Clinical Approach of Rheumatoid Arthritis

#### **Chapter 4**

## Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current and Herbal Treatment

*Sunil T. Galatage, Aditya S. Hebalkar, Sayali S. Gaikwad, Pranav S. Kumbhar, Nikhil N. Patil, Kranti D. Desai, Sonam U. Kanekar, Samruddhi S. Kadam, Rushikesh S. Sansare, Sonali S. Sansare and Suresh G. Killedar*

#### **Abstract**

Rheumatoid Arthritis is the autoimmune disorder occurs due to the change in life style, improper diet plans, smoking, excessive alcohol consumption etc. It generally affects the joints and creates swelling and severe pain in joints which leads to further destruction of bone and cartilages. Due to autoimmune responses the factors like Tumor Necrosis Factor-α, Interleukins-1 are introduced to synovial and synovial membrane which creates the swelling and pain. These factors further produce reactive oxygen species and inducing osteoclasts which destruct the bone and cartilages. Along with the drugs the several natural herbal treatments are also available for the treatment of rheumatoid arthritis. This includes varies medicinal plants form which *acacia* species is more potent and efficient. *Acacia Senegal* is the plant which blocks the receptors and decreases the level of tumor necrosis factor-α. Present work on rheumatoid arthritis mainly covers classification, factors responsible, pathophysiology, severity, current treatment and its drawbacks, herbal treatment and its benefits in treatment of Rheumatoid Arthritis.

**Keywords:** rheumatoid arthritis, swelling, interleukins, cartilages, interleukins, bone erosion, *Acacia Senegal*, herbal treatment

#### **1. Introduction**

Bones are the prime constituents of Human Body as they have been affected by chronic diseases [1]. Nowadays, in the developed countries about 1% of population is suffering from the bone related chronic disease; Rheumatoid Arthritis (RA) [2]. Rheumatoid arthritis is a chronic autoimmune inflammatory disease predominantly characterized by inflammation of connective tissue that lines the inside of the joint capsule. Commonly RA It is accompanied by multi-organ disorders, along with pain, swelling, and stiffness of multiple joints. Joint destruction progresses rapidly resulting in irreversible dysfunction and deformation of the affected joints. Large


#### **Table 1.**

*Criteria for classification of RA revised by American rheumatism association in 1987 [12].*


**Table 2.**

*Rheumatoid arthritis classification criterion in 2010 [13].*

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

numbers of peoples facing swelling and severe pain due to RA. There are several factors which leads to RA, but genuine causes are still unknown [3]. Generally occurrence of RA is due to genetic alterations and environments causes [4]. These genetic alterations are due to factors like change in lifestyle, smoking, autoimmune response excess alcohol consumption, etc. [5]. According to World health organism the Rheumatoid Arthritis is defined as autoimmune, inflammatory disease that is responsible for pain, stiffness, swelling, which further leads to the impairment in its function [6]. These are generally occurs in the joints like carpals, metacarpals and knee joints [7]. The respective joints which are suffered are becoming inflamed, leading to tissue damage, chronic pain, unsteadiness, and deformity [8]. Also the RA affects the eyes, lungs, heart, and mouth [9]. The untreated RA further leads to the bone and cartilage destruction and uncertain and sudden fractures [10]. The symptoms and further destruction can be reduced and prevented by proper treatment but total curation of RA is not yet invented [11]. Rheumatoid Arthritis classified as follow (**Tables 1** and **2**).

#### **2. General classification**

**Figure 1** [14].

#### **3. Pathophysiology**

The worldwide scientists and researchers are only known that autoimmune response is responsible for the RA and genuine pathophysiology is still unknown [15]. So the different researcher gives different pathophysiologies. Form them the important two are explained below [16]. Generally the joints are mostly affected like wrist, knees, hand, ankles and feet. It is the autoimmune disorder means the body attacked by itself [17]. The immune system attacks to the joints and organ tissue [18]. The WBCs moves into the joint. They release chemicals called cytokines which attacks the cell of the synovial membrane. These chemicals cause synovial cells to release the other chemicals. They also cause synovial membrane to grow

**Figure 1.**

*General classification of rheumatoid arthritis.*

new blood vessels and form a thicken area called pannus [19]. As the pannus grows day by day it invades and destructs the cartilages. Inflammation induces the fluid accumulation in the joint which lead to the further swelling and pain [20]. Due to this the free space between joints get decreases and form ankylosis and in some cases bones get fused to each other causing permanent disability of mobility of it (**Figure 2**) [21].

Another pathophysiology describes that around 7–65% of undifferentiated arthritis get converted into rheumatoid arthritis. In this the characteristic inflammatory mediators like monocytes and lymphocytes leaves the circulation and migrate to the synovium due to any autoimmune response occurs due to the reasons still unknown [22]. As the monocytes matured, the number of macrophases in the synovium gets increases. Some macrophages remain in the synovium further recruiting inflammatory cells. Other migrates towards or onto the hyperplastic synovial lining and get joined to the macrophage like and fibroblast like synovial sites. Simultaneously the APCs interact with the activated T-cells present, signaling the macrophages and they get bind to the synovial sites to release the inflammatory mediators like TNF-α and IL-1. TNF-α and IL-1 signals the additional recruitment of additional inflammatory cells from the blood, these cells also recruits the PMNs which migrate towards and crosses the hyperplastic synovial lining and enters in the joint space [23]. PMN releases the protease and ROs which get destroys nearby cartilages. Fibroblasts like synovial sites releases the additional proteases like MMP-1 and MMP-3 which also destructs the cartilages [24]. The fibroblast like synovial sites may release RANKL leading to nearby osteoclast which destruct the bones. This is the how RA get induced and develops [25].

#### **4. Biosynthesis of TNF-α protein**

On the cell membrane there are several receptors are present. There is a type known Toll-like receptors (TLR4) present on the cell membrane. When the lipopolysaccharides (LPS) are going to be attached to lipopolysaccharide binding proteins (LBP) and is transferred to CD14 (receptors of TNF superfamily). It activates two pathways from which one is for internucleus transcription of TNF mRNA and another is for intranucleus translation of TNF-α protein. In first activated pathway

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

through IRAK (Interleukin1 receptor associated kinase) and IKK (inducible I kappa β kinase) activates the p50 and p65 the NFkβs (nuclear factor kappa light chain enhancer). These NFkβs then get entered into the nucleus. Then due to them first transcription is done and pre-TNF mRNA forms which further converts into TNFmRNA by splicing maturation process. And then the TNFmRNA is exported to intranucleus portion. On other hand in the second pathway the MKK3,6 (mitogen activated protein kinase kinase) is activated and further activates p38. p38 then activates two constituents Mk2 (mitogen activated protein kinase activated protein kinase-2) and MNK1 (a kinase of the MAPKKADK family that can regulate

**Figure 3.** *Biosynthesis of TNF-*α *protein.*

**Figure 4.** *Risk factors responsible for rheumatoid arthritis.*

translation). They further promoted the formation of TTP (tristetroproline-zinc finger protein 36 homolog), hnRNP-A1 (heterogeneous nuclear ribonucleoprotein A1), TIA-1 (T-cell restricted Intracellular antigen 1), elF4E (eukaryotic translation initiation factor 4E), HuR. These all are further going in the process of translation along with the TNFmRNA and forms the TNF-α protein (**Figures 3** and **4**) [26].

### **5. Risk factors responsible for rheumatoid arthritis**

#### **5.1 Genetic factors**

If a person having occurrence of Rheumatoid Arthritis is his/her previous generations then he/she will be at high risk of availability of same disorder [27].

#### **5.2 Hormones**

There are some hormones present in human body which are responsible for RA. According to CDC (Centre of Disease control and prevention) the women are at high risk of RA as compare to the men [28]. The hormones responsible are as follows:


#### **5.3 Age**

According to CDC, persons in and after 60's are at more risk to suffering from RA [32].

#### **5.4 Smoking**

Smoking is a very dangerous addictive habit generally occurs in male, it leads to lots of life threatening diseases like lung cancer. It induces the autoimmune responses due to which RA happens [33].

#### **5.5 Stress**

As like above mentioned smoking the stress is also affects the immune system of human body and induces autoimmune responses which leads to traumatic experiences and further RA [34].

#### **5.6 Obesity**

Nowadays the world's most common disorder is obesity which create the various metabolic syndromes which leads to inflammation and further the RA [35].

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

#### **5.7 Early life factors**

According to the CDC the persons having low economic conditions are having higher exposure to RA. It is directly or indirect links to the factor Diet [36].

#### **5.8 Previous history**

The person having any history of occurrence of arthritis in his old generations then he/she might be on the high risk of arthritis.

#### **5.9 Diet**

Improper diet which leads to change in lifestyle is also responsible for occurrence of the rheumatoid arthritis [37–39].

#### **6. Treatment**

There are lot of research works done but yet no any proper treatment were found that will cure Rheumatoid Arthritis totally from its roots. Only some drugs were

**Figure 5.** *Current treatment for rheumatoid arthritis.*

evolved which reliefs from some of the symptoms and prevent further destructions of bones and cartilages [40, 41]. These drugs are having the side effects too. Some methods and aspects of treatment are as follows (**Figure 5**).

#### **6.1 Natural treatment**

There are varies species of plants available worldwide that are used for treatment of Rheumatoid Arthritis. Some majorly used plants are mentioned below with their Scientific name, Family, Local name (**Table 3**).

As like above mentioned plants there are many more plants are available with anti-rheumatic activity. The most efficient plant species is seems to be the Acacia species. Generally the Acacia species are act as a COX-1 and COX-2 inhibitors. The in vitro assay of Acacia species proved that they shows the COX-1 and COX-2 inhibitory action. Some species having activity with the extracts described below. The most potent species of Acacia is *Acacia Senegal* which is also called as Gum Arabica or Hashab gum. It is having properties or activity that decreases the level of TNF-α, ESR, SJC, TJC, VAS, DAS28 (**Table 4**) [42–44].

#### **6.2 Non-drug treatment**

#### *6.2.1 Physiotherapy*

Physiotherapy is one of the most prominent and painless technique to get rid off from rheumatoid arthritis which comes under non-drug treatment. It is a vital part


#### **Table 3.**

*Natural herbs used in effective treatment of rheumatoid arthritis.*

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*


#### **Table 4.**

*Plant species having COX-1 and COX-2 inhibitor activity.*

in the whole lines of treatment of rheumatoid arthritis in cases of both acute and chronic condition. These are several program as follows which are included in the physiotherapy as follows:


#### *6.2.2 Surgery*

This is the last line of treatment in rheumatoid arthritis. Drugs are only able to reduce the symptoms and give relief from pain. But when the situation of patient get critical then the surgery becomes mandatory. And this helps in restoration of joint and its movements. There are several surgeries like spinal surgery, hip replacement surgery, knee replacement surgery, total joint replacement, carpal tunnel release, synovectomy, bone and joint fusion surgery [45–47].

#### **6.3 Drug treatment (modern treatment strategies)**

In the drug treatment there are two categories in drugs one is DMARDs which is major one and another is Adjuvant drugs which is minor one. The main aim of this type of drug treatment is to minimize the inflammation, swelling and pain in joints of patient. Also it prevent the further bone erosion and damage of articular cartilage after the diagnosis. The drug treatment helps the patient to get relief from the deadly pains and stabilize the joint functions and its motility.

#### **6.4 DMARDs**

DMARDs are referred as Disease Modifying Anti-Rheumatoid Drugs or (SAARDs) Slow Acting Anti-Rheumatoid Drugs. From the very old days the first line of treatment for rheumatoid arthritis was use of NSAIDS, but recently after lots of research on various aspects of rheumatoid arthritis the DMARDs are considered to be the first line of treatment as a Modern Treatment for Rheumatoid Arthritis. It is better to take more than two drugs of same class i.e. DMARDs alternatively because the DMARDs loses its potency with prolonged use. DMARDs are of two types one is non-biological type and another is biological type as follows: (Following are the types or classes of drugs are explained in the form of their examples).

#### **6.5 Non biological drugs**

#### *6.5.1 Immunosuppressant*

#### *6.5.1.1 Azathioprine*

Azathioprine get converted into the 6-Mercaptopurine by the enzyme thiopurine methyl transferase (TPMT) and suppress the cell mediated immunity very potently. It comes under purine synthtase inhibitor class. The Azathioprine selectively affect differentiation and function of T-cells and natural killer cells. It also minimizes the inflammation. In the modern treatment the Azathiprine is given with the corticosteroids due its steroid sparing effect (**Figure 6**).

#### *6.5.1.2 Methotrexate*

It is the dihydrofolate reductese inhibitor which has very prominent immunosuppressant and tremendous anti-inflammatory property. Methotrexate helps the patient to get relief very rapidly within 3 to 6 weeks. Therefore, it is more preferable than any other medicaments in initial treatment. Among all the DMARDs methotrexate is the first choice due to its most predictable response and long term sustainability. Mostly combined regimens of DMARDs includes methotrexate. If the above DMARDs are failed to treat the patient then the immunosuppressant like cyclosporine, chlorambucil, cyclophosphamide were used [48].

#### *6.5.2 Other immunomodulators*

#### *6.5.2.1 Sulfasalazine*

It is the drug of choice in second line of treatment or in combined regimen with methotrexate. Sulfasalazine is synthesized from sulfapyrindine and 5-amino salicylic acid, it have the potent anti-infalmmatory activity which is used in bowl and in ulcerative colitis. The exact mechanism of action is still not known. The SSZ variant of sulfasalazine was designed in 1938 specially for the treatment of rheumatoid arthritis. The main pharmacological effects of sulfasalazine are affecting the bacterial flora, inflammatory cell function and immunological process. The approximate mechanism of action of Nf-kB, osteoprotegerin (OPG) and RANK-ligand.

#### *6.5.2.2 Hydroxychloroquin/chloroquin*

Hydroxychloroquin is the drug used mostly to treat the malaria patient. Along with malaria it is also used in treatment of rheumatoid arthritis due to its low

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

**Figure 6.** *Non-biological drugs for treatment of rheumatoid arthritis.*

toxicity. Its exact mechanism of action is not elaborated yet but approximately it reduces the monocyte interleukin-1 along with inhibition of B-lymphocytes. Also it have some proposed mechanism of actions like stabilization of lysozomes and processing of antigens. This drug is advised only when small quantity of damage to join can recorded and it is must be taken with methotrexate or sulfasalazine [49].

#### **6.6 Biological drugs**

#### *6.6.1 TNF-*α *inhibitors*

TNF-α (Tumor Necrosis Factor alpha) is the most important responsible factors for the cause of rheumatoid arthritis. So, in modern treatment the mostly used drug is TNF-α inhibitors (**Figure 7**).

**Figure 7.** *Biological drugs for treatment of rheumatoid arthritis.*

#### *6.6.2 Etanercept*

It is the subcutaneous injection which is composed of fusion protein of TNF – Receptor with FC portion of human IgG1. It binds and blocks the TNF-α from activating the TNF-α receptors. There are also some drugs available in the class of TNF-α inhibitors like infliximab, adalimumab, certolizumab, golimumab.

#### *6.6.3 Interleukin-1 (IL-1) inhibitors*

Along with TNF-α, IL-1 is also the important responsible protein in etiology of rheumatoid arthritis. The IL-1 inhibitors are like Anakinra, Rilonacept, Canakinumab.

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

#### *6.6.4 Anakinra*

In 2001, USA and in 2002, Europe first launched this drug which was specially derived for rheumatoid arthritis treatment. This bind and blocks the IL-1 to present the further joint damage. Initially Anakinra was the main drug of modern treatment but nowadays it is used more in the treatment of the gout and polyserosities as compare to rheumatoid arthritis.

#### *6.6.5 Interleukin-6 (IL-6) and interleukin-6 receptor inhibitor*

In 1986 scientists was found the key cytokine moiety in the pathogenesis of rheumatoid arthritis named IL-6 which having prominent pro-inflammatory activity. To prevent this IL-6 inhibitors are derived.

#### *6.6.6 Tocilizumab*

It is the very first humanized recombinant IgG1 monoclonal antibody which get binds to both the types of IL-6 that is soluble and membrane bound to block its action and to minimize the initiated inflammatory response.

#### *6.6.7 Sarilumab*

It is the second human immunoglobulin G1 IL-6 receptor antagonist monoclonal antibody working as same as above mentioned tocilizumab [50].

#### **6.7 Anti CD-20 antibody**

#### *6.7.1 Rituximab*

From 2006 onwards the rituximab was used in treatment of rheumatoid arthritis along with methotrexate and TNF-α as a combined dose regimen. It is the chimeric murine-human monoclonal antibody which get binds to CD-20 receptors which inhibits the circulation of B cells and activations of T cells.

#### **6.8 CD-80/86: CD 28 inhibitors**

#### *6.8.1 Abatacept*

It is the recombinant fusion protein given by in infusion and subcutaneous which is combination of part of FC domain of human IgG with extracellular domain of T cell inhibiting receptor CTLA4. It get binds to CD 80 and CD 86 along with CD 28 to inhibit the second signal of T cell co stimulations. It was given under combined dose regimen with methotrexate.

#### *6.8.2 JAK: inhibitors*

JAK (Janus-Kinase) is the cytoplasmic protein tyrosine kinase which is responsible for the signal transduction of the nucleus from the gamma chain (common) of plasma membrane receptor for the IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. These all interleukins are the very important medications of many pro-inflammatory and inflammatory components like cytokines, interferons, interleukin-6. So to prevent and inhibit this the JAK inhibition are approved by FDA in 2012 in USA and by

EMA in European Union in 2017. The two main JAK inhibitors are tofacitinib and bacricitinib. Tofacitinib is the inhibitor for JAK 1 and JAK 3 with large affinity and for JAK 2 and tyrosine kinase 2 in with little affinity. It is used for severe arthritis either in monotherapy or with methotrexate. Also the bacricitinib is also works as same as tofacitinib [51].

#### **6.9 Adjuvant drugs**

#### *6.9.1 Corticosteroids*

Glucocorticoid is the most potent corticosteroid that can used at any stage in treatment of rheumatoid arthritis in modern treatment. It is used to minimize the swelling, pain and slowing down the joint destruction along with preventions of bone erosion as it have promising anti-inflammatory and immunosuppressant activity. Though it is administered in combination with first and second line drugs in the form of intraarticular injection it does not give total relief from rheumatoid process.

#### **7. Drawbacks of modern treatment strategies**

Among the DMARDs the dihydrofolate reductase immunosuppressant are causes the bone marrow depression, oral ulceration and G.I. upset. Methotrexate causes the liver cirrhosis when its is used in prolonged therapy. It is contraindicated in pregnancy, breast feeding, liver disease, active infection, leucopenia and peptic ulcer, hematological abnormalities, congenital deformities in pregnancy. Sulfasalazine produces neutropenia, thrombocytopenia, hepatitis, idiosyncrasy, skin reaction, pheumonitis, agranulocytosis, hemolytic anemia, reduction in male fertility. The regular blood count monitoring is necessary in case of this treatment. In case of treatment with Immunomodulators; due to prolonged use of hydroxychloroquin get accumulated in tissue and produces toxicity and other adverse effects like retinal damage, corneal opacity, rashes, graying of hairs, irritable bowel syndrome, myopathy, neuropathy. TNF-α blockers causes redness, itching and swelling at injection site along with occasional chest infection. Higher use of adjuvant drugs leads to patient becoming the steroid dependent along with over threathening disease and vasculities. On other hand IL-1 causes itching, pain and redness at the site of injection along with severe infections, decrease in WBC and platelets in some patients. The IL-6 inhibiting causes diverticulitis, purulent peritonitis, lowering the GI perforation, fistula, abscess, neutropenia, thrombocytopenia, hyperlipidemia, infections, liver enzyme elevation. Abatacept is not able to give with TNF-α inhibits due to do rise of severe infections. Also it causes hypersensitivity, anaphylaxis, anaphylactoid reactions, tuberculosis, sepsis. There is no any study available regarding that whether the drug is safe for pregnant woman or not. The anti-CD 20 antibodies are responsible for headache, fever, skin rashes, dyspnea, hypotension, nausea, rhinitis, pruritus and mild angioedema along with hypogammaglobinemia. There is very limited information related to the administration of this drug to pregnant woman. Along with this the JAK-inhibitors produces the hypotension, nausea, diarrhea, increase in LDL, HDL and total cholesterol, vein thrombosis, pulmonary embolism, upper respiratory tract infections. The JAK-Inhibitors are contraindicated in the patients with neutropenia, tuberculosis, severe infections, severe liver impairment and pregnancy. To overcome this all drawbacks the use of natural treatment on large scale is prefereable [52].

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

**Figure 8.** *Survey on rheumatoid arthritis in Canada.*

#### **8. Severity**

The Rheumatoid Arthritis is most likely available disease now in all over the world [53]. There is one survey run in Canada on "Self-reported prevalence and number of individuals with arthritis by age and sex, household population aged 15 years and older", in 2007 and 2008 which is represented graphically below [54]. From the above graph it is clearly shown that the severity of RA is increased day by day and year by year in Canada in year 2007 and 2008 (**Figure 8**) [55].

#### **9. Severity and survey in India**

In India also the severity of RA is on large scale and the yearly surveys are done for its analysis and data were published. Following are some surveys made in various regions of India for RA by Indian Physicians and expert people of RA (**Table 5**) [56, 57].



#### **Table 5.**

*Survey on rheumatoid arthritis by physicians and expert in India.*

#### **10. Conclusion**

The Rheumatoid Arthritis is chronic autoimmune disorder occurs worldwide due to change in life style, unavailability of proper diet, hereditary characters, excessive alcohol consumption, etc. However the actual reason is still unknown. The Rheumatoid Arthritis is generally occurs in joints causing swelling and severe pain which further leads to destruction of bones and cartilages. First line treatment mainly includes synthetic drugs like Disease Modifying Anti-Rheumatic Drugs; monoclonal antibodies are now available for treatment for Rheumatoid Arthritis. Current treatment is not able to completely cure the Rheumatoid Arthritis form its roots as it has certain side effects such as bone marrow depression, oral ulceration, G.I. upset, skin reaction, pheumonitis, retinal damage, hypersensitivity, anaphylaxis, anaphylactoid reactions etc. So patients suffering from it require complete cure from it which leads to utilization of natural herbs for treatment of RA. Herbal treatment includes medicinal plants along with Acacia species which are mostly preferable because they are more potent, efficient; reduce pain and inflammation precisely along with lesser side effects. Medicinal herbs act is a blockers or inhibitors for the arthritis inducing factors. Due potential benefits of herbal medicines there is tremendous interest growing in medicinal herbs and there is need for more investigate in-vivo applicability. Currently severity of RA is rapidly growing day by day. Best current management pathway for RA contains identification, utilization of medicinally potent herbs along with physiotherapy which mainly include regular exercise like walking, running, cycling, yoga, swimming and acupuncture. As RA chronic disorder which creating permanent disability to joints which may leads to life threatening conditions; social awareness about RA and its remedies are needed.

#### **Acknowledgements**

The authors are thankful to Department of Pharmaceutics Sant Gajanan Maharaj College of Pharmacy Mahagaon and Trustees of Sant Gajanan Maharaj College of Pharmacy Mahagaon for providing required guidance and support.

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Notes/thanks/other declarations**

Special thanks to Professor Amar P. Patil Principal Riyajbhai Shamanji College of Pharmacy, Gadhinglaj for continuous support and guidance throughout the work.

### **Abbreviations**


#### **Author details**

Sunil T. Galatage1 \*, Aditya S. Hebalkar1 , Sayali S. Gaikwad1 , Pranav S. Kumbhar1 , Nikhil N. Patil1 , Kranti D. Desai1 , Sonam U. Kanekar1 , Samruddhi S. Kadam1 , Rushikesh S. Sansare2 , Sonali S. Sansare2 and Suresh G. Killedar1

1 Sant Gajanan Maharaj College of Pharmacy, Kolhapur, Maharashtra, India

2 Indra Institute of Pharmacy, Ratnagiri, Maharashtra, India

\*Address all correspondence to: gsunil201288@gmail.com

© 2021 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.

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[30] Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis Res. 2002;4(Suppl 3):S81-S90.

[31] Akhavani MA, Madden L, Buysschaert I, Sivakumar B, Kang N, Paleolog EM. Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis. Arthritis Res Ther. 2009;11(3):R64.

[32] Lebre M, Jongbloed, S, Tas S, Smeets TJ, McInnes IB, Tak PP. Rheumatoid arthritis synovium contains two subsets of CD83-DC-LAMPdendritic cells with distinct cytokine profiles. AmJ Pathol. 2008;172(4):940-950.

[33] Odojil JR, Miller SD. Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/ blockade in autoimmune disease therapy. Immunol Rev. 2009;229(1):337-355.

[34] Pieper J, Herrath J, Raghavan S, Muhammad K, Vollenhoven R, Malmstrom V. CTLA4-Ig (abatacept) therapy modulates T cell effector

functions in autoantibody-positive rheumatoid arthritis patients. BMC Immunol. 2013;14:34.

[35] Lohr J, Knoechel B, Caretto D, Abbas AK. Balance of Th1 and Th17 effector and peripheral regulatory T cells. Microbes Infect. 2009;11(5):589-593.

[36] Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950-957.

[37] Corvaisier M, Delneste Y, Jeanvoine H, et al. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation. PLoS Biol. 2012; 10(9):e1001395.

[38] Beech JT, Andreakos E, Ciesielski C, Green P, Foxwell BM, Brennan FM. T cell contact-dependent regulation of CC and CXC chemokine production in monocytes through differential involvement of NFB: Implications for rheumatoid arthritis. Arthritis Res Ther. 2006;8(6):R168.

[39] Tran CN, Lundy SK, White PT, et al. Molecular interactions between T cells and fibroblast-like synoviocytes: Role of membrane tumor necrosis factor-alpha on cytokine-activated T cells. Am J Pathol. 2007;171(5):1588-1598.

[40] Theivendren Panneer Selvam, Arumugam Siva Kumar, Parmekar Rachita Vinayak. Treatment of rheumatoid arthritis. Lambart Academic Publications. pp. 17-21.

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[42] Ebtihal Kamal, Lamis Abdel Gadir Kaddam, Maha Dahawi, Montaser Osman, Mohammed Abdelraman Salih, Alnour Alagib and Amal Saeed. Gum Arabic fibers decreased inflammatory markers and disease severity score among rheumatoid arthritis patients, phase II trial. Hindawi International Journal of Rheumatology. 2018;4-7.

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[50] Fiehn, C.; Holle, J.; Iking-Konert, C.; Leipe, J.; Weseloh, C.; Frerix, M.; Alten, R.; Behrens, F.; Baerwald, C.; Braun, J.; et al. S2e guideline: Treatment of rheumatoid arthritis with diseasemodifying drugs. Z Rheumatol 2018, 77, 3553.

*Rheumatoid Arthritis: Severity Classification, Factors Responsible, Pathophysiology, Current… DOI: http://dx.doi.org/10.5772/intechopen.99339*

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[54] Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology; European League against Rheumatism. American College of Rheumatology/ European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-586.

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[57] Van den Broek M, Dirven L, Kroon HM, et al. Early local swelling and tenderness are associated with large-joint damage after 8 years of treatment to target in patients with recent-onset rheumatoid arthritis. J Rheumatol. 2013;40(5):624-629.

#### **Chapter 5**

## Juvenile Idiopathic Arthritis

*Vadood Javadi Parvaneh and Khosro Rahmani*

#### **Abstract**

Juvenile idiopathic arthritis (JIA) is the most common form of chronic synovial joint inflammation in children. It potentially leads to disability and psychosocial outcomes for children and their families. In the absence of appropriate treatment, this can lead to joint destruction and disability. Thus, early diagnosis and aggressive treatment are essential. With the presentation of new biologic DMARDs, based on understanding the disease pathophysiology and molecular pathogenesis, the course of the disease and its outcome have been changed profoundly. In this chapter, the early diagnosis, appropriate treatment, and outcomes approaches are described. These include the latest diagnosis and management options.

**Keywords:** juvenile idiopathic arthritis, children, chronic arthritis, oligoarthritis, polyarthritis, spondyloarthritis, psoriatic arthritis

#### **1. Introduction**

Juvenile rheumatoid arthritis (JRA) is the most common rheumatic childhood disease and one of childhood's most common chronic diseases with unknown etiology and complex genetics. The new nomenclature applies the term juvenile idiopathic arthritis (JIA) [1].

Arthritis means intra-articular swelling or the presence of two signs or symptoms: limited range of motion, pain on motion, warmth, and redness. Intra-articular swelling may be due to intra-articular effusion or an increase in synovial thickness. In terms of the duration of arthritis, it can be divided into two categories: 1. Acute: for less than six weeks, 2. Chronic: more than six weeks [2]. In terms of the location of joint involvement, it can be divided into three categories: 1. Peripheral arthritis: means joints involvement of upper and lower limbs, 2. Axial: includes spinal joints involvement, and 3. Referral: includes the involvement of the hip joint [3]. In terms of the number of joints involved in a disease, arthritis can be divided into three categories: 1. Monoarthritis: means single joint involvement, 2. Oligoarthritis: means simultaneous involvement of four joints or less, and 3. Polyarthritis: it means the simultaneous involvement of more than four joints. In terms of the pattern and timing of arthritis spread, it can be divided into three categories: 1. Migratory: it means the rotation of the involved joints in a short period of several hours to a few days, which means that the affected joint improves and the other joint becomes involved. 2. Additive: this means that another joint or joints are added to the joint involved. 3. Intermittent: involvement occurs occasionally, and at intervals, the patient has no joint symptoms (such as Lyme disease or FMF [4]. In terms of the distribution of involved joints, arthritis can be symmetric or asymmetric. Symmetric arthritis refers to the involvement of the same joint on the opposite side, such as Rheumatoid arthritis, Systemic lupus erythematosus, and RF

positive polyarticular JIA. Asymmetric arthritis is characterized by the involvement of different joints in two sides of the body. This occurs in many childhood arthritis cases such as reactive arthritis, psoriatic arthritis, and Lyme disease. Arthritis can be inflammatory or non-inflammatory. In the case of inflammatory, inflammation of articular structures such as synovium, synovial cavity, and entheses occur. Noninflammatory arthritis is an articular disease caused by mechanical or structural changes in the joint. These joint diseases can be due to cartilage or meniscus injuries with or without accompanying changes in the subchondral bone or maybe changing in joint anatomy due to congenital, developmental, metabolic, or previous inflammatory diseases [3, 4].

Regarding juvenile idiopathic arthritis, according to the previous definitions, we are faced with chronic arthritis with a period of at least six weeks in the age group under 16 years without an unknown etiology.

#### **2. Epidemiology and immunopathogenesis**

Since different criteria and classifications (including previous definitions of JRA, JCA, and JIA) have been presented for this disease over the decades, conducting various epidemiological studies to determine the exact incidence and prevalence of the disease has faced severe challenges. The disease appears to be less common in African-American and Asian populations in the United States [5]. The disease has an average prevalence of about one per thousand children under the age of 16, similar to acute lymphoblastic leukemia and type 1 diabetes in children [6]. In most countries, the ratio of females to males is about two to one or three to one. However, these ratios vary depending on the age of onset and the type of disease. The peak of the disease is between two and four years old, although it varies depending on the sex and type of disease [7].

The pathogenesis and etiology of the disease are unknown. Like many autoimmune diseases, interactions between genetic factors, immune mechanisms, and environmental factors are involved in developing the disease. Patterns consistent with Mendelian or Monogenic inheritance have not been observed in this disease. In many cases, the level of risk to other family members has only slightly increased. HLA types are probably associated with the disease and its subtypes. Patients with early-onset oligoarticular JIA who have a relatively high concordance among siblings are most likely to have isolated associations with these subgroups. Some genes involved in JIA may be a risk factor for the disease but are sometimes neutral or even protective [8].

The primary clinical manifestation of JIA is chronic joint swelling that may lead to deformity of the affected joints due to stretching of the tendons and ligaments around the joint. Enzymes released from inflammatory cells inside the synovium or joint fluid may damage the collagen and proteoglycan matrix in the joint. Osteoclasts activation results from cytokine production by cells in inflammatory tissue, and the final pathway is probably bone demineralization and bone destruction [9].

One of the pathological hallmarks of JIA is a tumor-like spread of inflamed synovial tissue, which is called pannus, leading to further joint destruction. Pannus consists of the synoviocyte proliferation and the invasion of synovial tissue by inflammatory cells (including lymphocytes, macrophages, and dendritic cells). The infiltration of these cells into the synovium is due to vascular factors, cytokines, adhesive molecules, and chemokines. Various inflammatory cells have been found in synovial fluid. As the disease progresses, the pannus expands into the synovial space and attaches to the intra-articular cartilage, where joint destruction eventually occurs [9].

### **3. Classification**

Due to the heterogeneity of JIA disease, its classification remains a challenge. Classification criteria have been developed for research purposes and should not be used as diagnostic criteria at a patient's bedside. However, treatment and prognosis options may still help establish a common language and understanding of disease forms. International League of Associations of Rheumatology (ILAR) recognizes that this disease is an exclusive diagnosis. The characteristics of the disease and its etiology are the uncertainty of the disease onset before the age of 16 and its duration for at least six weeks.

According to ILAR classification, JIA is divided into seven subgroups (**Table 1**).

ILAR criteria are considered as standard, and still, the proposed new systems need further approval. With a greater understanding of the genetics and pathobiology of arthritis, it is hoped that future classifications will suggest more homogeneous JIA groups with biologically distinct diseases [2].

#### **3.1 Systemic JIA**

Systemic arthritis is considered a young adult still's disease. Arthritis is present in one or more joints with fever for at least two weeks. The disease most commonly presents with daily fevers, at least three days (quotidian spiking fevers). In addition, the child should have at least one of the following symptoms: evanescent erythematous rash, hepatomegaly or splenomegaly, generalized lymphadenopathy, or serositis.

Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease different from other forms of childhood arthritis and requires different treatments. In this disease, the child has symptoms of systemic involvement, which is less common in other forms of JIA. No autoantibodies are found in the serum of patients, and the primary disorder is in the inherited immune deficiencies system [2].

#### **3.2 Polyarthritis: rheumatoid factor (RF) positive or negative**

In addition to the involvement of at least five joints, patients with positive rheumatoid factor (RF) type should have at least two RF-IgM-positive results at least


#### **Table 1.**

*Classification criteria for juvenile idiopathic arthritis: 2001.*

#### *Rheumatoid Arthritis*

three months apart, although this test is often performed only once at the beginning of the diagnosis. Children with first-degree relatives with psoriasis, systemic arthritis, or manifestations of enthesitis-related arthritis are excluded from this category [10].

#### **3.3 Oligoarthritis, persistent or extended**

The disease involves a subset of patients previously classified as pauciarticular JRA. The disease is divided into two subgroups:

*Persistent arthritis* - refers to cases in which a child has one to four joints involved during the first six months of illness, but the number of joints involved never reaches five or more during the disease.

*Extended arthritis*- refers to children whose number of affected joints extends to five or more after the first six months of disease.

RF positive, first-degree relatives with psoriasis and concomitant or systemic manifestations are excluded from this classification [10].

#### **3.4 Enthesitis-related arthritis (ERA)**

This group of diseases refers to cases where enthesitis-related arthritis co-exist or enthesitis alone accompanies two or more of the following:


Children with first-degree relatives with psoriasis, RF positive, or systemic arthritis are excluded from this group.

This group includes some children formerly known as spondyloarthropathies. Also, some children may develop psoriatic arthritis in the future but do not currently fulfill its diagnostic criteria [10].

#### **3.5 Psoriatic arthritis**

Psoriatic arthritis is defined as children who have psoriasis and arthritis together or children with arthritis who have two of the following three:


Children with manifestations of arthritis associated with enthesitis or systemic, or RF+ are excluded from this group.

#### **3.6 Undifferentiated arthritis**

If patients do not meet the criteria mentioned in one of the above subgroups or have rejection manifestations, they fall into this subgroup. Also, if children meet the criteria of more than one group, they will be included in this group [10].

### **4. Diagnosis**

The diagnosis of JIA is based on the history and findings of the physical examination and the exclusion of all other possible causes. Further evaluation, such as plain x-ray, ultrasound, nuclear bone scan, or MRI, is recommended when a physical examination does not prove definite arthritis.

### **5. Laboratory examination**

Laboratory tests that may be performed to rule out other causes of arthritis or to determine the type or activity of the disease include the following [11]:


#### **6. Imaging studies**

Radiographic changes in JIA include [11]:


These changes are usually seen in children about one to two years after the onset of the disease and if not treated properly.

### **7. General principles of treatment**

The medical treatment includes pharmacological and non-pharmacological treatments performed by a multi-group team. The following are considered in the group of non-drug therapies [11];


#### **8. Disease course, outcome, and prognosis**

JIA is a nomenclature that includes different diseases with different pathophysiology, manifestations, course, and outcome. With early diagnosis and aggressive appropriate step-wise treatment, the long-term outcome of JIA has improved in the last forth decades. There are different criteria for determining disease outcomes. Wallace et al. defined a set of criteria for the evaluation of clinical outcomes in JIA. Inactive disease (according to Wallace) criteria was defined as a state of no active joints, no systemic symptoms, no uveitis, normal erythrocyte sedimentation rate (ESR), and/or C-reactive protein (CRP), and a physician's global assessment of disease activity indicating no disease activity. Furthermore, there are some different definitions for disease remission. The American College of Rheumatology criteria for complete remission of the disease are as follows [12]:


Also, different risk factors and prognostic factors exist for each of the subtypes. It potentially can cause serious complications, such as musculoskeletal deformities (including joint deformity and contracture), short stature, leg-length discrepancy, osteopenia and osteoporosis, increased risk of infections, cataract, decreased visual acuity, synechia, blindness, and macrophage activation syndrome. Each subtype's expected course, poor prognostic factors, and outcomes will be discussed later in detail.

#### **9. Systemic-onset JIA**

#### **9.1 Clinical manifestations and diagnosis**

Systemic JIA was formerly known as pediatric still's disease, systemic JRA, or systemic-onset juvenile idiopathic arthritis. This type of JIA is characterized by intermittent spiky fevers, evanescent erythematous rash, and arthritis. This disease is more similar to autoinflammatory diseases and may be different from other types of JIA. Diagnosis can be challenging because there are no specific diagnostic tests, and arthritis, which is essential for a definitive diagnosis, is often absent early in the disease. In addition, infections, malignancies, and other diagnoses should be ruled out before being labeled as these diseases can similarly cause fever, skin rashes, and joint pain. The diagnosis is clinical and is based on quotidian pattern (daily fevers spikes), typical evanescent erythematous rashes, and arthritis is characterized by typical laboratory findings, including leukocytosis with neutrophil predominance, elevated acute phase reactants including thrombocytosis, and high ferritin. In general, unfortunately, the disease does not have a specific diagnostic test. Differential diagnoses include infectious arthritis, other autoimmune and inflammatory disorders, malignancy, and malaria [13].

#### **9.2 Treatment**

In children with mild to moderate symptoms and without debilitating symptoms, a non-steroidal anti-inflammatory drug other than aspirin is recommended as initial treatment. In general, a drug test with non-steroidal anti-inflammatory drugs (NSAIDs) alone should not take more than a few weeks. The addition of adjuvant medication is common in children who find or continue to have significant symptoms despite treatment.

Traditionally, many pediatric rheumatologists add a glucocorticoid to the patient who has not responded to initial NSAIDs treatment or who has had a severe disease from the beginning. However, long-term use of glucocorticoids is associated with significant side effects. Biological agents, especially interleukin 1 and 6 blockers, are used as a primary and single treatment with increasing frequency. These factors are effective in reducing clinical symptoms in patients resistant to NSAIDs and glucocorticoids. There are growing findings that suggest that biological agents may also be helpful in the care of children with severe illness instead of glucocorticoids at the time of diagnosis. The decision to start treatment with a biological agent alone or combined with glucocorticoids is initially made considering the type of biological agent used, and after discussing the potential benefits and harms of treatment for the patient and family.

In patients who do not respond to the initial test of treatment with an NSAID alone, or in those whose early symptoms include high fever, other severe systemic symptoms, or debilitating polyarthritis, it is recommended that a biological agent such as Anakinra, Canakinumab, or Tocilizumab is added until a glucocorticoid is taken. Anakinra is used in some at a dose of 2 mg per kilogram of body weight daily up to a maximum of 100 mg. Canakinumab is usually given at a monthly dose of 4 mg per kilogram of child body weight with a maximum dose of 300 mg. Typically, 12 mg per kg intravenous injection or 162 mg subcutaneous injection is used every two weeks for children weighing less than 30 kg. Also, 8 mg per kg intravenous injection with a maximum dose of 800 mg every two weeks or 162 mg subcutaneous injection every week for higher body weights.

It is recommended that glucocorticoids be used when they do not respond immediately to a biological agent. When the current definition of an immediate response varies from center to center, some pediatric rheumatologists wait more than a week to add a glucocorticoid if polyarthritis, fever, and rash persist. They all add a glucocorticoid if there is evidence of severe macrophage activation syndrome or serositis. Both glucocorticoids and biological agents usually persist until disease control. Clinicians may then discontinue glucocorticoids first because the drug is associated with unavoidable intoxication in long-term use. Discontinuation of the biological agent may be possible if the disease is controlled. Prednisolone should be limited to o.5–1 mg/kg, although doses higher than 2 mg/kg or pulsed treatment with methylprednisolone may be necessary in severe cases. The treatment in cases with the polycyclic course and recurrent attacks is similar to the initial treatment. Treatment of the chronic and persistent disease depends on whether the patient has early systemic signs and symptoms (including fever, rash, and serositis), early arthritis, which can be progressive and destructive, or both. Interleukin 1 and 6 blockers are the most effective biological agents for early systemic disease and may also be effective for chronic arthritis. Tumor necrosis factor (TNF) alpha-blockers, concomitant T-cell stimulation blockers (Abatacept), and methotrexate can be used as adjunctive therapies to treat chronic arthritis. Other non-biological diseasemodifying anti-rheumatic drugs (DMARDs) such as cyclosporine and tacrolimus, and cytotoxic agents such as cyclophosphamide are complementary choices in cases that do not respond to standard treatment containing biological agents.

The potential toxicity of drugs used in systemic arthritis should be carefully evaluated compared to the progressive, debilitating side effects and often the persistence of uncontrolled disease. Therefore, patients presenting with severe manifestations of the disease or those who resist treatment with NSAIDs should be referred to an experienced pediatric rheumatologist for disease management. Screening and monitoring of the disease are essential in the patients being treated [14, 15].

#### **9.3 Course, prognosis, and complications**

The course of systemic JIA is highly variable, although there are three typical pre-biological patterns in the disease: monophasic, polycyclic, and persistent (chronic). In the monophasic pattern, complete remission usually occurs within 4 to 6 months (occasionally in two to four years) and does not recur. In polycyclic or relapsing form, flares of systemic manifestations are with mild arthritis, and among them, remission and inactivity of the disease occur. This period can vary from a few months to several years. Finally, persistent destructive arthritis is often present in the persistent type despite reducing systemic manifestations, usually the most common form of the disease (50%) [16].

Three patterns of chronic disease activity in patients with persistent systemic JIA:


Systemic JIA-induced morbidity and mortality have decreased with treatment progress, but mortality is still high in patients with severe disease, especially those with recurrent or unknown macrophage activation syndrome and severe pulmonary or vascular complications [17]. Patients with active disease (those with fever, arthritis, high platelet count, persistent need for glucocorticoids) six months after disease onset have a worse prognosis for disease persistence and destructive arthritis [18].

Macrophage activation syndrome is the most common complication of systemic JIA. With the early detection and application of biologic DMARDs such as IL1 and IL6 inhibitors, complications such as severe growth retardation and osteoporosis are currently less common. There may be an increased incidence of rare but severe pulmonary complications that require further investigation.

#### **9.4 Macrophage activation syndrome**

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic JIA that should be treated as a life-threatening emergency. Clinical and histopathological features of macrophage activation syndrome are similar to hereditary lymphohistiocytic hemophagocytosis or HLH. However, diagnostic criteria for it are often not used to diagnose MAS in systemic JIA. Evidence suggests that there is a common genetic component in patients with systemic arthritis and MAS, as well as protein-altering variants in genes associated with HLH [19].

#### *9.4.1 Clinical manifestations*

Typically, MAS occurs during the first few days or weeks after the systemiconset JIA, although it can occur at any time during the disease course. MAS occurs in 10% of children with systemic JIA but can develop subclinically in about 30–40% of other patients. Some patients have recurrent attacks of MAS. Triggers for this syndrome may be viral or bacterial infections or the administration of new drugs, but the initial irritating incident is often not apparent [20].

Children may present with spontaneous bleeding, bruising, liver dysfunction, drowsiness, seizures, coma, or shock. Persistent fever and skin rash (as opposed to intermittent daily fever and the typical evanescent skin rash of mild acute systemic JIA), lymphadenopathy, and hepatosplenomegaly are other common findings. White blood cell count, hemoglobin, platelet count, and serum fibrinogen typically decline abruptly. Liver function tests, triglycerides, and LDH increase rapidly. Ferritin can also reach as high as 10,000 ng/ml or even higher. In addition, a paradoxical decrease in erythrocyte sedimentation rate (ESR) due to fibrinogen consumption occurs, which is a vital diagnostic key. Typically, a bone marrow aspiration reveals multiple benign macrophages that indicate hemophagocytosis. However, not all bone marrow samples from patients with MAS show such a finding and may appear normal [20].

#### *9.4.2 Diagnosis*

Early diagnosis of MAS in a patient with systemic JIA may be difficult because systemic JIA flare-ups have similar clinical manifestations. In addition, a review of published literature suggests that patients treated with biologics may have fewer clinical manifestations of MAS, which may make it even more difficult to diagnose; for example, tocilizumab-treated patients have no fever or lower level of fever, and their CRP and ferritin levels are significantly lower. Diagnostic criteria for HLH are often not applicable to MAS in patients with systemic arthritis. Although these syndromes are clinically similar, HLH criteria are so strict that they cannot detect early MAS in patients with systemic JIA when they respond more to treatment. Part of the problem lies in the fact that patients with systemic JIA naturally have significantly increased levels of white blood cells and platelets along with acute-phase reactants such as ESR and fibrinogen so that normal premature levels of these blood tests can be misleading because they are caused by declining levels and is a signal of imminent MAS. For this reason, many efforts are underway to develop applicable clinical diagnostic criteria and scoring tools to diagnose MAS in patients with systemic JIA [21].

The 2016 classification criteria for MAS in systemic arthritis were expanded to identify more valuable criteria by combining consensus methods by experienced individuals and analyzing actual patients' data.

These criteria require increased ferritin and one of the other two criteria. These criteria include [22]:


A diagnostic scoring tool to differentiate MAS in systemic arthritis from active systemic JIA without MAS, called systemic MAS scoring MAS / sJIA (MS), was developed and validated in 2019. In this criterion, multinational patient data collected were used to classify the MAS in 2016. Fever is a mandatory criterion for diagnosis and does not fit into scoring, although, as noted above, it may not be present in patients with systemic JIA treated with tocilizumab even in the presence of MAS. This scoring still needs validation in the clinical field and may need to be revised to include biological use in its calculations. This tool can also differentiate between these two diseases with high sensitivity and specificity. The MAS / HLH (MH) score strongly confirms the age of onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. Having an age of 16 years or less at the onset of the disease and neutrophil of less than or equal to 1400 per liter are the most critical factors in differentiating HLH from macrophage activation syndrome involving systemic JIA [23].

#### *9.4.3 Treatment*

When MAS is diagnosed or suspected, treatment should be started urgently with high-dose glucocorticoids, often using a 30 mg/ml methylprednisolone pulse at a maximum dose of 1 gr daily intravenously. There have been case reports of successful treatment with cyclosporine, cyclophosphamide, etoposide, or anakinra. Treatment of resistant MAS cases in patients with systemic JIA is the same as treatment regimens for HLH [24].

#### **10. Oligoarticular JIA**

#### **10.1 Clinical manifestations and diagnosis**

Children with JIA of the oligoarticular type, formerly known as juvenile rheumatoid arthritis (JRA) of pauciarticular JRA type, have involvement of four joints or less during the first six months after the disease onset. These patients are divided into two main subgroups: 1. Patients who do not have more joint involvement after the first six months of the disease have persistent oligoarticular JIA. 2. Those with four or fewer joints are involved during the first six months of disease onset, but more joints are added over time, resulting in five or more joints eventually becoming involved, known as extended oligoarticular JIA [2].

Oligoarticular JIA is the most common group of JIA, accounting for almost half of all cases. In the USA and Europe, the disease is more common in girls than boys and peaks at two to three years of age. The typical manifestation of the disease is painless limping. Large joints, especially the knees and ankles, are the most commonly involved joints, but the pelvic joints are never the primary joints involved. Except for uveitis, there are no obvious systemic manifestations [25].

Diagnosis of oligoarticular JIA in children is made with arthritis of four joints or less during the first six months of the disease by excluding the other causes of oligoarthritis. There are no diagnostic laboratory tests for the disease. Antinuclear antibodies (ANA) are frequently present in these patients and are associated with an increased risk of iridocyclitis. Patients with an elevated ESR or unexplained anemia are more likely to have a recurrent disease and become an extended oligoarticular JIA. Differential diagnoses of oligoarticular JIA include the other types of JIA such as psoriatic arthritis, polyarticular JIA and ERA, Lyme disease, IBD, pigmented villonodular synovitis, other infectious, autoinflammatory, and autoimmune diseases, and malignancy, all of which may involve four or fewer joints at the onset [26, 27].

Recurrence occurs in approximately a quarter of initially healthy patients. Some patients with the oligoarticular disease eventually develop chronic degenerative arthritis. Manifestations in the first six months of the disease poor prognostic factors include symmetric involvement, ankle or wrist involvement, laboratory evidence of inflammation (elevation of ERS or CRP), radiographic evidence of joint destruction, and hip or cervical joints arthritis [28].

#### **10.2 Treatment**

Patients with mild to moderate disease activity, lack of risk factors for poor prognosis, and lack of joint stiffness usually respond to non-steroidal anti-inflammatory drugs and intra-articular injections of glucocorticoids. However, patients with more significant illnesses who do not respond to initial treatment for intraarticular injection or who initially have severe disease activity and poor prognostic risk factors require treatment with methotrexate or other DMARDs. Biological agents such as TNF blockers are used in patients with a moderate or severe disease with poor prognostic manifestations who do not respond to treatment with non-biological DMARDs. TNF blockers are also used in patients with progressive oligoarticular JIA and patients with uveitis [28–31].

#### **10.3 Course, prognosis, and complications**

Uveitis is the worst complication of the disease, occurring in approximately a quarter of patients with oligoarticular JIA. Patients with detectable ANA and those

#### *Rheumatoid Arthritis*

under the age of six at the time of diagnosis are at the highest risk. Mainly, there are no symptoms of uveitis, so routine screening is essential. An ophthalmologist should perform screening and a thorough examination with a slit lamp, and an alternative optometric or fundoscopic examination is insufficient. Complications include cataracts, synechia, glaucoma, band keratopathy, and macular edema (**Table 2**) [32].

The leg-length discrepancy is the second most common complication of oligoarticular JIA. This complication frequently occurs in both bone length and width. Injection of glucocorticoids into the knee and ankle joint early in the course of the disease may prevent this complication [33].

#### **Referral**

• Patients should be referred at the time of diagnosis, or suspicion, of JIA

#### **Initial screening examination**


#### **Ongoing screening**

	- Oligoarticular JIA, psoriatic arthritis, and enthesitis-related arthritis irrespective of ANA status onset under 11 years


#### **Table 2.**

*British society for pediatric and adolescent rheumatology/Royal College of ophthalmology guidelines for uveitis screening in JIA.*

### **11. Polyarticular JIA**

#### **11.1 Clinical manifestations**

The age of onset of polyarticular JIA onset has a bi-modal distribution. The first peak is between the ages of two and five, and the second peak is between ten and 14 years old. It is more common in girls than in boys of all ages [2].

The clinical presentation of polyarticular JIA varies and tends to show different patterns depending on the age of the disease onset. In children under ten years of age, polyarticular JIA often begins similar to oligoarticular disease with the involvement of one or two joints. The progression of the disease is often subtle until an intercurrent infection dramatically exacerbates the symptoms of the disease. The disease inevitably progresses and spreads to five or more joints during the first six months of disease onset. Joint involvement is typically symmetrical. Older children and adolescents usually have a rapid onset of multi-joint involvement, including a large number of small joints of hands and feet within two to three months of the disease onset [34].

There are no diagnostic laboratory findings for JIA. However, patients may have an ANA-positive test and an increased ESR of 40 mm in the first hour or so, anemia, and hypergammaglobulinemia. In most patients, the Rheumatoid factor is negative. In some patients in this group, rheumatoid factor (RF) or anti-cyclic citrullinated peptide (Anti-CCP) is positive, which is associated with the severity of the disease, symmetrical involvement of small or medium-sized joints, degenerative course of arthritis, and prolongation of the disease with a rheumatoid arthritis-like course. Other autoantibodies are not commonly seen in patients with polyarticular JIA [35].

#### **11.2 Diagnosis**

Diagnosis is made in children with arthritis in more than four joints during the first six months of the disease and by rejecting other causes of polyarthritis.

#### **11.3 Differential diagnoses**

include several diseases that may be self-limiting or chronic, including other forms of JIA such as psoriatic, systemic, enthesitis-related, reactive arthritis, earlyonset rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, sarcoidosis, inflammatory bowel disease, epiphyseal dysplasia, and minocyclineinduced autoimmunity [27].

#### **11.4 Treatment and prognosis**

Polyarticular JIA treatment aims to treat underlying synovitis and inflammation. Immediate treatment that relieves the patient's arthritic symptoms and protects the patient's function is essential for a better outcome. The treatment regimens chosen depend on prognostic factors, disease activity, as well as physician and family preferences, which are adjusted based on the clinical response. Risk factors include positive RF, positive anti-CCP, and joint degeneration. Disease activity is measured by the clinical Juvenile Disease Activity Score based on ten joints (cJADAS-10). It is recommended that initial treatment with a DMARD be performed in all patients with polyarticular JIA. Methotrexate is preferable to sulfasalazine, leflunomide, or a three-drug combination of methotrexate, sulfasalazine, and hydroxychloroquine. Methotrexate at a dose of 10 mg per square meter of the body per week in patients with low disease activity or an anti-TNF

biological agent with methotrexate in cases with moderate to severe disease activity is primarily used. Indications for using a TNF blocker with or in comparison with methotrexate include the presence of severe polyarthritis, inferior prognostic manifestations, or factors associated with a poor response to methotrexate, such as predominant involvement of the axial joints. The NSAIDs are not suitable as a single drug but as adjunctive therapy to relieve symptoms. Folic acid or folinic acid supplements are used in all children with JIA receiving methotrexate, which has been shown to have beneficial effects, and there is no convincing conflicting data against them. In patients who do not respond to treatment with methotrexate and a TNF blocker, treatment decisions are made on a case-by-case basis. The use of abatacept or tocilizumab is preferable to switching the TNF blocker. Choices include using a combination of DMARDs, other biological agents, or a small molecule inhibitor under the supervision of an experienced pediatric rheumatologist. Adolescents with positive RF and positive Anti-CCP are likely to show early onset of rheumatoid arthritis. For this reason, these children should be treated like adults with moderate to severe rheumatoid arthritis [36].

#### **12. Psoriatic JIA**

#### **12.1 Pathogenesis, clinical manifestations, and diagnosis**

Psoriatic JIA or psoriatic arthritis is clinically non-homogenous. In children, the age of onset of the disease is bimodal. The first peak occurs mainly in preschool girls and has a clinical picture similar to oligoarticular JIA with a high probability of positive ANA. The second peak is in mid-to-late childhood and resembles adult-onset psoriatic arthritis. The presentation and severity of the disease can be quite different, and the skin manifestations of psoriasis can occur long after the onset of arthritis. Articular involvement may vary from mild enthesitis to polyarticular involvement of the peripheral and axial joints. Inflammation may occur in only one joint or a large number of joints, with or without the involvement of the sacroiliac joints, spine, or peripheral entheses. Dactylitis or sausage-shaped swelling of the fingers is a common manifestation in younger children, while axial enthesitis-related arthritis is more common in older children. Enthesitis refers to inflammation of the joints where ligaments, tendons, capsules, fascia, and other fibrous structures attach to bone. Overt psoriasis Vulgaris may not be present. Nail pitting is more common in psoriatic JIA than skin-limited psoriasis. RF is typically negative and is considered an exclusion criterion. Inflammatory markers include ESR and CRP, and platelet counts may be mild to moderate but are often normal, even in the presence of polyarticular disease. Bone changes and joint space narrowing indicate significant cartilage loss, typically seen only after the advanced disease onset [37].

Psoriatic arthritis is currently diagnosed in children where arthritis occurs in the presence of established psoriasis. However, classic skin rash during presentation does not occur in about half of children with psoriatic arthritis and sometimes occurs even ten years or more after the onset of the joint symptoms. Besides, psoriasis in young children may be mild, atypical, and transient, often mistaken for eczema initially; therefore, diagnostic uncertainty is expected. Laboratory tests and radiologic studies have limited value in diagnosing psoriatic arthritis [37].

Differential diagnoses of psoriatic arthritis mainly include other subtypes of JIA, particularly oligoarticular and RF negative polyarticular and enthesitis-related arthritis. Apart from other types of JIA, differential diagnoses depend on the type of clinical presentation.

#### **12.2 Treatment, prognosis, and outcome**

Psoriatic arthritis is a relatively common subtype in JIA, but its clinical presentation can be very varied. Except for confirmation of suspected sacroiliitis by contrast-enhanced MRI, laboratory tests and radiological studies have limited value in managing psoriatic arthritis. Like other types of JIA, initial treatment for psoriatic arthritis depends on summing up all the clinical, laboratory, and radiographic manifestations of the disease to prevent cartilage or bone damage. The standard treatment algorithm for psoriatic arthritis is similar to other JIA cases, with a few exceptions. Some rheumatologists use NSAIDs as the primary treatment for monotherapy. However, NSAIDs do not typically induce remission; therefore, it is generally best used with a DMARD in patients with extensive or moderate to severe disease. Arthritis in the large joints, as well as dactylitis of the fingers, may be treated with glucocorticoid injections. DMARDs are indicated at diagnosis in patients with multiple joint involvements or those who have not remission with intra-articular injection of glucocorticoids. Failure to achieve disease remission is followed by the addition of a secondary DMARD, or more commonly by anti-TNF treatment. Systemic glucocorticoids are generally less commonly used, and antimalarial agents are avoided because of the risk of worsening psoriatic rash. The effectiveness of other biologic agents such as anti-IL-12/23, anti-IL-17, abatacept, apremilast, and Jak inhibitors has been shown in various studies [38].

Axial involvement in psoriatic arthritis is phenotypically similar to ankylosing spondylitis. Treatment should be started in patients with psoriatic arthritis who have symptoms of axial involvement or limited spinal mobility, even if these changes have not yet been shown on plain graphs. Anti-TNF agents are generally most effective, while NSAIDs can relieve symptoms in a group of patients. Other DMARDs have minimal impact. Interleukin-17 blocking agents, such as Janus kinase (JAK) inhibitor, appear to be allowed in adult studies. Monitoring and treatment of uveitis in psoriatic arthritis is similar to other subgroups [38].

Traditional treatment of psoriasis is indicated for skin disease associated with psoriatic arthritis. Usually, skin involvements are not very troublesome because joint manifestations occur early. After all, early use of systemic agents such as methotrexate and TNF inhibitors also has high effects on skin disease [39].

Poor outcomes and long-term disability are generally seen in patients who have a long delay in diagnosis or those who have not started effective treatment, although physicians or families often try to take necessary steps to induce disease remission [40].

#### **13. Spondyloarthritis**

#### **13.1 Clinical manifestations and diagnosis**

The terms spondyloarthropathy and spondyloarthritis refer to seronegative and related inflammatory diseases characterized by involvement of the spine (sacroiliitis and spondylitis), large joints (asymmetric oligoarthritis, especially of the lower extremities), and the entheses (enthesitis and enthesopathy). Diseases that fall into this category in children include enthesitis-related arthritis (undifferentiated spondyloarthritis), juvenile ankylosing spondylitis (differentiated spondyloarthritis), reactive arthritis, psoriatic arthritis, and arthritis with inflammatory bowel disease [41].

The onset of the disease is gradual but may initially be followed by a febrile illness or a musculoskeletal trauma. Arthritis is usually oligoarticular, asymmetric, and initially involves the large joints of the lower extremity. The knee, ankle, and mid-foot are the most common joints involved during the presentation. Common

manifestations accompanied include painful ligaments or tendons at the junction with the bone (enthesitis), inflammatory back pain or sacroiliac pain, morning stiffness, and limited spine movement [41].

Extra-articular manifestations include anterior uveitis, related skin manifestations, and recurrent gastrointestinal complaints. These manifestations may be associated with undifferentiated spondyloarthritis or suggest an alternative diagnosis, including a systemic disease such as inflammatory bowel disease and mechanical, developmental, and orthopedic disorders other than spondyloarthritis [41].

HLA-B27 is associated with enthesitis-related arthritis and has an increased incidence in all types of spondyloarthropathies. In juvenile ankylosing spondylitis, up to 90%, and in enthesitis-related arthritis, up to 50% can be positive.

#### **13.2 Treatment**

Treatment for spondyloarthritis aims to reduce symptoms, control inflammation, and prevent disability. The appropriate treatment depends on which manifestations are present, especially whether spinal involvement and whether spondyloarthritis is a manifestation of a systemic disease such as psoriatic arthritis, reactive arthritis, or inflammatory bowel disease. Traditional treatment with NSAIDs is recommended in all cases. In case of no response and active enthesitis, TNF inhibitor is preferable to methotrexate or sulfasalazine. In cases of TNF blocker contraindication, patients with mild enthesitis and patients with active peripheral polyarthritis, methotrexate or sulfasalazine can be used concomitantly. In cases of chronic active enthesitis, low-dose oral glucocorticoids can be used as bridge therapy in the short term (less than three months). In addition, this treatment can be used in cases of high disease activity, limited mobility, or significant symptoms [36].

#### **14. Conclusions**

JIA is the most common cause of chronic arthritis in children. In approach to a child with chronic arthritis, the physician should be alert about the wide differential diagnoses and consider and rule in or rule out the probable causes according to the history and examination. A full history and physical examination will provide a good background for an appropriate approach. Unfortunately, there is not a specific diagnostic laboratory test for confirming the diagnosis. Some important causes such as infections, malignancies, metabolic disorders, endocrine diseases, connective tissue disorders, and immune deficiencies should be in the mind of the physician. Early diagnosis and aggressive treatment are the principles of the management to prevent significant disease complications. Long-term clinical, laboratory, and ophthalmologic follow-up are necessary.

#### **Acknowledgements**

We would like to extend our sincere gratitude to all members of the Pediatric Rheumatology Ward in Mofid Children's Hospital, Tehran, Iran, and special thanks to Dr. Vahideh Zeinali, the head of the hospital library.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Juvenile Idiopathic Arthritis DOI: http://dx.doi.org/10.5772/intechopen.99686*

#### **Author details**

Vadood Javadi Parvaneh\* and Khosro Rahmani\* Shahid Beheshti University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: vadoodj@gmail.com and rahmani.kh88@gmail.com

© 2021 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.

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#### **Chapter 6**

## Cardiovascular Risk in Rheumatoid Arthritis

*Alexandru Caraba, Flavia Corina Babalic, Andreea Munteanu and Otilia Tomulescu*

#### **Abstract**

Rheumatoid arthritis (RA), one of the most common inflammatory rheumatic diseases. It is defined as a chronic destructive and deforming arthropathy; it also finds its expression through systemic manifestations. RA has an undulating evolution, with remissions and relapses. Atherosclerotic cardiovascular disease represents one of the most common extra-articular manifestations of RA. It is known that the cardiovascular (CV) morbidity and mortality represent one of the leading causes of reduced life expectancy in RA. Patients with RA develop a premature and accelerated atherosclerosis, explaining the high incidence and prevalence of angina, myocardial infarction, congestive heart failure, stroke, peripheral artery disease, and the need for revascularization. Traditional risk factors (arterial hypertension, obesity, smoking, dyslipidemia, insulin resistance and metabolic syndrome, diabetes mellitus, male gender, physical inactivity) interplay with RA-related risk factors, generating endothelial dysfunction, arterial stiffness, carotid plaque, and atherosclerosis. Traditional cardiovascular risk factors alone cannot explain the increased incidence of premature and accelerated atherogenesis. Chronic inflammation, hyperhomocysteinemia, and hypercoagulation act as novel cardiovascular risk factors. Rheumatoid inflammation exerts direct effects on vessels, or by means of altered traditional risk factors. Antirheumatic drugs may promote atherogenesis or by reducing systemic inflammation may decrease cardiovascular risk. EULAR recommendations require annual cardiovascular risk assessment.

**Keywords:** cardiovascular risk, rheumatoid arthritis

#### **1. Introduction**

Rheumatoid arthritis (RA), one of the most frequent rheumatic inflammatory diseases, is defined as a chronic destructive and deforming arthropathy, but it also expresses itself through systemic manifestations [1]. The incidence of RA reaches its peak around 50 years; this disease affects twice as many women than men [2]. Its evolution is undulating, marked by exacerbations and remissions, the burden being variable between patients. This fact makes long-term outcomes different between patients: some have relatively mild disease, while others have marked physical disabilities and reduced quality of life [1].

RA manifests itself in the form of a chronic symmetric polyarthritis that affects predominantly the small joints. But besides articular involvement, which generates severe disability, RA has extraarticular manifestations, which are responsible for

the increase in mortality by 1.5 times compared to that in the general population. Among these extraarticular manifestations, cardiovascular involvement generates increased morbidity and mortality in RA patients. This induces a real challenge in the treatment of these patients [2–7]. RA patients have an increased risk (50% higher than the general population) of premature mortality due to cardiovascular diseases [8–10].

In their meta-analysis, comprising 24 studies of RA mortality on 111,758 patients, Avina-Zubieta et al., reported that the cardiovascular mortality was increased by 50% in these patients. The authors identified that the RA patients with a short duration of disease evolution had had a lower risk of cardiovascular mortality compared to the patients with long evolution of RA [11]. In another study, Avina-Zubieta et al., showed that the patients with RA had a myocardial infarction relative risk of 1.68 (95% CI, 1.40–2.03), and cerebrovascular disease relative risk of 1.41 (95% CI, 1.414–1.4) [12]. Houri Levi et al., revealed in their study done on 12,000 patients with RA that the ischemic heart disease had a greater prevalence among RA patients compared with general population (16.6% versus 12.8%, p < 0.001) [13]. The RA patients may develop myocardial infarction at a younger age than the general population [14].

The risk of cerebrovascular events is increased by about 41% in RA patients [13]. Another atherosclerotic manifestation is represented by peripheral arterial disease. Baghdadi et al., studying 30,000 patients with RA, identified a higher incidence of peripheral arterial disease among them than the general population (HR 1.73, 95%CI 1.57–1.91). The association with high blood pressure or diabetes mellitus increased the risk of peripheral arterial disease among RA patients [15].

Heart failure is about 2 times more common in RA patients with a positive rheumatoid factor than in the general population (HR 1.87, 95% CI 1.47–2.39) [1].

In the following sections, the main aspects related to cardiovascular risk in RA are presented.

#### **2. Cardiovascular risk in patients with RA**

In European Society of Cardiology guidelines, RA is considered an independent cardiovascular risk factor [16]. Knowing the high incidence of cardiovascular diseases among RA patients, in 2016, the European League Against Rheumatism (EULAR) published a set of 10 recommendations for the screening, identification and management of cardiovascular risk factors in RA patients. These recommendations predicted that the cardiovascular risk scores obtained with the instruments used in the general population be multiplied by 1.5 in patients with RA. It is the task of the rheumatologist to identify and manage the cardiovascular risk factors in RA patients [17]. To date, the optimal control of RA inflammation has not been achieved [18].

High cardiovascular risk in RA patients may be explained by the interaction between traditional cardiovascular risk factors and those determined by RA [7]. But in RA patients, standard cardiovascular risk scores, like Reynold's Risk Score, Systematic Coronary Risk Evaluation (SCORE), and Framingham risk score minimizes the cardiovascular risk [19–21]. Lindharsen et al., demonstrated that the cardiovascular risk is related to the RA severity [14].

The traditional cardiovascular risk factors have a higher incidence among RA patients than in the general population, especially insulin resistance, obesity, diabetes, hypertension, and smoking; however, the presence of increased systemic inflammation has been shown to also provide a detrimental pro-atherogenic role in the RA patients [22]. It was demonstrated that the risk for cardiovascular morbidity

#### *Cardiovascular Risk in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.101259*

and mortality in RA patients keeps growing even after controlling for insulin resistance, dyslipidemia, body mass index, hypertension, and smoking. In metaanalysis published by Baghdadi et al., the cardiovascular risk induced by traditional cardiovascular risk factors is highlighted as follows: hypertension (RR 2.24, 95% CI 1.42–3.06), hypercholesterolemia (RR 1.73, 95% CI 1.03–2.44), diabetes mellitus (RR 1.94, 95% CI 1.58–2.30), smoking (RR1.50, 95% CI 1.15–1.84), and obesity (RR 1.16, 95% CI 1.03–1.29) [15]. RA-associated chronic inflammation may lead to atherosclerosis acting direct on the arterial walls, or by modifying traditional cardiovascular risk factors, especially insulin resistance and dyslipidemia [1]. Elevated levels of circulating cytokines are identified even before the onset of clinical signs of the disease [9]. Chronic systemic inflammation generates endothelial activation and dysfunction, and a pro-atherogenic and prothrombotic state, responsible of the increased cardiovascular risk in RA patients [23]. It has been identified that systemic inflammation acts on myocardial cells even before the occurrence of specific joint manifestations of RA. Therefore, it is very important that cardiovascular risk assessment be done right at the time of RA diagnosis [7].

Cardiovascular involvement in RA patients is based on two mechanisms: an ischemic one caused by accelerated atherosclerosis, as well as a non-ischemic one, produced by the structural changes of the myocardium, both of them induced by chronic inflammation [2].

#### **3. Inflammation and cardiovascular risk in RA**

The link between chronic inflammation and accelerated atherosclerosis is well known in RA patients, several studies supporting this fact [17, 21, 24–27]. Inflammation is implicated in both the development and progression of atherosclerotic plaques in the general population [1]. Chronic inflammation is associated with cardiovascular disease, independent of traditional cardiovascular risk factors [17]. In RA patients, a linear relation between chronic inflammation (elevated erythrocyte sedimentation rate, high levels of C reactive protein) and carotid intima-media thickness, independent of traditional cardiovascular risk factors, has been identified. Higher RA activity, evaluated by means of a composite index DAS28, is associated with higher cardiovascular risk [28]. In their study, carried out for a period of 10 years, Goodson et al., demonstrated the association between inflammation (evaluated by means of CRP levels) and higher cardiovascular mortality in patients with early inflammatory polyarthritis [29]. Agca el al. revealed that the RA patients presented more than twice cardiovascular events than the general population, even higher than the type 2 diabetes patients [30]. RA patients with coronary atherosclerotic disease have an unfavorable prognosis, presenting higher morbidity (recurrent ischemia episodes) and mortality than the non-RA patients [31]. RA patients are more likely to have silent myocardial ischemia and may develop heart failure and sudden death [32]. On the other hand, several studies showed that in the conditions of chronic inflammation, atherosclerotic plaques become vulnerable, unstable, with an increased risk of cardiovascular events [1].

But cardiac dysfunction may have a nonischemic origin, this dysfunction being associated with high inflammatory activity, but not rheumatoid factor positivity [33]. Cardiac dysfunction often goes undiagnosed, especially in asymptomatic patients or those with minor symptoms. Ferreira et al., studying 355 patients with RA, showed that only 7% of them were diagnosed with heart failure, but one third of RA patients met the symptoms of heart dysfunction [34]. The studies have shown that patients with high inflammatory activity (evidenced by elevated serum C-reactive protein levels) have the highest risk of developing heart dysfunction,

suggesting a role of inflammation in the cardiac dysfunction pathogenesis [1, 2]. High levels of C-reactive protein are associated with an increased risk of cardiac dysfunction, independent of the presence of traditional cardiovascular risk factors. The link between RA activity, measured by means of elevated levels of C-reactive protein and cardiovascular risk, indicates the fact that persistent systemic inflammation contributes to increased risk for cardiovascular events [35, 36].

Traditional cardiovascular risk factors acting together with systemic inflammation generate accelerated atherosclerosis and ischemic cardiac events, but systemic inflammation, even in the absence of traditional cardiovascular risk factors, determines the occurrence of cardiac dysfunction, as heart failure with preserved ejection fraction [1].

The involvement of systemic inflammation in heart failure with preserved ejection fraction is proved, acting by means of proinflammatory mediators [1, 35, 36]. This inflammatory environment induces endothelial activation and then dysfunction, and increased recruitment of leukocytes, especially monocytes into the cardiac tissue. In the myocardium, there is a reduction in the bioavailability of nitric oxide and consequently a reduction in cyclic guanosine monophosphate and protein kinase G. These changes lead to cardiac hypertrophy and increased resting tension, finally appearing as diastolic dysfunction [2, 33].

High levels of inflammatory cytokines (TNF-alpha, IL-1, IL-6) can be detected in patients' serum before the onset of RA symptoms [9]. They induce pro-atherogenic and pro-thrombotic states (insulin resistance, atherogenic dyslipidemia, oxidative stress, endothelium activation, and subsequent endothelial dysfunction). These cardiovascular changes appear even before the clinical RA onset [22].

The importance of systemic inflammation in cardiovascular morbidity and mortality of RA patients is revealed by the study published in 2019 by Provan et al., which showed that the RA patients diagnosed before 2003 had significantly elevated cardiovascular mortality compared with the patients diagnosed after 2004, who had a similar cardiovascular mortality risk as the general population [37].

#### **4. Dyslipidemia**

RA patients have lipid abnormalities, which promote accelerated atherogenesis. Chronic inflammation modifies lipid pattern in rheumatoid patients, favoring accelerated atherogenesis. In these patients, many studies showed a specific lipid pattern: decreased of total cholesterol, HDL-cholesterol, and LDL-cholesterol, and increased very-low density lipoprotein (VLDL), lipoprotein (a) (Lp(a)), apolipoprotein-B (apo-B), and free fatty acids (FFAs) [22, 38, 39]. Liao et al., described the "lipid paradox" in RA patients: decreased levels of total cholesterol and LDLcholesterol are associated with high cardiovascular risk. The decreased levels of total-cholesterol are due to low levels of HDL-cholesterol [39]. Sattar et al., reported an inverse relationship between rheumatoid activity reflected by high levels of C reactive protein and low levels of total cholesterol, LDL-cholesterol and HDLcholesterol [8]. Rheumatoid activity is associated with impaired HDL-cholesterol functions [39]. The impaired antioxidant activity of HDL-cholesterol is correlated with increased oxidized LDL-cholesterol and phagocytosis by macrophages, generating atherosclerotic plaques [40]. High levels of triglycerides are caused by VLDL increase and HDL-cholesterol decrease [8, 38, 40].

Kim et al., reported that the RA patients presented modified structure of lipoproteins, secondarily affecting their functions. The final result is represented by the increase of cardiovascular events incidence [40]. In RA patients, lipoproteins are oxidized and glycated, these processes are associated with a decrease in nitric

#### *Cardiovascular Risk in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.101259*

oxide generation, endothelial cell death, promoting endothelial dysfunction and atherosclerosis [40].

Ajeganova et al., studying the apolipoprotein pattern in RA patients, identified high levels of apo-B and a higher ratio of apo-B to apo-A, correlated with increased carotid intima-media thickness and the plaques presence [41]. Increased Lp(a) is common in patients with RA, especially when the disease is active. Lp (a) has dual actions: by binding to oxidized phospholipids, it is located in the vascular wall, contributing to atherosclerosis development, and on the other hand, by inhibition of plasmin activity, it promotes a thrombogenic effect [42].

#### **5. Hypertension**

Hypertension is known as an important cardiovascular risk factor. In RA patients, the hypertension incidence is between 4 and 73%, this incidence being dependent on the assessed patients and study design [43]. COMORA (COMOrbidities in Rheumatoid Arthritis) study reported a hypertension prevalence in RA patients of 40% [18]. Often, hypertension remains undiagnosed and consequently untreated in patients with RA, contributing to excessive cardiovascular morbidity and mortality [44, 45].

Chronic inflammation, by means of elevated levels of TNF-alpha, IL-1, IL-6, acts on the vascular endothelium, causing nitric oxide reduction, increase in endothelin, and upregulation of angiotensin II type 1 receptor, the final effect being represented by an excessive vasoconstriction and increased total peripheral resistance. Additional contributing factors for hypertension development are represented by genetic polymorphism, physical inactivity, RA medication (nonsteroidal anti-inflammatory drugs, corticosteroids, Leflunomide, Cyclosporin) [1].

#### **6. Insulin resistance, metabolic syndrome, and diabetes mellitus**

The existing data support the strong link between RA, insulin resistance and metabolic syndrome [1]. Lindhardsen et al. reported that the chronic inflammation represents the link between RA and atherogenesis [14]. In another study, Baghdadi et al., demonstrated a strong correlation between inflammatory syndrome, RA activity, insulin resistance, and subclinical atherosclerosis revealed by means of carotid intima-media thickness [15]. Metabolic syndrome and RA influence each other, the final result being represented by oxidative stress with secondary endothelial damage [1].

#### **7. Obesity**

Obesity is known as an important traditional cardiovascular risk factor. It is important to remind that the adipose tissue is not inert but is very biologically active through the synthesis of TNF-alpha, IL-6, cytokines involved in RA pathogenesis [1].

In RA patients, the prevalence of overweight is about 60%, and the prevalence of obesity is between 18 and 31%. These patients present a higher rheumatoid activity than in RA normal weight patients. But the obesity is associated with other traditional cardiovascular risk factors, as insulin resistance, metabolic syndrome, diabetes mellitus, hypertension, atherogenic dyslipidemia, and inactive lifestyle [46].

The RA patients with low body mass index (<20 kg/m2 ) present the elevated risk for cardiovascular disease development. Kremers et al., showed that patients with RA and low body mass index had a higher cardiovascular risk than those with normal weight [47]. Increased inflammatory activity, which characterized active RA, causes an increase in catabolic processes, with a consequent reduction in body weight, settling in the advanced stages of rheumatoid cachexia [1].

#### **8. Smoking**

Smoking is known as a traditional cardiovascular risk factor. But the recent data suggested that smoking is involved in RA pathogenesis. Smoking determined the increases the risk of RA. But the RA smoking patients present a higher activity of disease with RF positivity, erosions, nodules, and marked disability. In these patients, the potency of the csDMARD and bDMARDs is low, requiring higher doses of them [1].

#### **9. RA therapy and cardiovascular risk**

The therapeutic objectives are represented by the efficient control of the inflammatory process, as well as the prevention of the articular destructions [1]. By controlling the inflammatory process and its consequences on the vascular endothelium, the atherogenesis process is diminished, and consequently, the cardiovascular risk [48]. In order to diminish RA chronic inflammation, joint destruction and cardiovascular risk, EULAR recommended a sustained, aggressive control of disease activity, using several classes of drugs, as nonsteroidal anti-inflammatory drugs, glucocorticoids, csDMARD (conventional synthetic disease modifying antirheumatic drugs), bDMARD (biologic disease modifying antirheumatic drugs), tsDMARD (targeted synthetic disease modifying antirheumatic drug) [17]. All of these drugs, in addition to controlling the inflammatory process, can have side effects that can increase cardiovascular risk [48].

Nonsteroidal anti-inflammatory drugs represent a class of drugs widely used in the RA treatment. These patients used non-selective NSAIDs, or selective COX-2 inhibitors. The use of NSAIDs is associated with increased risk of cardiovascular events, especially in elderly RA patients. These drugs are associated with a high risk of arterial hypertension and atherothrombotic events development [49]. Selective-COX 2 inhibitors are contraindicated in patients with atherothrombotic risk factors, stroke, and ischemic heart disease. Therefore, Rofecoxib was withdrawn from use. But Etoricoxib can be used in RA patients in a dose of 90 mg daily. Due to side effects, these drugs should be used judiciously, but only in combination with DMARDs [1].

Corticosteroids effectively control inflammation, but they have many side effects, especially cardiovascular (uncontrolled arterial hypertension, atherogenic dyslipidemia, diabetes mellitus). The side effects of corticosteroids in RA patients have been evaluated in several studies. Del Rincon et al., demonstrated that the RA patients who received daily doses of glucocorticoids greater than 8 mg had an increase in dose-dependent cardiovascular morbidity and mortality [50]. In their meta-analysis, Roubille et al., showed that the RA patients treated with corticosteroids presented a 47% higher to develop cardiovascular events. The authors emphasized the role of inflammation in the occurrence of cardiovascular events [51]. Hazard ratios (HR) of cardiovascular mortality were 2.27 (95% CI 1.36–3.79) in RA patients who had been treated with oral corticosteroids in daily doses between 8 and

#### *Cardiovascular Risk in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.101259*

15 mg and 3.21 (95% CI 1.14–8.97) in RA patients who had been treated with doses above 15 mg [1]. The increased cardiovascular risk associated with corticosteroids is dependent on dose and time of use [49]. Based on these facts, EULAR recommends the use of glucocorticoids in RA therapy as the lowest effective dose for the shortest period of time, in order to control the inflammatory process while awaiting csD-MARD onset and minimize the risk of cardiovascular side effects [17]. csDMARD (conventional synthetic disease modifying antirheumatic drug) are represented by Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine. bDMARD are classified as TNF-alpha inhibitor (tumor necrosis factor inhibitor: Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab) and non-TNF-alpha inhibitor (non-tumor necrosis factor inhibitor: Anakinra, Abatacept, Tocilizumab, Sarilumab, Rituximab). tsDMARD (targeted synthetic disease modifying antirheumatic drug) are represented by Baricitinib, Tofacitinib, Upadacitinib. All these drugs have been shown to improve the cardiovascular risk, by the amelioration of sustained inflammation, and lipid profile improvement [39, 52–55].

Reducing inflammation very effectively, Methotrexate (MTX) is the gold standard of RA treatment, showing a reduction of cardiovascular events by 28% [51]. MTX influences the lipid profile, as increase the serum levels of HDL-cholesterol, total cholesterol, and LDL-cholesterol, decrease of lipoprotein (a) level, while the levels of apo-B and triglycerides remain unchanged [7].

Another csDMARD with similar efficacy as MTX in RA treatment is Leflunomide. But this drug is associated with arterial hypertension in 6–10% of treated RA patients. Therefore, it is very important to monitor blood pressure values at the initiation and then during treatment with this drug [56]. The use of this drug is not contraindicated in RA therapy, but it should be avoided in RA patients with uncontrolled arterial hypertension [48].

By interfering with platelet function, SSZ provides cardioprotection in RA patients. HDL-cholesterol levels are increased during treatment with SSZ alone, or in combination with MTX. On the other side, triple therapy with MTX, SSZ and Hydroxychloroquine confers a better lipid profile, consisting of higher HDLcholesterol levels and lower total cholesterol and LDL-cholesterol levels [7].

By using Hydroxychloroquine (HCQ ) in RA therapy, the risk of cardiovascular events has been reduced by 72%. This drug determined an anti-atherosclerotic lipid profile, consisted of lower total cholesterol, LDL-cholesterol and triglycerides, and higher HDL-cholesterol. A rare complication associated with HCQ therapy is cardiotoxicity, manifested in the form of dilated or restrictive cardiomyopathy, or atrioventricular block and bundle branch block. In order to avoid this condition, it is necessary to conduct regular screening using cardiac ultrasound and electrocardiography [7].

Active RA is characterized by increased cytokine levels. By effectively controlling inflammation and reducing cytokine levels, bDMARDs reduce the risk of cardiovascular events [48]. Among them, TNF-alpha has a very important role. Naerr et al., reported that by using anti TNF-alpha therapy, both the RA activity and cardiovascular risk decreased [57]. Halacoglu et al., showed a reduction of 30% in the risk of major cardiovascular events. The beneficial effects of anti TNF-alpha drugs are the consequence of blocking the actions that TNF-alpha has in the atherogenesis appearance [7]. Bergström et al., showed that the anti TNF-alpha therapy increased HDL-cholesterol, total cholesterol, and apo-B, and decreased the levels of Lp(a) [58]. But these drugs can cause or exacerbate heart failure; therefore, they are not indicated in moderate and severe forms of heart failure [59].

Abatacept is associated with the reduction of cardiovascular risk. The study performed by Jin Y et al., showed that the patients treated with Abatacept presented a 20% greater reduction in CV risk compared with TNF-alpha inhibitors [60].

The patients treated with Abatacept presented a significant increase in HDLcholesterol [61].

Rituximab determined a significant increase in total cholesterol and HDLcholesterol, and a significant decrease in inflammation (C reactive protein, ESR) and disease activity (evaluated by means of DAS28 score). The levels of LDLcholesterol have not undergone significant changes [56]. Hsue et al., reported that the therapy with Rituximab had been associated with endothelial function improvement [62].

Tocilizumab decreases inflammation, has a favorable effect on serum fibrinolytic activity and left ventricular systolic function in RA patients, but arterial hypertension is one of side effects of this drug [1, 63, 64]. Curtis et al., analyzing cardiovascular events in RA patients treated with Tocilizumab and anti-TNF-alpha agents, did not identify significant differences between the two groups in terms of myocardial infarction incidence and sudden cardiac death [65].

By using small molecule inhibitors of Janus kinase (JAK), lipid profile pattern is modified in the following manner: levels of total-cholesterol, LDL-cholesterol, HDLcholesterol, triglycerides, and apo-B levels are increased, and lipoprotein (a) is reduced (by baricitinib) or unchanged (by Tofacitinib) [53]. It is very important to note that with a dose of tofacitinib 10 mg twice daily, the risk of thrombosis has increased, this risk is not being noticed when reducing the dose at 5 mg twice daily [7].

In their meta-analysis, Ozen et al., showed that the risk of cardiovascular events was reduced by 28% by the use of MTX and by 30% by the use of anti-TNF-agents (Infliximab and Etanercept) use, while corticosteroid therapy increased the cardiovascular risk by 47% [66]. The use of Abatacept has also been associated with a reduction in cardiovascular risk [60].

It is important to note that in order to have cardioprotective effects, the dose of MTX must be higher than 15 mg/week [51]. These high doses of MTX reduce cardiovascular risk by controlling RA activity, but possibly also by direct effects on vascular endothelium [66].

Biologic DMARDs are associated with a lower risk of atherosclerotic cardiovascular disease than csDMARD [66]. Zhang et al., studying the risk of atherosclerotic cardiovascular disease in the RA elderly patients, showed that the risk is higher in patients treated with anti-TNF-agents compared to Abatacept and Tocilizumab [67]. By improving endothelial function, Rituximab would reduce the incidence of atherosclerotic cardiovascular disease [66].

In order to reduce the cardiovascular risk in RA patients, it is necessary to take some steps; at the time of RA diagnosing, the patient must be evaluated in order to detect subclinical atherosclerosis and cardiovascular risk factors. NSAIDs and corticoids should be used at the lowest doses, for the shortest period, and always associated with csDMARD. MTX dose should be over 15 mg/week. Administration of other csDMARDs (non-MTX csDMARD) will take into account the presence of cardiovascular risk factors. bDMARDs should be administered without delay, to control systemic inflammation and, implicitly, cardiovascular risk. But in the case of these drugs, the presence of cardiovascular risk factors will also be taken into account [48, 66, 67].

These are just a few aspects of cardiovascular risk in RA patients. Subsequent research will bring new data that will explain aspects related to cardiovascular risk in RA and will implement new therapeutic strategies to reduce it.

#### **Conflict of interest**

None.

*Cardiovascular Risk in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.101259*

#### **Author details**

Alexandru Caraba1 \*, Flavia Corina Babalic2 , Andreea Munteanu1 and Otilia Tomulescu3

1 Department of Internal Medicine, Division of Rheumatology, University of Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

2 Department of Pathophysiology, University of Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

3 Department of Cardiology, University of Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

\*Address all correspondence to: alexcaraba@yahoo.com

© 2021 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.

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#### **Chapter 7**

## Rheumatoid Arthritis and Periodontal Disease

*Apoorva B. Badiger and Triveni M. Gowda*

#### **Abstract**

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease (IMID), chronic progressive causing inflammation in the joints and resulting in painful deformity and immobility, especially in the fingers, wrists, feet, and ankles. Periodontitis is defined as an inflammatory disease of supporting tissues of teeth caused by specific microorganisms or their groups, resulting in progressive destruction of the periodontal ligament and alveolar bone with periodontal pocket formation, clinical attachment loss, or both. Individuals manifesting both periodontitis and RA may suffer from a unifying underlying systemic dysregulation of the inflammatory response. In the past few years, increasing attention has been given to aspects of oral health in patients with rheumatoid arthritis, especially related to associations with periodontal disease. In this chapter we will be reviewing about the pathophysiology of RA and role of inflammation, periodontal disease: a gateway to RA, oral manifestations of RA, immunogenetics of RA and periodontitis, treatment implications for RA and periodontitis based on common pathophysiology.

**Keywords:** Rheumatoid arthritis, periodontal pathogens, periodontitis

#### **1. Introduction**

The global RA prevalence estimate was 0.46%. Women are affected 2 to 3 times more often than men. Onset may be at any age, most often between 35 years to 50 years, but can also be during childhood. Several risk factors like smoking, genetic association, recovery from bacterial or viral infections, sedentary lifestyles have been associated with the development of RA. In India, an estimated prevalence rate of RA is 0.5%–0.75% [1]. The Surgeon General's report on *Oral Health in America*, published in 2000, documented the significance of dental health on the overall general health and well-being of a patient. Research findings indicate possible relationships between chronic oral infections, such as periodontitis, and systemic disorders, such as diabetes, cardiovascular and lung diseases, stroke, osteoporosis, and rheumatoid arthritis [2]. A recent meta-analysis revealed an increased risk of RA in patients with periodontitis. The cross-sectional study was conducted to assess the impact of periodontitis (PD) on the health-related quality of life (HRQoL) and oral health-related QoL (OHRQoL) of subjects with rheumatoid arthritis (RA) and PD and found that the interaction effect of both diseases significantly conferred impacts on their OHRQoL and HRQoL [3]. Snyderman and McCarty reported common inflammatory mechanisms are shared by RA and periodontal disease (PD). Periodontitis is an inflammatory disease affecting periodontium caused by specific microorganisms like *P. gingivalis* (Pg), Aggregatibacteractinomycetemcomitans

(Aa), *T. denticola*, *T. forsythia*. Interestingly, these bacteria are also noted in the serum and synovial fluid of the joints of RA patients [4]. Mainly Pg and Aa can indirectly cause inflammatory reactions in the body. A study was conducted by Paola et al. on 4461 participants, of whom 103 were classified as having RA. Participants with RA had more missing teeth when compared to non-RA patients. It was concluded that there is a stronger association between periodontitis and tooth loss with RA [5].

#### **2. Pathophysiology of RA & role of inflammation**

RA is one of the more common autoimmune disorders, affecting approximately 1% of the population worldwide, and is characterized by dysregulated inflammatory processes in the synovium of the joint eventually leading to the destruction of both cartilaginous and bony elements of the joint, resulting in pain and disability. In a susceptible individual, the interface of environment and genes results in a loss of tolerance of self-proteins that contain a citrulline residue. The recognition of antibodies is directed against citrullinated peptides in RA. Enzymes like peptidylarginine deiminases (PADs)cause citrullination to occur. Citrullination is a normal process, vital for normal skin formation and other physiologic functions. But, in RA an autoimmune response develops against citrullinated peptides detected as anti-citrullinated peptide antibodies (ACPA). One of the tests to detect these antibodies detects anti-cyclic citrullinated peptides (anti-CCP). The presence of anti-CCP is>98% specific for the diagnosis of RA; though not all patients with RA will develop anti-CCP antibodies [6].

In the synovial fluid of patients with RA, a significant increase of T cells bearing the CD4+, 4B4+ helper-inducer receptor phenotype, and a significant decrease in CD4+, 2H4+ suppressor-inducer receptor phenotype was found in the peripheral blood of RA patients. The predominant feature is inflammation, mainly in the synovium. The synovial membrane in RA becomes hyperplastic. There is an amplified amount of synoviocytes and are infiltrated with immune and inflammatory cells, particularly macrophages, B- and T-lymphocytes, plasma cells, and dendritic cells. Increased levels of cytokines play a vital role in the dissemination of synovial inflammation.

There is a rising interest in the associations between oral health and autoimmune and inflammatory diseases. Several epidemiologic studies have described associations between rheumatoid arthritis and periodontal disease. Recent clinical studies are increasingly linked with biological assessments to better understand the nature of these relationships. These elicit the body to create antibodies – known as autoantibodies that include rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) in turn produces tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-1, IL-6, IL-8, transforming growth factor-beta (TGF-β), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) that damage the body's cartilage, bone, tendons, and ligaments, resulting in the symptoms of RA [7].

#### **3. Periodontal disease: a gateway to RA**

In the case of rheumatoid arthritis, the initiating factor is an autoimmune response to structural components of the joint; in periodontitis, the initiating factor is the subgingival biofilm. In both cases, the destructive inflammatory events are remarkably similar, although the pathogenesis varies as a result of the

#### *Rheumatoid Arthritis and Periodontal Disease DOI: http://dx.doi.org/10.5772/intechopen.99583*

different anatomy. There has been a longstanding association described between periodontal disease with RA, However, it is now recognized that a specific species of bacteria, esp. *P. gingivalis*, colonizes patients with periodontal disease and marks the progression from gingivitis to aggressive periodontitis that can cause citrullination of proteins the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker. This gets converted to a citrullinated peptide in presence of the Peptidylarginine deiminase enzyme in turn forming immune complexes activating complement system releasing various inflammatory mediators causing joint destruction [3]. High levels of citrullinated proteins at the infection sites of *P. gingivalis* and their presence and serum levels correlate strongly with disease severity.

Concerning underlying pathophysiology, Chronic Periodontitis and RA share many pathological features and release several mediators that are common to both conditions(interleukin 1-beta and prostaglandin E2). Likewise, collagenase that specifically degrades collagen, activity is greater in GCF of periodontitis patients than healthy controls, also is elevated in RA synovial fluid, gingival crevicular fluid (GCF), and gingival tissue. A systematic review demonstrated that disease activity of RA relates with serum levels of IL-6, TNF alpha, and C Reactive Protein may influence an increase in inflammation leading to bleeding on probing (BOP). Antibodies to cyclic citrullinated peptides are connected with more aggressive and erosive rheumatoid disease [5]. Persistent periodontal disease as a trigger for chronic arthritis in vulnerable individuals via dysregulation in oral microbiota and host immune barriers. This prespective indicates that RA could be a consistent risk factor for chronic periodontitis, in contrary, newer theories emphasize that periodontal disease is a risk factor for RA (**Figure 1**) [1].

Though osteoclast precursors (OCPs) are produced in the bone marrow, circulate in the blood and enter active bone resorptive sites, and differentiate to osteoclasts. Periodontal bacteria-induced systemic IL-6 drives the expansion of OCPs that traffic to sites of bone resorption to boost osteoclastogenesis in response to locally produced RANKL, signifying changes in the bone marrow that link periodontitis to other disorders of bone loss, such as rheumatoid arthritis.

**Figure 1.** *Role of P.gingivalis in pathophysiology of RA.*

Periodontal disease yields an excess of citrullinated protein, that causes a break of tolerance with anti-CCP stimulation. *A. actinomycetemcomitans* induces citrullination in neutrophils by neutrophil extracellular trap(NET) activation and release through leukotoxin A. *P. gingivalis*, which has a specific deiminase enzyme, that could be most liable(Dr. Marotte) Also, research demonstrates it will be critical to address periodontal disease at its initial stage perhaps when it is associated with anti-CCP in preclinical RA, improved oral care and possible vaccination are probable treatment options. Targeting periodontal disease in RA patients or after the effects of anti-CCP is too late to make any changes for the individual. Rituximab and tocilizumab, two medications used to treat RA, also reduce the gingival inflammation and gingival bone destruction in periodontitis cases. However, infliximab enhances gingival inflammation while preventing periodontal bone loss [2].

Systematic review and meta-analysis revealed significantly increased risk of periodontitis in people with RA compared to healthy controls with a significantly raised mean probing depth, risk of bleeding on probing (BOP), and clinical attachment loss. Also, a study reported the presence of *P. gingivalis* and periodontal disease can be a trigger in individuals at risk for developing rheumatoid arthritis. Phase 1 therapy(scaling and root planing) has been effective as a therapy for established rheumatoid arthritis. Periodontal disease could also have probable downstream effects that impact additional related diseases [3, 8].

#### **4. Oral manifestations of RA**

The clinical manifestations of periodontal destruction is a result of the complex interplay among etiologic agents like bacterial plaque. Usually, it can be controlled by the body's defense mechanisms without destruction; however, when dysbiosis happens (like increased susceptibility, high bacterial load, or pathogenic infections/systemic infections) periodontal destruction could occur. Also, the recent outbreak of coronavirus infection throughout the world is a matter of global emergency. Patients with comorbidities, in their old age, and with a compromised immune system are at the highest risk of mortality.

Patients with autoimmune diseases, like lupus and rheumatoid arthritis (RA), already have a compromised immune system which is coupled with the prescribed immunosuppressive agents they take—making them more susceptible to infections. Rheumatoid arthritis has been associated with different oral manifestations, such as temporomandibular joint disorders, xerostomia, secondary Sjögren's syndrome, and periodontal disease (PD) [9].

#### **5. Immunogenetics of RA and periodontitis**

RA has various features typical of a complex genetic disease, such as multiple gene involvement, genetic variance, and incomplete penetrance. Susceptibility to rheumatoid arthritis (RA) is associated with defined HLA-DRB1 alleles. This specific regulation of DRB1 gene expression in RA patients represents one of the molecular mechanisms involved in the interrelation of HLA DRB1 genes. RA has several features typical of a complex genetic disease, such as genetic variance, incomplete penetrance, and multiple gene involvement. To date, the HLA complex is a strongly associated genetic factor for RA. DNA sequencing demonstrated that the actual disease-conferring portion of the D region of the HLA-DRB1 gene [10].

Various periodontal pathogens are involved in the process of periodontitis. Biofilm of periodontal disease supplies abundant Lipopolysaccharide(LPS).

#### *Rheumatoid Arthritis and Periodontal Disease DOI: http://dx.doi.org/10.5772/intechopen.99583*

Local production of IgA and IgM rheumatoid factor(RF) in periodontal disease has been documented. In particular, the HLA antigens A9, A28, BW15, and DR4 are associated with early-onset forms of periodontitis. The severity of RA and periodontal disease are partially due to intrinsic differences in the monocyte/T cell response traits. In both diseases, antigenic challenge (e.g. LPS) to the monocytic/lymphocytic axis would result in the secretion of catabolic cytokines and inflammatory mediators that would dominate. Also, IL-1 Genetic polymorphisms of cytokines have been associated with the susceptibility, severity, and clinical outcomes of inflammatory diseases, such as periodontitis and chronic arthritis [11].

#### **6. Treatment implications for RA and periodontitis based on common pathophysiology**

Many systemic conditions can alter the host's susceptibility to periodontitis. For instance, immunosuppressive subjects unable to mount an effective host response to subgingival microorganisms, thereby causing accelerated periodontal destruction. Contrarily, individuals with a substantial rise in the proinflammatory mediators may respond to periodontal pathogens with a boisterous inflammatory reaction causing periodontal tissue destruction. Though the interrelation of many systemic disorders on the periodontium is well documented, evidence suggests that periodontal infection may significantly increase the risk for various systemic diseases or may modify the natural course of systemic conditions.

Reports of the American Dental Association (ADA), American Academy of Oral Medicine (AAOM), British Society for Antimicrobial Chemotherapy (BSAC) American Academy of Orthopedic Surgeons (AAOS), suggest that routine antibiotic prophylaxis before dental treatment is not indicated for most patients with prosthetic joint replacement. However, antibiotic prophylaxis is indicated for almost all patients within the first 2 years after joint replacement patients, rheumatoid arthritis, systemic lupus erythematosus, etc. Many researchers cogitate patients with severe periodontal disease or other dental infections to be at great risk, and antibiotic prophylaxis may be indicated before dental treatment [2].

Several treatment approaches have been introduced to aim the host response to LPS-mediated tissue destruction. Either topically/systemic or in combination with scaling and root planing or surgical therapy. Pharmacologic inhibitors of NF-kB and sp38 MAPK pathways are actively being developed to manage rheumatoid arthritis and inflammatory bone diseases and they have been applied in periodontal disease models with noteworthy accomplishments. MMP inhibits the signal transduction pathways involved in inflammation. With the use of this novel strategy, inflammatory mediators including pro-inflammatory cytokines (e.g., IL-1, TNF, IL-6), MMPs, and others would be inhibited at the level of the cell-signaling pathways required for the transcription factor activation [12].

NSAIDs such as aspirin, naproxen, diclofenac and ibuprofen are the first line of treatment for RA. Also, the use of NSAIDs in managing periodontal disease has been extensively studied and the results are promising. Disease-modifying anti-rheumatic drugs (DMARDs) are second-line drugs used in RA. Effects of administration of systemic gold salts were associated with significantly less periodontal destruction. Chemically modified antibiotics and genetically engineered proteins (monoclonal antibodies and pro-inflammatory cytokines correct the imbalance between the pro-inflammatory and anti-inflammatory cytokines involved in the pathogenesis of RA and periodontitis. Tenidap inhibits cyclooxygenase and PGE2 production with inhibition of IL-1, IL-6, and TNF-a production that reduces bone resorption and cartilage degradation as activating collagenase and stromelysin in RA patients [2].

Tetracyclines like Doxycycline have been advocated for treatment of patients with systemic diseases such as diabetes, rheumatoid arthritis that has led to improvements in the periodontal health and enhance reattachment or stimulate new attachment of the supporting apparatus and osseous formation. in the future, HMTs will likely be developed as adjunctive treatments for periodontitis. Novel *anti-cytokine drugs* developed for the management of rheumatoid arthritis, a disease with pathophysiology similar to that of periodontitis. Cytokines like TNF-\_ have been targeted by TNF-\_ antagonists mainly infliximab, etanercept which are effective in treating rheumatoid arthritis [12].

Rheumatic diseases cause patients to seek care for musculoskeletal pain or dysfunction or other problems. Temporomandibular Joint (TMJ) involvement follows the course of most joint involvement. Adherence to articular surfaces, Capsular scarring, and shrinkage may further reduce joint mobility. NSAIDs are routinely used. Education, rest, and physio therapy complete the regimen for treatment. A study by Kononen et al. reported that the subjective symptoms and the clinical signs of CranioMandibular Disorders (CMD) in RA, Psoriatic Arthritis(PA), and Ankylosing spondylitis(AS) are caused mainly by the respective general joint diseases, which directly affect the masticatory system, especially the TMJ. Further, signs and symptoms of CMD are more frequent and severe in RA than in PA or AS [13].

#### **7. Conclusion**

RA, being a common autoimmune disease, is associated with inflammation of the joint and, if left untreated, results in joint destruction and resultant disability. Periodontal disease is an infectious process that necessitates bacterial presence and host response that is affected and modified by local, environmental, systemic, and genetic factors. Both RA and periodontitis have remarkably similar pathology. Numerous studies documented interrelationships between them. Individuals suffering from RA more likely to experience significant periodontal problems compared to non-RA patients. With this understanding that the imbalance between pro and anti-inflammatory cytokines in the pathogenesis of RA and periodontitis, emerging therapies have focused on the inhibition of destructive proteases and proinflammatory cytokines. These therapies hold tremendous promise in altering the course of progressive forms of RA and periodontitis. Closer attention to oral health in these patients will improve quality of life by providing insights for treatment and prevention.

*Rheumatoid Arthritis and Periodontal Disease DOI: http://dx.doi.org/10.5772/intechopen.99583*

### **Author details**

Apoorva B. Badiger1 \* and Triveni M. Gowda<sup>2</sup>

1 Periodontist and Oral Implantologist, Bangalore, India

2 Department of Periodontics, Bapuji Dental College and Hospital, Rajiv Gandhi University of Health Sciences, Davangere, Karnataka, India

\*Address all correspondence to: drapoorvabadiger@gmail.com

© 2021 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] The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review Khalid Almutairi

[2] Newman MG, Carranza FA, Takei H, Klokkevold PR. *Carranzas clinical Periodontology.* 10th ed. Elsevier health sciences; 2006.

[3] Rheumatoid arthritis risk in periodontitis patients: A systematic review and meta analysis YiqiangQiaoa1ZaoWangab1 YafangLiabYafeiHana YanhengZhoua XuanpingCao<sup>a</sup> )

[4] Snyderman R, McCarty GA. Analogous mechanisms of tissue destruction in rheumatoid arthritis and periodontal disease. In: Genco RJ, Mergenhagen SE, editors. Host-parasite interaction in periodontal diseases. Washington: American Society of Microbiology; 1982. p. 354-62.

[5] De Pablo P, Dietrich T, McAlindon TE. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. The Journal of rheumatology. 2008 Jan 1;35(1):70-6.

[6] Gibofsky A. Current therapeutic agents and treatment paradigms for the management of rheumatoid arthritis. The American journal of managed care. 2014 May 1;20(7 Suppl):S136-44.

[7] Anić B, Mayer M. Pathogenesis of rheumatoid arthritis. Reumatizam. 2014 Oct 23;61(2):19-23.

[8] Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: a systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Frontiers in immunology. 2016 Mar 2;7:80.

[9] Hajishengallis G, Chavakis T. Local and systemic mechanisms linking

periodontal disease and inflammatory comorbidities. Nature Reviews Immunology. 2021 Jan 28:1-5.

[10] Kerlan-Candon S, Combe B, Vincent R, Clot J, Pinet V, Eliaou JF. HLA-DRB1 gene transcripts in rheumatoid arthritis. Clinical & Experimental Immunology. 2001 Apr;124(1):142-9.

[11] Havemose-Poulsen A, Sørensen LK, Stoltze K, Bendtzen K, Holmstrup P. Cytokine profiles in peripheral blood and whole blood cell cultures associated with aggressive periodontitis, juvenile idiopathic arthritis, and rheumatoid arthritis. Journal of periodontology. 2005 Dec;76(12):2276-85.

[12] Kobayashi T, Ito S, Kuroda T, Yamamoto K, Sugita N, Narita I, Sumida T, Gejyo F, Yoshie H. The interleukin-1 and Fcγ receptor gene polymorphisms in Japanese patients with rheumatoid arthritis and periodontitis. Journal of periodontology. 2007 Dec;78(12):2311-8.

[13] Könönen M, Wenneberg B, Kallenberg A. Craniomandibular disorders in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a clinical study. Acta Odontologica Scandinavica. 1992 Jan 1;50(5):281-8.

#### **Chapter 8**

## The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment of Chronic Knee Osteoarthritis

*Mohammed Mesfer Al Kahtani, Ali H. Al Yami, Sarah Saleh Al Qahtani and Sihem Aouabdi*

#### **Abstract**

Osteoarthritis (OA) is one of the most prevalent conditions resulting to disability particularly in elderly population About 13% of women and 10% of men aged 60 years and older have symptomatic knee OA. The proportions of people affected with symptomatic knee OA is likely to increase due to the aging of the population and the rate of obesity or overweight in the general population. There are multiple factors associated with this progressive disease such as obesity, female gender, and repetitive trauma. Pain is the most common symptom in knee OA, a leading cause of chronic disability, clinical diagnosis will be supported by certain radiological findings. There are numerous conservative therapies that help to relive symptoms depend on severity of Osteoarthritis, and knee replacement remains standard of care in advance disease. Fat Micrografting is evolving technique with promising result in selected patients with regenerative and reparative effect of adipocyte-derived stem cell toward damaged cartilage and bone, which supported by clinical evidence.

**Keywords:** autologous fat micrograft, knee osteoarthritis, intra-articular injection, cartilage degeneration, adipocyte stem cells

#### **1. Introduction**

Rheumatic and musculoskeletal diseases (RMDs) constitute a group of more than 150 Conditions that are commonly characterized by progressive lesions and painful symptomatology. Altogether, they account for the leading cause of morbidity and disability worldwide, giving rise to tremendous health expenditures and professional incapacity. Osteoarthritis (OA), one of the RMDs, is a degenerative condition that principally involves the joint's cartilage, leading to its progressive destruction. It is related to aging and lifelong continual stress on the most functional articulations such as the knees, hips, and fingers, and the lower spine region. OA ranks among the ten most disabling conditions in developed countries. The global prevalence of symptomatic OA is estimated as 9.6% in males and 18.0% in

females over 60 years of age. Further, 80% of individuals with OA would experience significant movement limitations, and 25% would have serious handicap to perform routine activities of the daily life [1].

The prevalence of OA varies in different regions of the world, with rates ranging from 3.8–70%, depending on the methodology of studies, whether clinical, radiographic, patient self- reporting, or physician diagnosis [2]. As the incidence and prevalence of OA increase with age, the extending life expectancy results in a growing number of people afflicted with OA, with a proportional risk of disability. In the United Kingdom, 20–30% of the elderly population (aged 60 years and above) are diagnosed with symptomatic OA [3]. In the Middle East countries, including Iraq, Yemen, Saudi Arabia, and Syria, more than one million people are estimated to have OA [4]. Approximately 85% of individuals over the age of 75 experience some symptoms of OA [5].

Knee pain represents more than 80% of the total burden of OA [6]. High body mass Index (BMI) has become an epidemic in the US in recent decades and is a wellknown risk factor for knee OA [7]. In Saudi Arabia, a clinically based epidemiological study, at a primary healthcare clinic, by Al-Shammari et al. showed a prevalence of OA as high as 57.2%. Other data by Al Arfaj estimated the prevalence of knee OA as 53.3% and 60.9% in males and females respectively [8, 9].

The treatment of knee OA may use conservative measures including medications, Physiotherapy, and local injections, or surgical approach including total knee arthroplasty (TKA). TKA is highly effective in reducing articular pain and is associated with acceptable functional outcomes. The procedure of TKA is safe and is considered one of the most common and successful procedures in orthopedics.

#### **2. Risk factors**

Blagojevicy et al. did a systemic review and meta-analysis to study the risk factors of Knee OA in older patients. They included 85 out of 2233 studies screened. The main risk factors found were obesity, previous trauma, hand OA, female gender and older age [10].

High body mass index (BMI) is associated with development of knee OA, and it was proven that the physical disability of the patients affected by knee OA reduced after weight reduction [11].

Another meta analysis conducted by Muthuri et al. showed that knee injury's history is one of the major risk factors associated with Knee OA and it should be included in any prevention program since it is preventable factor [12]. Genetic factor as shown in different studies is also associated with OA [13]. Increased loading or mal alignment of the joints is considered to be other factors that may lead to OA. So, in summary the risk factors can be classified into patient related factors like BMI, genetic, gender and age and joint related like previous injury, abnormal loading or malalignment [14].

#### **3. Staging**

In research, multiple variations of the Kellgren and Lawrence staging system have been used. However, the original one is: [15].


*The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment… DOI: http://dx.doi.org/10.5772/intechopen.99370*


#### **4. Management**

General and clinical assessment of the patient will help in determining the appropriate. Treatment of osteoarthritis. The assessment of OA effect on patient's function, daily activity, social relationship and quality of life should precede any treatment. The. Management plan has to be discussed with the patient thoroughly including the education of osteoarthritis, benefits and risks of various treatment options.

#### **4.1 Non-surgical management**

There are different non-surgical methods to treat joint OA. According to the Osteoarthritis Research society International (OARSI) guidelines published in 2019, patient education and land-based exercise with or without management of dietary weight are core treatments of knee related osteoarthritis. Non-steroid anti-inflammatory drugs (NSAIDs) are recommended in OA.

Management and its topical derivative are strongly recommended for patients with knee OA. COX-2 inhibitors or NSAIDs with proton pump inhibitor should be utilized in patients with gastrointestinal pathology. Oral NSAIDs are not recommended for patients with cardiovascular diseases. Intraarticular injection with corticosteroids or hyaluronic acid is mainly used for knee OA. It is not recommended for poly articular or even hip OA. All these non-surgical methods are associated with different level of evidence in the literature [16].

#### **4.2 Surgical management**

Before surgical intervention is considered, the patient should have received the core conservative treatment. Arthroscopic debridement and lavage are not routinely recommended unless there is a clear justification such as mechanical block that can be resolved arthroscopically [17]. After failure of all non-surgical treatments and in advanced joint arthritis, the total joint arthroplasty using artificial joint is the best option. It should be done before the patient gets advanced functional limitations. It is very safe procedure and associated with sound outcome. Pre- and post-operative patient engagement in terms of having proper education and well-structured physiotherapy is crucial to end up with great results. The American Academy of Orthopedic Surgeons (AAOS) in their 2nd edition evidence-based guideline for the treatment of knee OA has published 15 recommendations. This includes selfmanagement exercise programs, weight reduction for painful knee and BMI < 25 and NSAIDs (oral or topical) or tramadol for symptomatic patients. They could not recommend the use of glucosamine and chondroitin, Intra articular Hyaluronic acid injection and arthroscopic lavage and or debridement for patient diagnosed with knee OA. They were unable to recommend for or against the using of knee corticosteroid, growth factor, platelet rich plasma (PRP) intraarticular injections and arthroscopic partial meniscectomy for a torn meniscus in patients with

symptomatic OA. They also have stated that high tibial vulgus osteotomy might be performed for patients with painful medial knee joint OA [18].

#### **5. Fat graft evolution**

Neuber presented history of fat transplantation in literature initially in 1893 and he stated that smaller fat parcels tend to undergo less absorption [19], followed by communication from Czerny [20] Lexer [21], and Rehn [22]. In 1911, Bruning was the first to transfer autologous fat into the subcutaneous tissue for the purpose of soft-tissue augmentation [23]. 1950 Peer published 1st book about fat grafting in 300 pages, mentioned that survival rate of fat graft could be 50% and determined the viability of fat tissue which injected [24], in 1980 s liposuction technique evolved which improved technically over time, 1985 Illouz [25] and Fournier [26] developed an comprehensive approach to fat transfer by syringe harvesting, called "microlipoinjection". Fat harvest from liposuction became the simplest and easiest method to pursue fat grafting, which indicated to treat soft tissue depression and contour deformity. 1990 Coleman described steps of fat injection procedure and coins the term Lipostructure [27].

There is numerous indications for fat graft in esthetic and regenerative medicine, Fat grafting technique evolved over period of time and become standard of care use in esthetic and reconstructive cases, in era of regenerative medicine, Lipoaspirate is consider source of fat micrograft which contains adipocyte derived stem cell (ADCS), growth factors, preadipocytes and cytokines demonstrate promising clinical application in wide spectrum of pathology to regenerate and reform damaged biological structure and improve outcome as in Osteoarthritis which consider leading cause to disability particularly in elderly population [28].

#### **6. The use of microfat graft for cartilage repair**

Cartilage contain a small number of cells known as chondrocytes, which are responsible for maintaining a large extracellular matrix, 85% of cartilage constitutes water and two categories of molecules: collagenous and noncollagenous [29], The main function of cartilage is to protect underlying bone from friction and act as gliding surface to enable motion, Articular cartilage is characterized as avascular, aneural, and alymphatic and, at maturity, of low metabolic activity [30], which entitle cartilage to special tissue with difficult task to repair it self, It has been demonstrated that early in the process of cartilage damage there is a rapid loss of glycosaminoglycans from the tissue [31]. Thus, most large defects fail to heal, leading to a long-term prognosis of osteoarthritis [32].

#### **7. Surgical technique to harvest fat**

Fat is readily available and simple to harvest, with the fat grafting surgery itself shows a low donor-site morbidity, and is inexpensive and repeatable. Liposuction is considered one of the most frequently performed surgical procedures all over the world, Since its introduction in 1982 using a blunt cannula attached to a suction generating device, the procedure has been improved [33]. Current technology for liposuction includes suction-assisted lipectomy, ultrasound-assisted, powerassisted, laser-assisted, and radiofrequency-assisted liposuction [34].

*The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment… DOI: http://dx.doi.org/10.5772/intechopen.99370*

#### **7.1 Harvesting of the adipose tissue**

The first step in fat transfer to harvest fat by Many different liposuction techniques, all with the aim of minimizing adipocyte damage and increasing its survival Chosen Donor site is pretreated with a tumescent solution which containing an anesthetic mixture of Lidocaine, Sodium bicarbonate to overcome the acidity of mixture and to reduce pain and discomfort at injection site,epinephrine to control bleeding by vasoconstrictive action and Normal saline, proportionally mixed according to surgeon preference, volume to be injected determine by the desire volume of fat harvest and accordingly 2–3 cc of tumescent mixture to each 1 cc of anticipated fat harvest.

There are a variety of suction methods from which one may choose. The standard techniques are the manual (Coleman technique) or suction-assisted liposuction (SAL). Negative pressure is applied With the Coleman technique and SAL in combination with gentle forward and backward movement of the cannula, causing physical disruption, thus allowing fat tissue harvest. These methods represent the current gold standard, and reports show a lack of stem cell damage and preservation of their regenerative potential [35].

There are multiple modifications of this method, including power-assisted liposuction (PAL), water jet- assisted liposuction (WAL), laser-assisted liposuction (LAL), ultrasound-assisted liposuction (UAL), and VASER (Vibration Amplification of Sound Energy at Resonance).

They all are developed to further facilitate the process of suctioning, with minimal trauma to the donor site and maximal outcome in the requested esthetic result.

Large-bore cannulas decrease the mechanical sheer stress on the harvested cells, and subsequently increase the total number of viable aspirated cells, and Studies have showed an inverse relationship between cellular damage and the diameter of the instrument used to extract fat [36].

#### **8. Processing of lipoaspirate**

The goal of processing is to eliminate cellular debris, a cellular oil and excess of infiltrated solution [37]. These elements cause inflammation at the recipient site, which can be unfavorable for the fat graft. Also, blood must be removed as it accelerates the degradation of the transplanted fat.

Sedimentation: little traumatic and gives a large number of vital and intact adipocytes. However, this method contains smaller concentrations of stem cells and a substantial amount of cellular debris and thus making it harmful to graft survival [38].

Filtration techniques: more efficient in producing viable graft material for large-volume fat transfers. One example is Puregraft filtration system; which is a closed-membrane filtration system that was originally designed to prepare fat for isolation of the stromal vascular fraction. Another example of filtration is lipoaspirate filtered with cotton gauze; this results in concentrating the fat and separating it from the infiltrated solution, oil and cellular debris. This method, as compared to centrifugation, showed no significant differences in the viability of transplanted fat cells.

Washing with normal saline: this preserves mesenchymal stem cells as well as a great number of adipocytes.

Centrifugation: considered the most frequently used technique. It separates fat from substances that increase the degradation such as blood, proteases, lipids, lipases, and it may concentrate the adipose stem cell fraction, potentially enhancing

#### *Rheumatoid Arthritis*

graft survival, Coleman suggested a processing method where centrifugation speed is 3000 rpm for 3 min. This creates multiple layers; the upper level is composed primarily of oil, the middle portion is fatty tissue, and the lowest portion, which is the densest layer, is composed of fluids and blood. This method obtains the highest possible concentration of stem cells within aspirate. It has also the increased content of angiogenic growth factors such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). To note that excessive centrifugal force may damage intact adipocytes and on the other hand better graft viability with low centrifugal forces.

#### **9. Microfat graft preparation**

Processing micro fat graft that require to process harvested fat graft through multiple micro pores filters that allow micro fat graft to pass through, these filters have different sizes that connected to Leur-leur 1–10 cc syringe.

#### **10. Fat graft injection**

Adipose tissue is injected in to the transplantation site through cannulas, where multiple tunnels are created on insertion, and fat is injected during withdrawal of the cannula. Graft through nutrition by tissue fluid absorption can survive up to 48 h. Meanwhile, neovascularization is being established. Therefore, the diameter of the graft should not be more than 2 mm to avoid central necrosis. The osteoarthritic knee joint was injected with autologous intra-articular fat micrograft 15–20 mL through the lateral approach according to the case in an amount that did not produce high pressure inside the joint and did not produce pain to the patients due to tension of the joint capsule [39].

#### **11. Postoperative care**

Postoperative care include antibiotics for one week, pain killers, and garment pressure dressing at injection and donor sites, encourage exercise and physiotherapy, massage to reduce swelling.

#### **12. Complications**

Infection is the most devastating encounter complication which presented as redness, hotness, increase pain, and purulent collection, treatment depend on severity of infection ranging from I.V antibiotics in addition to incision and drainage.

#### **13. Fat is source of adipocyte derived stem cells (ADSC)**

Adipose tissue composed of mature adipocytes (>90%) and a stromal vascular fraction (SVF), which includes preadipocytes, fibroblasts, vascular smooth muscle cells, endothelial cells, resident monocytes/macrophages, lymphocytes, ADSC, cytokines and growth factors [40–46], led to a growing interest for the use fat graft as regenerative therapy for common bone and joint diseases, with promising

therapeutic clinical application of ADSC into skeletal system with underlying structure such as Muscle, cartilage, ligament, tendon, and bone with regenerative and reparative potential and ADCs are considered as an ideal source of cell therapy for different types of diseases including bone and joint diseases [47].

#### **14. Adipocyte derived stem cell role in regenerate knee osteoarthritis**

Adult stem cells, represented mainly by the mesenchymal stem cells (MSCs) are present in most organs and tissues of the human body; they intend to replace damaged cells as a normal process [48]. These stem cells do not have ethical or legal concerns as compared to the embryonic and fetal stem cells [49]. Mesenchymal stem cells are a promising tool for tissue regeneration. They are multipotent adult stem cells obtained from different sources like bone marrow (BM), adipose tissue, umbilical cord, placenta, synovial membrane [50]. These cells because they are located in fat and synovial membrane, they are most suitable for the treatment of osteoarthritis (OA) [51].

The International Society of Cellular Therapy (ISCT) defines mSCs by three characteristics [52]. They need to be plastic adherent, express specific markers like the CD105, CD90, and negative for CD34, CD45, HLA-DR [47, 53, 54]. MSCs can differentiate to mesodermal lineage cells (osteocytes, adipocytes, chondrocytes) [54]. These cells differentiate also into many other cell types, like myocytes, neurons [55], cardiomyocytes and hepatocytes [56] in vitro and in vivo [57–59].

They are non-immunogenic cells as they lack the expression HLDR receptor, which makes them suitable for allogeneic transplantation [59]. These cells are capable of suppressing lymphocyte reactivity [60] and inhibit the production of inflammatory cytokines in vitro [61]. MSCs express cytokine and chemokine receptors on their cell surface, which allows them to migrate to the site of injury [62]. The ability to suppress the immune response enabled their use in graft-versus-host disease and transplant rejection [63].

Each of the MSCs depending on their origins presents some differences. The BM-MSCs have high differentiation capability, but are difficult to get from bone marrow. The adipose MSCs are easily obtained from adipose tissue with high yield and strong suppressive capabilities [64]. The umbilical cord MSCs are easy to get after birth, they have high self-renewable and differentiation capacities. The synovial-MSCs have high proliferative and differentiation capacities and very low immunogenicity [64].

MSCs from BM from mouse and from human were the first to be identified and are the most studied [54, 58]. Adipose stem cells (ASCs) were first identified as stem cells in 2001, capable to differentiate into cartilage, bone and adipose cells [65].

The age of the donor reflects on the differentiation potential of the cells [66]. Umbilical cord MSCs (UC-MSCs) showed to be highly proliferative and with differentiation potentials [67]. The drawbacks of the BM-MSCs are that the procedure to obtain the cells is painful, costly and does not yield high number of cells for cell therapy [49, 68, 69]. Besides, the procedure for BM isolation can result in potential infections [54].

Synovial-MSCs (S-MSCs) isolated and characterized first in 2001, are also promising tools for the treatment OA due to their natural homing in this site [70]. They were shown to have high chondrogenic differentiation capacities, high expression of type II collagen, compared to other sources of MSCs [71, 72]. S-MSCs are isolated in low numbers from different sites, like styloid fossa and paralabral synovium [73, 74]. They have low immunogenicity with high proliferation potentials [75, 76].

The adipose MSCs (A-MSCs) represent many advantages compared to other sources of the MSCs. They are abundant in the adipose tissue, adipose tissue is easier to get compared to BM, they have strong immunosuppressive capacities [47].

More research is needed to unveil the differences in the traits of A-MSCs isolated from different sites and their implications in therapy. Previously, it was shown that A-MSCs could differentiate from one site to another in term of their cell markers. The A-MSCs isolated from abdominal adipose tissue had high expression in CD31, CD45 and HLA-DR compared to the cells isolated from orbital adipose and had lower expression of CD73, CD90, CD105 and CD146 [77]. MSCs from adipose tissue represent a good and a promising alternative to bone marrow MSCs. They share the same phenotype as MSCs from bone marrow apart from few. They differentiate similarly to BM-MSCs into the three lineages, chondrocytes, adipocytes and osteocytes. Most importantly, they are easily obtained from liposuction aspirate of patients undertaking plastic surgery [65]. Adipose tissue contains greater number of stem cells than bone marrow (10 times higher) [59]. A large number of cells are required for transplantation. Stem cells isolated from adipose tissue or another source like bone marrow, need to be scaled up. At least 2x106 of MSCs is required per kilogram body weight [78].

MSCs from different sites (BM, adipose) tissue are heterogeneous cell population [79]. Although MSCs from bone marrow and from adipose tissue have similar differentiation potential, there are minor differences. ASCs showed higher chondrogenic potential than MSCs from bone marrow [80]. Other study however, showed no significant differences between these two populations for chondrogenic differentiation in 2D culture but the BM-MSCs showed higher chondrogenic differentiation in 3D culture [81]. Proliferative capacities and osteogenic differentiation of the MSCs from bone marrow are reduced with age [82]. According to previous report, MSCs can be affected differently depending on the disease. For example, it was reported that the BM- MSCs from osteoporotic patients had reduced osteogenic activity [82], whereas the BM-MSCs from OA patients did not show any differences with the normal patient [83]. In another, the chondrogenic and adipogenic differentiation of the MSCs were reduced in OA patients but not the osteogenic differentiation [84].

The expression of CD36 differed between donors from no expression to highly expressed [85]. However, all ASC extracted from different donors showed the expression of the CD90, CD73 and CD105. ASCs markers can change in expression depending on the age of cells in culture. CD106 is expressed in MSCs from bone marrow but not in ASCs where this latter expresses CD49b [52]. ASCs and BM-MSCs express CD29 (beta-1 integrin, important factor in angiogenesis) [74] and CD44 (hyaluronate receptor, important for neoextracellular matrix) and CD49e (alpha-5 integrin, important for cell adhesion to fibronectin) [59]. ASCs and BM-MSCs have been shown to secrete angiogenic growth factors, like VEGF, P1GF, bFGF, angiogenin, GM-CSF, MCP-1 and SDF-1alpha (Rehman, 2004; Kinnaird et al.; 2004), these could be involved in increased angiogenesis in ischaemic tissue [59]. CD117 (stem cell factor) a marker for totipotency and pluripotency, was expressed in ASCs and BM-MSCs [85]. Based on the International Society for Cellular Therapy, the minimum criteria to define mesenchymal stem cells are CD105 and CD90, their potential to differentiate to adipocytes, chondrocytes and osteocytes and they are plastic adherent [86]. The expression of the CD34 is only reported on the adipose derived mesenchymal stem cells but the expression decreases in culture [87, 88] and the expression of CD105 increases [89] (Braun et al.; 2013). CD34 is expressed on ASCs before they are isolated from the stromal vascular fraction (SVF) [89] (Braun et al., 2013). The International Society for Cellular Therapy (ISCT) and the International Federation for Adipose Therapeutics

*The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment… DOI: http://dx.doi.org/10.5772/intechopen.99370*

and Science (IFATS) agreed on these changes in phenotype of ASCs in SVF (uncultured) or when cultured [90]. The SVF is referred to the cellular pellet containing ASCs and endothelial progenitor cells without adipocytes and immune cells, [89]. When the SVF is plated, the ASCs adhere to the surface and the rest of the cell population including non-adherent and non-proliferating cells, are removed [89]. ASCs could be isolated from SVF by culture or by magnetic-activated cell sorting (MACS) [89]. The advantage of the MACS isolation is cells can be prepared in few hours as required in clinical application. When cells need to be expanded, isolating the ASCs with culture is the best method. ASCs and SVF could be used for transplant but the number of cells obtained from patients could limit the use of SVF. ASCs could be expanded to a large number of cells, which could be used for autologous transplant or banked for allogeneic transplant [89]. These differences could be due to site differences or due to the lack of standardized isolation method [91].

#### **14.1 Clinical trials with ASCs**

MSCs showed to have a big potential in clinical applications. The first clinical trials run on the application of bone marrow MSCs in patients with Hurler syndrome and metachromatic leukodystrophy (MLD) after allogeneic hematopeitic stem cells transplant, showed no toxicity secondary to the bone marrow MSCs transplant and the recovery of some of the symptoms were suggested to be due to the transplanted MSCs [92]. Since then, hundreds of MSCs clinical trials were run on many conditions including neurological diseases, cardiovascular, autoimmune and bone and cartilage diseases [93]. So far, there have been few approved clinical application for the MSCs in different countries. Few examples, are the application of allogeneic MSCs for the treatment of graft versus host disease (GVHD) in Japan, autologous bone marrow MSCs for amyotrophic lateral sclerosis and autologous adipose MSCs for Chron's fistula, human umbilical cord blood-derived MSCs for osteoarthritis in South Korea, and in Europe the application of allogenic adipose MSCs for the treatment of fistulas in Crohn's disease [70].

There are few procedures for the treatment of cartilage injuries; the arthroplasty, microfat grafting and the autologous transplant of chondrocytes but a curative therapy still need to be developed [94, 95].

The autologous chondrocytes implantation is a surgical procedure that involves the isolation of autologous chondrocytes, expanding them in vitro then transplanting them back to the patient [96]. The application of MSCs for knee repair showed to be more effective with fewer side effects from the surgical procedure of the isolation of chondrocytes [96]. There are many clinical trials on the applications of the MSCs for OA [70].

OA is a very common condition in adults, which affects articular cartilage, subchondral bone, synovial tissue and meniscus of the joint. This leads to cartilage degeneration, osteophytes formation, subchondral sclerosis and synovial hyperplasia [97]. OA may be caused by joint injuries, obesity, aging and could be inherited condition [97].

Previous applications of MSCs for cartilage repair showed good outcomes. The BM-MSCs transplant in patients for defects in their knee cartilage and in athletes with the defect in femoral cartilage showed a good recovery of their functions [98].

MSC isolated from bone marrow, adipose tissue, umbilical cord, synovial membrane were previously used for the treatment of OA [64].

Since the discovery of ASCs, they have been used in many clinical trials for different diseases [90]. Success has been reported from different clinical trials using ASCs, but the mechanism of action is still not clear on whether cells would differentiate into the tissue or modulate the immune system [89]. Direct application of the

human ASCs improved cardiac function when injected in animals with myocardial infarction [99]. This effect was believed to be due to trophic factors released by the stem cells and differentiation of the ASCs. Local administration of ASCs accelerated the wound healing in normal and diabetic animals through differentiation into epithelial and endothelial lineage and neovascularization [100]. ASCs were applied to an injured skin due to radiotherapy, showed good healing process compared to the control [101]. ASCs although they have been used successfully in clinical trials, but their effects are not always achieved. There are many reasons that could impact the success of the use of ACS from one trial to another like cell separation, delivery methods, cell homing, engraftment and their survival [89]. Other factors might have an impact on the success of the use of ASCs like the type of liposuction procedure, site of liposuction, age of the patient and the body mass index (BMI). These factors are being investigated. Extraction of fat with different techniques might have an impact on cell viability of stem cells, their proliferation and the phenotype due to the trauma generated during the procedure. It is important to examine the different liposuction techniques and their impact on the ASCs phenotype, proliferation, and stress level for downstream applications either in research or in clinical applications.

#### **15. Conclusion**

Knee osteoarthritis is most prevalence musculoskeletal disease which cause functional limitations and affect a person's quality of life, there are known factors related to underling OA pathology such as Obesity, female gender and repetitive trauma to knee, Radiological finding such as subchondral cyst and narrowing of joint space, will support clinical diagnosis and staging of the disease using Kellgren and Lawrence staging system. Which will dictate the treatment modalities, in early stages conservative treatment such as modification of life style, rehabilitation, NSAID. Where advance stage surgical interventions ranging from arthroscopic debridement and lavage in case of blockage to total knee arthroplasty, which is being standard of care in severe condition.

Evolution of fat graft application in wide spectrum of clinical applications and have shown promising outcome to alleviate OA symptoms, where its contain adipocyte stem cells which known with reparative and regenerative process with presence of signal cofactors such as platelets derived growth factors and other growth factors to repaired damaged cartilage, fat graft being harvested from donor site mostly from abdomen, then;lipoaspirate will undergo further processing to isolate pure fat out from oil and fluid layer, then fat graft filtered with connector to reach pure micro fat graft ready to inject into affected knee under sterile process with local anesthesia.

Numerous clinical trials conducted to examine efficacy of microfat graft and ASC injection into knee with OA which demonstrated improvement in the overall condition, and further research with larger samples being in the process of publication to support clinical application and examine safety of patients.

*The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment… DOI: http://dx.doi.org/10.5772/intechopen.99370*

#### **Author details**

Mohammed Mesfer Al Kahtani1 \*, Ali H. Al Yami1 , Sarah Saleh Al Qahtani<sup>2</sup> and Sihem Aouabdi1,3

1 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia

2 Department of Plastic Surgery, Université de Picardie Jules Verne, Amiens, France

3 King Abdullah International Medical Research Center, Jeddah, Saudia Arabia

\*Address all correspondence to: drhababi@gmail.com

© 2021 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.

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#### **Chapter 9**

## The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical Parameters of Post-Menopausal Women with Rheumatoid Arthritis

*Pedro Aleixo, Tiago Atalaia, José Vaz Patto and João Abrantes*

### **Abstract**

This study aimed to assess the effects of a proprioceptive exercises programme on disease activity and on ankle kinematic and kinetic parameters of post-menopausal women with rheumatoid arthritis. Twenty-seven post-menopausal women with rheumatoid arthritis were allocated to exercise group (n = 15) or control group (n = 12). Exercise group intervention: proprioceptive exercises (12 weeks; 3 oneon-one workouts/week; 30 min/workout). Control group intervention: stretching exercises (12 weeks; 1 one-on-one workout every two weeks; 30 min/workout). Disease Activity Score (28 joints) was used to assess disease activity. A 3D motion analysis system (9 cameras, 200 Hz) and a force plate (1000 Hz) were used to collect kinematic and kinetic data during a barefoot walking at self-selected speed. For each subjects' foot, 7 trials of the stance phase were collected. One subject withdrawal was registered in exercise group. Post-intervention, exercise group' subjects yielded higher gait speed, shorter stance phase, shorter controlled dorsiflexion sub-phase, and higher ankle power peak (p < 0.05), however, they showed no differences in Disease Activity Score, ankle moment of force peak, and variability of biomechanical parameters; control group' subjects showed no differences in all parameters. Proprioceptive exercises seemed to be a safe option to gain gait biomechanical improvements in post-menopausal women with rheumatoid arthritis.

**Keywords:** rheumatoid arthritis, proprioceptive exercises, disease activity, gait, ankle kinematics, ankle kinetics

#### **1. Introduction**

Patients with rheumatoid arthritis (RA) present damaged joints and pain [1], low muscle strength values [2], and cachexia [3, 4], while post-menopausal women represent the greater percentage of these patients [5]. Otherwise, patients with RA [6] and post-menopausal women [7] also present an increased risk of fall. So,

interventions aimed to reduce the risk and to prevent falls seem to be advisable for patients with RA, especially in the post-menopausal women group.

Falls have been associated with different identifiable risk factors [7, 8], which includes an unsteady gait [8] and an ineffective postural stability [9]. Gait and postural stability are dependent of motor control processes, assured by the central nervous system at different levels. According to literature, foot and ankle play a significant role to keep an effective postural stability in bipedal or unipedal activities [10], namely during gait [11, 12]. Furthermore, foot and ankle problems are associated with an increment of the risk of falls [13]. The control of the foot and ankle kinematics is especially important in the gait stance phase [14]. At gait stance phase, the ankle execute, in the sagittal plane, three different angular displacements, which were defined in prior studies as controlled plantar flexion, controlled dorsiflexion, and powered plantar flexion sub-phases [15–17]. These three angular displacements sub-phases are associated with the three objectives of foot control, mentioned in the literature [18, 19], that occurs in the gait stance phase: first, to control the impact on the ground; second, to control the foot as a stable limb; and third, to control the foot to propel the body. Consequently, ankle angular positions, ankle moment of force peak, and ankle power peak during stance phase have been reported as important biomechanical parameters for foot function measurement [20, 21]. Patients with RA have differences in ankle kinematics and kinetics during the gait stance phase, when compared with healthy controls, namely: at ankle angles [20–24]; lower ankle power peak [21, 22]; and lower ankle moment of force peak [21, 23, 24]. Moreover, previous studies [21, 24] correlated lower gait speeds – observed in these patients – with a reduced ankle moment of force peak and ankle power peak. According to the literature [23, 25], an impaired ankle power can reduce the capacity of adjustment and increment of gait speed, leading to a lower functional capacity. A subsequent study [14] specifically compared a group of post-menopausal women with RA with a group of age-matched healthy post-menopausal women. Data from this study showed that these patients yielded a lower ankle moment of force and a lower power performance during the powered plantar flexion sub-phase. The authors of this study concluded that it should be important to improve these kinetic values in post-menopausal women with RA, since they were vital concerning foot and ankle function, functional capacity, and fall prevention. According to the same study [14], post-menopausal women with RA also showed a higher stride-to-stride variability in the ankle moment of force peak. According to the literature, an increment of motor variability was also found in elders with history of falls [26–28], which could be a manifestation of an impaired motor control [29].

The nervous system, composed by the central nervous system and the peripheral nervous system, allows motor control during human movement. The central nervous system controls movement through three different levels (cerebral cortex, brain stem, and spinal cord), which are hierarchically organized, interdependent and connected between them: (1) the most complex voluntary movements are regulated by the cerebral cortex – upper level; (2) postural stability, as well as the automatic and stereotyped movements, are regulated by the brain stem – middle level; (3) movement is also regulated at the spinal cord – lower level [30, 31]. The peripheral nervous system enables the connection of the periphery with the middle and lower levels of the central nervous system [32]. Otherwise, the somatosensory information, composed by the mechanoreceptive, thermoreceptive, and nociceptive information arising from the periphery, also plays an important role in movement control [31]. Proprioception, a subcomponent of the somatosensory information, encompasses the afferent information arising from mechanoreceptors (located at the periphery) and contributes to joint and postural stability control [31]. This proprioceptive information is transmitted to the three levels of the central

#### *The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

nervous system, providing an optimization of the motor control [33]. The reciprocal innervation, an essential mechanism of the spinal cord regulation of the movement, is dependent on the quality of proprioceptive information (e.g., information arising from neuromuscular spindle, Golgi tendon organ, and mechanoreceptors located in joints) [34]. Accordingly, the quality of the movement is reliant on proprioception, both at a global (postural) level and at a local (joint) level [33, 35]. Therefore, a specific exercise programme could be conducted specifically to challenge and improve proprioceptive mechanisms, enhancing motor control processes [36]. This kind of exercise, made with this goal, could achieve the denomination of proprioceptive exercise [37]. According to a systematic review [38], there is evidence that proprioceptive exercises programmes can lead to improvements in proprioception and somatosensory function, namely programmes lasting 6 or more weeks (longer programmes have a greater effect); however, authors also concluded that there was a great variability and lack of detail concerning the training parameters (e.g., weekly frequency and workout duration) defined in the selected studies, making impossible to know the optimal dose–response.

Several interventions to prevent falls in elderly (e.g., exercises programme, educational programme, medication optimisation, environmental modification, and multiple interventions) have been established and evaluated [39]. Exercise programmes can prevent falls in elderly, especially those that include "balance" exercises [40, 41]. "Balance", "coordination", and "postural" exercises were classified as proprioceptive exercises in previous studies [36, 42]. According to a previous study [43], the incidence of falls in elderly was reduced after a proprioceptive exercise program. Thus, exercise is a good contribution for preventing falls; however, proprioceptive exercises, with their specificity, contribute in a more decisive way, stimulating and enhancing motor control processes.

Patients with RA benefit from the safety of the aerobic training, strength training, and from combinations of both. This is evidenced in published systematic reviews and meta-analysis [44–47]. Nonetheless, it was concluded in a prior systematic review [42] that there is a lack of studies that approach the safety and effectiveness of proprioceptive exercises regarding the improvement of functional capacity of these patients. Although these authors had not found any randomized or controlled clinical trial, a more recent systematic review [48] concluded that there is some evidence that, the so called, proprioceptive exercises are safe to apply in patients with RA and helpful in the increment of their functional capacity. In parallel, proprioceptive exercises programmes have revealed effective in elderly regarding improvements of their gait biomechanical parameters [49–51]. Exercise programmes are important to prevent falls [40, 41, 43], however, proprioceptive exercises programmes differs from others by its capacity to stimulate and enhance proprioception and somatosensory function [38]. However, it is noted that to the best of our knowledge, the effects of a proprioceptive exercises programme on gait biomechanical parameters were not studied in patients with RA. Furthermore, researches that evaluate the safety of this kind of exercises, in patients with RA, are also required.

The previous rational supported the twofold aim of the present study. First, it aimed to evaluate the effects of a proprioceptive exercises programme on disease activity of post-menopausal women with RA. Second, it also aimed to evaluate the effects on ankle kinematics and kinetics during the gait stance phase and on its variability.

#### **2. Methods**

To achieve the defined aims, a prospective, single-blind, controlled but nonrandomized trial study was conducted. The study was concepted in respect of the Declaration of Helsinki [52] and approved by the Ethical Committee for Health of the Portuguese Institute of Rheumatology, Lisbon, Portugal.

#### **2.1 Participants**

The selected post-menopausal women with RA (n = 27) were recruited from the Portuguese Institute of Rheumatology, Lisbon, Portugal, and participated voluntarily in this study. Inclusion criteria were defined as follow, to allow a coherent sample: (1) diagnosis of RA was made according to the 2010 Rheumatoid Arthritis Classification Criteria [1]; (2) patients underwent, for at least 4 weeks before, a stable dose of disease-modifying antirheumatic drugs; this period was necessary to achieve the anticipated effects of medication on joint pain and disease activity; (3) absence of early RA (disease duration <2 years); (4) diagnosis of post-menopausal status [53]; (5) absence of early menopause [54]; (6) absence of an unstable heart condition, chronic obstructive pulmonary disease or cancer; (7) absence of prosthetics in the lower limb joints; (8) nonparticipation in any kind of exercise programme in the last 3 months; and (9) documented ability to walk barefoot and unassisted for >7 m (without current walking aids).

The selected patients were allocated to the exercise group (EG) or to the control group (CG). A power analysis using GPower 3.0.10 software was performed, indicating the need of a sample of 51 subjects in each group, for an independent-samples t-test, to reach a power of 0.8, an effect size of 0.5 with the significance level adjusted to 0.05. Despite the volunteering interest for the study, some patients had logistical difficulties to move to the training centre. Therefore, to reach the greatest possible sample, the allocation process in groups cannot be random. Consequently, this process was defined as following: whenever as possible, the patients were allocated to EG until an n = 15 was attained; the patients who did not have the possibility to meet the workout schedule in EG but had in CG, were allocated to CG; then, the selected patients were allocated to CG, adding to prior allocated patients. Thus, 15 patients were allocated to EG and 12 to CG. The patients read and signed an informed consent form before their participation in the study.

#### **2.2 Exercises programmes**

EG' subjects accomplished a proprioceptive exercises programme: 12 weeks; 3 workouts/week; 30 min/workout – 25 min of proprioceptive exercises and 5 min of stretching exercises (15 s/exercise). Proprioceptive exercises were specially designed to improve lower limbs movements, according to the description framework defined in introduction. These exercises can be viewed at http:// pera.ulusofona.pt/exercise-programs/exercise-group/ and **Figure 1** presents an example.

An expert of the health and exercise field controlled just one subject in each individual workout (one-on-one session). This expert, who was not blind concerning allocation process, selected the proprioceptive exercises for all subjects (from the defined exercises). The selection of each exercise was made according to its level of complexity and each subject's capacity to perform the exercise. Exercise complexity was increased along the programme period (whenever the exercise was easily performed by the subject). 3 sets of 3 repetitions were performed in each exercise (performed under conditions without fatigue).

The selection of exercises for the CG programme presupposed that these exercises should not have any influence in the evaluated parameters. Thus, CG' subjects accomplished the following programme: 12 weeks; 1 workout every two weeks; 30 min/workout. Each session was composed by stretching exercises for trunk and

*The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

#### **Figure 1.**

*Example of an exercise used in exercise group (exercise goal: Improve proprioception related to postural stability and local motor control – Lower limb joints of the support leg and hip of the swing leg; exercise description: in single leg stand position, performed flexion and extension of the swing leg hip).*

upper limbs (15 s/exercise). At http://pera.ulusofona.pt/exercise-programs/controlgroup/ are presented these exercises. The training sessions in this group were also performed individually (one-on-one).

#### **2.3 Assessment of disease activity**

The Disease Activity Score–28 joints (DAS-28) was used to assess disease activity. DAS-28 score was calculated from: number of swollen and tender joints; visual analogue scale (VAS) to assess global health; and erythrocyte sedimentation rate [55]. One experienced rheumatologist evaluated the number of swollen and tender joints and applied the VAS. Erythrocyte sedimentation rate was assessed in a laboratory. The experienced rheumatologist and the laboratory were blind in relation to allocation process. Although the emphasis of the exercise programme was on lower limbs, most joints included in DAS-28 were located in the upper limbs. Therefore, the number of swollen or tender lower limb joints was also used to assess disease activity. To complement the aforementioned data, subjects answered to a VAS to measure pain perception regarding previous day [56]. This VAS is completed in a comprehensive way to the subjects: at the beginning of every workout session a horizontal straight line of 100 mm was presented in a white paper; the end anchors of the line were labeled as "no pain" on one end and "pain as bad as it could possibly be" on the other end; subjects responded to the VAS by placing a mark through the line already defined; this mark represented the subject's subjective pain perception regarding previous day. The VAS was scored by measuring the distance, in millimeters, between the anchor end labeled as "no pain" and the subject's mark on the line.

The demographic characteristics as well as reproductive and medical history of each subject were also collected by the experienced rheumatologist (age, body mass, height, duration of menopause, nature of menopause, disease duration, and pharmacological therapies).

#### **2.4 Gait biomechanical assessment**

An optoelectrical 3D motion analysis was used to assess gait biomechanical parameters. The Vicon® Motion Capture MX System (VICON Motion Systems, Oxford, UK) composed by 9 MX infrared cameras (7 × 1.3 MP; 2 × 2.0 MP), was synchronized with a force plate (model BP400600, AMTI, Watertown, MA, USA).

Each trial session had distinct parts: laboratory preparation, subject preparation, and data collection. The laboratory preparation included the calibration of the system made in accordance with the Vicon® technical specifications. Kinematic data was recorded at 200 Hz and ground reaction force data at 1000 Hz.

Subject preparation started with the collection of anthropometric data and the placement of 39 spherical reflective markers (9.5 mm diameter) that compose the Plug-In Gait Full-Body model (VICON Motion Systems, Oxford, UK). To assure the same measure and marker placement criteria, these tasks were performed by the same team researcher, who was not blind to the allocation process. The collection of the anthropometric data was carried out using a SECA 764 station (Hamburg Germany) and Siber-Hegner instruments (Siber & Hegner, Zurich, Switzerland).

Kinematic and kinetic data was recorded using the Vicon Nexus software (version 1.7.1). The test protocol used the guidelines specified in previous studies [14, 17]: (1) subjects walked barefoot in a gait corridor of 7 m long and 2 m wide, on which the force platform was mounted; (2) at the end of the corridor, the subjects turned around; (3) subjects were asked to walk at a natural and self-selected speed – representing the most comfortable walking speed that minimized possible discomfort that could have been caused if a pre-determined speed was determined [57] and minimized the induction of subjects into a transitioning stage, that is, a stage marked by an increased variability [58]; (4) seven valid trials of the gait stance phase were collected for each foot (trials were considered valid only when one foot stepped entirety on the force plate; this information was not given to the subjects to avoid changes in individual gait patterns); and (5) to avoid gait performance deterioration related to fatigue, subjects rested for 2 min by sitting on a chair every 20 trials.

All trials were processed using the Vicon Nexus software (version 1.7.1) and a quintic spline routine (Woltring filtering) was applied. The next gait biomechanical parameters were evaluated in the stride that started at heel strike on force plate: gait speed (m/s) – determined as described in a previous study [59]; stance phase time (s); time of the controlled plantar flexion sub-phase (s); time of the controlled dorsiflexion sub-phase (s); time of the powered plantar flexion sub-phase (s); ankle angular position in sagittal plane at the – heel strike (°), final of the controlled plantar flexion sub-phase (°), final of the controlled dorsiflexion sub-phase (°), toe off (°) – in these four angular positions, positive values means dorsiflexion and negative values means plantar flexion; ankle angular displacement along the – controlled plantar flexion sub-phase (°), controlled dorsiflexion sub-phase (°), and powered plantar flexion sub-phase (°); ankle moment of force peak in sagittal plane (Nm/ kg); and ankle power peak (W/kg).

#### **2.5 Assessment of body composition**

For this study, an octopolar bioimpedance spectroscopy analyzer (InBody 720, Biospace, Korea) was used to assess body composition. This equipment analyses

*The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

independently five body sections (i.e., trunk, both upper limbs, and both lower limbs). In a previous study [60], the accuracy of InBody 720 was tested using energy X-ray absorptiometry as a reference standard. Data revealed, in females, excellent agreements between InBody 720 and dual-energy X-ray for the quantification of the lower limb muscle mass (intraclass correlation coefficient ≥ 0.83) and percentage of fat mass (intraclass correlation coefficient = 0.93). Therefore, in this study were evaluated the muscle mass values (kg and % of total body mass) and the percentage of fat mass (%). These data was included in this chapter in order to improve the quality of the discussion. These assessments were carried out in accordance with the procedures presented in the equipment user manual [61].

#### **2.6 Statistical analyses**

In patients with RA, right and left lower limb joints can be differently affected during the course of the disease. Accordingly, intra-individual differences between lower limbs of post-menopausal women with RA, concerning ankle kinematics and kinetics, were observed in a prior study [14]. Consequently, randomly selected and measured only one lower limb per subject could conduct to loss of valuable information. According to literature [62], the statistical analyses should consider both sides for analyses when right and left lower limbs are independent. Therefore, each limb/ankle/foot dataset was independently considered for the statistical analyses. To this end, the mean and the coefficient of variation (CV) of the biomechanical parameters of each ankle/foot were calculated (from the seven trials collected for the contact of each foot on force plate). These data were inserted in the SPSS software for Windows, version 17 (SPSS, Inc., Chicago, IL), in order to perform the statistical analyses. Variability was studied through the CV.

The t-test's significance level can be almost exact for sample sizes greater than 12, even if the distribution was not normal [63]. Therefore, a two-tailed pairedsamples t-test was used to compare baseline and post intervention in each group. For the purpose of comparison between groups after intervention, the differences between baseline and post intervention were viewed as variables. A two-tailed independent-samples t-test was used to compare groups at baseline and post intervention. Differences were considered statistically significant at p values <0.05.

#### **3. Results**

One withdrawal was registered in EG: the post-menopausal woman with RA failed to meet the training schedule, precluding her inclusion in statistical analyses. Thus, in the EG only fourteen post-menopausal women with RA were included in the statistical analyses. In EG and CG, the rate of adherence to the programme was 86.1 ± 10.5% and 95.8 ± 27.5%, respectively.

#### **3.1 Clinical, demographic, and body composition data**

**Table 1** presents the descriptive statistics of the clinical, demographic, and body composition data for EG and CG, at baseline and post exercises programmes. In these parameters no statistically significant intergroup difference was found at baseline.

Most of the post-menopausal woman with RA, in both groups, presented at least one swollen or tender lower limb joint: one in EG and two in CG had no swollen or tender joints to report. One post-menopausal woman with RA in EG and two in CG had an induced menopause (i.e., bi-lateral oophorectomy) – remaining women had a natural menopause. Furthermore, two post-menopausal women with RA in each


*1 lower limb joints.*

*CG – control group; DAS-28 – Disease Activity Score (28 joints); EG – exercise group; p value – differences between baseline and post intervention were considered statistically significant at p values <0.05; sd – standard deviation; VAS – visual analogue scale to measure pain perception in relation to previous day.*

#### **Table 1.**

*Clinical, demographic, and body composition data at baseline and post intervention.*

group were undergoing hormone therapy. Eleven post-menopausal women with RA in EG and nine in CG were using glucocorticoids.

Between baseline and post exercises programmes, both groups presented a tendency to reduction in the DAS-28 score, as well as in the number of tender or swollen lower limb joints. Between the first and last workout session, the EG' subjects presented a decrease of the value of the VAS to measure pain perception regarding previous day (p < 0.001). **Figure 2** shows this reduction along the proprioceptive exercises programme sessions. In the CG, no statistically significant difference between the first and last workout session was observed.

Concerning body composition, no differences were observed between baseline and post exercises programmes in both groups.

#### **3.2 Gait biomechanical data**

**Table 2** describes the gait biomechanical data at baseline and post exercises programmes. At baseline, no statistically significant intergroup difference was found. **Figure 3** presents the curves of the ankle power and ankle moment of force of both groups, during the stance phase.

*The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

#### **Figure 2.**

*Mean ± standard deviation curves of the visual analogue scale to measure pain perception regarding previous day [56] – Answered by EG' subjects at each workout session (0–100 mm).*



*Ankle angular position is positive during dorsiflexion and negative during plantar flexion; CG – control group; EG – exercise group; p value – differences between groups concerning* Δ*; sd – standard deviation;* Δ *– difference between baseline and post exercises programme.*

*† p < 0.05 (differences between baseline and post intervention.*

*‡ p < 0.01 (differences between baseline and post intervention).*

*\*p < 0.05.*

#### **Table 2.**

*Gait biomechanical data at baseline and post exercises programmes.*

#### **Figure 3.**

*Mean ± standard deviation curves of the ankle power and ankle moment of force of both groups, during the stance phase (normalized to 100% of the stance phase).*

Between baseline and post intervention, EG' subjects yielded a higher gait speed (p = 0.027), a shorter stance phase (p = 0.014), a shorter controlled dorsiflexion sub-phase (p = 0.009), and a greater ankle power peak (p = 0.016). A trend towards *The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

reduction in ankle angular position at final controlled dorsiflexion sub-phase and in ankle angular displacement during controlled dorsiflexion sub-phase were observed in EG (p = 0.090 and p = 0.059, respectively). In the other gait biomechanical parameters of the EG' subjects, no statistically significant intragroup differences were found.

In CG, no statistically significant differences were found in gait biomechanical parameters after intervention, except for an increase of the time of powered plantar flexion sub-phase (p = 0.043).

Contrary to baseline, intergroup differences were found after intervention in gait speed, stance phase time, time of controlled dorsiflexion sub-phase, and ankle power peak (p < 0.05).

Variability of the gait biomechanical parameters showed no statistically significant intergroup or intragroup differences at baseline and post exercises programmes.

#### **4. Discussion**

A number of systematic reviews and meta-analysis [44–47] described the safety of using aerobic exercises, strength exercises, and the combination of both in patients with RA. Nonetheless, there was a need of researches that evaluate the effects of proprioceptive exercises on disease activity of patients with RA. Therefore, the first aim of this study was to describe the effects of a proprioceptive exercises programme on the disease activity of post-menopausal women with RA. Data from this study (DAS-28 and number of swollen or tender lower limb joints) showed no disease activity increase as a result of the exercise programme implementation; quite the reverse, data showed a trend towards reduction. Moreover, EG' subjects presented a reduction of the pain perception between the beginning and ending of the proprioceptive exercises programme. These results indicate that is safe to use proprioceptive exercises in post-menopausal women with RA.

A second aim was to evaluate the effects of the programme on ankle kinematics and kinetics of post-menopausal women with RA, during the gait stance phase. To the best of our knowledge, this was the first study that researched this topic in patients with RA, and specifically in post-menopausal women with RA. Data showed that a proprioceptive exercises programme had effects on ankle kinematics and ankle kinetics, as well as on gait speed, i.e.: higher gait speed, shorter stance phase and controlled dorsiflexion sub-phase, and higher ankle power peak. Otherwise, CG' subjects presented no changes post intervention. These results corroborated those of a prior study [50], which also found an increase of gait speed in elderly women after the participation in a proprioceptive training programme. Moreover, elderly also improved postural control after a proprioceptive exercises programme [49, 51]. However, none of them studied the effects of these programmes on ankle kinematics and kinetics during gait. As concluded in a recent study [14], post-menopausal women with RA should improve ankle kinematic and kinetic parameters during the propulsive phase of gait, which are important parameters for foot function, functional capacity, and fall prevention. Therefore, data presented in this study showed that a proprioceptive exercises programme had effects on those parameters, namely on the stance phase duration, controlled dorsiflexion sub-phase duration, and ankle power peak value. Thus, the improvement in foot function after the proprioceptive exercise programmes seems to point out that using this kind of interventions is indicated as an option for therapy in post-menopausal women with RA.

According to literature [14, 21–24], a lower ankle power and moment of force peaks were observed in patients with RA, and specifically in post-menopausal women with RA. Therefore, interventions to improve these gait biomechanical parameters are desirable, with exercises programmes being a possible option, namely proprioceptive exercise programmes. In the present study, post-menopausal women with RA yielded a higher ankle power peak as a result of the proprioceptive exercises programme; nonetheless, the ankle moment of force peak showed no change. Thus, the proprioceptive exercises programme enhanced joint power of the post-menopausal women with RA during the powered plantar flexion sub-phase, a parameter that may play an important role in the risk of fall. Otherwise, the inability of this programme to enhance muscle mass and ankle moment of force peak may indicate another reason is behind of the better performance during the powered plantar flexion sub-phase. According to a systematic review [38], there is evidence that proprioceptive exercises programmes can lead to improvements in proprioception and somatosensory function. According to this, we can speculate that the reason for a better performance was an improvement of proprioception and motor control as a result of the proprioceptive exercises programme.

Another aim was to evaluate the effects of the proprioceptive exercises programme on the ankle biomechanical variability. According to literature, an increased stride-to-stride variability was attributed to a probable loss of motor control [29] and post-menopausal women with RA yielded an increased variability of the ankle moment of force peak [14]. In this study, it was conjectured that the variability of the ankle moment of force peak could be decreased as consequence of the proprioceptive exercises programme; however, data showed no differences between pre and post intervention. Thus, another question arises, which can be answered by future research: "Could other kind of exercises programmes change variability of ankle kinematic and kinetic parameters during the gait stance phase?"

Strength training enhanced muscle mass of patients with RA [64, 65], however, the effect of a proprioceptive exercise programme on muscle mass was unknown. Between baseline and post exercise programmes, data showed no changes in low limbs muscle mass, pointing that these types of programmes had no effect on this parameter. Nonetheless, more research is required to clarify this question. On the other hand, post-menopausal hormone therapy, vitamin D and protein intakes, and menopause nature can influence muscle status [66, 67]. The use of hormone therapy could influence positively muscle status, whereas an induced menopause (e.g., bilateral oophorectomy) could be responsible of a greater impairment of muscle status. These parameters were not considered along the selection and allocation processes; nevertheless, data revealed that both groups of post-menopausal women with RA presented similar characteristics. Higher vitamin D and protein intakes could restrict muscle fiber atrophy; nonetheless, these variables were not evaluated in this study and thus, it can be considered as a limitation.

The presence of higher fat mass values could predispose to hypertension, diabetes, and risk for cardiovascular disease [68] and patients with RA showed high percentages of fat mass [69–72]. Fat tissue is an important font of inflammatory cytokines that could contribute to the systemic inflammation [72]. Following this deduction, it would be important to reduce fat mass in patients with RA, and to achieve this, physical exercise appears as an important strategy. However, the proprioceptive exercises programmes assessed in our study had no effect on fat mass of post-menopausal women with RA. To the best of our knowledge, this was the first study that researched this issue. Previous studies researched the effects of other types of physical exercise on fat mass of patients with RA. Two studies showed no change of the fat mass after strength training programmes [65, 73]. Otherwise, a combined strength and endurance training programme decreased the subcutaneous

#### *The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

fat thickness and this should not be dissociated from the inclusion of aerobic exercises in the training programme [74]. Accordingly, aerobic exercises are the best option for decreasing fat mass [75]. The importance of proprioceptive exercises is recognized with the findings showed in the present study; however, as described in literature [64], an exercise programme for patients with RA must contain aerobic, strength, mobility and proprioceptive exercises to achieve all benefits.

According to the literature [47], exercises programmes for patients with RA should be cautiously designed to the individual. The methodology of our exercise programme followed this indication. However, according to a number of systematic reviews [44–48], most studies that evaluated the effects of physical exercise on patients with RA applied group training sessions in their programmes. Consequently, it is imperative to emphasize the kind of exercise programme used in the present research (an individualized and personalized exercise programme). In the present study, the one-on-one workout sessions could have contributed to the high adherence rates of the programmes and to the observed results. Moreover, the clinical community can easily apply a similar programme due to the type of equipment used, i.e., low-cost equipment.

In accordance with the aforementioned, the use of proprioceptive exercise in clinical practice with women with RA is suggested, especially in patients in the following situations: patients with low physical activity; after periods of immobility; in recovery phases from an active disease; in aftercare for joint replacement surgery (total hip or knee prosthesis); in elderly patients, those with rheumatoid cachexia, those with a history of falls; after the first fracture; and in patients with moderate to severe osteoporosis.

#### **5. Conclusions**

A proprioceptive exercises programme had effects on the ankle biomechanical performance of post-menopausal women with RA, during the gait stance phase: increasing ankle power peak and shortening controlled dorsiflexion sub-phase. The programme also increased gait speed and shortened stance phase, although it had no effects on body composition. Finally, it seems to be safe in post-menopausal women with RA.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Rheumatoid Arthritis*

#### **Author details**

Pedro Aleixo1 \*, Tiago Atalaia2 , José Vaz Patto3 and João Abrantes4

1 Centre for Research in Sport, Physical Education, Exercise and Health, Lusófona University, Lisbon, Portugal

2 Portuguese Red Cross Health School, Lisbon, Portugal

3 Portuguese Institute of Rheumatology, Lisbon, Portugal

4 Centre for Research in Applied Communication, Culture and New Technologies, Lusófona University, Lisbon, Portugal

\*Address all correspondence to: pedro.aleixo@ulusofona.pt

© 2021 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.

*The Effect of a Proprioceptive Exercises Programme on Disease Activity and Gait Biomechanical… DOI: http://dx.doi.org/10.5772/intechopen.99462*

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### Section 3
