects determined by factors like distribution, expression, dimerization, splice variant ER isoforms, signaling pathways triggered, physiological stage, and interaction with specific co-activators/repressors [62]. One example of the distribution of these receptors is given in T lymphocytes, CD4+ cells which have higher ERα levels, B cells have higher ERβ expression than ERα and CD8+ cells have lower expression of both receptors [66], murine splenic DCs express ERα but has negligible ERβ expression and bone marrow-derived and peritoneal macrophages also express ERα and few if any ERβ [67, 68], so given the expression, lower or higher concentrations of estrogens will be needed to activate the receptors with the lowest expression [69].

In general terms, the effect of ERα on the immune system is more prominent than ERβ due to regulating multiple NF-kB pathway members to control cytokine responses. This, given that ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription [70]. Also, its promotion of strong antigen-specific Th1 cell responses was demonstrated in ERαdeficient mice where E2 effects on Th1 responses were not observed [71], apart from but this receptor is not only delimited to the cells at periphery, its expression seems to have effects in the thymus and spleen since deletion of ERα led to hypoplasia of both organs and contribute to the increased frequency of immature CD4 + CD8+ thymocytes and decreased CD4 + CD8 cells [72].

#### **4.2 Estrogen dose and receptor dependent effects**

As mentioned previously, estrogen receptors (ER) are expressed in the immune cells; TaqMan RT-PCR analyses indicate that in CD4 + T-helper cells express higher concentrations of ERα, B cells ERβ, and CD8+ T cells; monocytes express both ERs at lower concentrations [66]; this proportion is important because despite both receptors are present in all PBMCs, the functions elicited by their activation vary depending on the proportion of each receptor on such cells. A wider description of such differential effects is made for several cell types:

T cells: CD4+ T responds to E2 administration at low physiological levels (of 60–100 pg/ml in castrated female mice) increasing antigen specific responses, production of IFNγ and IL2 as well as inducing FoxP3 positive Treg cell differentiation [71, 73–75]. During the reproductive cycle CD4+, T cells increase on preovulatory (late follicular) [76], decrease in the luteal phase (60–150 pg/ml) compared to the early follicular phase (30–100 pg/mL) [77] and increased in the first trimester of pregnancy (8.9%, vs. 4.4% of controls) and 6–8 weeks following delivery [78]. Regarding CD8+ T cells, there is not much evidence, in models of collagen-II induce

#### *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

RA, CD8+, lymphocytes were significantly diminished in the spleen of the estradioltreated animals and were suppressed in the thymus [79].

Fibroblast-like synoviocytes: on FLS (**Figure 1**), estrogens induce an increase of MMP invasion of cartilage when these cells were transfected with ERα, thus estrogen levels can influence joint erosion degradation of extracellular matrix [80]. Regarding this antecedent, an increase in hormonal levels at synovia could influence cytokine levels but it is not clear if the effects of estrogen upon certain cytokines like TNF-α, IL-10, and IL-6 are unidirectional or could be an initial trigger of aromatase activity. For example, TNF-α, IL-1, and IL-6 stimulate fibroblast aromatase activity in a dose-dependent manner; the aromatase enzyme complex is involved in the peripheral conversion of androgens (testosterone and androstenedione) to estrogens (estrone and estradiol, respectively) [81].

B cells: concentrations of E2 ranging 75 pg/ml or above activate ERs, leading to an upregulation of CD22, SHP-1, BCL-2, and V-CAM-1. This can alter the survival of immature B cells that would normally be deleted [82]. Also a decrease in transitional B cells and increased marginal zone B cells [83] has been observed. In the presence of estrogen, BAFF increased its expression by 5-fold, but this characteristic was more pronounced in cells isolated from women than in those from man [84]. An overexpression of BAFF in transgenic mice leads to manifestations of autoimmune disease [85], and similar BAFF increase has been reported in the serum of patients with RA, [86] even at early stages of RA and correlates with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (R = 0.76 and R = 0.49) [87]. It has been hypothesized that high levels of estrogens during pregnancy could prevent B cell apoptosis and therefore enhance survival of autoreactive cells [88]. Implications of estrogen signaling on auto reactive B cell expansion and autoantibodies production have not been evaluated in the clinical setting.

#### **Figure 1.**

*E2 cell receptors in different cell populations: different effects of estrogen concentrations upon estrogen receptors ER-α and ER-β present on each cell. Left: receptors and cells were they are present. Horizontal red arrow: gradient of estrogen concentrations. Blue arrows: decrease of an effect by estrogen concentration. Red arrows: increase of an effect by estrogen concentrations. This is an original image made explicitly for this publication and not subject to copyright.*

Another field with scarce exploration and understudied outcome of the estrogen therapy on RA is the modification and decrease of autoantibodies by estrogen action. This novel mechanism is not clearly elucidated and a lot of investigation in this topic is needed, but the little existing evidence demonstrate that estrogens can influence antibodies production and activity by modification of glycosylation of antibodies like galactosylation of human IgG in healthy individuals [89]. The changes in immunogenesis of antibodies by estrogens was demonstrated in an experiment were the induction of anti-C11 autoantibodies was measured, lower anti-C11 levels were observed in the estrogen treated group as compared with their controls [90]. The same behavior was observed by Nielsen et al. [91] and further investigations demonstrated than on CIA models sustained levels of 0.36 mg of estradiol (comparable to estrus phase) had similar quantities of IgG anti-CII antibodies than controls but have not developed RA, this was due to the different Ig subclasses. Estradiol-treated mice produced more IgG1, and mice from the placebo group produced significantly higher levels of IgG3 [92]. Other changes that estrogens induce in autoantibodies are an increase in sialylation, which has been observed during pregnancy and within 3 months post-delivery (when RA risk is presumably higher) [93]. Antibodies sialylation affects inflammation; in the case of RA, the transition from preclinical asymptomatic autoimmunity to clinical phases is associated with a change in the sialylation of antibodies [94–96]. Changes in sialylation by estrogens have been explored already in RA patients. E2 treatment increases sialylation on postmenopausal RA women [97], so taken together if E2 induces anti-inflammatory IgG by inducing St6Gal1 expression in antibodyproducing cells [98].

(10<sup>9</sup> M) equivalent to therapeutic concentrations of estradiol for 24 reduced LPSinduced TNF-α production [106]. Despite all evidence there is no clear explanation about how estrogens (estradiol or estriol) interfere in the clinical outcomes and immune response in RA depending on ERα/ERβ or evidence of the effects associated to a certain dose range. This could be useful for the development of more

Estrogen chemical modifications: as mentioned before, a correlation exists between estrogen concentration in synovial fluid and serum estrogens (R = 0.79, P < 0.0003), and concentration of free estrogens (E2) is higher in RA as compared to controls [13–15]. Therefore, measured estrogen concentration in synovia could reflect a general overview of estrogen body concentrations. There is a significantly higher level of androstenedione (a precursor of estrone and estradiol) in synovial fluid of RA patients as estrone (E1), suggesting that these higher levels are the result of an elevated activity of aromatase [14]. Available steroid pre-hormones are rapidly converted to estrogens, which seems to have pro-inflammatory activity in the synovial tissue. When analyzed more in detail, it was found that increased estrogen concentrations in RA synovial fluid (in women as in men) were 16α-hydroxyestrone and 4-hydroxyestradiol (hydroxylated forms), while the estrone levels were detected increased on RA patients, the 2-hydroxyestrone showed no differences comparing RA vs. healthy controls [14], and depending on its modifications, estrogens can trigger very different effect in the body. For example, the hydroxylated forms of estradiol, 16OH-E2 and 2OH-E2 enhance the proliferation of THP-1 (**Figure 2**) monocytes at high concentrations (10<sup>9</sup> M). Meanwhile, the hydroxylated estrones 4OH-E1 and 2OH-E1 enhance cell proliferation at low concentration (10<sup>10</sup> M), [107], which are inhibited by antiestrogen drugs [108], except for 2OH-E1, which still induced proliferative effect (10<sup>10</sup> M) [107]. In some cases, estrogens produce the same affect but have different target cells in a dose dependent manner because of the proportion of expression of ERs; E2 and endocrine disrupting chemicals (EDCs) affect cell mutagenesis through ERα. At 10–8 M is observed an inhibition on the mitogenesis of B cells and at 10–6 M in T cells. For the EDCs

*Estrogen modifications and concentrations: image showing the differences between the effects depending of the estrogen modifications. Activity of different estrogen modifications upon proliferation of THP-1 cells and concentrations needed for achieve the effect. Green lines: increase in proliferation. Red lines: decrease in proliferation. This is an original image made explicitly for this publication and not subject to copyright.*

selective ERα or ERβ agonists and antagonists.

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

**Figure 2.**

**25**

#### **4.3 Estrogen effects: dependency on concentration and chemical modifications**

Estrogen concentration: it seems to exist a cut-off point in the concentration of estrogens that determine different effects, because sensitivity of receptors even at sub physiological concentrations of estrogens. For example, in a model of collageninduced arthritis (CIA) in female mice, after type II collagen (CII) immunization those treated with the ER antagonist ICI 182,780 (which binds to both ERα and ERβ but not to the surface receptor) doses that insufficient to block estrus cycle, were sufficient for block the E3-mediated suppression of CIA [99, 100]. On the range of higher concentrations, estradiol (E2) can inhibit the production of proinflammatory cytokines, like TNF-α, (IL)-1 β, and IL-6 and induce antiinflammatory cytokines such as IL-4, IL-10, and TGF-β (Th2 phenotype). On the contrary, low concentration of E2 stimulates TNF, INF-γ, and IL-1 β production and exerts an inhibitor effect on NK cells [101, 102]. In brain tissue, it was demonstrated that 2-OH-estradiol protects neurons from oxidative stress at nanomolar concentrations (10 nmol/L) but 17-β-estradiol showed oxidative effects only at micromolar concentrations (1–10 μmoI/L); these concentrations were in the order of magnitude expected to activate their receptors (10–1000 nmol/L) demonstrating that physiological levels of estradiol may protect through receptor-dependent mechanisms from mitochondrial ROS, whereas higher concentrations may act through independent ER mechanisms [103]. This wide range of dose dependent effects could suggest us that a difference exists in the actions of estrogens between reproductive organs and its effects in the immune system. With respect to pro inflammatory cytokines such as TNF-αβ IL-1 and IL-6, estrogen effects seem to be bimodal where pharmacological concentrations (**Table 3**) of 50,000–100,000 pg/ml (equivalent to 100 μg/L or 10<sup>6</sup> M) decrease or inhibit the cytokine production and physiological concentrations of 5000 pg/ml increase cytokine production [104, 105]; this agree with other results where macrophages treated with doses of 0.001–100 nM

#### *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

(10<sup>9</sup> M) equivalent to therapeutic concentrations of estradiol for 24 reduced LPSinduced TNF-α production [106]. Despite all evidence there is no clear explanation about how estrogens (estradiol or estriol) interfere in the clinical outcomes and immune response in RA depending on ERα/ERβ or evidence of the effects associated to a certain dose range. This could be useful for the development of more selective ERα or ERβ agonists and antagonists.

Estrogen chemical modifications: as mentioned before, a correlation exists between estrogen concentration in synovial fluid and serum estrogens (R = 0.79, P < 0.0003), and concentration of free estrogens (E2) is higher in RA as compared to controls [13–15]. Therefore, measured estrogen concentration in synovia could reflect a general overview of estrogen body concentrations. There is a significantly higher level of androstenedione (a precursor of estrone and estradiol) in synovial fluid of RA patients as estrone (E1), suggesting that these higher levels are the result of an elevated activity of aromatase [14]. Available steroid pre-hormones are rapidly converted to estrogens, which seems to have pro-inflammatory activity in the synovial tissue. When analyzed more in detail, it was found that increased estrogen concentrations in RA synovial fluid (in women as in men) were 16α-hydroxyestrone and 4-hydroxyestradiol (hydroxylated forms), while the estrone levels were detected increased on RA patients, the 2-hydroxyestrone showed no differences comparing RA vs. healthy controls [14], and depending on its modifications, estrogens can trigger very different effect in the body. For example, the hydroxylated forms of estradiol, 16OH-E2 and 2OH-E2 enhance the proliferation of THP-1 (**Figure 2**) monocytes at high concentrations (10<sup>9</sup> M). Meanwhile, the hydroxylated estrones 4OH-E1 and 2OH-E1 enhance cell proliferation at low concentration (10<sup>10</sup> M), [107], which are inhibited by antiestrogen drugs [108], except for 2OH-E1, which still induced proliferative effect (10<sup>10</sup> M) [107]. In some cases, estrogens produce the same affect but have different target cells in a dose dependent manner because of the proportion of expression of ERs; E2 and endocrine disrupting chemicals (EDCs) affect cell mutagenesis through ERα. At 10–8 M is observed an inhibition on the mitogenesis of B cells and at 10–6 M in T cells. For the EDCs

#### **Figure 2.**

*Estrogen modifications and concentrations: image showing the differences between the effects depending of the estrogen modifications. Activity of different estrogen modifications upon proliferation of THP-1 cells and concentrations needed for achieve the effect. Green lines: increase in proliferation. Red lines: decrease in proliferation. This is an original image made explicitly for this publication and not subject to copyright.*

(diethylstilbestrol, bisphenol-A, p-nonylphenol, and di-2-ethylhexylphthalate), the concentrations needed for this effect were higher, from 10 to 6 to 10–5 M [69].

therapy (HRP) for RA. In a study of association between postmenopausal hormone therapy (PMH) use and the risk of rheumatoid arthritis (RA) in a subset of the Epidemiological Investigation of RA (EIRA) study, the users of PMH had a decreased risk of ACPA-positive RA compared with never users, mainly with a combined therapy (estrogen plus progestagens), they propose that PMH use might reduce the risk of ACPA-positive RA in post-menopausal women over 50 years of

Regarding the role of OCP use in RA, there is a theory which explains that recent decrease in incidence of RA in women in the past 50 years may be in part due to increased use of the OCP, even when may be confounded by OC use being related to pregnancy avoidance and high social class [115]. During a 14 month period, 23,000 women who were using oral contraceptives were recruited, and a similar number of those who had never used OCP as controls and evaluated every 6 month intervals. Patients were classified as "current user," "former user," and "never user." The cases were categorized according to the woman's contraceptive status at the time of RA diagnosis (event). The trend for former users was χ2 = 5.7, (p < 0.02) and for the never users χ2 = l5.0, (p < 0.01) but the current users χ2=0–85, (p > 005) and for those who were aged 40–44 years at diagnosis had a significantly lower risk of rheumatoid arthritis than similarly aged never users (relative risk 0.29). At the end of the follow-up, women who were using the pill at the time of diagnosis had a statistically non-significant 20% reduction in their risk of rheumatoid arthritis but early in the study current users had a significant 50% risk reduction [116]. The same cohort was classified in groups of "takers" and "never takers" and was analyzed too for the incidence of RA. The standardized rate for takers was 49% of the control rate (p < 0.01) and resulted interesting an observed tendency for an increased incidence of RA forward 35 years; this tendency was conserved

only in the group of "never takers" and suppressed in the takers [117].

ACPA-negative RA (p = 0.0356) compared to never users of OCP [118].

funnel plots and quantified by the Egger's test, as a sensitivity analysis was performed to investigate the influence of potential confounding factors like age, smoking, parity/pregnancy, body mass index, and social class on risk of develop RA. Here, no statistically significant association was observed between oral contraceptives and RA risk (RR = 0.88, 95% CI = 0.75–1.03) concluding that OCP consump-

HRT (hormone replacement therapy) has been studied in regard to RA newonset. On a study in a prospective cohort of 31,336 Iowa women (from 55 to

tion was not significantly associated with RA risk [120].

**27**

wIn the Swedish EIRA study (population-based case-control) including 2641 cases and 4251 controls participants were questioned about OCP (oral contraceptive pill) full term need to be mentioned consumption, and potential confounders in order to calculate the ORs adjusted for age, residential area, smoking, and alcohol consumption. Compared with never users, the OCP users had a decreased risk of ACPA-positive RA (OR = 0.84) (95% CI 0.74–0.96) compared to the never users. Also the consumption for more than 7 years decreased the risk of both ACPA-positive (p = 0.0037) and

Most of the studies agree that the current or ever use of the OCP has a protective effect against RA, probably more delaying the onset rather than a preventing RA. But until now there is not a final conclusion because even the meta-analysis results are contradictory. In the meta-analysis of six case-control and three longitudinal studies, the overall pooled odds ratio of the studies was 0.73 for the adjusted results (95% CI 0.61–0.85) with the conclusion that OCP consumption prevents the progression to severe disease by modifying the disease process [119]. On the contrary in a meta-analysis performed by Qi et al. in 2014, the authors identified 1116 publications in PubMed and EMBASE databases. The meta-analysis of 12 case-control and 5 cohort studies were analyzed. Potential publication bias was evaluated using Begg's

age, but not of ACPA-negative RA [114].

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

### **5. Estrogens and their possible ameliorative effect upon arthritis: therapeutic approach**

Given the previously displayed effects of estrogens on the immune system and in RA, it is natural to suppose that a hormone therapy could have certain effects upon the disease but, the studies exploring this possibility are scarce. Three major considerations have been identified as roadblock for such research to be conducted: (1) cut-off point in estrogen levels determining the effects of this molecule on the immune system, (2) the various effects of the same molecule at different concentrations lead to different effects depending ERα or ERβ receptor, and (3) effects dependent of the chemical modification (hydroxylation) of estrogens.

The hypothesis that hormonal therapy could ameliorate RA arises from the evidence of reported improvement in multiple pregnancies and contraceptive use [109], but this evidence became more solid when the estrogen at physiological levels administration in models of type II collagen-induced arthritis model (CIA) ameliorated arthritis and suppressed T-cell-dependent autoimmune reactions [52, 90]. In this experiment, female mice were implanted with E2 release devices, which induced a chronic estrous phase, the high doses of E2 caused a 35-day delay of the onset of RA disease but without affecting frequency and severity; this delay was reduced to 10 days with lower E2 concentrations of 25 days with physiological E3 proved to be as efficient as the high dose E2 causing a 25 day delay [90]. E3 seems to have more pronounced effects than E2; this estrogen E3 is mainly produced in pregnancy [51, 52]. In EAE models, it seems that the estrogen-mediated protection is dependent upon ERα. For example in EAE homozygous ERαKO treated with estriol, no protective effect was registered, while WT mice presented a significant decrease in disease severity and significant reductions in pro inflammatory cytokines TNF, IFNγ, IL-2, and an increase in levels of the Th2 cytokine IL-5 [110]. The effect of estrogens at interact with ERα receptor is not only limited to the immune response; in murine ovariectomized mice with estrogen treatment by pellet implantation, a dramatic increase in bone mass was observed. This was mediated by ERα-mediated apoptosis of osteoclasts through activating FasL/Fas signaling [111]. This could be an indicator that similar protective effects of estrogens may be present in immune cells due to the expression of ERα in CD4 + T lymphocytes.

Estrogens have been demonstrated to have anti-inflammatory activity. In CIA models, estrogen supplementation reduced paw inflammation efficiently and decreased paw volume by 48% (P < 001) [91], but we need to be aware that the activity of several estrogens (E1, E2, E3, and E4) is different and it depends not only on the hormone itself but also by the specific disease or even the specific clinical profile of the patient that is taking them. 2-methoxyestradiol on CIA model (20 days after the injection of type II collagen) produce a significant decrease in the arthritis index compared with that in the control mice (P < 0.05) despite it was not as efficient as estradiol [112]. Despite this is the most tested estrogen among studies for its effect in RA, Estradiol E2, in clinical applications, shows several side effects such as: hypertension, increased coagulation, and cancer incidence but a feature that both share is that they are protective in experimental autoimmune encephalomyelitis (EAE) and CIA [113].

The clinical data available is scarce and most of the available trials only evaluate the protective effect of OCP (oral contraceptive pill) and hormone replacement

#### *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

therapy (HRP) for RA. In a study of association between postmenopausal hormone therapy (PMH) use and the risk of rheumatoid arthritis (RA) in a subset of the Epidemiological Investigation of RA (EIRA) study, the users of PMH had a decreased risk of ACPA-positive RA compared with never users, mainly with a combined therapy (estrogen plus progestagens), they propose that PMH use might reduce the risk of ACPA-positive RA in post-menopausal women over 50 years of age, but not of ACPA-negative RA [114].

Regarding the role of OCP use in RA, there is a theory which explains that recent decrease in incidence of RA in women in the past 50 years may be in part due to increased use of the OCP, even when may be confounded by OC use being related to pregnancy avoidance and high social class [115]. During a 14 month period, 23,000 women who were using oral contraceptives were recruited, and a similar number of those who had never used OCP as controls and evaluated every 6 month intervals. Patients were classified as "current user," "former user," and "never user." The cases were categorized according to the woman's contraceptive status at the time of RA diagnosis (event). The trend for former users was χ2 = 5.7, (p < 0.02) and for the never users χ2 = l5.0, (p < 0.01) but the current users χ2=0–85, (p > 005) and for those who were aged 40–44 years at diagnosis had a significantly lower risk of rheumatoid arthritis than similarly aged never users (relative risk 0.29). At the end of the follow-up, women who were using the pill at the time of diagnosis had a statistically non-significant 20% reduction in their risk of rheumatoid arthritis but early in the study current users had a significant 50% risk reduction [116]. The same cohort was classified in groups of "takers" and "never takers" and was analyzed too for the incidence of RA. The standardized rate for takers was 49% of the control rate (p < 0.01) and resulted interesting an observed tendency for an increased incidence of RA forward 35 years; this tendency was conserved only in the group of "never takers" and suppressed in the takers [117].

wIn the Swedish EIRA study (population-based case-control) including 2641 cases and 4251 controls participants were questioned about OCP (oral contraceptive pill) full term need to be mentioned consumption, and potential confounders in order to calculate the ORs adjusted for age, residential area, smoking, and alcohol consumption. Compared with never users, the OCP users had a decreased risk of ACPA-positive RA (OR = 0.84) (95% CI 0.74–0.96) compared to the never users. Also the consumption for more than 7 years decreased the risk of both ACPA-positive (p = 0.0037) and ACPA-negative RA (p = 0.0356) compared to never users of OCP [118].

Most of the studies agree that the current or ever use of the OCP has a protective effect against RA, probably more delaying the onset rather than a preventing RA. But until now there is not a final conclusion because even the meta-analysis results are contradictory. In the meta-analysis of six case-control and three longitudinal studies, the overall pooled odds ratio of the studies was 0.73 for the adjusted results (95% CI 0.61–0.85) with the conclusion that OCP consumption prevents the progression to severe disease by modifying the disease process [119]. On the contrary in a meta-analysis performed by Qi et al. in 2014, the authors identified 1116 publications in PubMed and EMBASE databases. The meta-analysis of 12 case-control and 5 cohort studies were analyzed. Potential publication bias was evaluated using Begg's funnel plots and quantified by the Egger's test, as a sensitivity analysis was performed to investigate the influence of potential confounding factors like age, smoking, parity/pregnancy, body mass index, and social class on risk of develop RA. Here, no statistically significant association was observed between oral contraceptives and RA risk (RR = 0.88, 95% CI = 0.75–1.03) concluding that OCP consumption was not significantly associated with RA risk [120].

HRT (hormone replacement therapy) has been studied in regard to RA newonset. On a study in a prospective cohort of 31,336 Iowa women (from 55 to

69 years) followed up during 11 years, 158 incident cases of RA were registered. Of the factors that showed an inverse association with RA, the authors identified pregnancy (P trend =0.01) and age at menopause (P trend =0.03), whereas polycystic ovary syndrome (relative risk [RR], 2.58; 95% confidence interval [CI], 1.06–6.30), endometriosis (RR, 1.72; 95% CI, 0.93–3.18), and hormone replacement therapy (RR, 1.47; 95% CI, 1.04–2.06) were positively associated with RA. If HRT is administered before RA is associated with a higher risk of developing the disease, studies suggest that when HRT is administered during RA, they have a favorable effect. In 88 postmenopausal women with RA who received HRT, vitamin D3, and calcium supplementation or vitamin D3 and calcium supplementation alone for 2 years, HRT use had a significant effect upon active RA, ameliorating effects on inflammation (ESR p = 0.025) DAS28 (p = 0.036) and was associated with slower progression of radiological joint destruction (p = 0.026) [121]. The continuous hormonal therapy given to suppress menstruation for regulation of menstrual bleeding, pelvic pain, and dysmenorrhea seems to have demonstrated improvement in RA [122].

**Conflict of interest**

**Author details**

Zacatecas, México

México

**29**

San Luis Potosí, San Luis Potosí, México

provided the original work is properly cited.

Zacatecas, Zacatecas, México

Zacatecas, México

No conflict of interest is declared.

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

Maria Fernanda Romo-García1,2, Martín Zapata-Zuñiga3,4,5,

3 Hospital Rural # 51, IMSS, Villanueva, Zacatecas, México

José Antonio Enciso-Moreno<sup>1</sup> and Julio Enrique Castañeda-Delgado1,6\*

1 Cátedras-CONACyT-Unidad de Investigación Biomédica de Zacatecas, IMSS,

4 Hospital General Jerez Zacatecas, Servicios de Salud de Zacatecas, Zacatecas,

5 Facultad de Medicina Humana y Ciencias de la Salud, Universidad Autónoma de

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

6 Cátedras-CONACyT-Unidad de Investigación Biomédica de Zacatecas-IMSS,

\*Address all correspondence to: julioenrique\_castaeda@yahoo.com.mx

2 Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de

#### **6. Novel hormone analogs in RA**

Recently, novel hormone analogs have been developed. ERB-041 is a selective ERβ agonist and has showed interesting effects in several inflammatory rodent models, including endometriosis, rheumatoid arthritis, inflammatory bowel, and sepsis [123, 124] where a strong effect on reduction of inflammation was observed. This selective effect was the antecedent for the development of other ERβ agonists like MF101 [125] that could be useful to modulate the inflammation and cytokine production in RA. No clinical trial data on these molecules have been published so far.

#### **7. Conclusions**

Given the higher prevalence of RA cases that occur in women, is natural to suspect that such differences are due to sexual hormones, specifically estrogens, which have been explored as part of pathophysiology, development, and progression of RA disease. Antecedents point to estrogens as strong modulators of immune response and function associated to RA. The role that sex hormones play in the development, cell activation, and alterations in immune function in autoimmune diseases is still a matter of intense research. The administration of estrogens may have a protective effect on RA development or in the onset of disease, delaying it. Also, experimental evidence suggests that estrogens demonstrated anti-inflammatory activity in animal models of RA. Such effects are mediated by modifications in antibody production and in post-translational modification of antibodies like sialylation (addition of syalic acid), involved on increased risk of RA in conditions with low estrogen levels such as menopause. Estrogens administration to RA patients could be a strategy to improve the quality of life through hormone replacement therapy (HRT). This, in resource limited settings were biological therapy cannot be afforded and in patients that are refractory to standard MTX therapy or that have failed to respond to such therapies.

#### **Acknowledgements**

Maria Fernanda Romo García thanks CONACyT (Consejo Nacional de Ciencia y Tecnologia); National Council of Science and Technology for scholarship 297364/ CVU 560269.

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

### **Conflict of interest**

No conflict of interest is declared.

## **Author details**

Maria Fernanda Romo-García1,2, Martín Zapata-Zuñiga3,4,5, José Antonio Enciso-Moreno<sup>1</sup> and Julio Enrique Castañeda-Delgado1,6\*

1 Cátedras-CONACyT-Unidad de Investigación Biomédica de Zacatecas, IMSS, Zacatecas, México

2 Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México

3 Hospital Rural # 51, IMSS, Villanueva, Zacatecas, México

4 Hospital General Jerez Zacatecas, Servicios de Salud de Zacatecas, Zacatecas, México

5 Facultad de Medicina Humana y Ciencias de la Salud, Universidad Autónoma de Zacatecas, Zacatecas, México

6 Cátedras-CONACyT-Unidad de Investigación Biomédica de Zacatecas-IMSS, Zacatecas, México

\*Address all correspondence to: julioenrique\_castaeda@yahoo.com.mx

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Pelaez-Ballestas I, Sanin LH, Moreno-Montoya J, Alvarez-Nemegyei J, Burgos-Vargas R, Garza-Elizondo M, et al. Epidemiology of the rheumatic diseases in Mexico. A study of 5 regions based on the COPCORD methodology. The Journal of Rheumatology. 2011;**86**: 3-8. Available from: http://www.jrhe um.org/cgi/doi/10.3899/jrheum.100951 [cited 14 December 2016]

[2] Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology Criteria: A systematic review. Seminars in Arthritis and Rheumatism. 2006; **36**(3):182-188. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 17045630 [cited 18 September 2018]

[3] Szekanecz Z, Soós L, Szabó Z, Fekete A, Kapitány A, Végvári A, et al. Anti-citrullinated protein antibodies in rheumatoid arthritis: As good as it gets? Clinical Reviews in Allergy & Immunology. 2008;**34**(1):26-31. Available from: http://www.ncbi.nlm. nih.gov/pubmed/18270854 [cited 14 September 2017]

[4] Weyand CM, Klimiuk PA, Goronzy JJ. Heterogeneity of rheumatoid arthritis: From phenotypes to genotypes. Seminars in Immunopathology. 1998;**20** (1–2):5-22. Available from: http://link. springer.com/10.1007/BF00831996 [cited 30 October 2018]

[5] van der Pouw KTCTM, Wijbrandts CA, van Baarsen LGM, Voskuyl AE, Rustenburg F, Baggen JM, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: Assignment of a type I interferon signature in a subpopulation of patients. Annals of the Rheumatic Diseases. 2007;**66**(8): 1008-1014. Available from: http://www. ncbi.nlm.nih.gov/pubmed/17223656 [cited 12 January 2018]

[6] Courvoisier DS, Alpizar-Rodriguez D, Gottenberg JE, Hernandez MV, Iannone F, Lie E, et al. Rheumatoid arthritis patients after initiation of a new biologic agent: Trajectories of disease activity in a large multinational cohort study. EBioMedicine. 2016;**11**:302-306. Available from: http://www.ncbi.nlm. nih.gov/pubmed/27558858 [cited 30 October 2018]

relation with axial bone density. Annals of the Rheumatic Diseases. 1993;**52**(3): 211-214. Available from: http://www. ncbi.nlm.nih.gov/pubmed/8484674

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

gov/pubmed/19935037 [cited 03 October

[17] Altemus M, Deuster PA, Galliven E, Carter CS, Gold PW. Suppression of hypothalmic-pituitary-adrenal axis responses to stress in lactating women. The Journal of Clinical Endocrinology and Metabolism. 1995;**80**(10):2954-2959

[18] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and

[19] Fairweather D, Rose NR. Women and autoimmune diseases. Emerging Infectious Diseases. 2004;**10**(11): 2005-2011. Available from: http://www. ncbi.nlm.nih.gov/pubmed/15550215

[20] Wolfe AM, Kellgren JH, Masi AT. The epidemiology of rheumatoid arthritis: A review. II. Incidence and diagnostic criteria. Bulletin on the Rheumatic Diseases. 1968;**19**(3): 524-529. Available from: http://www. ncbi.nlm.nih.gov/pubmed/4884388

29 October 2018]

[cited 29 October 2018]

[cited 29 October 2018]

[21] van Vollenhoven RF. Sex differences in rheumatoid arthritis: More than meets the eye. BMC

[cited 21 September 2018]

19 September 2018]

Medicine. 2009;**7**(1):12. Available from: http://bmcmedicine.biomedcentral.c om/articles/10.1186/1741-7015-7-12

[22] Forslind K, Hafström I, Ahlmén M, Svensson B, BARFOT Study Group. Sex: A major predictor of remission in early rheumatoid arthritis? Annals of the Rheumatic Diseases. 2007;**66**(1):46-52. Available from: http://www.ncbi.nlm. nih.gov/pubmed/17158139 [cited

estimated population burden of selected autoimmune diseases in the United States. Clinical Immunology and Immunopathology. 1997;**84**(3):223-243. Available from: http://www.ncbi.nlm. nih.gov/pubmed/9281381 [cited

2018]

[12] Cash JM, Crofford LJ, Gallucci WT, Sternberg EM, Gold PW, Chrousos GP,

responsiveness to ovine corticotropin releasing hormone in patients with rheumatoid arthritis treated with low dose prednisone. The Journal of Rheumatology. 1992;**19**(11):1692-1696. Available from: http://www.ncbi.nlm.nih.

[cited 28 September 2018]

et al. Pituitary-adrenal axis

gov/pubmed/1337108 [cited 28

[13] Cutolo M, Villaggio B, Craviotto C, Pizzorni C, Seriolo B, Sulli A. Sex hormones and rheumatoid arthritis. Autoimmunity Reviews. 2002;**1**(5): 284-289. Available from: https://www. sciencedirect.com/science/article/pii/ S1568997202000642?via%3Dihub [cited

September 2018]

18 September 2018]

[14] Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. The Journal of Rheumatology. 2003;**30**(12):

[cited 18 September 2018]

10.1002/art.22384

**31**

2597-2605. Available from: http://www. ncbi.nlm.nih.gov/pubmed/14719200

[15] Richette P, Laborde K, Boutron C, Bardin T, Corvol M-T, Savouret J-F. Correlation between serum and synovial fluid estrogen concentrations: Comment on the article by Sowers et al. Arthritis & Rheumatology. 2007;**56**(2):698-698. Available from: http://doi.wiley.com/

[16] Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies. Obstetrics & Gynecology. 2009;**114**(6):1326-1331. Available from: http://www.ncbi.nlm.nih.

[7] Leitman DC, Paruthiyil S, Vivar OI, Saunier EF, Herber CB, Cohen I, et al. Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. Current Opinion in Pharmacology. 2010;**10**(6): 629-636. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20951642 [cited 14 August 2018]

[8] Ps H. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Proceedings of the Staff Meetings. Mayo Clinic. 1938;**13**:161-167

[9] Nolten WE, Lindheimer MD, RUECKERT PA, Oparil S, Ehrlich EN. Diurnal patterns and regulation of cortisol secretion in pregnancy. The Journal of Clinical Endocrinology & Metabolism. 1980;**51**(3):466-472. Available from: http://www.ncbi.nlm. nih.gov/pubmed/7410530 [cited 12 September 2018]

[10] Deighton CM, Watson MJ, Walker DJ. Sex hormones in postmenopausal HLA-identical rheumatoid arthritis discordant sibling pairs. The Journal of Rheumatology. 1992;**19**(11):1663-1667. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 1491383 [cited 28 September 2018]

[11] Hall GM, Perry LA, Spector TD. Depressed levels of dehydroepiandrosterone sulphate in postmenopausal women with rheumatoid arthritis but no relation with axial bone density. Annals of the Rheumatic Diseases. 1993;**52**(3): 211-214. Available from: http://www. ncbi.nlm.nih.gov/pubmed/8484674 [cited 28 September 2018]

[12] Cash JM, Crofford LJ, Gallucci WT, Sternberg EM, Gold PW, Chrousos GP, et al. Pituitary-adrenal axis responsiveness to ovine corticotropin releasing hormone in patients with rheumatoid arthritis treated with low dose prednisone. The Journal of Rheumatology. 1992;**19**(11):1692-1696. Available from: http://www.ncbi.nlm.nih. gov/pubmed/1337108 [cited 28 September 2018]

[13] Cutolo M, Villaggio B, Craviotto C, Pizzorni C, Seriolo B, Sulli A. Sex hormones and rheumatoid arthritis. Autoimmunity Reviews. 2002;**1**(5): 284-289. Available from: https://www. sciencedirect.com/science/article/pii/ S1568997202000642?via%3Dihub [cited 18 September 2018]

[14] Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. The Journal of Rheumatology. 2003;**30**(12): 2597-2605. Available from: http://www. ncbi.nlm.nih.gov/pubmed/14719200 [cited 18 September 2018]

[15] Richette P, Laborde K, Boutron C, Bardin T, Corvol M-T, Savouret J-F. Correlation between serum and synovial fluid estrogen concentrations: Comment on the article by Sowers et al. Arthritis & Rheumatology. 2007;**56**(2):698-698. Available from: http://doi.wiley.com/ 10.1002/art.22384

[16] Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies. Obstetrics & Gynecology. 2009;**114**(6):1326-1331. Available from: http://www.ncbi.nlm.nih. gov/pubmed/19935037 [cited 03 October 2018]

[17] Altemus M, Deuster PA, Galliven E, Carter CS, Gold PW. Suppression of hypothalmic-pituitary-adrenal axis responses to stress in lactating women. The Journal of Clinical Endocrinology and Metabolism. 1995;**80**(10):2954-2959

[18] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clinical Immunology and Immunopathology. 1997;**84**(3):223-243. Available from: http://www.ncbi.nlm. nih.gov/pubmed/9281381 [cited 29 October 2018]

[19] Fairweather D, Rose NR. Women and autoimmune diseases. Emerging Infectious Diseases. 2004;**10**(11): 2005-2011. Available from: http://www. ncbi.nlm.nih.gov/pubmed/15550215 [cited 29 October 2018]

[20] Wolfe AM, Kellgren JH, Masi AT. The epidemiology of rheumatoid arthritis: A review. II. Incidence and diagnostic criteria. Bulletin on the Rheumatic Diseases. 1968;**19**(3): 524-529. Available from: http://www. ncbi.nlm.nih.gov/pubmed/4884388 [cited 29 October 2018]

[21] van Vollenhoven RF. Sex differences in rheumatoid arthritis: More than meets the eye. BMC Medicine. 2009;**7**(1):12. Available from: http://bmcmedicine.biomedcentral.c om/articles/10.1186/1741-7015-7-12 [cited 21 September 2018]

[22] Forslind K, Hafström I, Ahlmén M, Svensson B, BARFOT Study Group. Sex: A major predictor of remission in early rheumatoid arthritis? Annals of the Rheumatic Diseases. 2007;**66**(1):46-52. Available from: http://www.ncbi.nlm. nih.gov/pubmed/17158139 [cited 19 September 2018]

[23] Couderc M, Gottenberg J-E, Mariette X, Pereira B, Bardin T, Cantagrel A, et al. Influence of gender on response to rituximab in patients with rheumatoid arthritis: Results from the autoimmunity and rituximab registry. Rheumatology. 2014;**53**(10): 1788-1793. Available from: https://acade mic.oup.com/rheumatology/articlelookup/doi/10.1093/rheumatology/ke u176 [cited 21 September 2018]

[24] Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, et al. Women, men, and rheumatoid arthritis: Analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Research & Therapy. 2009;**11**(1):R7. Available from: http://www.ncbi.nlm. nih.gov/pubmed/19144159 [cited 03 September 2018]

[25] Alpízar-Rodríguez D, Pluchino N, Canny G, Gabay C, Finckh A. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology. 2016;**56**(8):kew318. Available from: https://academic.oup. com/rheumatology/article-lookup/doi/ 10.1093/rheumatology/kew318 [cited 31 October 2018]

[26] Chen H, Zhu H, Zhang K, Chen K, Yang H. Estrogen deficiency accelerates lumbar facet joints arthritis. Scientific Reports. 2017;**7**(1):1379. Available from: http://www.nature.com/articles/s41598- 017-01427-7 [cited 31 October 2018]

[27] Merlino LA, Cerhan JR, Criswell LA, Mikuls TR, Saag KG. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum. September 2003;**33**(2):72-82

[28] Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: A survey analysis.

Human Reproduction. 2002;**17**(10): 2715-2724. Available from: http://www. ncbi.nlm.nih.gov/pubmed/12351553 [cited 24 September 2018]

rheumatoid arthritis and ankylosing spondylitis using validated clinical instruments. Annals of the Rheumatic Diseases. 2004;**63**(10):1212-1217. Available from: http://www.ncbi.nlm. nih.gov/pubmed/15361373 [cited

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

Allergy and Immunology. 2011;**40**(1):

Autoimmunity Reviews. 2012;**11**(6–7): A465-A470. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 22155203 [cited 12 September 2018]

[41] Shelly S, Boaz M, Orbach H. Prolactin and autoimmunity.

[42] Brennan P, Silman A. Breastfeeding and the onset of rheumatoid arthritis. Arthritis & Rheumatology. 1994;**37**(6):808-813. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 8003052 [cited 12 September 2018]

[43] Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: The role of the immune system at the implantation site. Annals of the New York Academy of Sciences. 2011; **1221**(1):80-87. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 21401634 [cited 13 September 2018]

[44] Steiner M, Haskett RF, Carroll BJ. Premenstrual tension syndrome: The development of research diagnostic criteria and new rating scales. Acta Psychiatrica Scandinavica. 1980;**62**(2): 177-190. Available from: http://www. ncbi.nlm.nih.gov/pubmed/7193399

[45] Rudge SR, Kowanko IC, Drury PL, Bartholomew S. Menstrual cyclicity of finger joint size and grip strength in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. August 1983; **42**(4):425-430. Available from: http://ard. bmj.com/ [cited 20 September 2018]

[46] Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. The American Journal of Medicine. 1983;**74**(6):957-960. Available from: http://linkinghub.else vier.com/retrieve/pii/0002934383907891

[cited 20 September 2018]

[cited 21 September 2018]

[47] McDonagh JE, Singh MM,

Griffiths ID, McDonagh ID, Griffiths JE. Menstrual arthritis. Annals of the

50-59

[35] Oka M. Effect of pregnancy on the onset and course of rheumatoid arthritis. Obstetrical and Gynecological Survey. 1954;**9**(2):180-181. Available from: http://ard.bmj.com/ [cited 13 September

[36] Del Junco DJ, Annegers JF,

Coulam CB, Luthra HS. The relationship between rheumatoid arthritis and reproductive function. British Journal of Rheumatology. 1989;**28** (Suppl 1):33; discussion 42-5. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/2819346 [cited 13 September

[37] Nelson JL, Ostensen M. Pregnancy and rheumatoid arthritis. Rheumatic Disease Clinics of North America. 1997; **23**(1):195-212. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 9031383 [cited 06 September 2018]

[38] Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis & Rheumatology. 1992;**35**(2):152-155. Available from: http://www.ncbi.nlm. nih.gov/pubmed/1734904 [cited

12 September 2018]

[39] Skomsvoll JF, Ostensen M, Irgens LM, Baste V. Pregnancy complications and delivery practice in women with connective tissue disease and inflammatory rheumatic disease in

Norway. Acta Obstetricia et

[cited 12 September 2018]

**33**

Gynecologica Scandinavica. 2000;**79**(6): 490-495. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10857874

[40] Jara LJ, Medina G, Saavedra MA, Vera-Lastra O, Navarro C. Prolactin and autoimmunity. Clinical Reviews in

12 September 2018]

2018]

2018]

[29] Lleo A, Battezzati PM, Selmi C, Gershwin ME, Podda M. Is autoimmunity a matter of sex? Autoimmunity Reviews. 2008;**7**(8): 626-630. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18603021 [cited 03 September 2018]

[30] Häupl T, Østensen M, Grützkau A, Radbruch A, Burmester G-R, Villiger PM. Reactivation of rheumatoid arthritis after pregnancy increased phagocyte and recurring lymphocyte gene activity. Arthritis & Rheumatology. 2008;**58**(10):2981-2992. Avaielable from: https://onlinelibrary. wiley.com/doi/pdf/10.1002/art.23907 [cited 06 September 2018]

[31] Kanik KS, Wilder RL. Hormonal alterations in rheumatoid arthritis, including the effects of pregnancy. Rheumatic Disease Clinics of North America. 2000;**26**(4):805-823. Available from: http://linkinghub.elsevier.com/ retrieve/pii/S0889857X05701708

[32] Barrett JH, Brennan P, Fiddler M, Silman AJ. Does rheumatoid arthritis remit during pregnancy and relapse postpartum?: Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis & Rheumatology. 1999;**42**(6): 1219-1227. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10366115 [cited 06 September 2018]

[33] Iijima T, Tada H, Hidaka Y, Yagoro A, Mitsuda N, Kanzaki T, et al. Prediction of postpartum onset of rheumatoid arthritis. Annals of the Rheumatic Diseases. 1998;**57**:460-463. Available from: http://ard.bmj.com/ [cited 06 September 2018]

[34] Ostensen M, Fuhrer L, Mathieu R, Seitz M, Villiger PM. A prospective study of pregnant patients with

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

rheumatoid arthritis and ankylosing spondylitis using validated clinical instruments. Annals of the Rheumatic Diseases. 2004;**63**(10):1212-1217. Available from: http://www.ncbi.nlm. nih.gov/pubmed/15361373 [cited 12 September 2018]

[35] Oka M. Effect of pregnancy on the onset and course of rheumatoid arthritis. Obstetrical and Gynecological Survey. 1954;**9**(2):180-181. Available from: http://ard.bmj.com/ [cited 13 September 2018]

[36] Del Junco DJ, Annegers JF, Coulam CB, Luthra HS. The relationship between rheumatoid arthritis and reproductive function. British Journal of Rheumatology. 1989;**28** (Suppl 1):33; discussion 42-5. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/2819346 [cited 13 September 2018]

[37] Nelson JL, Ostensen M. Pregnancy and rheumatoid arthritis. Rheumatic Disease Clinics of North America. 1997; **23**(1):195-212. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 9031383 [cited 06 September 2018]

[38] Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis & Rheumatology. 1992;**35**(2):152-155. Available from: http://www.ncbi.nlm. nih.gov/pubmed/1734904 [cited 12 September 2018]

[39] Skomsvoll JF, Ostensen M, Irgens LM, Baste V. Pregnancy complications and delivery practice in women with connective tissue disease and inflammatory rheumatic disease in Norway. Acta Obstetricia et Gynecologica Scandinavica. 2000;**79**(6): 490-495. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10857874 [cited 12 September 2018]

[40] Jara LJ, Medina G, Saavedra MA, Vera-Lastra O, Navarro C. Prolactin and autoimmunity. Clinical Reviews in

Allergy and Immunology. 2011;**40**(1): 50-59

[41] Shelly S, Boaz M, Orbach H. Prolactin and autoimmunity. Autoimmunity Reviews. 2012;**11**(6–7): A465-A470. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 22155203 [cited 12 September 2018]

[42] Brennan P, Silman A. Breastfeeding and the onset of rheumatoid arthritis. Arthritis & Rheumatology. 1994;**37**(6):808-813. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 8003052 [cited 12 September 2018]

[43] Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: The role of the immune system at the implantation site. Annals of the New York Academy of Sciences. 2011; **1221**(1):80-87. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 21401634 [cited 13 September 2018]

[44] Steiner M, Haskett RF, Carroll BJ. Premenstrual tension syndrome: The development of research diagnostic criteria and new rating scales. Acta Psychiatrica Scandinavica. 1980;**62**(2): 177-190. Available from: http://www. ncbi.nlm.nih.gov/pubmed/7193399 [cited 20 September 2018]

[45] Rudge SR, Kowanko IC, Drury PL, Bartholomew S. Menstrual cyclicity of finger joint size and grip strength in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. August 1983; **42**(4):425-430. Available from: http://ard. bmj.com/ [cited 20 September 2018]

[46] Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. The American Journal of Medicine. 1983;**74**(6):957-960. Available from: http://linkinghub.else vier.com/retrieve/pii/0002934383907891 [cited 21 September 2018]

[47] McDonagh JE, Singh MM, Griffiths ID, McDonagh ID, Griffiths JE. Menstrual arthritis. Annals of the

Rheumatic Diseases. 1993;**52**:65-66. Available from: http://ard.bmj.com/ [cited 20 September 2018]

[48] Østensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Seminars in Immunopathology. 2007;**29**(2):185-191. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17621703 [cited 03 September 2018]

[49] Krause ML, Makol A. Management of rheumatoid arthritis during pregnancy: Challenges and solutions. Open Access Rheumatology: Research and Reviews. 2016;**8**:23-36. Available from: http://www.ncbi.nlm.nih.gov/pub med/27843367 [cited 03 September 2018]

[50] de Man YA, Dolhain RJEM, van de Geijn FE, Willemsen SP, Hazes JMW. Disease activity of rheumatoid arthritis during pregnancy: Results from a nationwide prospective study. Arthritis & Rheumatology. 2008;**59**(9): 1241-1248. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18759316 [cited 06 September 2018]

[51] Jansson L, Holmdahl R. Estrogenmediated immunosuppression in autoimmune diseases. Inflammation Research. 1998;**47**(7):290-301. Available from: http://www.ncbi.nlm. nih.gov/pubmed/9719493 [cited 18 September 2018]

[52] Jansson L, Olsson T, Holmdahl R. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. Journal of Neuroimmunology. 1994;**53**(2):203-207. Available from: http://www.ncbi.nlm. nih.gov/pubmed/8071434 [cited 18 September 2018]

[53] Holinka CF, Diczfalusy E, Coelingh Bennink HJT. Estetrol: A unique steroid in human pregnancy. Journal of Steroid Biochemistry and Molecular Biology. 2008;**110**(1–2):138-143. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/ 18462934 [cited 08 October 2018]

doi.wiley.com/10.1111/j.1600-0897.2006. 00417.x [cited 13 September 2018]

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

[65] Paruthiyil S, Cvoro A, Zhao X, Wu Z, Sui Y, Staub RE, et al. Drug and cell type-specific regulation of genes with different classes of estrogen receptor β-selective agonists. PLOS One. 2009;**4**(7):e6271. Laudet V, editor. Available from: http://www.ncbi.nlm. nih.gov/pubmed/19609440 [cited 03

September 2018]

[66] Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunology Letters. 2005;**97**(1):107-113. Available from: https://www.sciencedirect.com/science/ article/abs/pii/S0165247804002792

[cited 27 September 2018]

20 September 2018]

[68] Curran EM, Berghaus LJ,

Vernetti NJ, Saporita AJ, Lubahn DB, Estes DM. Natural killer cells express estrogen receptor-α and estrogen receptor-β and can respond to estrogen via a non-estrogen receptor-α-mediated pathway. Cellular Immunology. 2001; **214**(1):12-20. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 11902825 [cited 20 September 2018]

[69] Sakazaki H, Ueno H, Nakamuro K. Estrogen receptor alpha in mouse splenic lymphocytes: Possible

involvement in immunity. Toxicology Letters. 2002;**133**(2–3):221-229. Available from: http://www.ncbi.nlm. nih.gov/pubmed/12119130 [cited

[70] Kovats S. Estrogen receptors regulate innate immune cells and

19 September 2018]

[67] Mao A, Paharkova-Vatchkova V, Hardy J, Miller MM, Kovats S. Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells. The Journal of Immunology. 2005;**175**(8):5146-5151. Available from: http://www.ncbi.nlm. nih.gov/pubmed/16210618 [cited

[60] Colangelo K, Haig S, Bonner A, Zelenietz C, Pope J. Self-reported flaring varies during the menstrual cycle in systemic lupus erythematosus compared

with rheumatoid arthritis and fibromyalgia. Rheumatology. 2011; **50**(4):703-708. Available from: https:// academic.oup.com/rheumatology/ article-lookup/doi/10.1093/ rheumatology/keq360 [cited 19

[61] Costenbader KH, Feskanich D,

Reproductive and menopausal factors

erythematosus in women. Arthritis & Rheumatology. 2007;**56**(4):1251-1262. Available from: http://www.ncbi.nlm. nih.gov/pubmed/17393454 [cited 24

[62] Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer. 22 July 2011;**11**(8):597-608.

[63] Tee MK, Rogatsky I, Tzagarakis-Foster C, Cvoro A, An J, Christy RJ, et al. Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Molecular Biology of the Cell. 2004;**15**(3):

1262-1272. Available from: http://www. ncbi.nlm.nih.gov/pubmed/14699072

[64] Stossi F, Barnett DH, Frasor J,

Katzenellenbogen BS. Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor (ER) α or ERβ in human osteosarcoma cells: Distinct and common target genes for these receptors. Endocrinology. 2004; **145**(7):3473-3486. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 15033914 [cited 03 September 2018]

[cited 03 September 2018]

Komm B, Lyttle CR,

**35**

Stampfer MJ, Karlson EW.

and risk of systemic lupus

September 2018]

September 2018]

DOI: 10.1038/nrc3093

[54] Groen B, van der Wijk A-E, van den Berg PP, Lefrandt JD, van den Berg G, Sollie KM, et al. Immunological adaptations to pregnancy in women with type 1 diabetes. Scientific Reports. 2015;**5**:13618. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 26391604 [cited 12 September 2018]

[55] Veenstra van Nieuwenhoven AL, Heineman MJ, Faas MM. The immunology of successful pregnancy. Human Reproduction Update. 2003; **9**(4):347-357. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 12926528 [cited 12 September 2018]

[56] Russell AS, Johnston C, Chew C, Maksymowych WP. Evidence for reduced Th1 function in normal pregnancy: A hypothesis for the remission of rheumatoid arthritis. The Journal of Rheumatology. 1997;**24**(6): 1045-1050. Available from: http://www. ncbi.nlm.nih.gov/pubmed/9195507

[57] Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunology. 2004;**5**(3):266-271. Available from: http://www.ncbi.nlm. nih.gov/pubmed/14758358 [cited 13 September 2018]

[58] Bulmer JN, Pace D, Ritson A. Immunoregulatory cells in human decidua: Morphology, immunohistochemistry and function. Reproduction Nutrition Development. 1988;**28**(6B):1599-1613. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 3073448 [cited 13 September 2018]

[59] Shimada S, Nishida R, Takeda M, Iwabuchi K, Kishi R, Onoe K, et al. Natural killer, natural killer T, helper and cytotoxic T cells in the decidua from sporadic miscarriage. American Journal of Reproductive Immunology. 2006; **56**(3):193-200. Available from: http://

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

doi.wiley.com/10.1111/j.1600-0897.2006. 00417.x [cited 13 September 2018]

[60] Colangelo K, Haig S, Bonner A, Zelenietz C, Pope J. Self-reported flaring varies during the menstrual cycle in systemic lupus erythematosus compared with rheumatoid arthritis and fibromyalgia. Rheumatology. 2011; **50**(4):703-708. Available from: https:// academic.oup.com/rheumatology/ article-lookup/doi/10.1093/ rheumatology/keq360 [cited 19 September 2018]

[61] Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis & Rheumatology. 2007;**56**(4):1251-1262. Available from: http://www.ncbi.nlm. nih.gov/pubmed/17393454 [cited 24 September 2018]

[62] Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer. 22 July 2011;**11**(8):597-608. DOI: 10.1038/nrc3093

[63] Tee MK, Rogatsky I, Tzagarakis-Foster C, Cvoro A, An J, Christy RJ, et al. Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Molecular Biology of the Cell. 2004;**15**(3): 1262-1272. Available from: http://www. ncbi.nlm.nih.gov/pubmed/14699072 [cited 03 September 2018]

[64] Stossi F, Barnett DH, Frasor J, Komm B, Lyttle CR, Katzenellenbogen BS. Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor (ER) α or ERβ in human osteosarcoma cells: Distinct and common target genes for these receptors. Endocrinology. 2004; **145**(7):3473-3486. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 15033914 [cited 03 September 2018]

[65] Paruthiyil S, Cvoro A, Zhao X, Wu Z, Sui Y, Staub RE, et al. Drug and cell type-specific regulation of genes with different classes of estrogen receptor β-selective agonists. PLOS One. 2009;**4**(7):e6271. Laudet V, editor. Available from: http://www.ncbi.nlm. nih.gov/pubmed/19609440 [cited 03 September 2018]

[66] Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunology Letters. 2005;**97**(1):107-113. Available from: https://www.sciencedirect.com/science/ article/abs/pii/S0165247804002792 [cited 27 September 2018]

[67] Mao A, Paharkova-Vatchkova V, Hardy J, Miller MM, Kovats S. Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells. The Journal of Immunology. 2005;**175**(8):5146-5151. Available from: http://www.ncbi.nlm. nih.gov/pubmed/16210618 [cited 20 September 2018]

[68] Curran EM, Berghaus LJ, Vernetti NJ, Saporita AJ, Lubahn DB, Estes DM. Natural killer cells express estrogen receptor-α and estrogen receptor-β and can respond to estrogen via a non-estrogen receptor-α-mediated pathway. Cellular Immunology. 2001; **214**(1):12-20. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 11902825 [cited 20 September 2018]

[69] Sakazaki H, Ueno H, Nakamuro K. Estrogen receptor alpha in mouse splenic lymphocytes: Possible involvement in immunity. Toxicology Letters. 2002;**133**(2–3):221-229. Available from: http://www.ncbi.nlm. nih.gov/pubmed/12119130 [cited 19 September 2018]

[70] Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cellular Immunology. 2015;**294**(2):63-69. Available from: http://linkinghub.else vier.com/retrieve/pii/S000887491 500026X [cited 20 September 2018]

[71] Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, et al. Estradiol enhances primary antigenspecific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor α expression in hematopoietic cells. European Journal of Immunology. 2003;**33**(2):512-521. Available from: http://doi.wiley.com/ 10.1002/immu.200310027 [cited 14 September 2018]

[72] Erlandsson MC, Ohlsson C, Gustafsson JA, Carlsten H. Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus. Immunology. 2001;**103**(1):17-25. Available from: http://www.ncbi.nlm. nih.gov/pubmed/11380688 [cited 27 September 2018]

[73] Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. Journal of Neuroimmunology. 2005;**170** (1–2):85-92. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 16253347 [cited 18 September 2018]

[74] Tan IJ, Peeva E, Zandman-Goddard G. Hormonal modulation of the immune system — A spotlight on the role of progestogens. Autoimmunity Reviews. 2015;**14**(6):536-542. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 25697984 [cited 12 September 2018]

[75] Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4+ CD25+ regulatory T cells by promoting their proliferation. Immunology. 2006;**118**(1):58-65. Available from: http://www.ncbi.nlm. nih.gov/pubmed/16630023 [cited 19 September 2018]

[76] Arruvito L, Sanz M, Banham AH, Fainboim L. Expansion of CD4+CD25 +and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: Implications for human reproduction. The Journal of Immunology. 2007;**178**(4): 2572-2578. Available from: http://www. ncbi.nlm.nih.gov/pubmed/17277167 [cited 19 September 2018]

Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor alpha. Molecular and Cellular Endocrinology. 1994;**106**(1–2):17-21. Available from: http://www.ncbi.nlm. nih.gov/pubmed/7895904 [cited 18

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

[86] Eilertsen GØ, Van Ghelue M, Strand H, Nossent JC. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: A case–control study. Rheumatology. 2011;**50**(12):2197-2205. Available from: https://academic.oup. com/rheumatology/article-lookup/doi/ 10.1093/rheumatology/ker282 [cited 20

[87] Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D, et al. Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. The Journal

1256-1264. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18528969

[88] Peeva E, Venkatesh J, Diamond B. Tamoxifen blocks estrogen-induced B cell maturation but not survival. The Journal of Immunology. 2005;**175**(3): 1415-1423. Available from: http://www. ncbi.nlm.nih.gov/pubmed/16034077

of Rheumatology. 2008;**35**(7):

[cited 20 September 2018]

[cited 19 September 2018]

[89] Ercan A, Kohrt WM, Cui J, Deane KD, Pezer M, Yu EW, et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight. 2017;**2**(4):e89703. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 28239652 [cited 17 September 2018]

[90] Jansson L, Mattsson A, Mattsson R,

collagen T-cell dependent immunity and stimulates polyclonal B-cell activity. Journal of Autoimmunity. 1990;**3**(3): 257-270. Available from: https://www. sciencedirect.com/science/article/pii/ 089684119090145I [cited 18 September

Holmdahl R. Estrogen induced suppression of collagen arthritis V: Physiological level of estrogen in DBA1 mice is therapeutic on established arthritis, suppresses anti-type II

2018]

September 2018]

[82] Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. The Journal of Clinical Investigation. 2002;**109**(12):1625-1633. Available from: http://www.ncbi.nlm. nih.gov/pubmed/12070310 [cited 19

September 2018]

September 2018]

[83] Grimaldi CM, Michael DJ, Diamond B. Cutting edge: Expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. The Journal of Immunology. 2001;**167**(4): 1886-1890. Available from: http://www. ncbi.nlm.nih.gov/pubmed/11489967

[cited 19 September 2018]

[84] Manuela D, Dalila S, Yara M, Souza Iliada LS. BAFF expression is modulated by female hormones in human immune cells. Biochemical Genetics. 2016;**54**(5): 722-730. Available from: https://web.a. ebscohost.com/abstract?direct=true& profile=ehost&scope=site&authtype= crawler&jrnl=00062928&AN= 118005841&h=oqMhwcHnmf 8F6Nm4QzoiydPzgd2uvK%

2FM1L02Uq3iC1h5Yib2LNu3PyDFDz 8ZTfz5F16wIe3IhL3PgeVvFkJSig%3D% 3D&crl=f&resultNs=AdminWebAuth& resultLocal= [cited 20 September 2018]

[85] Morimoto S, Nakano S, Watanabe T, Tamayama Y, Mitsuo A, Nakiri Y, et al. Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: The role of BAFF in T cell-dependent B cell pathogenic autoantibody production. Rheumatology. 2007;**46**(7):1083-1086. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17500077 [cited 20 September 2018]

**37**

[77] Lee S, Kim J, Jang B, Hur S, Jung U, Kil K, et al. Fluctuation of peripheral blood T, B, and NK cells during a menstrual cycle of normal healthy women. The Journal of Immunology. 2010;**185**(1):756-762. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20530263 [cited 19 September 2018]

[78] Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology. 2004;**112**(1):38-43. Available from: http://www.ncbi.nlm. nih.gov/pubmed/15096182 [cited 19 September 2018]

[79] Josefsson E, Tarkowski A, Dahlin A-G, Crafoord F, Thuring I, Lundgren M, et al. Suppression of type I1 collagen-induced arthritis by the endogenous estrogen metabolite 2 methoxyestradiol [internet]. Arthritis and Rheumatism. 1997;**40**. Available from: https://onlinelibrary.wiley.com/ doi/pdf/10.1002/art.1780400120 [cited 18 September 2018]

[80] Khalkhali-Ellis Z, Seftor EA, Nieva DR, Handa RJ, Price RH, Kirschmann DA, et al. Estrogen and progesterone regulation of human fibroblast-like synoviocyte function in vitro: Implications in rheumatoid arthritis. The Journal of Rheumatology. 2000;**27**(7):1622-1631. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 10914842 [cited 18 September 2018]

[81] Macdiarmid F, Wang D, Duncan LJ, Purohit A, Ghilchick MW, Reed MJ.

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor alpha. Molecular and Cellular Endocrinology. 1994;**106**(1–2):17-21. Available from: http://www.ncbi.nlm. nih.gov/pubmed/7895904 [cited 18 September 2018]

[82] Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. The Journal of Clinical Investigation. 2002;**109**(12):1625-1633. Available from: http://www.ncbi.nlm. nih.gov/pubmed/12070310 [cited 19 September 2018]

[83] Grimaldi CM, Michael DJ, Diamond B. Cutting edge: Expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. The Journal of Immunology. 2001;**167**(4): 1886-1890. Available from: http://www. ncbi.nlm.nih.gov/pubmed/11489967 [cited 19 September 2018]

[84] Manuela D, Dalila S, Yara M, Souza Iliada LS. BAFF expression is modulated by female hormones in human immune cells. Biochemical Genetics. 2016;**54**(5): 722-730. Available from: https://web.a. ebscohost.com/abstract?direct=true& profile=ehost&scope=site&authtype= crawler&jrnl=00062928&AN= 118005841&h=oqMhwcHnmf 8F6Nm4QzoiydPzgd2uvK% 2FM1L02Uq3iC1h5Yib2LNu3PyDFDz 8ZTfz5F16wIe3IhL3PgeVvFkJSig%3D% 3D&crl=f&resultNs=AdminWebAuth& resultLocal= [cited 20 September 2018]

[85] Morimoto S, Nakano S, Watanabe T, Tamayama Y, Mitsuo A, Nakiri Y, et al. Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: The role of BAFF in T cell-dependent B cell pathogenic autoantibody production. Rheumatology. 2007;**46**(7):1083-1086. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 17500077 [cited 20 September 2018]

[86] Eilertsen GØ, Van Ghelue M, Strand H, Nossent JC. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: A case–control study. Rheumatology. 2011;**50**(12):2197-2205. Available from: https://academic.oup. com/rheumatology/article-lookup/doi/ 10.1093/rheumatology/ker282 [cited 20 September 2018]

[87] Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D, et al. Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. The Journal of Rheumatology. 2008;**35**(7): 1256-1264. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18528969 [cited 20 September 2018]

[88] Peeva E, Venkatesh J, Diamond B. Tamoxifen blocks estrogen-induced B cell maturation but not survival. The Journal of Immunology. 2005;**175**(3): 1415-1423. Available from: http://www. ncbi.nlm.nih.gov/pubmed/16034077 [cited 19 September 2018]

[89] Ercan A, Kohrt WM, Cui J, Deane KD, Pezer M, Yu EW, et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight. 2017;**2**(4):e89703. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 28239652 [cited 17 September 2018]

[90] Jansson L, Mattsson A, Mattsson R, Holmdahl R. Estrogen induced suppression of collagen arthritis V: Physiological level of estrogen in DBA1 mice is therapeutic on established arthritis, suppresses anti-type II collagen T-cell dependent immunity and stimulates polyclonal B-cell activity. Journal of Autoimmunity. 1990;**3**(3): 257-270. Available from: https://www. sciencedirect.com/science/article/pii/ 089684119090145I [cited 18 September 2018]

[91] Nielsen RH, Christiansen C, Stolina M, Karsdal MA. Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced arthritis in rats. Clinical & Experimental Immunology. 2008; **152**(1):21-27. Available from: http://www. ncbi.nlm.nih.gov/pubmed/18241229 [cited 18 September 2018]

[92] Latham KA, Zamora A, Drought H, Subramanian S, Matejuk A, Offner H, et al. Estradiol treatment redirects the isotype of the autoantibody response and prevents the development of autoimmune arthritis. The Journal of Immunology. 2003;**171**(11):5820-5827. Available from: http://www.ncbi.nlm. nih.gov/pubmed/14634091 [cited 14 September 2018]

[93] van de Geijn FE, Wuhrer M, Selman MH, Willemsen SP, de Man YA, Deelder AM, et al. Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: Results from a large prospective cohort study. Arthritis Research & Therapy. 2009;**11**(6):R193. Available from: http://www.ncbi.nlm. nih.gov/pubmed/20015375 [cited 17 September 2018]

[94] Böhm S, Schwab I, Lux A, Nimmerjahn F. The role of sialic acid as a modulator of the anti-inflammatory activity of IgG. Seminars in Immunopathology. 2012;**34**(3):443-453. Available from: http://www.ncbi.nlm. nih.gov/pubmed/22437760 [cited 17 September 2018]

[95] Rombouts Y, Ewing E, van de Stadt LA, Selman MHJ, Trouw LA, Deelder AM, et al. Anti-citrullinated protein antibodies acquire a proinflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Annals of the Rheumatic Diseases. 2015;**74**(1): 234-241. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24106048 [cited 17 September 2018]

[96] Ohmi Y, Ise W, Harazono A, Takakura D, Fukuyama H, Baba Y, et al. Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis. Nature Communications. 2016; **7**:11205. Available from: http://www. ncbi.nlm.nih.gov/pubmed/27046227 [cited 17 September 2018]

Reviews. 2007;**28**(5):521-574. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/17640948 [cited 12 September

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

Hydroxylated estrogen metabolites influence the proliferation of cultured human monocytes: Possible role in synovial tissue hyperplasia. Clinical and Experimental Rheumatology. 2008;**26**(5): 903-909. Available from: http://www.ncb i.nlm.nih.gov/pubmed/19032826 [cited 18

[108] Yu F, Bender W. The mechanism

[109] Ateka-Barrutia O, Nelson-Piercy C. Management of rheumatologic diseases in pregnancy. International Journal of Clinical Rheumatology. 2012;**7**:541-558. Available from: https://www.medscape. com/viewarticle/773344 [cited 14

[110] Lubahn DB, RRVHLKKLKPJA. Estrogen receptor α mediates estrogen's immune protection in autoimmune disease. Journal of Immunology Research. 2003;**171**:6936-6940.

Available from: http://www.jimmunol. org/content/171/12/6936http://www. jimmunol.org/content/171/12/6936. full#ref-list-1 [cited 04 October 2018]

[111] Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007;**130**(5): 811-823. Available from: http://www. ncbi.nlm.nih.gov/pubmed/17803905

[112] Josefsson E, Tarkowski A, Dahlin A-G, Crafoord F, Thuring I, Lundgren M, et al. Suppression of type II collageninduced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol. Arthritis & Rheumatism. January 1997;

[cited 27 September 2018]

**40**(1):154-163. DOI: 10.1002/

art.1780400120

of tamoxifen in breast cancer prevention. Breast Cancer Research. 2001;**3**(S1):A74. Available from: http:// breast-cancer-research.biomedcentral. com/articles/10.1186/bcr404 [cited 08

September 2018]

October 2018]

September 2018]

Jørgensen TN. Suppressive effects of androgens on the immune system. Cellular Immunology. 2015;**294**(2): 87-94. Available from: http://www.ncbi. nlm.nih.gov/pubmed/25708485 [cited

[103] Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, et al. Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury. Proceedings of the National Academy of Sciences. 2001; **98**(4):1952-1957. Available from: http:// www.pnas.org/content/98/4/1952.long

[104] Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. The Journal of Immunology. 1998;**161**(7):3365-3374. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 9759853 [cited 17 September 2018]

[105] Hu SK, Mitcho YL, Rath NC. Effect of estradiol on interleukin 1 synthesis by

Immunopharmacology. 1988;**10**(3): 247-252. Available from: http://www. ncbi.nlm.nih.gov/pubmed/3263330

[106] Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. The Journal of Immunology. 2010;**184**(9): 5029-5037. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20351193

[107] Capellino S, Montagna P, Villaggio B,

macrophages. International

[cited 17 September 2018]

[cited 21 September 2018]

**39**

Soldano S, Straub RH, Cutolo M.

[102] Trigunaite A, Dimo J,

12 September 2018]

[cited 04 October 2018]

2018]

[97] Chen G, Wang Y, Qiu L, Qin X, Liu H, Wang X, et al. Human IgG Fcglycosylation profiling reveals associations with age, sex, female sex hormones and thyroid cancer. Journal of Proteomics. 2012;**75**(10):2824-2834. Available from: http://www.ncbi.nlm. nih.gov/pubmed/22365975 [cited 17 September 2018]

[98] Engdahl C, Bondt A, Harre U, Raufer J, Pfeifle R, Camponeschi A, et al. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: A potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Research & Therapy. 2018;**20**(1):84. Available from: http://www.ncbi.nlm. nih.gov/pubmed/29720252 [cited 17 September 2018]

[99] Stefano GB, Prevot V, Beauvillain JC, Fimiani C,Welters I, Cadet P, et al. Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: Evidence for an estrogen surface receptor. The Journal of Immunology. 1999;**163**(7): 3758-3763. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10490972 [cited 18 September 2018]

[100] Hess RA, Bunick D, Lee K-H, Bahr J, Taylor JA, Korach KS, et al. A role for oestrogens in the male reproductive system. Nature. 1997; **390**(6659):509-512. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 9393999 [cited 18 September 2018]

[101] Straub RH. The complex role of estrogens in inflammation. Endocrine *The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

Reviews. 2007;**28**(5):521-574. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/17640948 [cited 12 September 2018]

[102] Trigunaite A, Dimo J, Jørgensen TN. Suppressive effects of androgens on the immune system. Cellular Immunology. 2015;**294**(2): 87-94. Available from: http://www.ncbi. nlm.nih.gov/pubmed/25708485 [cited 12 September 2018]

[103] Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, et al. Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury. Proceedings of the National Academy of Sciences. 2001; **98**(4):1952-1957. Available from: http:// www.pnas.org/content/98/4/1952.long [cited 04 October 2018]

[104] Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. The Journal of Immunology. 1998;**161**(7):3365-3374. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 9759853 [cited 17 September 2018]

[105] Hu SK, Mitcho YL, Rath NC. Effect of estradiol on interleukin 1 synthesis by macrophages. International Immunopharmacology. 1988;**10**(3): 247-252. Available from: http://www. ncbi.nlm.nih.gov/pubmed/3263330 [cited 17 September 2018]

[106] Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. The Journal of Immunology. 2010;**184**(9): 5029-5037. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20351193 [cited 21 September 2018]

[107] Capellino S, Montagna P, Villaggio B, Soldano S, Straub RH, Cutolo M.

Hydroxylated estrogen metabolites influence the proliferation of cultured human monocytes: Possible role in synovial tissue hyperplasia. Clinical and Experimental Rheumatology. 2008;**26**(5): 903-909. Available from: http://www.ncb i.nlm.nih.gov/pubmed/19032826 [cited 18 September 2018]

[108] Yu F, Bender W. The mechanism of tamoxifen in breast cancer prevention. Breast Cancer Research. 2001;**3**(S1):A74. Available from: http:// breast-cancer-research.biomedcentral. com/articles/10.1186/bcr404 [cited 08 October 2018]

[109] Ateka-Barrutia O, Nelson-Piercy C. Management of rheumatologic diseases in pregnancy. International Journal of Clinical Rheumatology. 2012;**7**:541-558. Available from: https://www.medscape. com/viewarticle/773344 [cited 14 September 2018]

[110] Lubahn DB, RRVHLKKLKPJA. Estrogen receptor α mediates estrogen's immune protection in autoimmune disease. Journal of Immunology Research. 2003;**171**:6936-6940. Available from: http://www.jimmunol. org/content/171/12/6936http://www. jimmunol.org/content/171/12/6936. full#ref-list-1 [cited 04 October 2018]

[111] Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007;**130**(5): 811-823. Available from: http://www. ncbi.nlm.nih.gov/pubmed/17803905 [cited 27 September 2018]

[112] Josefsson E, Tarkowski A, Dahlin A-G, Crafoord F, Thuring I, Lundgren M, et al. Suppression of type II collageninduced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol. Arthritis & Rheumatism. January 1997; **40**(1):154-163. DOI: 10.1002/ art.1780400120

[113] Lubahn DB. Estrogen receptor α mediates estrogen's immune protection in autoimmune disease. The Journal of Immunology. 2003;**171**:6936-6940

[114] Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L, Bengtsson C. Postmenopausal hormone therapy and the risk of rheumatoid arthritis: Results from the Swedish EIRA population-based case-control study. European Journal of Epidemiology. 2015;**30**(5):449-457. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 25762170 [cited 24 September 2018]

[115] Oliver JE, Silman AJ. Why are women predisposed to autoimmune rheumatic diseases? Arthritis Research & Therapy. 2009;**11**(5):252

[116] Hannaford PC, Kay CR, Hirsch S. Oral contraceptives and rheumatoid arthritis: New data from the Royal College of general practitioners' oral contraception study. Annals of the Rheumatic Diseases. 1990; **49**(10):744-746. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 2241261

[117] Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. The Lancet. 1978; **311**(8064):569-571. Available from: https://linkinghub.elsevier.com/retrie ve/pii/S014067367891022X [cited 11 September 2019]

[118] Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L, Bengtsson C. Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: Results from the Swedish EIRA study. Annals of the Rheumatic Diseases. 2017;**76**(11): 1845-1852. Available from: http://www. ncbi.nlm.nih.gov/pubmed/28818831 [cited 11 September 2019]

[119] Spector TD, Hochberg MC. The protective effect of the oral contraceptive pill on rheumatoid

arthritis: An overview of the analytic epidemiological studies using metaanalysis. Journal of Clinical Epidemiology. 1990;**43**(11):1221-1230. Available from: http://www.ncbi.nlm. nih.gov/pubmed/2147033 [cited 11 September 2019]

[125] Cvoro A, Tatomer D, Tee M-K, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. The Journal of Immunology. 2008;**180**(1):630-636. Available from: http://www.ncbi.nlm. nih.gov/pubmed/18097065 [cited 20

*DOI: http://dx.doi.org/10.5772/intechopen.93371*

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology*

September 2018]

**41**

[120] Qi S, Xin R, Guo W, Liu Y. Metaanalysis of oral contraceptives and rheumatoid arthritis risk in women. Therapeutics and Clinical Risk Management. 2014;**10**:915-923. Available from: http://www.ncbi.nlm.nih.gov/pub med/25395857 [cited 21 September 2018]

[121] D'Elia HF, Larsen A, Mattsson L-A, Waltbrand E, Kvist G, Mellström D, et al. Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. The Journal of Rheumatology. 2003; **30**(7):1456-1463. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/ 12858441 [cited 17 September 2018]

[122] Hillard PA. Menstrual suppression: Current perspectives. International Journal of Women's Health. 2014;**6**: 631-637. Available from: http://www. ncbi.nlm.nih.gov/pubmed/25018654 [cited 21 September 2018]

[123] Cristofaro PA, Opal SM, Palardy JE, Parejo NA, Jhung J, Keith JC, et al. WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock. Critical Care Medicine. 2006;**34**(8): 2188-2193. Available from: http://www. ncbi.nlm.nih.gov/pubmed/16755255 [cited 20 September 2018]

[124] Harris HA, Bruner-Tran KL, Zhang X, Osteen KG, Lyttle CR. A selective estrogen receptor-β agonist causes lesion regression in an experimentally induced model of endometriosis. Human Reproduction. 2005;**20**(4):936-941. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 15618247 [cited 20 September 2018]

*The Role of Estrogens in Rheumatoid Arthritis Physiopathology DOI: http://dx.doi.org/10.5772/intechopen.93371*

[125] Cvoro A, Tatomer D, Tee M-K, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. The Journal of Immunology. 2008;**180**(1):630-636. Available from: http://www.ncbi.nlm. nih.gov/pubmed/18097065 [cited 20 September 2018]

**43**

**Chapter 3**

**Abstract**

treatments appropriately.

rheumatology

**1. Introduction**

Understanding the Mechanisms of

Pain is a debilitating feature of rheumatoid arthritis (RA) and is often described

**Keywords:** pain, rheumatoid arthritis, inflammation, pain sensitisation, nociceptors,

Rheumatoid arthritis (RA) is a systemic inflammatory disease with a prevalence of between 0.5 to 1% in different worldwide populations [1]. Inflammation predominantly affects the joints causing synovitis, pannus formation and if left untreated, joint destruction. Patients with RA classically present with tender and swollen joints, early morning joint stiffness and systemic symptoms such as fatigue. Severe pain is a particularly debilitating feature of RA that is commonly described as patients' most important symptom [2]. In addition to causing a significant impact on quality of life, studies have shown that RA pain is associated with psychological distress, impaired physical and social function and increased healthcare costs [3]. The pathogenesis of pain in RA is multifactorial. Traditionally, pain was entirely

attributed to synovitis and consequent joint destruction. With the advent of increasingly effective disease modifying agents, joint inflammation has become a more treatable cause of pain and joint destruction is preventable. Indeed, the randomised controlled trials (RCTs) that supported the use of classical disease modifying anti-rheumatic drugs (DMARDs), showed statistically and clinically significant reduction in pain with treatment [4]. However, despite effective control of inflammation and disease remission, patients have continued to report troublesome pain at follow-up [5]. The same has been shown in patients taking biologic DMARDs [6]. This suggests that pain does not always fully resolve with the effective suppression of synovitis [7]. Observational studies have also highlighted the complex relationship between pain and inflammation in patients with RA. For example, large discrepancies between objective measures of inflammation such as acute-phase proteins and reported pain, have been shown in some patients with RA [8].

by patients as their most important symptom. Rheumatoid arthritis pain has traditionally been attributed solely to joint inflammation, however despite the advent of increasingly effective disease modifying agents, patients continue to report pain at long term follow up. The cause for ongoing pain is multifactorial and includes joint damage and pain sensitisation. In this book chapter, we will describe the mechanisms underlying the distinct components of pain which are manifest in rheumatoid arthritis and discuss why a thorough assessment of pain is vital to target

Pain in Rheumatoid Arthritis

*Kathryn Biddle and Nidhi Sofat*

### **Chapter 3**

## Understanding the Mechanisms of Pain in Rheumatoid Arthritis

*Kathryn Biddle and Nidhi Sofat*

### **Abstract**

Pain is a debilitating feature of rheumatoid arthritis (RA) and is often described by patients as their most important symptom. Rheumatoid arthritis pain has traditionally been attributed solely to joint inflammation, however despite the advent of increasingly effective disease modifying agents, patients continue to report pain at long term follow up. The cause for ongoing pain is multifactorial and includes joint damage and pain sensitisation. In this book chapter, we will describe the mechanisms underlying the distinct components of pain which are manifest in rheumatoid arthritis and discuss why a thorough assessment of pain is vital to target treatments appropriately.

**Keywords:** pain, rheumatoid arthritis, inflammation, pain sensitisation, nociceptors, rheumatology

#### **1. Introduction**

Rheumatoid arthritis (RA) is a systemic inflammatory disease with a prevalence of between 0.5 to 1% in different worldwide populations [1]. Inflammation predominantly affects the joints causing synovitis, pannus formation and if left untreated, joint destruction. Patients with RA classically present with tender and swollen joints, early morning joint stiffness and systemic symptoms such as fatigue. Severe pain is a particularly debilitating feature of RA that is commonly described as patients' most important symptom [2]. In addition to causing a significant impact on quality of life, studies have shown that RA pain is associated with psychological distress, impaired physical and social function and increased healthcare costs [3].

The pathogenesis of pain in RA is multifactorial. Traditionally, pain was entirely attributed to synovitis and consequent joint destruction. With the advent of increasingly effective disease modifying agents, joint inflammation has become a more treatable cause of pain and joint destruction is preventable. Indeed, the randomised controlled trials (RCTs) that supported the use of classical disease modifying anti-rheumatic drugs (DMARDs), showed statistically and clinically significant reduction in pain with treatment [4]. However, despite effective control of inflammation and disease remission, patients have continued to report troublesome pain at follow-up [5]. The same has been shown in patients taking biologic DMARDs [6]. This suggests that pain does not always fully resolve with the effective suppression of synovitis [7]. Observational studies have also highlighted the complex relationship between pain and inflammation in patients with RA. For example, large discrepancies between objective measures of inflammation such as acute-phase proteins and reported pain, have been shown in some patients with RA [8].

Taken together, this evidence suggests that inflammation and joint destruction alone cannot account for the total pain manifesting in RA. Indeed, increasing evidence supports a role for aberrant pain processing, including peripheral and central pain sensitisation, in the pathogenesis of pain in RA. Throughout this book chapter, we will explore the different mechanisms underlying the perception of pain in patients with RA.

### **2. Inflammation in RA**

RA is a pathologically heterogenous autoimmune condition. The disease can broadly be divided into sero-positive and sero-negative subtypes. In sero-positive patients, the presence of anti-citrullinated peptide antibodies (ACPAs), is associated with more severe joint damage and increased mortality [9]. In these patients, ACPAs bind to citrullinated autoantigens including fibrinogen, vimentin, collagen type 4 and α-enolase, resulting in the formation of immune complexes (ICs) [10]. ICs activate the complement system and trigger inflammatory cell infiltration within the synovium [11].

The pathology of RA is characterised by the activation of cells of both the innate and adaptive immune system within the synovial matrix. The innate immune response consists of macrophages, mast cells and dendritic cells. These cells produce inflammatory mediators including cytokines, chemokines, lipids, proteases and growth factors. These mediators attract neutrophils and activate cells of the adaptive immune system, such as T cells, B cells and plasma cells. The inflammatory cytokines produced during the innate immune response shape the subsequent activation of the adaptive immune system. For example, cytokines produced in the early phases of inflammation regulate the differentiation of naïve T helper cells into T helper cell subsets and the subsequent T cell response.

In RA, the inflammatory milieu within the synovium is characterised by complex cytokine and chemokine interactions. Cytokines including TNF-α and IL-6 appear to be particularly important, and biologic agents targeting these mediators are well-established treatments for RA [12].

Inflammation results in a catabolic state within the joint. One of the pathognomonic features of RA is the synovial pannus, a hypertrophied area of synovium with tissue destructive properties [13]. Within the pannus, synovial fibroblasts assume an inflammatory phenotype resulting in enhanced cartilage catabolism and synovial osteoclastogenesis [14]. Cytokine-mediated chondrocyte activation results in the stimulation of catabolic pathways. Enzymes including matrix metalloproteinases (MMPs) are activated to degrade the cartilage matrix [15]. Bone erosion is stimulated by the interaction between RANK-L on fibroblasts, T and B cells and its receptor RANK on dendritic cells, macrophages and pre-osteoclasts [16]. Ultimately, this process can result in cartilage and bone destruction and joint deformity.

Therapies that target inflammation such as conventional DMARDs and biologic therapies are effective at suppressing synovitis and reducing joint destruction. The treat-to-target approach is widely recommended for the management of RA. This strategy involves regular monitoring of disease activity, using validated scoring measures such as the DAS28, and escalation of treatment if a target is not reached. RCTs have found that this approach substantially improves disease activity, radiographic progression, quality of life and physical function [17]. These immunomodulatory agents have been shown to reduce pain, albeit not completely [18]. Throughout the next section of this chapter, we will discuss the inflammatory basis of pain in RA.

**45**

**Figure 1.**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

nomenon that we will discuss later in this chapter.

**2.2 Synovial joint structures and pain**

Inflammation has long been accepted to cause pain. Indeed, pain was one of the cardinal features of inflammation, as defined by Celsus in the first century [19]. Pain secondary to inflammation can be classified into acute or chronic pain. The neurotransmission of acute pain signals in response to noxious stimulation involves the activation of a specialised subset of sensory neurons called nociceptors. Nociceptors innervate peripheral tissues, including joints, and transmit painful stimuli to the dorsal root ganglion (DRG). There are many subsets of nociceptors, each responding to different types of noxious stimuli. Aδ and C fibres are the two main types of primary afferent nociceptors [20]. Whilst both Aδ and C fibres are found in superficial organs, such as the skin, C-fibres generally supply deeper structures such as joints [20]. C-fibres are activated by thermal, chemical or mechanical stimulation, resulting in poorly localised, dull pain

The activation of nociceptors involves the stimulation of ligand-gated and voltage-gated ion channels including transient receptor potential cation channel, subfamily A, member 1 (TRPV1), transient receptor potential cation channel, subfamily A, member 1 (TRPA1), Nav1.7, Nav1.8, and Nav1.9 channels, which are expressed on peripheral nerve terminals [21]. Activation of these channels results in the stimulation of intracellular signalling pathways and the transmission of acute pain signals [21]. In the longer term, chronic inflammation results in long lasting changes in nociceptor signalling resulting in peripheral pain sensitisation, a phe-

Arthritic pain is thought to be mediated by nociceptors that innervate the synovium and subchondral bone. In contrast, under physiological conditions, cartilage is an aneural and avascular tissue. This is illustrated in **Figure 1**.

In RA, chronic inflammation is thought to result in structural and functional changes in the peripheral innervation of joints. This has been shown in animal

*Diagram of a synovial joint. A synovial joint consists of two articulating cartilage surfaces surrounded by a synovial membrane. Synovial fluid fills the synovium. Under physiological conditions, cartilage is avascular and aneural. Nociceptors innervating the synovium and subchondral bone are responsible for arthritic pain. In* 

*contrast, stretch receptors, innervating the fibrous capsule are responsible for proprioception.*

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

**2.1 Pain and joint inflammation**

sensation [20].

### **2.1 Pain and joint inflammation**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

pain in patients with RA.

**2. Inflammation in RA**

within the synovium [11].

Taken together, this evidence suggests that inflammation and joint destruction alone cannot account for the total pain manifesting in RA. Indeed, increasing evidence supports a role for aberrant pain processing, including peripheral and central pain sensitisation, in the pathogenesis of pain in RA. Throughout this book chapter, we will explore the different mechanisms underlying the perception of

RA is a pathologically heterogenous autoimmune condition. The disease can broadly be divided into sero-positive and sero-negative subtypes. In sero-positive patients, the presence of anti-citrullinated peptide antibodies (ACPAs), is associated with more severe joint damage and increased mortality [9]. In these patients, ACPAs bind to citrullinated autoantigens including fibrinogen, vimentin, collagen type 4 and α-enolase, resulting in the formation of immune complexes (ICs) [10]. ICs activate the complement system and trigger inflammatory cell infiltration

The pathology of RA is characterised by the activation of cells of both the innate

In RA, the inflammatory milieu within the synovium is characterised by complex cytokine and chemokine interactions. Cytokines including TNF-α and IL-6 appear to be particularly important, and biologic agents targeting these mediators

Inflammation results in a catabolic state within the joint. One of the pathognomonic features of RA is the synovial pannus, a hypertrophied area of synovium with tissue destructive properties [13]. Within the pannus, synovial fibroblasts assume an inflammatory phenotype resulting in enhanced cartilage catabolism and synovial osteoclastogenesis [14]. Cytokine-mediated chondrocyte activation results in the stimulation of catabolic pathways. Enzymes including matrix metalloproteinases (MMPs) are activated to degrade the cartilage matrix [15]. Bone erosion is stimulated by the interaction between RANK-L on fibroblasts, T and B cells and its receptor RANK on dendritic cells, macrophages and pre-osteoclasts [16]. Ultimately, this process can result in cartilage and bone destruction and joint

Therapies that target inflammation such as conventional DMARDs and biologic therapies are effective at suppressing synovitis and reducing joint destruction. The treat-to-target approach is widely recommended for the management of RA. This strategy involves regular monitoring of disease activity, using validated scoring measures such as the DAS28, and escalation of treatment if a target is not reached. RCTs have found that this approach substantially improves disease activity, radiographic progression, quality of life and physical function [17]. These immunomodulatory agents have been shown to reduce pain, albeit not completely [18]. Throughout the next section of this chapter, we will discuss the inflammatory basis

and adaptive immune system within the synovial matrix. The innate immune response consists of macrophages, mast cells and dendritic cells. These cells produce inflammatory mediators including cytokines, chemokines, lipids, proteases and growth factors. These mediators attract neutrophils and activate cells of the adaptive immune system, such as T cells, B cells and plasma cells. The inflammatory cytokines produced during the innate immune response shape the subsequent activation of the adaptive immune system. For example, cytokines produced in the early phases of inflammation regulate the differentiation of naïve T helper cells into

T helper cell subsets and the subsequent T cell response.

are well-established treatments for RA [12].

**44**

of pain in RA.

deformity.

Inflammation has long been accepted to cause pain. Indeed, pain was one of the cardinal features of inflammation, as defined by Celsus in the first century [19]. Pain secondary to inflammation can be classified into acute or chronic pain. The neurotransmission of acute pain signals in response to noxious stimulation involves the activation of a specialised subset of sensory neurons called nociceptors. Nociceptors innervate peripheral tissues, including joints, and transmit painful stimuli to the dorsal root ganglion (DRG). There are many subsets of nociceptors, each responding to different types of noxious stimuli. Aδ and C fibres are the two main types of primary afferent nociceptors [20]. Whilst both Aδ and C fibres are found in superficial organs, such as the skin, C-fibres generally supply deeper structures such as joints [20]. C-fibres are activated by thermal, chemical or mechanical stimulation, resulting in poorly localised, dull pain sensation [20].

The activation of nociceptors involves the stimulation of ligand-gated and voltage-gated ion channels including transient receptor potential cation channel, subfamily A, member 1 (TRPV1), transient receptor potential cation channel, subfamily A, member 1 (TRPA1), Nav1.7, Nav1.8, and Nav1.9 channels, which are expressed on peripheral nerve terminals [21]. Activation of these channels results in the stimulation of intracellular signalling pathways and the transmission of acute pain signals [21]. In the longer term, chronic inflammation results in long lasting changes in nociceptor signalling resulting in peripheral pain sensitisation, a phenomenon that we will discuss later in this chapter.

### **2.2 Synovial joint structures and pain**

Arthritic pain is thought to be mediated by nociceptors that innervate the synovium and subchondral bone. In contrast, under physiological conditions, cartilage is an aneural and avascular tissue. This is illustrated in **Figure 1**.

In RA, chronic inflammation is thought to result in structural and functional changes in the peripheral innervation of joints. This has been shown in animal

#### **Figure 1.**

*Diagram of a synovial joint. A synovial joint consists of two articulating cartilage surfaces surrounded by a synovial membrane. Synovial fluid fills the synovium. Under physiological conditions, cartilage is avascular and aneural. Nociceptors innervating the synovium and subchondral bone are responsible for arthritic pain. In contrast, stretch receptors, innervating the fibrous capsule are responsible for proprioception.*

models where chronic synovitis results in increased innervation of the synovium and increased spontaneous and mechanical-induced firing of articular primary afferents [22, 23].

#### **2.3 Nociceptor pathways**

Nociceptor pathways mediating acute pain perception in response to inflammation are well defined. In the periphery, local immune cells release inflammatory mediators, such as cytokines, that act on the peripheral nerve terminals of nociceptor neurons. This activates the nociceptors to transmit signals via the DRG through the spinothalamic tract to the higher cortical centres, resulting in the perception of pain. It is also well accepted that inflammation can result in heightened nociceptor sensitivity to both noxious and innocuous stimuli. In this case, the activation of nociceptors by inflammatory mediators triggers intracellular signalling cascades that reduce the threshold for nociceptor neurons to fire action potentials [21]. This results in heightened pain sensitivity which can manifest as allodynia; the sensation of pain arising from a non-painful stimulus, or hyperalgesia; a heightened sensation of pain in response to painful stimulation. Throughout the next section of this chapter, we will discuss the inflammatory mediators that stimulate nociceptor activation and sensitisation in RA.

#### **2.4 Pain and innate immunity**

Cells of the innate immune system, including neutrophils, mast cells and macrophages, release noxious inflammatory mediators and have been shown to stimulate pain and pain sensitisation in a wide range of models and systems. For example, in mouse models of carrageenan-induced inflammatory pain, neutrophils migrate to tissues and sustain pain through the production of cytokines and prostaglandin E2 [24]. In incisional wound injury, macrophages (CD11b + myeloid cells) have been shown to mediate acute pain and pain sensitisation [25]. Mast cell degranulation activates nociceptor firing acutely and may also contribute to pathology of chronic pain and mast cells have been shown accumulate in chronic inflammatory conditions such as complex regional pain syndrome [26, 27]. Throughout the next part of the chapter, we will discuss the noxious inflammatory mediators that are released by innate immune cells.

#### **2.5 Lipid mediators of pain**

Pro-inflammatory lipids include cyclooxygenase (COX) dependent molecules such as prostanoids (prostaglandins, prostacyclins and thromboxanes). COXdependent molecules are well known to cause pain and pain sensitisation and inhibition of the COX enzyme, using non-steroidal anti-inflammatory drugs (NSAIDs), is used for the suppression of pain and inflammation. Indeed, NSAIDs are potent analgesic and anti-inflammatory medications which are effective for the treatment of acute inflammatory pain including synovitis [28].

Studies have investigated the mechanism of action underlying the noxious effect of prostaglandins. Prostaglandin E2 (PGE2) has been shown to activate nociceptors through the binding of EP1-EP4 receptors. This stimulates pain and pain sensitisation via multiple mechanisms. PGE2 stimulates proximal ion channels in nociceptive neurons. This sensitises the neurons to painful stimuli [29]. PGE2 activates more persistent pain sensitisation via PKA and PKC-mediated activation of NFκB in the dorsal root ganglion neurons [30].

**47**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

sphingosine-1-phosphate are produced during inflammation and have been shown to activate nociceptors leading to increased TRPV1 activity [31]. Leukotrienes may also have an noxious effect and the injection of leukotriene B4 has been shown to activate C and Aδ-fibres in rat models and induce hyperalgesia in humans [21, 32]. More recent work has also demonstrated a role for anti-inflammatory and proresolving lipids in the silencing of pain. For example, pro-resolving lipids, including lipoxins, resolvins and protectins have generally been shown to have analgesic effects [33]. Further work is required to characterise the underlying molecular pathways but these mediators may represent targets for the future treatment of

Innate immune cells release neurotransmitters capable of modulating pain transmission. For example, mast cells contain histamine and serotonin that are released on degranulation. Histamine triggers pain sensitisation through the activation of H1 and H2 receptors expressed on nociceptors [34]. This results in increased expression

Inflammatory cytokines represent another important class of molecules that stimulate nociceptors and activate pain sensitisation. IL-1β was the first cytokine to be described as hyperalgesic [36]. This finding was seminal in the field of neuroimmunology and represented early evidence for the cross-talk between the immune system and pain sensitisation. Cytokines have now been found to play important roles in pain modulation in most painful conditions, including RA. Notably, proinflammatory cytokines including IL-1β, IL-6, TNF-α, IL-17A and IL-5, have all

IL-1β sensitises nociceptors through different intra-cellular signalling pathways. Firstly, IL-1β activates the p38 MAPK-mediated phosphorylation of Nav1.8 sodium channels resulting in increased action potential generation and an associated mechanical and thermal hyperalgesia [37]. Secondly, the activation of IL-1R1 by IL1-β, has also been shown to result in increased TRPV1 expression on nociceptors,

IL-6 stimulates pain sensitisation directly and indirectly. Directly, IL-6 activates nociceptors via the signal transducer gp 130 leading to increased TRPV1 and TRPA1 expression [39]. Indirectly, IL-6 activates nociceptors via the production of prostaglandins [39]. TNF-α also induces pain sensitisation via TRPA1 and TRPV1, however TNF-α mediated inflammatory pain appears to be dependent on prostaglandins [40]. Indeed, COX-2 inhibitors have been shown to inhibit TNF-α induced capsaicin responsiveness in cultured nociceptors [41]. TNF-α also modulates nociceptor sensitivity through the activation of p38 MAPK mediated phosphorylation of Nav.18

Increasing work suggests a role for IL-17 in pain sensitisation. Indeed, many painful autoimmune diseases, such as RA and psoriasis, are characterised by a Th17 immune response. IL-17A has been shown to be broadly expressed by nociceptors and IL-17 has been demonstrated to induce a rapid increase in neuronal excitability [43]. In animal models of RA, IL-17 has been shown to induce hyperalgesia, through a mechanism dependent on the amplification of TNF-α, IL-1B, CXCL-1, endothelin

In summary, IL-1β, IL-6, TNF-α and IL-17 stimulate pain and pain sensitisation through the synthesis of prostaglandins and/or the activation of sodium or TRP

of Nav1.8 channels and increased sensitivity to noxious stimuli [34, 35].

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

**2.6 Neurotransmitters and pain**

been shown to active nociceptors directly [21].

and Nav1.9 sodium channels [42].

1 and prostaglandins [44].

resulting in thermal pain sensitisation in animal models [38].

**2.7 Cytokines and pain**

pain [33].

Many other classes of pro-inflammatory lipids are thought to be involved in the activation of nociceptor activity. For example, lysophosphatidic acid and

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

sphingosine-1-phosphate are produced during inflammation and have been shown to activate nociceptors leading to increased TRPV1 activity [31]. Leukotrienes may also have an noxious effect and the injection of leukotriene B4 has been shown to activate C and Aδ-fibres in rat models and induce hyperalgesia in humans [21, 32].

More recent work has also demonstrated a role for anti-inflammatory and proresolving lipids in the silencing of pain. For example, pro-resolving lipids, including lipoxins, resolvins and protectins have generally been shown to have analgesic effects [33]. Further work is required to characterise the underlying molecular pathways but these mediators may represent targets for the future treatment of pain [33].

#### **2.6 Neurotransmitters and pain**

Innate immune cells release neurotransmitters capable of modulating pain transmission. For example, mast cells contain histamine and serotonin that are released on degranulation. Histamine triggers pain sensitisation through the activation of H1 and H2 receptors expressed on nociceptors [34]. This results in increased expression of Nav1.8 channels and increased sensitivity to noxious stimuli [34, 35].

#### **2.7 Cytokines and pain**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

afferents [22, 23].

**2.3 Nociceptor pathways**

**2.4 Pain and innate immunity**

by innate immune cells.

**2.5 Lipid mediators of pain**

of acute inflammatory pain including synovitis [28].

the dorsal root ganglion neurons [30].

models where chronic synovitis results in increased innervation of the synovium and increased spontaneous and mechanical-induced firing of articular primary

Nociceptor pathways mediating acute pain perception in response to inflammation are well defined. In the periphery, local immune cells release inflammatory mediators, such as cytokines, that act on the peripheral nerve terminals of nociceptor neurons. This activates the nociceptors to transmit signals via the DRG through the spinothalamic tract to the higher cortical centres, resulting in the perception of pain. It is also well accepted that inflammation can result in heightened nociceptor sensitivity to both noxious and innocuous stimuli. In this case, the activation of nociceptors by inflammatory mediators triggers intracellular signalling cascades that reduce the threshold for nociceptor neurons to fire action potentials [21]. This results in heightened pain sensitivity which can manifest as allodynia; the sensation of pain arising from a non-painful stimulus, or hyperalgesia; a heightened sensation of pain in response to painful stimulation. Throughout the next section of this chapter, we will discuss the inflammatory mediators that stimulate nociceptor activation and sensitisation in RA.

Cells of the innate immune system, including neutrophils, mast cells and macrophages, release noxious inflammatory mediators and have been shown to stimulate pain and pain sensitisation in a wide range of models and systems. For example, in mouse models of carrageenan-induced inflammatory pain, neutrophils migrate to tissues and sustain pain through the production of cytokines and prostaglandin E2 [24]. In incisional wound injury, macrophages (CD11b + myeloid cells) have been shown to mediate acute pain and pain sensitisation [25]. Mast cell degranulation activates nociceptor firing acutely and may also contribute to pathology of chronic pain and mast cells have been shown accumulate in chronic inflammatory conditions such as complex regional pain syndrome [26, 27]. Throughout the next part of the chapter, we will discuss the noxious inflammatory mediators that are released

Pro-inflammatory lipids include cyclooxygenase (COX) dependent molecules such as prostanoids (prostaglandins, prostacyclins and thromboxanes). COXdependent molecules are well known to cause pain and pain sensitisation and inhibition of the COX enzyme, using non-steroidal anti-inflammatory drugs (NSAIDs), is used for the suppression of pain and inflammation. Indeed, NSAIDs are potent analgesic and anti-inflammatory medications which are effective for the treatment

Studies have investigated the mechanism of action underlying the noxious effect of prostaglandins. Prostaglandin E2 (PGE2) has been shown to activate nociceptors through the binding of EP1-EP4 receptors. This stimulates pain and pain sensitisation via multiple mechanisms. PGE2 stimulates proximal ion channels in nociceptive neurons. This sensitises the neurons to painful stimuli [29]. PGE2 activates more persistent pain sensitisation via PKA and PKC-mediated activation of NFκB in

Many other classes of pro-inflammatory lipids are thought to be involved in the activation of nociceptor activity. For example, lysophosphatidic acid and

**46**

Inflammatory cytokines represent another important class of molecules that stimulate nociceptors and activate pain sensitisation. IL-1β was the first cytokine to be described as hyperalgesic [36]. This finding was seminal in the field of neuroimmunology and represented early evidence for the cross-talk between the immune system and pain sensitisation. Cytokines have now been found to play important roles in pain modulation in most painful conditions, including RA. Notably, proinflammatory cytokines including IL-1β, IL-6, TNF-α, IL-17A and IL-5, have all been shown to active nociceptors directly [21].

IL-1β sensitises nociceptors through different intra-cellular signalling pathways. Firstly, IL-1β activates the p38 MAPK-mediated phosphorylation of Nav1.8 sodium channels resulting in increased action potential generation and an associated mechanical and thermal hyperalgesia [37]. Secondly, the activation of IL-1R1 by IL1-β, has also been shown to result in increased TRPV1 expression on nociceptors, resulting in thermal pain sensitisation in animal models [38].

IL-6 stimulates pain sensitisation directly and indirectly. Directly, IL-6 activates nociceptors via the signal transducer gp 130 leading to increased TRPV1 and TRPA1 expression [39]. Indirectly, IL-6 activates nociceptors via the production of prostaglandins [39]. TNF-α also induces pain sensitisation via TRPA1 and TRPV1, however TNF-α mediated inflammatory pain appears to be dependent on prostaglandins [40]. Indeed, COX-2 inhibitors have been shown to inhibit TNF-α induced capsaicin responsiveness in cultured nociceptors [41]. TNF-α also modulates nociceptor sensitivity through the activation of p38 MAPK mediated phosphorylation of Nav.18 and Nav1.9 sodium channels [42].

Increasing work suggests a role for IL-17 in pain sensitisation. Indeed, many painful autoimmune diseases, such as RA and psoriasis, are characterised by a Th17 immune response. IL-17A has been shown to be broadly expressed by nociceptors and IL-17 has been demonstrated to induce a rapid increase in neuronal excitability [43]. In animal models of RA, IL-17 has been shown to induce hyperalgesia, through a mechanism dependent on the amplification of TNF-α, IL-1B, CXCL-1, endothelin 1 and prostaglandins [44].

In summary, IL-1β, IL-6, TNF-α and IL-17 stimulate pain and pain sensitisation through the synthesis of prostaglandins and/or the activation of sodium or TRP

channels. The different cytokines appear to act via different intracellular signalling pathways, however it remains unclear whether different immune responses (e.g. Th1, Th2 or Th17) induce different pain characteristics through the activation of specific nociceptors and pain receptors.

### **2.8 Immune derived growth factors in pain**

Innervation by nociceptors is a dynamic process affected by neurotrophic factors. These factors are often upregulated in response to inflammation or tissue injury and are important to restore the density of innervation post-injury [21]. If there is inappropriate or excessive release of neurotrophic factors, heightened pain sensitivity can occur [21]. Nerve growth factor (NGF) is an important neurotrophic factor that is secreted by innate immune cells during the acute phase of inflammation. NGF activates the receptor TrkA on nociceptors, stimulating the P13K/Src kinase pathway and the phosphorylation of TRPV1 and its translocation into the cell membrane [45]. This results in the rapid sensitisation of nociceptors in response to stimulation by NGF. In the longer term, NGF has been shown to stimulate axonal terminal sprouting, contributing to increased pain sensitivity [46].

### **2.9 A role for ACPAs in pain in RA**

It is well established that arthralgia can precede overt joint inflammation and that joint pain is often one of the first symptoms of emerging RA. The mechanism underlying arthralgia preceding inflammation remains unclear but a role for ACPAs has been suggested. Observational studies have shown that ACPAs frequently occur in the preclinical phase of disease and can be detected months to years prior

#### **Figure 2.**

*Inflammatory mediators and pain. Figure 2 Summarises the inflammatory mediators that have been shown to activate and sensitise nociceptors21. As illustrated, innate and adaptive immune cells release inflammatory mediators that act on their respective receptors to activate nociceptors and sensitise pain signalling through Nav and TRP channels.*

**49**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

to diagnosis [47]. Experimental studies have raised the possibility that ACPAs can induce pain via a pathway independent of joint inflammation. In one study, mice injected with human or murine ACPAs developed increased pain sensitivity, despite no signs of joint inflammation. In this study, ACPAs were shown to bind to osteoclasts in the bone marrow, and induce CXCL1/2 expression and release. Intra-articular injection of CXCL1/2 was shown to evoke pain-like behaviour and this was inhibited by an IL-8 inhibitor, reparixin [48]. Further work is required to confirm this hypothesis. If correct, it could alter the management of ACPA positive

arthralgia and offer new therapeutic targets in the management of early RA. In summary, inflammation is a well-accepted cause of pain in RA and many inflammatory mediators have been shown to stimulate nociceptor activation and

Despite the important role for inflammation in pain in RA, the extent of inflammation does not always correlate with the severity of total pain reported RA patients. Indeed, observational studies have shown that changes in inflammation account for only 40% of changes in pain in RA patients [49]. Furthermore, factors associated with the degree of inflammation such as serology, acute phase response and joint damage correlate poorly with pain prognosis in RA patients [7]. Moreover, in common with other chronic pain conditions, psychosocial factors and female gender predict pain prognosis more accurately than the severity of inflammation [7]. Therefore, additional mechanisms must be responsible for the pain experienced in RA. These mechanisms include joint damage and aberrant pain

The contribution of structural joint changes to the total pain in RA is controversial. In patients with advanced RA, erosions and joint space narrowing are associated with disability and make a small but significant contribution to total reported pain [50]. Moreover, patients with advanced disease show an improvement in pain following joint replacement surgery [51]. However, as more effective disease modifying protocols have been developed, structural joint damage in RA has decreased and corresponding rates of orthopaedic surgery have declined [52]. The prevention of joint damage has produced superior pain outcomes but it is not clear how much of this can be attributed to the prevention of structural damage versus the suppression of inflammation or prevention of pain sensitisation. In recent studies, radiographically assessed joint damage appears to make a small contribution to pain in RA patients [53]. However, some of this pain may be explained by coincident osteoarthritis (OA), which occurs in a similar demo-

The correlation between joint damage and pain severity appears weak, although

investigation on this subject has primarily occurred in patients with OA and relatively little data exists for patients with RA. In OA, structural joint changes do not correlate well with joint pain [54]. The severity of radiographic OA has been shown to explain <20% of the variance in pain intensity [54]. Furthermore, postjoint replacement, many patients continue to report pain. 10% of patients posttotal hip replacement (THR) and 20% post-total knee replacement (TKR) report unfavourable long term pain outcomes [55]. This suggests that structural joint damage alone cannot explain the total pain experienced in OA. Like in RA, central pain sensitisation has been proposed to explain the pain not accounted for by joint

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

sensitisation, as summarised in **Figure 2**.

sensitisation.

**3. Joint damage and pain**

graphic of patients.

destruction [56].

#### *Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

specific nociceptors and pain receptors.

pain sensitivity [46].

**2.9 A role for ACPAs in pain in RA**

**2.8 Immune derived growth factors in pain**

channels. The different cytokines appear to act via different intracellular signalling pathways, however it remains unclear whether different immune responses (e.g. Th1, Th2 or Th17) induce different pain characteristics through the activation of

Innervation by nociceptors is a dynamic process affected by neurotrophic factors. These factors are often upregulated in response to inflammation or tissue injury and are important to restore the density of innervation post-injury [21]. If there is inappropriate or excessive release of neurotrophic factors, heightened pain sensitivity can occur [21]. Nerve growth factor (NGF) is an important neurotrophic factor that is secreted by innate immune cells during the acute phase of inflammation. NGF activates the receptor TrkA on nociceptors, stimulating the P13K/Src kinase pathway and the phosphorylation of TRPV1 and its translocation into the cell membrane [45]. This results in the rapid sensitisation of nociceptors in response to stimulation by NGF. In the longer term, NGF has been shown to stimulate axonal terminal sprouting, contributing to increased

It is well established that arthralgia can precede overt joint inflammation and that joint pain is often one of the first symptoms of emerging RA. The mechanism underlying arthralgia preceding inflammation remains unclear but a role for ACPAs has been suggested. Observational studies have shown that ACPAs frequently occur in the preclinical phase of disease and can be detected months to years prior

**48**

**Figure 2.**

*and TRP channels.*

*Inflammatory mediators and pain. Figure 2 Summarises the inflammatory mediators that have been shown to activate and sensitise nociceptors21. As illustrated, innate and adaptive immune cells release inflammatory mediators that act on their respective receptors to activate nociceptors and sensitise pain signalling through Nav*  to diagnosis [47]. Experimental studies have raised the possibility that ACPAs can induce pain via a pathway independent of joint inflammation. In one study, mice injected with human or murine ACPAs developed increased pain sensitivity, despite no signs of joint inflammation. In this study, ACPAs were shown to bind to osteoclasts in the bone marrow, and induce CXCL1/2 expression and release. Intra-articular injection of CXCL1/2 was shown to evoke pain-like behaviour and this was inhibited by an IL-8 inhibitor, reparixin [48]. Further work is required to confirm this hypothesis. If correct, it could alter the management of ACPA positive arthralgia and offer new therapeutic targets in the management of early RA.

In summary, inflammation is a well-accepted cause of pain in RA and many inflammatory mediators have been shown to stimulate nociceptor activation and sensitisation, as summarised in **Figure 2**.

Despite the important role for inflammation in pain in RA, the extent of inflammation does not always correlate with the severity of total pain reported RA patients. Indeed, observational studies have shown that changes in inflammation account for only 40% of changes in pain in RA patients [49]. Furthermore, factors associated with the degree of inflammation such as serology, acute phase response and joint damage correlate poorly with pain prognosis in RA patients [7]. Moreover, in common with other chronic pain conditions, psychosocial factors and female gender predict pain prognosis more accurately than the severity of inflammation [7]. Therefore, additional mechanisms must be responsible for the pain experienced in RA. These mechanisms include joint damage and aberrant pain sensitisation.

### **3. Joint damage and pain**

The contribution of structural joint changes to the total pain in RA is controversial. In patients with advanced RA, erosions and joint space narrowing are associated with disability and make a small but significant contribution to total reported pain [50]. Moreover, patients with advanced disease show an improvement in pain following joint replacement surgery [51]. However, as more effective disease modifying protocols have been developed, structural joint damage in RA has decreased and corresponding rates of orthopaedic surgery have declined [52]. The prevention of joint damage has produced superior pain outcomes but it is not clear how much of this can be attributed to the prevention of structural damage versus the suppression of inflammation or prevention of pain sensitisation. In recent studies, radiographically assessed joint damage appears to make a small contribution to pain in RA patients [53]. However, some of this pain may be explained by coincident osteoarthritis (OA), which occurs in a similar demographic of patients.

The correlation between joint damage and pain severity appears weak, although investigation on this subject has primarily occurred in patients with OA and relatively little data exists for patients with RA. In OA, structural joint changes do not correlate well with joint pain [54]. The severity of radiographic OA has been shown to explain <20% of the variance in pain intensity [54]. Furthermore, postjoint replacement, many patients continue to report pain. 10% of patients posttotal hip replacement (THR) and 20% post-total knee replacement (TKR) report unfavourable long term pain outcomes [55]. This suggests that structural joint damage alone cannot explain the total pain experienced in OA. Like in RA, central pain sensitisation has been proposed to explain the pain not accounted for by joint destruction [56].

### **4. Central pain sensitisation and RA**

Processing by the central nervous system (CNS) can affect pain reporting, sensitivity, intensity and pain characteristics [57]. Aberrant pain processing can result in central pain sensitisation; an amplified response of the central nervous system to peripheral nociceptive input [58]. The term central sensitisation was coined in 1989 by Woolf and colleagues based on work in the rat model showing hyperexcitability of spinal cord neurons in response to peripheral tissue injury [58]. Physiologically, central sensitisation represents a state of hyperexcitability of spinal and supraspinal structures due to amplified neuronal signalling involving enhanced synaptic and neurotransmitter activities [59].

An increasing abundance of evidence supports the role for central pain sensitisation in RA and an understanding of central sensitisation is important to optimise patient treatment. Clinically, pain secondary to an inflammatory flare must be differentiated from pain secondary to central sensitisation as they require vastly different management approaches. Throughout the next part of this chapter, we will discuss the molecular basis of pain transmission from the periphery to the CNS, clinical evidence supporting a role for pain sensitisation in RA and some proposed mechanisms for pain sensitisation in the DRG and in the cerebral cortex.

#### **4.1 Molecular basis of pain sensitisation**

As discussed previously, A-δ and C nociceptive neurons are activated by inflammatory mediators in the periphery. These fibres converge at the DRG, along with non-noxious A-β fibres. Following activation, nociceptor fibres release substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, aspartate and NGF at the afferent nerve endings into the synaptic cleft [60]. These neurotransmitters activate their corresponding receptors on post-synaptic neurons. Activation of postsynaptic receptors results in intracellular signalling changes. For example, activation of NMDA receptors results in increased membrane permeability, intracellular entry of calcium, activation of protein kinases and the expression of c-fos [61]. These signalling changes result in the hyperexcitability of the secondary neurons and amplification of the peripheral noxious stimulus. Post-synaptic neurons ascend in the spinothalamic tract to the thalamus, hypothalamus, limbic system and the somatosensory cortex [61]. These signalling pathways are summarised in **Figure 3**.

Animal models of RA have been used to investigate the molecular mechanisms underlying spinal pain sensitisation. In these models, molecular changes have been shown to occur in the DRG, spinal neurons and spinoreticular neurons. For example, in complete Freund's adjuvant (CFA) induced arthritis models, increased expression of SP, CGRP, NPY, c-fos, TRPV1, P2X3 and Trk-A receptors in the DRG have been demonstrated [62]. These changes are thought to result in hyperexcitability of spinal neurons and enhanced sensitivity to nociceptor signalling.

#### **4.2 Clinical evidence for a role of pain sensitisation in RA**

Patients with RA show widespread reductions in pain threshold and increased pain sensitivity, not only over inflamed joints but at distant, non-articular sites [62]. Evidence to support this has come from clinical studies using techniques such as quantitative sensory testing (QST). This technique involves the application of stimuli under standardised testing protocols and the quantification of the participants sensory experience. QST employs different tools for the assessment of the perception of vibration, touch, proprioception, pinprick or blunt pressure

**51**

**Figure 3.**

**4.3 Neuropathic pain in RA**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

sensitivity. RA patients have a lower pain threshold than healthy controls with QST [63]. Furthermore, sensitisation has been shown to affect a wide range of sensory

*A simplified diagram of pain signalling pathways. As illustrated, noxious stimulation activates A-δ and C fibres in the periphery. These fibres converge at the DRG and activate post-synaptic neurons that ascend to* 

Studies have demonstrated that pain thresholds vary substantially between patients with RA. Multiple factors have been shown to correlate with differences in pain threshold. Importantly, these include high tender joint count and prolonged disease duration [64]. This suggests that the persistence of nociceptive stimulation results in long-term changes in pain processing resulting in central pain sensitisation. Other factors that have been shown to influence pain threshold include sleep

Repetitive sensory stimulation, also known as temporal summation, is another experimental model that has been used to investigate central sensitisation in RA. Temporal summation occurs when the time between stimuli is short enough to prevent the dissipation of postsynaptic action potentials before re-activation [66]. This results in a higher membrane potential, increasing the probability that further stimulation will result in post-synaptic activation. In healthy controls, repetitive stimulation results in the reduction of pressure pain thresholds [62]. Studies have shown that this response is augmented in RA patients [67]. This has also been demonstrated electrophysiologically through the measurement of action potentials in response to repetitive stimulation. In healthy controls, there is an increase in the amplitude of action potential evoked from repetitive stimulation using noxious stimulation. This response is amplified in RA patients and has been shown to cor-

In addition to measuring pain thresholds, pain characteristics can be analysed to assess the possible contribution of pain sensitisation to overall pain experience. Specifically, pain questionnaires are commonly used to detect the presence of neuropathic-sounding pain. Neuropathic pain is the perception of pain in the absence of nociceptive input or peripheral tissue damage and is caused by pathology

modalities, including thermal and mechanical stimulation.

*higher cortical centres via the spinothalamic tract.*

quality, psychosocial factors and analgesic use [65].

relate with disease activity scores and high tender joint counts [68].

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

#### *Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

#### **Figure 3.**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

Processing by the central nervous system (CNS) can affect pain reporting, sensitivity, intensity and pain characteristics [57]. Aberrant pain processing can result in central pain sensitisation; an amplified response of the central nervous system to peripheral nociceptive input [58]. The term central sensitisation was coined in 1989 by Woolf and colleagues based on work in the rat model showing hyperexcitability of spinal cord neurons in response to peripheral tissue injury [58]. Physiologically, central sensitisation represents a state of hyperexcitability of spinal and supraspinal structures due to amplified neuronal signalling involving enhanced synaptic

An increasing abundance of evidence supports the role for central pain sensitisation in RA and an understanding of central sensitisation is important to optimise patient treatment. Clinically, pain secondary to an inflammatory flare must be differentiated from pain secondary to central sensitisation as they require vastly different management approaches. Throughout the next part of this chapter, we will discuss the molecular basis of pain transmission from the periphery to the CNS, clinical evidence supporting a role for pain sensitisation in RA and some proposed

As discussed previously, A-δ and C nociceptive neurons are activated by inflammatory mediators in the periphery. These fibres converge at the DRG, along with non-noxious A-β fibres. Following activation, nociceptor fibres release substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, aspartate and NGF at the afferent nerve endings into the synaptic cleft [60]. These neurotransmitters activate

mechanisms for pain sensitisation in the DRG and in the cerebral cortex.

their corresponding receptors on post-synaptic neurons. Activation of postsynaptic receptors results in intracellular signalling changes. For example, activation of NMDA receptors results in increased membrane permeability, intracellular entry of calcium, activation of protein kinases and the expression of c-fos [61]. These signalling changes result in the hyperexcitability of the secondary neurons and amplification of the peripheral noxious stimulus. Post-synaptic neurons ascend in the spinothalamic tract to the thalamus, hypothalamus, limbic system and the somatosensory cortex [61]. These signalling pathways are summarised in **Figure 3**. Animal models of RA have been used to investigate the molecular mechanisms

underlying spinal pain sensitisation. In these models, molecular changes have been shown to occur in the DRG, spinal neurons and spinoreticular neurons. For example, in complete Freund's adjuvant (CFA) induced arthritis models, increased expression of SP, CGRP, NPY, c-fos, TRPV1, P2X3 and Trk-A receptors in the DRG have been demonstrated [62]. These changes are thought to result in hyperexcitabil-

Patients with RA show widespread reductions in pain threshold and increased pain sensitivity, not only over inflamed joints but at distant, non-articular sites [62]. Evidence to support this has come from clinical studies using techniques such as quantitative sensory testing (QST). This technique involves the application of stimuli under standardised testing protocols and the quantification of the participants sensory experience. QST employs different tools for the assessment of the perception of vibration, touch, proprioception, pinprick or blunt pressure

ity of spinal neurons and enhanced sensitivity to nociceptor signalling.

**4.2 Clinical evidence for a role of pain sensitisation in RA**

**4. Central pain sensitisation and RA**

and neurotransmitter activities [59].

**4.1 Molecular basis of pain sensitisation**

**50**

*A simplified diagram of pain signalling pathways. As illustrated, noxious stimulation activates A-δ and C fibres in the periphery. These fibres converge at the DRG and activate post-synaptic neurons that ascend to higher cortical centres via the spinothalamic tract.*

sensitivity. RA patients have a lower pain threshold than healthy controls with QST [63]. Furthermore, sensitisation has been shown to affect a wide range of sensory modalities, including thermal and mechanical stimulation.

Studies have demonstrated that pain thresholds vary substantially between patients with RA. Multiple factors have been shown to correlate with differences in pain threshold. Importantly, these include high tender joint count and prolonged disease duration [64]. This suggests that the persistence of nociceptive stimulation results in long-term changes in pain processing resulting in central pain sensitisation. Other factors that have been shown to influence pain threshold include sleep quality, psychosocial factors and analgesic use [65].

Repetitive sensory stimulation, also known as temporal summation, is another experimental model that has been used to investigate central sensitisation in RA. Temporal summation occurs when the time between stimuli is short enough to prevent the dissipation of postsynaptic action potentials before re-activation [66]. This results in a higher membrane potential, increasing the probability that further stimulation will result in post-synaptic activation. In healthy controls, repetitive stimulation results in the reduction of pressure pain thresholds [62]. Studies have shown that this response is augmented in RA patients [67]. This has also been demonstrated electrophysiologically through the measurement of action potentials in response to repetitive stimulation. In healthy controls, there is an increase in the amplitude of action potential evoked from repetitive stimulation using noxious stimulation. This response is amplified in RA patients and has been shown to correlate with disease activity scores and high tender joint counts [68].

#### **4.3 Neuropathic pain in RA**

In addition to measuring pain thresholds, pain characteristics can be analysed to assess the possible contribution of pain sensitisation to overall pain experience. Specifically, pain questionnaires are commonly used to detect the presence of neuropathic-sounding pain. Neuropathic pain is the perception of pain in the absence of nociceptive input or peripheral tissue damage and is caused by pathology of the peripheral or central nerves. A classic example of neuropathic pain is sciatica. This pain has distinct characteristics such as burning, radiation, shooting, tingling and sensitivity to non-painful stimuli (i.e. allodynia). RA can be associated with neuropathic pain through several mechanisms including compression neuropathy (e.g. carpal tunnel syndrome), co-morbidities (e.g. diabetes), vasculitis (resulting in mononeuritis multiplex) or drug therapies (e.g. gold or leflunomide). Nevertheless, emerging evidence suggests that RA itself can result in neuropathic pain through the induction of aberrant pain processing.

The painDETECT questionnaire enables the classification of pain into likely, possibly or unlikely to be of neuropathic origin. Patients with RA often describe pain with neuropathic features and painDETECT questionnaires can yield between 5 to 20% fulfilling criteria for "likely neuropathic pain" [62]. A significant proportion of these patients have no underlying evidence of neuropathy. One study demonstrated that only 33% of RA patients fulfilling clinical criteria for neuropathic pain had clinical evidence of neuropathy [69]. Of the remaining patients, 57% were shown to have subclinical or axonal neuropathy [70]. This left a significant number of patients with RA who reported neuropathic-sounding pain in the absence of objective nerve injury. It has been suggested that this pain occurs secondary to pain sensitisation however, this has not been proven. Nevertheless, neuropathicsounding pain is an important clinical feature as it predicts inferior pain outcomes. Indeed, a positive correlation between VAS pain scores and painDETECT scores has been demonstrated and patients with probable or likely neuropathic pain have been shown to report significantly higher VAS scores than patients without neuropathicsounding pain [71].

Although the painDETECT questionnaire is a useful tool for characterising pain, care must be taken to interpret results based only on questionnaires. Furthermore, confounding effects with pain severity may affect interpretation. Patients with fibromyalgia demonstrate high painDETECT scores, although evidence of pathology in the peripheral or central nervous system has been difficult to demonstrate. This raises the question of whether painDETECT scores identify pain with similar features to neuropathic pain rather than neuronal pathology itself. Further work is required to fully understand the significance of neuropathic sounding pain in RA.

#### **4.4 Fibromyalgia-RA**

The association between fibromyalgia and RA sheds light on the complex relationship between inflammation, pain and central pain sensitisation. Fibromyalgia (FM) is the prototypical central pain sensitivity syndrome. Clinically, FM is characterised by chronic widespread pain, sleep disturbance and impaired cognition [72]. Observational studies have shown that the prevalence of fibromyalgia in RA patients is much higher than in the general population with estimated prevalence of 18-24%, compared to 2-4% in non-RA cohorts [73, 74].

Two groups of fibromyalgia (FM) have been characterised. Patients with "primary" FM report pain in the absence of identifiable nociceptive input [72]. These patients generally report regional pain syndromes that progress to widespread pain phenotypes with time. "Secondary" FM occurs when aberrant centralised pain processing occurs in the context of identifiable nociceptive input, for example in inflammatory arthritis [72]. It is not yet clear whether these conditions represent the same or different diseases.

The co-existence of FM in RA patients is associated with increased pain scores, a poorer quality of life and worse patient-reported outcomes. In a meta-analysis of 18 studies, RA patients with co-morbid FM had significantly higher pooled DAS28 scores than those without FM [73]. When studies reported individual components

**53**

tion in RA.

**4.6 Brain neuroimaging and pain**

augmented pain responses.

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

problems are more prevalent in both FM and RA.

**4.5 Central mechanisms of pain sensitisation**

of the DAS28, patients with co-existent FM had significantly higher tender joint counts and higher patient global assessment scores than those without FM [73]. Objective measurements including swollen joints and inflammatory markers were not significantly different between RA patients with and without FM [73]. Other scoring systems including the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) were also higher in RA patients with comorbid FM [75]. A large study of 11,866 RA patients reported that those with comorbid FM had

increased pain, poorer quality of life and greater functional limitation [76].

both RA and FM commonly present with pain and fatigue. Differentiation of the conditions and diagnosis of co-morbidity is vital for patient management as different treatment approaches are required. In FM-RA patients, characterisation of the pain is imperative to manage patients appropriately. For example, inflammatory flares must be differentiated from painful flares secondary to FM. Secondly; recognition of patients with secondary FM offers an important insight into the pathogenesis of pain centralisation which is currently poorly understood. Nevertheless, caution should be used when interpreting the association between inflammatory arthritis and FM as the FM diagnostic tools have not been validated in RA. Furthermore, confounding factors including female sex and mental health

The recognition of FM in RA patients is important for multiple reasons. Firstly,

Central pain sensitisation is thought to occur at both spinal and supraspinal levels [62]. At the level of the DRG, spinal hyperexcitability occurs secondary to ongoing nociceptive input and pain transmission can be modified by inhibitory or facilitating neurones that can be modulated by descending signals from supraspinal levels [72]. Spinal pain facilitation is thought to be responsible for the spread of mechanical allodynia beyond the innervated field of cutaneous neurons. This has been shown in models using the intradermal injection of capsaicin [77]. Both ipsilateral and contralateral pain facilitation is thought to occur secondary to chronic inflammation and in RA patients, enhanced responses to noxious stimulation occurs at sites distal from inflamed joints [78]. Pain sensitisation is also thought to occur at supraspinal levels and brain imaging has demonstrated changes in cerebral activation secondary to chronic pain. Throughout the next section of the chapter, we will discuss the evidence of supraspinal pain sensitisa-

Imaging studies have attempted to characterise the neuronal circuitry resulting in cerebral sensitisation in RA. Structural MRI studies have shown increased grey matter density in the basal ganglia of RA patients compared to controls. This area is involved in both motor function and in pain processing [79]. Functional imaging has been used to investigate neuronal activation in response to pain. Functional MRI (fMRI) studies have demonstrated differences in resting state functional connectivity between RA patients and controls. In RA patients, there is increased connectivity between frontal midline regions that are implicated in pain processing, including the supplementary motor area and the mid-cingulate cortex, to sensorimotor regions [80]. Moreover, in RA patients, increased EEG activity has been reported in response to repetitive painful stimuli [81]. These studies suggest that aberrant pain cerebral pain processing may occur in RA and therefore, may result in

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

#### *Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

pain through the induction of aberrant pain processing.

of the peripheral or central nerves. A classic example of neuropathic pain is sciatica. This pain has distinct characteristics such as burning, radiation, shooting, tingling and sensitivity to non-painful stimuli (i.e. allodynia). RA can be associated with neuropathic pain through several mechanisms including compression neuropathy (e.g. carpal tunnel syndrome), co-morbidities (e.g. diabetes), vasculitis (resulting in mononeuritis multiplex) or drug therapies (e.g. gold or leflunomide). Nevertheless, emerging evidence suggests that RA itself can result in neuropathic

The painDETECT questionnaire enables the classification of pain into likely, possibly or unlikely to be of neuropathic origin. Patients with RA often describe pain with neuropathic features and painDETECT questionnaires can yield between 5 to 20% fulfilling criteria for "likely neuropathic pain" [62]. A significant proportion of these patients have no underlying evidence of neuropathy. One study demonstrated that only 33% of RA patients fulfilling clinical criteria for neuropathic pain had clinical evidence of neuropathy [69]. Of the remaining patients, 57% were shown to have subclinical or axonal neuropathy [70]. This left a significant number of patients with RA who reported neuropathic-sounding pain in the absence of objective nerve injury. It has been suggested that this pain occurs secondary to pain sensitisation however, this has not been proven. Nevertheless, neuropathicsounding pain is an important clinical feature as it predicts inferior pain outcomes. Indeed, a positive correlation between VAS pain scores and painDETECT scores has been demonstrated and patients with probable or likely neuropathic pain have been shown to report significantly higher VAS scores than patients without neuropathic-

Although the painDETECT questionnaire is a useful tool for characterising pain, care must be taken to interpret results based only on questionnaires. Furthermore, confounding effects with pain severity may affect interpretation. Patients with fibromyalgia demonstrate high painDETECT scores, although evidence of pathology in the peripheral or central nervous system has been difficult to demonstrate. This raises the question of whether painDETECT scores identify pain with similar features to neuropathic pain rather than neuronal pathology itself. Further work is required to fully understand the significance of neuropathic sounding pain in RA.

The association between fibromyalgia and RA sheds light on the complex relationship between inflammation, pain and central pain sensitisation. Fibromyalgia (FM) is the prototypical central pain sensitivity syndrome. Clinically, FM is characterised by chronic widespread pain, sleep disturbance and impaired cognition [72]. Observational studies have shown that the prevalence of fibromyalgia in RA patients is much higher than in the general population with estimated prevalence of

Two groups of fibromyalgia (FM) have been characterised. Patients with "primary" FM report pain in the absence of identifiable nociceptive input [72]. These patients generally report regional pain syndromes that progress to widespread pain phenotypes with time. "Secondary" FM occurs when aberrant centralised pain processing occurs in the context of identifiable nociceptive input, for example in inflammatory arthritis [72]. It is not yet clear whether these conditions represent

The co-existence of FM in RA patients is associated with increased pain scores, a poorer quality of life and worse patient-reported outcomes. In a meta-analysis of 18 studies, RA patients with co-morbid FM had significantly higher pooled DAS28 scores than those without FM [73]. When studies reported individual components

18-24%, compared to 2-4% in non-RA cohorts [73, 74].

**52**

sounding pain [71].

**4.4 Fibromyalgia-RA**

the same or different diseases.

of the DAS28, patients with co-existent FM had significantly higher tender joint counts and higher patient global assessment scores than those without FM [73]. Objective measurements including swollen joints and inflammatory markers were not significantly different between RA patients with and without FM [73]. Other scoring systems including the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) were also higher in RA patients with comorbid FM [75]. A large study of 11,866 RA patients reported that those with comorbid FM had increased pain, poorer quality of life and greater functional limitation [76].

The recognition of FM in RA patients is important for multiple reasons. Firstly, both RA and FM commonly present with pain and fatigue. Differentiation of the conditions and diagnosis of co-morbidity is vital for patient management as different treatment approaches are required. In FM-RA patients, characterisation of the pain is imperative to manage patients appropriately. For example, inflammatory flares must be differentiated from painful flares secondary to FM. Secondly; recognition of patients with secondary FM offers an important insight into the pathogenesis of pain centralisation which is currently poorly understood. Nevertheless, caution should be used when interpreting the association between inflammatory arthritis and FM as the FM diagnostic tools have not been validated in RA. Furthermore, confounding factors including female sex and mental health problems are more prevalent in both FM and RA.

### **4.5 Central mechanisms of pain sensitisation**

Central pain sensitisation is thought to occur at both spinal and supraspinal levels [62]. At the level of the DRG, spinal hyperexcitability occurs secondary to ongoing nociceptive input and pain transmission can be modified by inhibitory or facilitating neurones that can be modulated by descending signals from supraspinal levels [72]. Spinal pain facilitation is thought to be responsible for the spread of mechanical allodynia beyond the innervated field of cutaneous neurons. This has been shown in models using the intradermal injection of capsaicin [77]. Both ipsilateral and contralateral pain facilitation is thought to occur secondary to chronic inflammation and in RA patients, enhanced responses to noxious stimulation occurs at sites distal from inflamed joints [78]. Pain sensitisation is also thought to occur at supraspinal levels and brain imaging has demonstrated changes in cerebral activation secondary to chronic pain. Throughout the next section of the chapter, we will discuss the evidence of supraspinal pain sensitisation in RA.

#### **4.6 Brain neuroimaging and pain**

Imaging studies have attempted to characterise the neuronal circuitry resulting in cerebral sensitisation in RA. Structural MRI studies have shown increased grey matter density in the basal ganglia of RA patients compared to controls. This area is involved in both motor function and in pain processing [79]. Functional imaging has been used to investigate neuronal activation in response to pain. Functional MRI (fMRI) studies have demonstrated differences in resting state functional connectivity between RA patients and controls. In RA patients, there is increased connectivity between frontal midline regions that are implicated in pain processing, including the supplementary motor area and the mid-cingulate cortex, to sensorimotor regions [80]. Moreover, in RA patients, increased EEG activity has been reported in response to repetitive painful stimuli [81]. These studies suggest that aberrant pain cerebral pain processing may occur in RA and therefore, may result in augmented pain responses.

A further level of complexity is introduced when the biopsychosocial model of pain is considered. This suggests that cognitive and emotional processes are also critical contributors to the overall perception of pain. Indeed, the transmission of nociceptive information is influenced by multiple higher-level factors, such as mood, attention and cognitive factors, to form the resulting pain experience [82]. Mood is a particularly important cognitive factor in RA and meta-analysis has revealed that 16.8% of patients with RA meet the criteria for a major depressive episode [83].

In RA patients, depressive symptoms have been found to correlate significantly with tender joint count [84]. The medial prefrontal cortex has been suggested to play an important role in mediating the relationship between pain severity and depressive symptoms. Evidence has demonstrated an association between depressive scores (measured using the Becks depression index), tender joint count and MPFC activation during provoked joint pain. In the same study, MPFC activation co-varied significantly with limbic activation, an area involved in affective processing. This led the authors to suggest that the MPFC engages areas important for self-relevant processing to mediate the relationship between pain and affective symptoms [84]. In summary, pain processing by higher brain centres affects pain perception and the affective response to pain in RA. Although we are beginning to shed light on higher processing using functional imaging studies, more work is required to fully appreciate the complexities of central pain processing in RA.

#### **5. Management of pain in RA**

The cornerstone of RA treatment is the suppression of inflammation using the treat to target approach. However, disease remission will not lead to the complete resolution of pain in all patients and a multi-modal approach to pain management is very important. This approach has been recommended by rheumatology associations. For example, EULAR have recommended a patient centred approach to pain management where a biopsychosocial framework should be adopted [85]. Specifically, clinicians should differentiate between local and generalised pain and should be guided by patient needs, preferences, pain characteristics, inflammation and psychological factors. Treatments should include education, psychical therapies, orthotics, psychosocial interventions, sleep hygiene, pharmacological and joint-specific treatment options. Throughout this section of the review, we will discuss the different facets of pain management.

#### **5.1 Pharmacological therapies**

Pharmacological treatments include analgesic agents and immunomodulatory medications. Many analgesic agents are used in the management of RA pain although their use is rarely supported by high-quality RCTs [62]. Commonly used analgesic medications include paracetamol, NSAIDs, opioids and tricyclic anti-depressants. Optimal pain management should involve the characterisation of pain phenotype, in particular, differentiation of peripheral and central pain mechanisms. Pain phenotype could alter the choice of analgesic agent. For example, NSAIDs have been shown to reduce inflammatory pain in RA but not central pain in FM [86]. More work is required to define optimal analgesic use in different subsets of RA patients.

The cornerstone of RA management is the suppression of inflammation. Medications that reduce synovial inflammation are well known to reduce pain in RA patients. Immunomodulatory medications used in RA include glucocorticoids,

**55**

**6. Conclusion**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

conventional synthetic DMARDs and biologic DMARDs. Glucocorticoids are commonly used to treat acute inflammatory flares and have been shown to provide significant pain relief [87]. Extensive evidence supports the efficacy of traditional DMARDs, including methotrexate, sulfasalazine and leflunomide, in reducing joint pain. The analgesic effect of cDMARDs parallels the suppression over a time course of weeks to months [62]. Combination therapy has been shown to be superior than monotherapy and the addition of a biologic agent has been shown to reduce pain even further [88, 89]. Nevertheless, pain improvement may plateau despite effective suppression of inflammation and studies have shown that this plateau is worse that the UK mean [7]. Persisting pain may result from centrally mediated pain hypersensitivity and may respond better to neuropathic agents or non-pharmacological treatments including education, exercise and cognitive behavioural therapy (CBT) than those treatments focusing on management on nociceptive triggers alone.

Neuromodulatory medications used for the treatment of neuropathic pain include antidepressants such as tricyclic antidepressants (e.g. amitriptyline) and serotonin-noradrenaline re-uptake inhibitors (e.g. duloxetine) or anti-convulsants, e.g., pregabalin or gabapentin [90]. The clinical efficacy of these medications well well-established in conditions including neuropathic pain and generalised pain sensitisation syndromes such as fibromyalgia [91, 92]. Neuropathic agents are sometimes used for the treatment of pain in RA however evidence from high quality RCTs is lacking [93]. However, in other localised pain conditions such as hand OA, pregabalin has been shown to improve pain and function [94]. Further work is required to establish the role for neuropathic medications in RA patients.

Psychological pain management programmes, including cognitive behavioural approaches and mindfulness, have an important role in the management of chronic pain. An abundance of evidence supports the efficacy of psychosocial approaches to pain management in chronic pain conditions [95]. In RA, CBT has the best evidence base for the management of pain with multiple meta-analyses confirming efficacy [96, 97]. In addition to benefiting pain symptoms, CBT has been shown to improve other symptoms including fatigue in RA patients [98]. Psychosocial therapy may be most efficacious when offered early in the disease course however further work is required to determine which subset of patients should be offered psychosocial

Exercise based therapies have an important role in the management of RA. Evidence has shown that resistance exercises decrease disability and functional impairment [100]. Furthermore, a meta-analysis of five studies revealed that resistance exercises resulted in a trend towards a small positive effect on VAS pain [100].

In conclusion, pain remains a significant problem for many patients with RA and is associated with psychological distress, fatigue and reduced quality of life.

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

**5.2 Neuropathic agents**

**5.3 Psychosocial therapies**

**5.4 Exercise based therapies**

therapies and at which time-point in their illness [99].

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

conventional synthetic DMARDs and biologic DMARDs. Glucocorticoids are commonly used to treat acute inflammatory flares and have been shown to provide significant pain relief [87]. Extensive evidence supports the efficacy of traditional DMARDs, including methotrexate, sulfasalazine and leflunomide, in reducing joint pain. The analgesic effect of cDMARDs parallels the suppression over a time course of weeks to months [62]. Combination therapy has been shown to be superior than monotherapy and the addition of a biologic agent has been shown to reduce pain even further [88, 89]. Nevertheless, pain improvement may plateau despite effective suppression of inflammation and studies have shown that this plateau is worse that the UK mean [7]. Persisting pain may result from centrally mediated pain hypersensitivity and may respond better to neuropathic agents or non-pharmacological treatments including education, exercise and cognitive behavioural therapy (CBT) than those treatments focusing on management on nociceptive triggers alone.

#### **5.2 Neuropathic agents**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**5. Management of pain in RA**

**5.1 Pharmacological therapies**

discuss the different facets of pain management.

A further level of complexity is introduced when the biopsychosocial model of pain is considered. This suggests that cognitive and emotional processes are also critical contributors to the overall perception of pain. Indeed, the transmission of nociceptive information is influenced by multiple higher-level factors, such as mood, attention and cognitive factors, to form the resulting pain experience [82]. Mood is a particularly important cognitive factor in RA and meta-analysis has revealed that 16.8% of patients with RA meet the criteria for a major depressive episode [83].

In RA patients, depressive symptoms have been found to correlate significantly with tender joint count [84]. The medial prefrontal cortex has been suggested to play an important role in mediating the relationship between pain severity and depressive symptoms. Evidence has demonstrated an association between depressive scores (measured using the Becks depression index), tender joint count and MPFC activation during provoked joint pain. In the same study, MPFC activation co-varied significantly with limbic activation, an area involved in affective processing. This led the authors to suggest that the MPFC engages areas important for self-relevant processing to mediate the relationship between pain and affective symptoms [84]. In summary, pain processing by higher brain centres affects pain perception and the affective response to pain in RA. Although we are beginning to shed light on higher processing using functional imaging studies, more work is required to fully appreciate the complexities of central pain processing in RA.

The cornerstone of RA treatment is the suppression of inflammation using the treat to target approach. However, disease remission will not lead to the complete resolution of pain in all patients and a multi-modal approach to pain management is very important. This approach has been recommended by rheumatology associations. For example, EULAR have recommended a patient centred approach to pain management where a biopsychosocial framework should be adopted [85]. Specifically, clinicians should differentiate between local and generalised pain and should be guided by patient needs, preferences, pain characteristics, inflammation and psychological factors. Treatments should include education, psychical therapies, orthotics, psychosocial interventions, sleep hygiene, pharmacological and joint-specific treatment options. Throughout this section of the review, we will

Pharmacological treatments include analgesic agents and immunomodulatory medications. Many analgesic agents are used in the management of RA pain although their use is rarely supported by high-quality RCTs [62]. Commonly used analgesic medications include paracetamol, NSAIDs, opioids and tricyclic anti-depressants. Optimal pain management should involve the characterisation of pain phenotype, in particular, differentiation of peripheral and central pain mechanisms. Pain phenotype could alter the choice of analgesic agent. For example, NSAIDs have been shown to reduce inflammatory pain in RA but not central pain in FM [86]. More work is required to define optimal analgesic use in different subsets

The cornerstone of RA management is the suppression of inflammation. Medications that reduce synovial inflammation are well known to reduce pain in RA patients. Immunomodulatory medications used in RA include glucocorticoids,

**54**

of RA patients.

Neuromodulatory medications used for the treatment of neuropathic pain include antidepressants such as tricyclic antidepressants (e.g. amitriptyline) and serotonin-noradrenaline re-uptake inhibitors (e.g. duloxetine) or anti-convulsants, e.g., pregabalin or gabapentin [90]. The clinical efficacy of these medications well well-established in conditions including neuropathic pain and generalised pain sensitisation syndromes such as fibromyalgia [91, 92]. Neuropathic agents are sometimes used for the treatment of pain in RA however evidence from high quality RCTs is lacking [93]. However, in other localised pain conditions such as hand OA, pregabalin has been shown to improve pain and function [94]. Further work is required to establish the role for neuropathic medications in RA patients.

#### **5.3 Psychosocial therapies**

Psychological pain management programmes, including cognitive behavioural approaches and mindfulness, have an important role in the management of chronic pain. An abundance of evidence supports the efficacy of psychosocial approaches to pain management in chronic pain conditions [95]. In RA, CBT has the best evidence base for the management of pain with multiple meta-analyses confirming efficacy [96, 97]. In addition to benefiting pain symptoms, CBT has been shown to improve other symptoms including fatigue in RA patients [98]. Psychosocial therapy may be most efficacious when offered early in the disease course however further work is required to determine which subset of patients should be offered psychosocial therapies and at which time-point in their illness [99].

#### **5.4 Exercise based therapies**

Exercise based therapies have an important role in the management of RA. Evidence has shown that resistance exercises decrease disability and functional impairment [100]. Furthermore, a meta-analysis of five studies revealed that resistance exercises resulted in a trend towards a small positive effect on VAS pain [100].

#### **6. Conclusion**

In conclusion, pain remains a significant problem for many patients with RA and is associated with psychological distress, fatigue and reduced quality of life. In RA patients, pain results from a combination of joint inflammation, structural joint changes and pain sensitisation. In order to treat patients effectively, it is vital to differentiate between different types of pain, as each type should be targeted differently. Effective pain management approaches using a multimodal approach are vital to increase patient well-being, functioning and to reduce individual and societal costs [85].

## **List of abbreviations**


**57**

**Author details**

Kathryn Biddle and Nidhi Sofat\*

University of London, London, United Kingdom

\*Address all correspondence to: nsofat@sgul.ac.uk

provided the original work is properly cited.

Musculoskeletal Research Group, Institute for Infection and Immunity, St George's,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

ACPA anti-citrullinated peptide antibodies CBT cognitive behavioural therapy CDAI clinical disease activity index CGRP calcitonin gene-related peptide

CXCL chemokine (C-X-C motif) ligand

DMARDs disease modifying anti-rheumatic drugs

EULAR European league against rheumatism

MAPK mitogen activated protein kinase

MMP matrix mellatoproteinase MPFC medial prefrontal cortex MRI magnetic resonance imaging

PI3K phosphoinositide 3-kinases

QST quantitative sensory testing RA rheumatoid arthritis

RCT randomised control trials SDAI simple disease activity index

TrkA tropomyosin receptor kinase A

THR total hip replacement TKR total knee replacement TNF tumour necrosis factor

VAS visual analogue scale

fMRI functional magnetic resonance imaging

NSAIDs non-steroidal anti-inflammatory drugs

RANK receptor activator of nuclear factor kappa beta RANK-L receptor activator of nuclear factor kappa beta ligand

NFκB nuclear factor kappa-light-chain-enhancer of activated B cells

TRPA1 transient receptor potential cation channel, subfamily A, member 1 TRPV1 transient receptor potential cation channel subfamily V member 1

CNS central nervous system COX cyclooxygenase

DAS disease activity score

DRG dorsal root ganglia EEG electroencephalogram

IC immune complexes

NGF nerve growth factor NPY neuropeptide Y

OA osteoarthritis

SP substance P

PGE prostaglandin E PK protein kinase

FM fibromyalgia

IL interleukin

societal costs [85].

**List of abbreviations**

In RA patients, pain results from a combination of joint inflammation, structural joint changes and pain sensitisation. In order to treat patients effectively, it is vital to differentiate between different types of pain, as each type should be targeted differently. Effective pain management approaches using a multimodal approach are vital to increase patient well-being, functioning and to reduce individual and

**56**

### **Author details**

Kathryn Biddle and Nidhi Sofat\* Musculoskeletal Research Group, Institute for Infection and Immunity, St George's, University of London, London, United Kingdom

\*Address all correspondence to: nsofat@sgul.ac.uk

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Y. Alamanos, P. V. Voulgari, and A. A. Drosos, "Incidence and Prevalence of Rheumatoid Arthritis, Based on the 1987 American College of Rheumatology Criteria: A Systematic Review," Semin. Arthritis Rheum., 2006.

[2] T. Heiberg and T. K. Kvien, "Preferences for improved health examined in 1,024 patients with rheumatoid arthritis: Pain has highest priority," Arthritis Rheum., 2002.

[3] G. da Rocha Castelar Pinheiro, R. K. Khandker, R. Sato, A. Rose, and J. Piercy, "Impact of rheumatoid arthritis on quality of life, work productivity and resource utilisation: An observational, cross-sectional study in Brazil," Clin. Exp. Rheumatol., 2013.

[4] H. J. Williams et al., "Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A Controlled Clinical Trial," Arthritis Rheum., 1985.

[5] R. Altawil, S. Saevarsdottir, S. Wedrén, L. Alfredsson, L. Klareskog, and J. Lampa, "Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate," Arthritis Care Res., 2016.

[6] D. F. McWilliams and D. A. Walsh, "Factors predicting pain and early discontinuation of tumour necrosis factor-α-inhibitors in people with rheumatoid arthritis: Results from the British society for rheumatology biologics register," BMC Musculoskelet. Disord., 2016.

[7] D. F. McWilliams, W. Zhang, J. S. Mansell, P. D. W. Kiely, A. Young, and D. A. Walsh, "Predictors of change in bodily pain in early rheumatoid arthritis: An inception cohort study," Arthritis Care Res., 2012.

[8] S. J. Bartlett et al., "Identifying core domains to assess flare in rheumatoid arthritis: An OMERACT international patient and provider combined Delphi consensus," Ann. Rheum. Dis., 2012.

[9] D. Aletaha, F. Alasti, and J. S. Smolen, "Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials," Arthritis Res. Ther., 2015.

[10] L. Klareskog, K. Lundberg, and V. Malmström, "Autoimmunity in Rheumatoid Arthritis: Citrulline Immunity and Beyond," in Advances in Immunology, 2013.

[11] X. Zhao et al., "Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis," Arthritis Res. Ther., 2008.

[12] M. Feldmann and S. R. N. Maini, "Role of cytokines in rheumatoid arthritis: An education in pathophysiology and therapeutics," Immunological Reviews. 2008.

[13] C. M. Weyand and J. J. Goronzy, "Immunometabolism in early and late stages of rheumatoid arthritis," Nature Reviews Rheumatology. 2017.

[14] I. B. McInnes and G. Schett, "The pathogenesis of rheumatoid arthritis.," The New England journal of medicine. 2011.

[15] J. Martel-Pelletier, D. J. Welsch, and J. P. Pelletier, "Metalloproteases and inhibitors in arthritic diseases," Best Pract. Res. Clin. Rheumatol., 2001.

[16] K. Redlich et al., "Osteoclasts are essential for TNF-α-mediated joint destruction," J. Clin. Invest., 2002.

[17] C. Grigor et al., "Effect of a treatment strategy of tight control for

**59**

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

[26] A. Aich, L. B. Afrin, and K. Gupta, "Mast cell-mediated mechanisms of nociception," International Journal of

[27] W. W. Li, T. Z. Guo, D. Y. Liang, Y. Sun, W. S. Kingery, and J. D. Clark, "Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat

fracture model of complex regional pain syndrome," Anesthesiology, 2012.

[28] C. Gunaydin and S. S. Bilge, "Effects of nonsteroidal anti-inflammatory drugs at the molecular level," Eurasian

[29] S. H. FERREIRA, "Prostaglandins, Aspirin-like Drugs and Analgesia," Nat.

[30] G. R. Souza et al., "Involvement of nuclear factor kappa B in the

hypernociception," Pharmacol.

[32] H. A. Martin, A. I. Basbaum, G. C. Kwiat, E. J. Goetzl, and J. D. Levine, "Leukotriene and

high-threshold C- and A-delta

physiology," Nature. 2014.

[34] J. X. Yue et al., "Histamine Upregulates Nav1.8 Expression in Primary Afferent Neurons via H2 Receptors: Involvement in Neuropathic Pain," CNS Neurosci. Ther., 2014.

prostaglandin sensitization of cutaneous

mechanonociceptors in the hairy skin of rat hindlimbs," Neuroscience, 1987.

[33] C. N. Serhan, "Pro-resolving lipid mediators are leads for resolution

[35] C. A. Parada, C. H. Tambeli, F. Q. Cunha, and S. H. Ferreira, "The major

Biochem. Behav., 2015.

[31] A. Nieto-Posadas et al., "Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site," Nat. Chem. Biol., 2012.

maintenance of persistent inflammatory

Molecular Sciences. 2015.

Journal of Medicine. 2018.

New Biol., 1972.

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial," Lancet, 2004.

[18] E. Krock, A. Jurczak, and C. I. Svensson, "Pain pathogenesis in rheumatoid arthritis-what have we learned from animal models?," Pain.

[19] D. W. Gilroy and D. Bishop-Bailey, "Lipid mediators in immune regulation and resolution," British Journal of

[20] M. F. Yam, Y. C. Loh, C. S. Tan, S. K. Adam, N. A. Manan, and R. Basir, "General pathways of pain sensation and the major neurotransmitters involved in pain regulation," International Journal of Molecular

[21] F. A. Pinho-Ribeiro, W. A. Verri, and I. M. Chiu, "Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation," Trends in

[22] M. Shinoda et al., "Nerve terminals extend into the temporomandibular joint of adjuvant arthritic rats," Eur. J.

[23] Y. Yamazaki, K. Ren, M. Shimada,

[24] T. M. Cunha et al., "Crucial role of neutrophils in the development of mechanical inflammatory hypernociception," J. Leukoc. Biol.,

[25] N. Ghasemlou, I. M. Chiu, J. P. Julien, and C. J. Woolf, "CD11b+Ly6Gmyeloid cells mediate mechanical inflammatory pain hypersensitivity," Proc. Natl. Acad. Sci. U. S. A., 2015.

and K. Iwata, "Modulation of paratrigeminal nociceptive neurons following temporomandibular joint inflammation in rats," Exp. Neurol.,

2018.

Pharmacology. 2019.

Sciences. 2018.

Immunology. 2017.

Pain, 2003.

2008.

2008.

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial," Lancet, 2004.

[18] E. Krock, A. Jurczak, and C. I. Svensson, "Pain pathogenesis in rheumatoid arthritis-what have we learned from animal models?," Pain. 2018.

[19] D. W. Gilroy and D. Bishop-Bailey, "Lipid mediators in immune regulation and resolution," British Journal of Pharmacology. 2019.

[20] M. F. Yam, Y. C. Loh, C. S. Tan, S. K. Adam, N. A. Manan, and R. Basir, "General pathways of pain sensation and the major neurotransmitters involved in pain regulation," International Journal of Molecular Sciences. 2018.

[21] F. A. Pinho-Ribeiro, W. A. Verri, and I. M. Chiu, "Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation," Trends in Immunology. 2017.

[22] M. Shinoda et al., "Nerve terminals extend into the temporomandibular joint of adjuvant arthritic rats," Eur. J. Pain, 2003.

[23] Y. Yamazaki, K. Ren, M. Shimada, and K. Iwata, "Modulation of paratrigeminal nociceptive neurons following temporomandibular joint inflammation in rats," Exp. Neurol., 2008.

[24] T. M. Cunha et al., "Crucial role of neutrophils in the development of mechanical inflammatory hypernociception," J. Leukoc. Biol., 2008.

[25] N. Ghasemlou, I. M. Chiu, J. P. Julien, and C. J. Woolf, "CD11b+Ly6Gmyeloid cells mediate mechanical inflammatory pain hypersensitivity," Proc. Natl. Acad. Sci. U. S. A., 2015.

[26] A. Aich, L. B. Afrin, and K. Gupta, "Mast cell-mediated mechanisms of nociception," International Journal of Molecular Sciences. 2015.

[27] W. W. Li, T. Z. Guo, D. Y. Liang, Y. Sun, W. S. Kingery, and J. D. Clark, "Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome," Anesthesiology, 2012.

[28] C. Gunaydin and S. S. Bilge, "Effects of nonsteroidal anti-inflammatory drugs at the molecular level," Eurasian Journal of Medicine. 2018.

[29] S. H. FERREIRA, "Prostaglandins, Aspirin-like Drugs and Analgesia," Nat. New Biol., 1972.

[30] G. R. Souza et al., "Involvement of nuclear factor kappa B in the maintenance of persistent inflammatory hypernociception," Pharmacol. Biochem. Behav., 2015.

[31] A. Nieto-Posadas et al., "Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site," Nat. Chem. Biol., 2012.

[32] H. A. Martin, A. I. Basbaum, G. C. Kwiat, E. J. Goetzl, and J. D. Levine, "Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs," Neuroscience, 1987.

[33] C. N. Serhan, "Pro-resolving lipid mediators are leads for resolution physiology," Nature. 2014.

[34] J. X. Yue et al., "Histamine Upregulates Nav1.8 Expression in Primary Afferent Neurons via H2 Receptors: Involvement in Neuropathic Pain," CNS Neurosci. Ther., 2014.

[35] C. A. Parada, C. H. Tambeli, F. Q. Cunha, and S. H. Ferreira, "The major

**58**

2016.

Disord., 2016.

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

[8] S. J. Bartlett et al., "Identifying core domains to assess flare in rheumatoid arthritis: An OMERACT international patient and provider combined Delphi consensus," Ann. Rheum. Dis., 2012.

[9] D. Aletaha, F. Alasti, and J. S. Smolen, "Rheumatoid factor, not

antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials," Arthritis Res. Ther., 2015.

[10] L. Klareskog, K. Lundberg, and V. Malmström, "Autoimmunity in Rheumatoid Arthritis: Citrulline Immunity and Beyond," in Advances in

[11] X. Zhao et al., "Circulating immune

rheumatoid arthritis: An education in pathophysiology and therapeutics," Immunological Reviews. 2008.

[13] C. M. Weyand and J. J. Goronzy, "Immunometabolism in early and late stages of rheumatoid arthritis," Nature

[14] I. B. McInnes and G. Schett, "The pathogenesis of rheumatoid arthritis.," The New England journal of medicine.

[15] J. Martel-Pelletier, D. J. Welsch, and J. P. Pelletier, "Metalloproteases and inhibitors in arthritic diseases," Best Pract. Res. Clin. Rheumatol., 2001.

[16] K. Redlich et al., "Osteoclasts are essential for TNF-α-mediated joint destruction," J. Clin. Invest., 2002.

[17] C. Grigor et al., "Effect of a treatment strategy of tight control for

Reviews Rheumatology. 2017.

2011.

complexes contain citrullinated fibrinogen in rheumatoid arthritis,"

[12] M. Feldmann and S. R. N. Maini, "Role of cytokines in

Arthritis Res. Ther., 2008.

Immunology, 2013.

[1] Y. Alamanos, P. V. Voulgari, and A. A. Drosos, "Incidence and Prevalence of Rheumatoid Arthritis, Based on the 1987 American College of Rheumatology Criteria: A Systematic Review," Semin. Arthritis Rheum.,

[2] T. Heiberg and T. K. Kvien, "Preferences for improved health examined in 1,024 patients with rheumatoid arthritis: Pain has highest priority," Arthritis Rheum., 2002.

[3] G. da Rocha Castelar Pinheiro, R. K. Khandker, R. Sato, A. Rose, and J. Piercy, "Impact of rheumatoid arthritis on quality of life, work productivity and resource utilisation: An observational, cross-sectional study in Brazil," Clin.

[4] H. J. Williams et al., "Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A Controlled Clinical Trial,"

Exp. Rheumatol., 2013.

Arthritis Rheum., 1985.

[5] R. Altawil, S. Saevarsdottir, S. Wedrén, L. Alfredsson, L. Klareskog, and J. Lampa, "Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate," Arthritis Care Res.,

[6] D. F. McWilliams and D. A. Walsh, "Factors predicting pain and early discontinuation of tumour necrosis factor-α-inhibitors in people with rheumatoid arthritis: Results from the British society for rheumatology biologics register," BMC Musculoskelet.

[7] D. F. McWilliams, W. Zhang, J. S. Mansell, P. D. W. Kiely, A. Young, and D. A. Walsh, "Predictors of change in bodily pain in early rheumatoid arthritis: An inception cohort study,"

Arthritis Care Res., 2012.

2006.

**References**

role of peripheral release of histamine and 5-hydroxytryptamine in formalininduced nociception," Neuroscience, 2001.

[36] S. H. Ferreira, B. B. Lorenzetti, A. F. Bristow, and S. Poole, "Interleukin-1β as a potent hyperalgesic agent antagonized by a tripeptide analogue," Nature, 1988.

[37] A. M. Binshtok et al., "Nociceptors are interleukin-1β sensors," J. Neurosci., 2008.

[38] M. Ebbinghaus et al., "The role of interleukin-1β in arthritic pain: Main involvement in thermal, but not mechanical, hyperalgesia in rat antigeninduced arthritis," Arthritis Rheum., 2012.

[39] P. Malsch et al., "Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression," J. Neurosci., 2014.

[40] E. S. Fernandes et al., "A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis," Arthritis Rheum., 2011.

[41] G. D. Nicol, J. C. Lopshire, and C. M. Pafford, "Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons," J. Neurosci., 1997.

[42] S. Gudes, O. Barkai, Y. Caspi, B. Katz, S. Lev, and A. M. Binshtok, "The role of slow and persistent ttxresistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability," J. Neurophysiol., 2015.

[43] F. Richter et al., "Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents," Arthritis Rheum., 2012.

[44] L. G. Pinto et al., "IL-17 mediates articular hypernociception in antigeninduced arthritis in mice," Pain, 2010.

[45] M. A. Eskander et al., "Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms," J. Neurosci., 2015.

[46] L. S. Ro, S. T. Chen, L. M. Tang, and J. M. Jacobs, "Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve," Pain, 1999.

[47] W. H. Bos et al., "Arthritis development in patients with arthralgia is strongly associated with anticitrullinated protein antibody status: A prospective cohort study," Ann. Rheum. Dis., 2010.

[48] G. Wigerblad et al., "Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism," Ann. Rheum. Dis., 2016.

[49] K. L. Druce, G. T. Jones, G. J. MacFarlane, and N. Basu, "Determining pathways to improvements in fatigue in rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register for rheumatoid arthritis," Arthritis Rheumatol., 2015.

[50] K. W. Drossaers-Bakker et al., "Long-term outcome in rheumatoid arthritis: A simple algorithm of baseline parameters can predict radiographic damage, disability, and disease course at 12-year followup," Arthritis Rheum., 2002.

[51] A. Judge et al., "Predictors of outcomes of total knee replacement surgery," Rheumatol. (United Kingdom), 2012.

**61**

1988.

2012.

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

Nosology and Psychobiology)," Curr.

[60] N. Sofat, V. Ejindu, and P. Kiely, "What makes osteoarthritis painful? The evidence for local and central pain processing," Rheumatology. 2011.

[61] A. I. Basbaum, D. M. Bautista, G. Scherrer, and D. Julius, "Cellular and Molecular Mechanisms of Pain," Cell.

[62] D. F. McWilliams and D. A. Walsh, "Pain mechanisms in rheumatoid arthritis," Clin. Exp. Rheumatol., 2017.

[63] A. S. Leffler, E. Kosek, T. Lerndal,

B. Nordmark, and P. Hansson, "Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis," Eur. J. Pain,

[64] L. C. Pollard, F. Ibrahim, E. H. Choy, and D. L. Scott, "Pain thresholds in rheumatoid arthritis: The effect of tender point counts and disease duration," J. Rheumatol., 2012.

[65] Y. C. Lee et al., "The relationship between disease activity, sleep,

[66] S. D. Boyden, I. N. Hossain, A. Wohlfahrt, and Y. C. Lee, "Non-

[67] J. Wendler et al., "Patients with rheumatoid arthritis adapt differently to repetitive painful stimuli compared to healthy controls," J. Clin. Neurosci.,

[68] M. Mms. C. O. B. I. M. R. R. E. P. Yvonne C. Lee et al., "Pain Sensitization is Associated with Disease Activity

Rheumatology Reports. 2016.

inflammatory Causes of Pain in Patients with Rheumatoid Arthritis," Current

psychiatric distress and pain sensitivity in rheumatoid arthritis: A crosssectional study," Arthritis Res. Ther.,

Rheumatol. Rev., 2015.

2009.

2002.

2009.

2001.

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

[52] E. Nikiphorou et al., "Hand and foot surgery rates in rheumatoid arthritis have declined from 1986 to 2011, but large-joint replacement rates remain unchanged: Results from two UK inception cohorts," Arthritis

[53] T. Sokka, A. Kankainen, and P. Hannonen, "Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic

scores," Arthritis Rheum., 2000.

[54] S. L. Murphy, A. K. Lyden, K. Phillips, D. J. Clauw, and D. A. Williams, "Association between pain, radiographic

severity, and centrally-mediated symptoms in women with knee

[55] A. D. Beswick, V. Wylde, R. Gooberman-Hill, A. Blom, and P. Dieppe, "What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of Prospective studies in unselected patients," BMJ Open.

[56] V. Wylde, A. Sayers, A. Odutola, R. Gooberman-Hill, P. Dieppe, and A. W. Blom, "Central sensitization as a determinant of patients' benefit from total hip and knee replacement," Eur. J.

[57] D. A. Walsh and D. F. McWilliams, "Mechanisms, impact and management of pain in rheumatoid arthritis," Nature

[58] C. J. Woolf, S. W. N. Thompson, and A. E. King, "Prolonged primary afferent induced alterations in dorsal horn neurones, an intracellular analysis in vivo and in vitro," J. Physiol. (Paris).,

[59] M. Yunus, "Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of

Pain (United Kingdom), 2017.

Reviews Rheumatology. 2014.

osteoarthritis," Arthritis Care Res., 2011.

Rheumatol., 2014.

#### *Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

[52] E. Nikiphorou et al., "Hand and foot surgery rates in rheumatoid arthritis have declined from 1986 to 2011, but large-joint replacement rates remain unchanged: Results from two UK inception cohorts," Arthritis Rheumatol., 2014.

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

to arthritic pain through neuronal interleukin-17 receptors in rodents,"

[44] L. G. Pinto et al., "IL-17 mediates articular hypernociception in antigeninduced arthritis in mice," Pain, 2010.

[45] M. A. Eskander et al., "Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms," J. Neurosci.,

[46] L. S. Ro, S. T. Chen, L. M. Tang, and J. M. Jacobs, "Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of

the sciatic nerve," Pain, 1999.

[47] W. H. Bos et al., "Arthritis

is strongly associated with anti-

Ann. Rheum. Dis., 2016.

[49] K. L. Druce, G. T. Jones, G. J.

[50] K. W. Drossaers-Bakker et al., "Long-term outcome in rheumatoid arthritis: A simple algorithm of baseline parameters can predict radiographic damage, disability, and disease course at 12-year followup," Arthritis Rheum.,

[51] A. Judge et al., "Predictors of outcomes of total knee replacement surgery," Rheumatol. (United

development in patients with arthralgia

citrullinated protein antibody status: A prospective cohort study," Ann. Rheum.

[48] G. Wigerblad et al., "Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism,"

MacFarlane, and N. Basu, "Determining pathways to improvements in fatigue in rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register for rheumatoid arthritis," Arthritis Rheumatol., 2015.

Arthritis Rheum., 2012.

2015.

Dis., 2010.

2002.

Kingdom), 2012.

role of peripheral release of histamine and 5-hydroxytryptamine in formalininduced nociception," Neuroscience,

[36] S. H. Ferreira, B. B. Lorenzetti, A. F. Bristow, and S. Poole, "Interleukin-1β as a potent hyperalgesic agent antagonized by a tripeptide analogue," Nature, 1988.

[37] A. M. Binshtok et al., "Nociceptors are interleukin-1β sensors," J. Neurosci.,

[38] M. Ebbinghaus et al., "The role of interleukin-1β in arthritic pain: Main involvement in thermal, but not mechanical, hyperalgesia in rat antigeninduced arthritis," Arthritis Rheum.,

[39] P. Malsch et al., "Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression," J.

[40] E. S. Fernandes et al., "A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis,"

[41] G. D. Nicol, J. C. Lopshire, and C. M. Pafford, "Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons," J. Neurosci., 1997.

[42] S. Gudes, O. Barkai, Y. Caspi, B. Katz, S. Lev, and A. M. Binshtok, "The role of slow and persistent ttxresistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability," J.

[43] F. Richter et al., "Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes

2001.

2008.

2012.

Neurosci., 2014.

Arthritis Rheum., 2011.

Neurophysiol., 2015.

**60**

[53] T. Sokka, A. Kankainen, and P. Hannonen, "Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic scores," Arthritis Rheum., 2000.

[54] S. L. Murphy, A. K. Lyden, K. Phillips, D. J. Clauw, and D. A. Williams, "Association between pain, radiographic severity, and centrally-mediated symptoms in women with knee osteoarthritis," Arthritis Care Res., 2011.

[55] A. D. Beswick, V. Wylde, R. Gooberman-Hill, A. Blom, and P. Dieppe, "What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of Prospective studies in unselected patients," BMJ Open. 2012.

[56] V. Wylde, A. Sayers, A. Odutola, R. Gooberman-Hill, P. Dieppe, and A. W. Blom, "Central sensitization as a determinant of patients' benefit from total hip and knee replacement," Eur. J. Pain (United Kingdom), 2017.

[57] D. A. Walsh and D. F. McWilliams, "Mechanisms, impact and management of pain in rheumatoid arthritis," Nature Reviews Rheumatology. 2014.

[58] C. J. Woolf, S. W. N. Thompson, and A. E. King, "Prolonged primary afferent induced alterations in dorsal horn neurones, an intracellular analysis in vivo and in vitro," J. Physiol. (Paris)., 1988.

[59] M. Yunus, "Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)," Curr. Rheumatol. Rev., 2015.

[60] N. Sofat, V. Ejindu, and P. Kiely, "What makes osteoarthritis painful? The evidence for local and central pain processing," Rheumatology. 2011.

[61] A. I. Basbaum, D. M. Bautista, G. Scherrer, and D. Julius, "Cellular and Molecular Mechanisms of Pain," Cell. 2009.

[62] D. F. McWilliams and D. A. Walsh, "Pain mechanisms in rheumatoid arthritis," Clin. Exp. Rheumatol., 2017.

[63] A. S. Leffler, E. Kosek, T. Lerndal, B. Nordmark, and P. Hansson, "Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis," Eur. J. Pain, 2002.

[64] L. C. Pollard, F. Ibrahim, E. H. Choy, and D. L. Scott, "Pain thresholds in rheumatoid arthritis: The effect of tender point counts and disease duration," J. Rheumatol., 2012.

[65] Y. C. Lee et al., "The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: A crosssectional study," Arthritis Res. Ther., 2009.

[66] S. D. Boyden, I. N. Hossain, A. Wohlfahrt, and Y. C. Lee, "Noninflammatory Causes of Pain in Patients with Rheumatoid Arthritis," Current Rheumatology Reports. 2016.

[67] J. Wendler et al., "Patients with rheumatoid arthritis adapt differently to repetitive painful stimuli compared to healthy controls," J. Clin. Neurosci., 2001.

[68] M. Mms. C. O. B. I. M. R. R. E. P. Yvonne C. Lee et al., "Pain Sensitization is Associated with Disease Activity

in Rheumatoid Arthritis Patients: A Cross-Sectional Study," Arthritis Care Res (Hoboken), Feb-2018. [Online]. Available: https://www.ncbi.nlm. nih.gov/pmc/articles/PMC5654691/. [Accessed: 30-Jun-2020].

[69] M. K. Sim, D. Y. Kim, J. Yoon, D. H. Park, and Y. G. Kim, "Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms," Ann. Rehabil. Med., 2014.

[70] V. Agarwal et al., "A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis," Clin. Rheumatol., 2008.

[71] S. Ahmed, T. Magan, M. Vargas, A. Harrison, and N. Sofat, "Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting," J. Pain Res., 2014.

[72] W. Häuser et al., "Fibromyalgia," Nat. Rev. Dis. Prim., 2015.

[73] S. S. Zhao, S. J. Duffield, and N. J. Goodson, "The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis," Best Practice and Research: Clinical Rheumatology. 2019.

[74] L. P. Queiroz, "Worldwide Epidemiology of Fibromyalgia," Curr. Pain Headache Rep., 2013.

[75] S. J. Duffield, N. Miller, S. Zhao, and N. J. Goodson, "Concomitant fibromyalgia complicating chronic inflammatory arthritis: a systematic review and meta-analysis," Rheumatology (Oxford)., 2018.

[76] F. Wolfe and K. Michaud, "Severe Rheumatoid Arthritis (RA), Worse Outcomes, Comorbid Illness, and Sociodemographic Disadvantage Characterize RA Patients with Fibromyalgia," J. Rheumatol., 2004.

[77] V. H. Morris, S. C. Cruwys, and B. L. Kidd, "Characterisation of capsaicininduced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis," Pain, 1997.

[78] N. G. Shenker, R. C. Haigh, P. I. Mapp, N. Harris, and D. R. Blake, "Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man," Rheumatology, 2008.

[79] K. Wartolowska, M. G. Hough, M. Jenkinson, J. Andersson, B. P. Wordsworth, and I. Tracey, "Structural changes of the brain in rheumatoid arthritis," Arthritis Rheum., 2012.

[80] P. Flodin et al., "Intrinsic brain connectivity in chronic pain: A restingstate fMRI study in patients with rheumatoid arthritis," Front. Hum. Neurosci., 2016.

[81] T. Hummel, C. Schiessl, J. Wendler, and G. Kobal, "Peripheral and central nervous changes in patients with rheumatoid arthritis in response to repetitive painful stimulation," Int. J. Psychophysiol., 2000.

[82] P. Rainville, Q. V. H. Bao, and P. Chrétien, "Pain-related emotions modulate experimental pain perception and autonomic responses," Pain, 2005.

[83] F. Matcham, L. Rayner, S. Steer, and M. Hotopf, "The prevalence of depression in rheumatoid arthritis: A systematic review and meta-analysis," Rheumatol. (United Kingdom), 2013.

[84] P. Schweinhardt, N. Kalk, K. Wartolowska, I. Chessell, P. Wordsworth, and I. Tracey, "Investigation into the neural correlates of emotional augmentation of clinical pain," Neuroimage, 2008.

**63**

2016.

Rheum. Dis., 2017.

*Understanding the Mechanisms of Pain in Rheumatoid Arthritis*

[94] N. Sofat et al., "The effect of pregabalin or duloxetine on arthritis pain: A clinical and mechanistic study in people with hand osteoarthritis," J. Pain

[95] A. C. d. C. Williams, C. Eccleston, and S. Morley, "Psychological therapies for the management of chronic pain (excluding headache) in adults," Cochrane Database of Systematic

[96] J. A. Astin, W. Beckner, K. Soeken, M. C. Hochberg, and B. Berman, "Psychological interventions for

rheumatoid arthritis: A meta-analysis of randomized controlled trials," Arthritis

[98] S. Hewlett et al., "Reducing arthritis fatigue impact: Two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT)," Ann. Rheum. Dis., 2019.

management of chronic pain in patients with rheumatoid arthritis: Challenges and solutions," Journal of Pain Research.

[100] A. Baillet, M. Vaillant, M. Guinot, R. Juvin, and P. Gaudin, "Efficacy of resistance exercises in rheumatoid arthritis: Meta-analysis of randomized controlled trials," Rheumatology, 2012.

[99] L. Sharpe, "Psychosocial

[97] K. Knittle, S. Maes, and V. De Gucht, "Psychological interventions for rheumatoid arthritis: Examining the role of self-regulation with a systematic review and meta-analysis of randomized controlled trials," Arthritis

Res., 2017.

Reviews. 2012.

Rheum., 2002.

Care Res., 2010.

2016.

*DOI: http://dx.doi.org/10.5772/intechopen.93829*

management in inflammatory arthritis and osteoarthritis," Ann. Rheum. Dis.,

[86] K. Kroenke, E. E. Krebs, and M. J. Bair, "Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews," Gen. Hosp.

[87] J. R. Kirwan, "The effect of glucocorticoids on joint destruction in rheumatoid arthritis," N. Engl. J. Med.,

[88] S. M. Van Der Kooij et al., "Patientreported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis," Arthritis Care Res., 2009.

[89] E. C. Keystone et al., "Radiographic, Clinical, and Functional Outcomes of Treatment with Adalimumab (a Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients with Active Rheumatoid Arthritis Receiving Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled,"

"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-

[91] M. Kremer, E. Salvat, A. Muller, I. Yalcin, and M. Barrot, "Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights," Neuroscience.

[92] G. J. Macfarlane et al., "EULAR revised recommendations for the management of fibromyalgia," Ann.

[93] B. L. Richards, S. L. Whittle, and R. Buchbinder, "Neuromodulators for pain management in rheumatoid arthritis," Cochrane Database Syst. Rev., 2012.

Arthritis Rheum., 2004.

[90] N. B. Finnerup et al.,

analysis," Lancet Neurol., 2015.

professional's approach to pain

2018.

1995.

Psychiatry, 2009.

[85] R. Geenen et al., "EULAR recommendations for the health *Understanding the Mechanisms of Pain in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.93829*

professional's approach to pain management in inflammatory arthritis and osteoarthritis," Ann. Rheum. Dis., 2018.

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

[77] V. H. Morris, S. C. Cruwys, and B. L. Kidd, "Characterisation of capsaicininduced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid

[78] N. G. Shenker, R. C. Haigh, P. I. Mapp, N. Harris, and D. R. Blake, "Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man," Rheumatology, 2008.

[79] K. Wartolowska, M. G. Hough, M. Jenkinson, J. Andersson, B. P. Wordsworth, and I. Tracey, "Structural changes of the brain in rheumatoid arthritis," Arthritis Rheum., 2012.

[80] P. Flodin et al., "Intrinsic brain connectivity in chronic pain: A restingstate fMRI study in patients with rheumatoid arthritis," Front. Hum.

[81] T. Hummel, C. Schiessl, J. Wendler, and G. Kobal, "Peripheral and central nervous changes in patients with rheumatoid arthritis in response to repetitive painful stimulation," Int. J.

[82] P. Rainville, Q. V. H. Bao, and P. Chrétien, "Pain-related emotions modulate experimental pain perception and autonomic responses," Pain, 2005.

[83] F. Matcham, L. Rayner, S. Steer, and M. Hotopf, "The prevalence of depression in rheumatoid arthritis: A systematic review and meta-analysis," Rheumatol. (United Kingdom), 2013.

[84] P. Schweinhardt, N. Kalk, K. Wartolowska, I. Chessell, P. Wordsworth, and I. Tracey,

pain," Neuroimage, 2008.

[85] R. Geenen et al., "EULAR recommendations for the health

"Investigation into the neural correlates of emotional augmentation of clinical

Neurosci., 2016.

Psychophysiol., 2000.

arthritis," Pain, 1997.

in Rheumatoid Arthritis Patients: A Cross-Sectional Study," Arthritis Care Res (Hoboken), Feb-2018. [Online]. Available: https://www.ncbi.nlm. nih.gov/pmc/articles/PMC5654691/.

[69] M. K. Sim, D. Y. Kim, J. Yoon, D. H. Park, and Y. G. Kim, "Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms," Ann. Rehabil.

[70] V. Agarwal et al., "A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis," Clin. Rheumatol., 2008.

[71] S. Ahmed, T. Magan, M. Vargas, A. Harrison, and N. Sofat, "Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting," J. Pain Res., 2014.

[72] W. Häuser et al., "Fibromyalgia,"

[73] S. S. Zhao, S. J. Duffield, and N. J. Goodson, "The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis," Best Practice and Research: Clinical Rheumatology.

[74] L. P. Queiroz, "Worldwide

Pain Headache Rep., 2013.

review and meta-analysis," Rheumatology (Oxford)., 2018.

Epidemiology of Fibromyalgia," Curr.

[75] S. J. Duffield, N. Miller, S. Zhao, and N. J. Goodson, "Concomitant fibromyalgia complicating chronic inflammatory arthritis: a systematic

[76] F. Wolfe and K. Michaud, "Severe Rheumatoid Arthritis (RA), Worse Outcomes, Comorbid Illness, and Sociodemographic Disadvantage Characterize RA Patients with Fibromyalgia," J. Rheumatol., 2004.

Nat. Rev. Dis. Prim., 2015.

[Accessed: 30-Jun-2020].

Med., 2014.

**62**

2019.

[86] K. Kroenke, E. E. Krebs, and M. J. Bair, "Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews," Gen. Hosp. Psychiatry, 2009.

[87] J. R. Kirwan, "The effect of glucocorticoids on joint destruction in rheumatoid arthritis," N. Engl. J. Med., 1995.

[88] S. M. Van Der Kooij et al., "Patientreported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis," Arthritis Care Res., 2009.

[89] E. C. Keystone et al., "Radiographic, Clinical, and Functional Outcomes of Treatment with Adalimumab (a Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients with Active Rheumatoid Arthritis Receiving Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled," Arthritis Rheum., 2004.

[90] N. B. Finnerup et al., "Pharmacotherapy for neuropathic pain in adults: A systematic review and metaanalysis," Lancet Neurol., 2015.

[91] M. Kremer, E. Salvat, A. Muller, I. Yalcin, and M. Barrot, "Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights," Neuroscience. 2016.

[92] G. J. Macfarlane et al., "EULAR revised recommendations for the management of fibromyalgia," Ann. Rheum. Dis., 2017.

[93] B. L. Richards, S. L. Whittle, and R. Buchbinder, "Neuromodulators for pain management in rheumatoid arthritis," Cochrane Database Syst. Rev., 2012.

[94] N. Sofat et al., "The effect of pregabalin or duloxetine on arthritis pain: A clinical and mechanistic study in people with hand osteoarthritis," J. Pain Res., 2017.

[95] A. C. d. C. Williams, C. Eccleston, and S. Morley, "Psychological therapies for the management of chronic pain (excluding headache) in adults," Cochrane Database of Systematic Reviews. 2012.

[96] J. A. Astin, W. Beckner, K. Soeken, M. C. Hochberg, and B. Berman, "Psychological interventions for rheumatoid arthritis: A meta-analysis of randomized controlled trials," Arthritis Rheum., 2002.

[97] K. Knittle, S. Maes, and V. De Gucht, "Psychological interventions for rheumatoid arthritis: Examining the role of self-regulation with a systematic review and meta-analysis of randomized controlled trials," Arthritis Care Res., 2010.

[98] S. Hewlett et al., "Reducing arthritis fatigue impact: Two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT)," Ann. Rheum. Dis., 2019.

[99] L. Sharpe, "Psychosocial management of chronic pain in patients with rheumatoid arthritis: Challenges and solutions," Journal of Pain Research. 2016.

[100] A. Baillet, M. Vaillant, M. Guinot, R. Juvin, and P. Gaudin, "Efficacy of resistance exercises in rheumatoid arthritis: Meta-analysis of randomized controlled trials," Rheumatology, 2012.

**65**

Section 3

Clinical Challenges in

Rheumatoid Arthritis

Patients

## Section 3
