Preface

Rheumatoid arthritis is a chronic, systemic, inflammatory autoimmune disease that typically targets the synovial joints, with a spectrum of extra-articular manifestations. The disease is the most common form of inflammatory arthritis and contributes to considerable disability, morbidity, and mortality. The last two decades experienced an unprecedented leap in the management paradigm of rheumatoid arthritis from treat to relieve, to treat, to target and beyond.

This book examines the disease process of rheumatoid arthritis including information on immune-pathogenic theories, classification criteria, available composite measures of disease assessment, and latest available therapeutic approaches. It also discusses various clinically relevant disease-related problems and comorbidities such as vascular involvement and myopenia. The volume additionally examines the potential benefit of hormones in disease amelioration with a focus on the effect of pregnancy hormones and lactation on the inflammatory process in rheumatoid arthritis. Finally, the book provides updates on pharmaceuticals and patient self-management for better outcomes.

*Rheumatoid Arthritis - Other Perspectives towards Better Practice* sheds light on different disease-related perspectives that we believe can provide a better understanding of disease-related pathologies and support to improve long-term patient care and minimize related comorbidities.

> **Reem Hamdy A. Mohammed MD, PhD, FACR, FRCP** Professor, Professor of Rheumatology and Clinical Immunology, Department of Rheumatology and Rehabilitation,

> > Kasr Alaini School of Medicine, Cairo University, Egypt

**1**

Section 1

Introduction

Section 1 Introduction

**3**

**Figure 1.**

*Etio-pathogenic factors and disease evolution in rheumatoid arthritis.*

**Chapter 1**

*Reem H.A. Mohammed*

**1. Introduction**

dizygotic twins [2–4].

Introductory Chapter:

Rheumatoid Arthritis - Overview

Rheumatoid arthritis (RA) is a chronic multi-system inflammatory autoimmune disease of indefinite etiology. The disease primarily affects synovial joints eventually progressing to ongoing inflammation, destruction of both cartilaginous and bony elements of the joint, with resultant pain and disability. The disease additionally displays a spectrum of extra-articular multisystem manifestations [1]. The worldwide prevalence of RA remains underestimated, data gathered from Western regions illustrated prevalence between 0.5 and 1% in white individuals, with prevalence rates ranging between 0.6 and 0.9% in the studied black individuals. The female to male ratio in rheumatoid arthritis is 2:1 to 3:1. A high concordance rate is observed in monozygotic twins 12–15% compared to 2–3% in

Theories behind the evolution of autoimmunity in rheumatoid arthritis are clearly multifactorial. The inflammatory process usually develops in a predisposed individual who is probably exposed to a provocative trigger of autoimmunity via epigenetic modifications. A number of risk factors comprising genetic as well non genetic elements provide the hostile environment for the change towards autoimmunity. Evidences revealed a significant impact of familial genetic risk factors featuring ≥50% of the total risk of developing seropositive RA, with highest incidence rates among first-degree relatives. Among the most influential non genetic risk factors there comes smoking. Smoking provides a stimulus to epigenetic transformation, particularly in individuals with high-risk RA-susceptibility alleles.

of Current Facts and Strategies

### **Chapter 1**

## Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies

*Reem H.A. Mohammed*

### **1. Introduction**

Rheumatoid arthritis (RA) is a chronic multi-system inflammatory autoimmune disease of indefinite etiology. The disease primarily affects synovial joints eventually progressing to ongoing inflammation, destruction of both cartilaginous and bony elements of the joint, with resultant pain and disability. The disease additionally displays a spectrum of extra-articular multisystem manifestations [1]. The worldwide prevalence of RA remains underestimated, data gathered from Western regions illustrated prevalence between 0.5 and 1% in white individuals, with prevalence rates ranging between 0.6 and 0.9% in the studied black individuals. The female to male ratio in rheumatoid arthritis is 2:1 to 3:1. A high concordance rate is observed in monozygotic twins 12–15% compared to 2–3% in dizygotic twins [2–4].

Theories behind the evolution of autoimmunity in rheumatoid arthritis are clearly multifactorial. The inflammatory process usually develops in a predisposed individual who is probably exposed to a provocative trigger of autoimmunity via epigenetic modifications. A number of risk factors comprising genetic as well non genetic elements provide the hostile environment for the change towards autoimmunity. Evidences revealed a significant impact of familial genetic risk factors featuring ≥50% of the total risk of developing seropositive RA, with highest incidence rates among first-degree relatives. Among the most influential non genetic risk factors there comes smoking. Smoking provides a stimulus to epigenetic transformation, particularly in individuals with high-risk RA-susceptibility alleles.

#### **Figure 1.**

*Etio-pathogenic factors and disease evolution in rheumatoid arthritis.*

Environmental risk factors also include; particulate exposure, periodontal disease, bronchiectasis, diet, obesity and the oral contraceptive impact, respiratory, oral, intestinal and genital tract mucosal sites [1, 5], **Figure 1**.

### **2. Role players in the initiation and propagation of autoimmunity in rheumatoid arthritis**

a.**Neo-epitopes generation**: genetic and environmental factors operate to ultimately result in the inflammatory and destructive synovial response. Stressors including cigarette smoke can act on cells in mucosal sites and promote posttranslational conversion of the amino acid arginine to citrulline in a range of proteins, including intracellular proteins (such as histones) and matrix proteins (for example, fibronectin, collagen, fibrinogen, enolase and vimentin) via induction of peptidyl arginine deaminases in a process called citrullination (also known as deimination) rendering them antigenic [6–8].

Citrullination may also be induced by the oral microbiota: *P. gingivalis*, common in periodontal disease which expresses peptidyl arginine deiminases and can induce citrullination. *A. actinomycetemcomitans*, also producing a toxin that increases calcium influx into neutrophils, can lead to citrullination of peptides and has been recently implicated in RA etiology. Posttranslational modifications (citrullination, carbamylation, and acetylation) are potentially capable of generating neo-epitopes (neo-peptide antigens). Animal and human data about autoimmunity in rheumatoid arthritis suggest a model in which multiple environmental influences mucosal immune function promoting epigenetic transformations with trafficking of proinflammatory PAMPs making use of the enhanced mucosal permeability. Hence, the initial shift towards autoimmunity may present at mucosal sites as reported in previous researches with sputum samples positive for ACPA-IgA and IgG [9, 10].


**5**

**Figure 2.**

*provider.*

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies*

promoting arthritis with cartilage and bone damage.

chemokines (CCL19, CCL21) [15–17].

neo-epitopes (neo-antigens) promoting a self-directed immune response. In addition to autoantibody production the activated B lymphocytes releases

d.**In situ activation of stromal cells**: fibroblast-like synoviocytes FLS, antigen presenting cells and macrophages within the synovial joints gets similarly and synchronously stimulated to release a cascade of pro-inflammatory mediators

FLS masters the intra-articular production of prodigious amounts of MMPs and small-molecule mediators such as MMPs, prostaglandins, leukotrienes, and RANKL. They additionally express IL-6 receptors and specific patterns of microRNAs that could contribute to their activated phenotype. FLS exhibit an invasive phenotype that is responsible for cartilage damage and can potentially migrate from joint to joint to propagate disease. The macrophages like synoviocytes participate actively via local release of TNF-α, IL-1, IL-6, IL-8 and

e.**Ectopic germinal centers**: the adaptive immune cells infiltrate the synovial sublining with almost half of the sublining cells CD4+ memory T cells that can either diffusely infiltrate the tissue or, in 15–20% of patients, form ectopic germinal centers in which mature B cells proliferate, differentiate and produce antibodies

(rheumatoid factor RF and anti-citrullinated C peptide ACCP) [18, 19].

*Proximal interphalangeal joint with macrophages, dendritic cell, T cell, B cells infiltrates with hypertrophied synovium, intra-synovial angiomatoids and pannus formation. "By Dr. Maya H Ibrahim" the original image* 

*DOI: http://dx.doi.org/10.5772/intechopen.92771*

IL-6 [13, 14].

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies DOI: http://dx.doi.org/10.5772/intechopen.92771*

neo-epitopes (neo-antigens) promoting a self-directed immune response. In addition to autoantibody production the activated B lymphocytes releases IL-6 [13, 14].

d.**In situ activation of stromal cells**: fibroblast-like synoviocytes FLS, antigen presenting cells and macrophages within the synovial joints gets similarly and synchronously stimulated to release a cascade of pro-inflammatory mediators promoting arthritis with cartilage and bone damage.

FLS masters the intra-articular production of prodigious amounts of MMPs and small-molecule mediators such as MMPs, prostaglandins, leukotrienes, and RANKL. They additionally express IL-6 receptors and specific patterns of microRNAs that could contribute to their activated phenotype. FLS exhibit an invasive phenotype that is responsible for cartilage damage and can potentially migrate from joint to joint to propagate disease. The macrophages like synoviocytes participate actively via local release of TNF-α, IL-1, IL-6, IL-8 and chemokines (CCL19, CCL21) [15–17].

e.**Ectopic germinal centers**: the adaptive immune cells infiltrate the synovial sublining with almost half of the sublining cells CD4+ memory T cells that can either diffusely infiltrate the tissue or, in 15–20% of patients, form ectopic germinal centers in which mature B cells proliferate, differentiate and produce antibodies (rheumatoid factor RF and anti-citrullinated C peptide ACCP) [18, 19].

#### **Figure 2.**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

oral, intestinal and genital tract mucosal sites [1, 5], **Figure 1**.

**rheumatoid arthritis**

IgA and IgG [9, 10].

Environmental risk factors also include; particulate exposure, periodontal disease, bronchiectasis, diet, obesity and the oral contraceptive impact, respiratory,

**2. Role players in the initiation and propagation of autoimmunity in** 

(also known as deimination) rendering them antigenic [6–8].

a.**Neo-epitopes generation**: genetic and environmental factors operate to ultimately result in the inflammatory and destructive synovial response. Stressors including cigarette smoke can act on cells in mucosal sites and promote posttranslational conversion of the amino acid arginine to citrulline in a range of proteins, including intracellular proteins (such as histones) and matrix proteins (for example, fibronectin, collagen, fibrinogen, enolase and vimentin) via induction of peptidyl arginine deaminases in a process called citrullination

Citrullination may also be induced by the oral microbiota: *P. gingivalis*, common in periodontal disease which expresses peptidyl arginine deiminases and can induce citrullination. *A. actinomycetemcomitans*, also producing a toxin that increases calcium influx into neutrophils, can lead to citrullination of peptides and has been recently implicated in RA etiology. Posttranslational modifications (citrullination, carbamylation, and acetylation) are potentially capable of generating neo-epitopes (neo-peptide antigens). Animal and human data about autoimmunity in rheumatoid arthritis suggest a model in which multiple environmental influences mucosal immune function promoting epigenetic transformations with trafficking of proinflammatory PAMPs making use of the enhanced mucosal permeability. Hence, the initial shift towards autoimmunity may present at mucosal sites as reported in previous researches with sputum samples positive for ACPA-

b.**Major histocompatibility complex binding and peptide presentation**: specific class II human leukocyte antigen (*HLA*; also known as major histocompatibility complex—MHC) loci, which encode MHC molecules *HLA-DRB1\*01* and *HLA-DRB1\*04* display a very strong association with RA. The altered peptides bind to MHC protein heterodimers on antigen presenting cells, especially those containing the shared epitope [a specific amino acid motif QKRAA commonly encoded by some alleles of the HLA-antigen D-related (DR) locus significantly associated with the risk of developing RA]. Being bound to MHC complex the antigenic epitope gets presented by the antigen-presenting cells (dendritic cells and macrophages) to the antigen-specific T lymphocyte receptor to stimulate T lymphocyte activation and differentiation. Over 100 non-HLA genetic risk factors (loci) including polymorphisms of PTPN22, TRAF1-C5, STAT4, TNFAIP3, and PADI4 have

been associated with an increased risk of developing RA [11, 12].

c.**The adaptive immune system**: the activated T lymphocyte stimulates the release of pro-inflammatory cytokines including RANKL, TNF-α, GM-CSF, IL-2, IL-17 and IFN-γ. The antigen-stimulated T lymphocyte then promotes B cell priming via T-B cell receptor signaling pathways then stimulate specific antibody responses by the stimulated B lymphocytes against the

**4**

*Proximal interphalangeal joint with macrophages, dendritic cell, T cell, B cells infiltrates with hypertrophied synovium, intra-synovial angiomatoids and pannus formation. "By Dr. Maya H Ibrahim" the original image provider.*

The development of manifest disease in rheumatoid susceptible patients usually requires a second hit driven by cross-reactivity, or molecular mimicry to pathogenspecific antigens, in the settings of an inevitable lag of pathogen-immune complex clearance (**Figure 2**).

### **3. Diagnosis of rheumatoid arthritis**

The diagnosis of rheumatoid arthritis requires the integration of proper history taking, careful clinical examination and investigations. Patients might face a period of delay in establishing their diagnosis from weeks to months due to incomplete or intermittent symptoms, defective/unaccomplished clinical/radiographic and laboratory assessments particularly with early disease [20].

### **4. Patients' journey to diagnosis**

Standard of care in rheumatoid arthritis aims at the following [21]:


The recently adopted American College of Rheumatology/European League Against Rheumatism ACR/EULAR classification criteria were established in 2010 with the aim to identify patients with early inflammatory arthritis that is mostly due to rheumatoid arthritis. They have been proposed by the faculty as classification rather than diagnostic criteria to facilitate stratifying patients with similar characteristics for clinical research studies particularly clinical trials with intent to

**7**

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies*

**5. ACR/EULAR 2010 classification criteria for rheumatoid arthritis**

The classification criteria proposed by the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) included clinical and serological variables that can be applied only to individuals with ≥1 swollen joint [22].

Any swollen or tender joint (excluding the distal interphalangeal joints of hands and feet, the first metatarsophalangeal joints and the first carpometacarpal joints) on clinical examination; additional evidence from MRI or ultrasonography may be

1–3 small joints (the metacarpophalangeal joint, the proximal interphalangeal joint, the second to fifth metatarsophalangeal joints, the interphalangeal joint of the

Additional small joints include the temporomandibular joint, sternoclavicular

This variable refers to the patient's self-report on the maximum duration of signs

and symptoms of any joint that is clinically involved at the time of assessment.

**5.3 Serology (according to respective laboratory standards): 0–3 points**

Negative for RF (equal or less than upper limit of normal) and negative for

Low-positive for RF (>1–3 times upper limit of normal) or low-positive for

**5.4 Acute-phase reactants (according to local laboratory standards): 0–1 points**

Normal CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate)

A score of ≥6 points is required for classification as definite rheumatoid

High-positive for RF(>3 times upper limit of normal) or high-positive for ACPA:

joint, acromio-clavicular joint and others, as reasonably expected in RA.

treat. The development of diagnostic criteria for RA as other autoimmune disorders is still challenged by inter/intra-individual variability and chances of misdiagnosis. However, the current criteria might be used to inform diagnostic decision making in

*DOI: http://dx.doi.org/10.5772/intechopen.92771*

**5.1 Joint involvement and distribution: 0–5 points**

>10 joints (of which ≥1 is a small joint): 5 points

Abnormal CRP levels or abnormal ESR: 1 point

1 large joint (shoulder, elbow, hip, knee or ankle): 0 points

used to identify additional joints.

2–10 large joints: 1 point

thumb and the wrist): 2 points 4–10 small joints: 3 points

**5.2 Symptom duration: 0–1 points**

<6 weeks: 0 points ≥6 weeks: 1 point.

ACPA: 0 points

ACPA: 2 points

levels: 0 points

arthritis (RA).

3 points.

clinical practice [22].

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies DOI: http://dx.doi.org/10.5772/intechopen.92771*

treat. The development of diagnostic criteria for RA as other autoimmune disorders is still challenged by inter/intra-individual variability and chances of misdiagnosis. However, the current criteria might be used to inform diagnostic decision making in clinical practice [22].

### **5. ACR/EULAR 2010 classification criteria for rheumatoid arthritis**

The classification criteria proposed by the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) included clinical and serological variables that can be applied only to individuals with ≥1 swollen joint [22].

#### **5.1 Joint involvement and distribution: 0–5 points**

Any swollen or tender joint (excluding the distal interphalangeal joints of hands and feet, the first metatarsophalangeal joints and the first carpometacarpal joints) on clinical examination; additional evidence from MRI or ultrasonography may be used to identify additional joints.

1 large joint (shoulder, elbow, hip, knee or ankle): 0 points

2–10 large joints: 1 point

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

laboratory assessments particularly with early disease [20].

Standard of care in rheumatoid arthritis aims at the following [21]:

• Designing the ideal way to successfully initiate synthetic non biologic

• Identifying other potential therapeutic targets in aggressive disease.

• Providing standardized measures for patient assessment, follow-up and treat-

The recently adopted American College of Rheumatology/European League Against Rheumatism ACR/EULAR classification criteria were established in 2010 with the aim to identify patients with early inflammatory arthritis that is mostly due to rheumatoid arthritis. They have been proposed by the faculty as classification rather than diagnostic criteria to facilitate stratifying patients with similar characteristics for clinical research studies particularly clinical trials with intent to

• Providing low remission rates with standard DMARDs.

• Ensuring availability and safety of biologic DMARDS.

clearance (**Figure 2**).

**3. Diagnosis of rheumatoid arthritis**

**4. Patients' journey to diagnosis**

• Establishing early diagnosis of RA.

DMARDS.

ment modulation.

• Identifying arthritis in need of treatment.

The development of manifest disease in rheumatoid susceptible patients usually requires a second hit driven by cross-reactivity, or molecular mimicry to pathogenspecific antigens, in the settings of an inevitable lag of pathogen-immune complex

The diagnosis of rheumatoid arthritis requires the integration of proper history taking, careful clinical examination and investigations. Patients might face a period of delay in establishing their diagnosis from weeks to months due to incomplete or intermittent symptoms, defective/unaccomplished clinical/radiographic and

**6**

1–3 small joints (the metacarpophalangeal joint, the proximal interphalangeal joint, the second to fifth metatarsophalangeal joints, the interphalangeal joint of the thumb and the wrist): 2 points

4–10 small joints: 3 points

>10 joints (of which ≥1 is a small joint): 5 points

Additional small joints include the temporomandibular joint, sternoclavicular joint, acromio-clavicular joint and others, as reasonably expected in RA.

#### **5.2 Symptom duration: 0–1 points**

This variable refers to the patient's self-report on the maximum duration of signs and symptoms of any joint that is clinically involved at the time of assessment.

<6 weeks: 0 points

≥6 weeks: 1 point.

#### **5.3 Serology (according to respective laboratory standards): 0–3 points**

Negative for RF (equal or less than upper limit of normal) and negative for ACPA: 0 points

Low-positive for RF (>1–3 times upper limit of normal) or low-positive for ACPA: 2 points

High-positive for RF(>3 times upper limit of normal) or high-positive for ACPA: 3 points.

#### **5.4 Acute-phase reactants (according to local laboratory standards): 0–1 points**

Normal CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) levels: 0 points

Abnormal CRP levels or abnormal ESR: 1 point

A score of ≥6 points is required for classification as definite rheumatoid arthritis (RA).


### **6. Disease activity scoring in rheumatoid arthritis**

*CDAI, Clinical Disease Activity Index; CRP, C-reactive protein (in SDAI in mg per dl); DAS, Disease Activity Score; DAS28, DAS using 28-joint counts; EGA, Evaluator Global Assessment (on a 0–10 cm scale); ESR, erythrocyte sedimentation rate; GH, global health (that is, patient global assessment); PGA, patient global assessment (on a 0–10 cm scale); RA, rheumatoid arthritis; SDAI, Simplified Disease Activity Index; SJC, swollen joint count (the number indicates the number of joints taken into account); TJC, tender joint count (the number indicates the number of joints taken into account) [23–25].*

### **7. Different definitions of remission**

### **7.1 American Rheumatism Association**

Five or more must be fulfilled for at least two consecutive months—morning stiffness not exceeding 15 minutes—no fatigue—no joint pain (by history)—no joint tenderness or pain on motion—no soft tissue swelling in joints or tendon sheaths— ESR (W) < 30 mm/h (f); <20 mm/h (m) [26].

#### **7.2 DAS/DAS 28 threshold for remission**

For the DAS: Ritchie joint index and 44 swollen joint count with either ESR or CRP versions, remission: <1.6

For the DAS28: 28 tender and swollen joint count with either ESR or CRP versions, remission: <2.6 [27].

#### **7.3 SDAI/CDAI remission**

SDAI = (28TJC) + (28SJC) + MDGA + PtGA + CRP\* CDAI = (28TJC) + (28SJC) + MDGA + PtGA\* SDAI remission ≤3.3\*\* × CDAI remission ≤2.8\*\* [28, 29].

#### **7.4 Boolean definitions**

Depend on meeting a (low) level in each of a series of separate disease activity measures Boolean-based definition at any time point, a patient must satisfy all of the following—Tender Joint Count ≤1—Swollen Joint Count ≤1—CRP ≤1 mg/dL— Patient Global Assessment ≤1 (on a 0–10 scale) [30].

### **7.5 ACR-EULAR 2011 definition of remission**

• For clinical trials: Boolean—SJC, TJS, PtGA, CRP all ≤1 or index-based— SDAI ≤3.3 [30]

**9**

**Figure 3.**

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies*

• For clinical practice: Boolean—SJC, TJC, PtGA all ≤1 or index-based—CDAI

Factors that contribute to poor prognosis in rheumatoid arthritis include the

• Persistently moderate or high disease activity despite conventional synthetic DMARD (csDMARD) therapy according to composite measures including

The treatment paradigm in rheumatoid arthritis has experienced a dramatic shift in the latest two decades. Recently, the strategy changed from a treat to relief to a treat to target. The current approaches in RA are concerned with early aggressive intervention with one or more conventional or traditional synthetic DMARDs (cs/tsDMARDs) and/ or biologic DMARDs (bDMARDs) either as mono or combination therapy, in addition to symptomatic anti-inflammatory therapy (NSAIDs, low-dose prednisone). This tight control policy aims to; normalize, sustain or maximize physical functionality via retardation or arrest of joint damage. The treat-to-target is the currently established management approach in the international recommendations provided by ACR, EULAR and the Asia Pacific League of Associations for Rheumatology [31, 32], **Figure 3**. Recent update on the guidelines of management of rheumatoid arthritis as provided by the EULAR European League Against Rheumatism in 2019 announcing

*Identified synthetic and biologic disease modifying anti-rheumatic drugs in rheumatoid arthritis.*

*DOI: http://dx.doi.org/10.5772/intechopen.92771*

• High acute phase reactant levels.

• Presence of RF and/or ACPA, especially at high levels.

• High swollen joint count.

• Presence of early erosions.

• Failure of two or more csDMARDs.

the following overarching principles [33]:

**8. The treat-to-target in rheumatoid arthritis**

≤2.8

joint counts.

following [25]:

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies DOI: http://dx.doi.org/10.5772/intechopen.92771*

• For clinical practice: Boolean—SJC, TJC, PtGA all ≤1 or index-based—CDAI ≤2.8

Factors that contribute to poor prognosis in rheumatoid arthritis include the following [25]:


*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**6. Disease activity scoring in rheumatoid arthritis**

EGA + CRP

Ritchie index, SJC44, ESR and GH

TJC28, SJC28, ESR (or CRP) and GH

SDAI SJC28 + TJC28 + PGA +

DAS Complex formula including the

DAS28 Complex formula including the

*indicates the number of joints taken into account) [23–25].*

**7. Different definitions of remission**

**7.1 American Rheumatism Association**

ESR (W) < 30 mm/h (f); <20 mm/h (m) [26].

SDAI = (28TJC) + (28SJC) + MDGA + PtGA + CRP\* CDAI = (28TJC) + (28SJC) + MDGA + PtGA\*

Patient Global Assessment ≤1 (on a 0–10 scale) [30].

**7.5 ACR-EULAR 2011 definition of remission**

SDAI remission ≤3.3\*\* × CDAI remission ≤2.8\*\* [28, 29].

**7.2 DAS/DAS 28 threshold for remission**

CRP versions, remission: <1.6

versions, remission: <2.6 [27].

**7.3 SDAI/CDAI remission**

**7.4 Boolean definitions**

SDAI ≤3.3 [30]

**Formula Disease activity states**

CDAI SJC28 + TJC28 + PGA + EGA ≤2.8 >2.8–10 >10–22 >22

*CDAI, Clinical Disease Activity Index; CRP, C-reactive protein (in SDAI in mg per dl); DAS, Disease Activity Score; DAS28, DAS using 28-joint counts; EGA, Evaluator Global Assessment (on a 0–10 cm scale); ESR, erythrocyte sedimentation rate; GH, global health (that is, patient global assessment); PGA, patient global assessment (on a 0–10 cm scale); RA, rheumatoid arthritis; SDAI, Simplified Disease Activity Index; SJC, swollen joint count (the number indicates the number of joints taken into account); TJC, tender joint count (the number* 

Five or more must be fulfilled for at least two consecutive months—morning stiffness not exceeding 15 minutes—no fatigue—no joint pain (by history)—no joint tenderness or pain on motion—no soft tissue swelling in joints or tendon sheaths—

For the DAS: Ritchie joint index and 44 swollen joint count with either ESR or

Depend on meeting a (low) level in each of a series of separate disease activity measures Boolean-based definition at any time point, a patient must satisfy all of the following—Tender Joint Count ≤1—Swollen Joint Count ≤1—CRP ≤1 mg/dL—

• For clinical trials: Boolean—SJC, TJS, PtGA, CRP all ≤1 or index-based—

For the DAS28: 28 tender and swollen joint count with either ESR or CRP

**Remission Low** 

**disease activity**

≤3.3 >3.3–11 >11–26 >26

≤1.6 >1.6–2.4 >2.4–3.7 >3.7

≤2.6 >2.6–3.2 >3.2–5.1 >5.1

**Moderate disease activity**

**High disease activity**

**Scoring system**

**8**


#### **8. The treat-to-target in rheumatoid arthritis**

The treatment paradigm in rheumatoid arthritis has experienced a dramatic shift in the latest two decades. Recently, the strategy changed from a treat to relief to a treat to target. The current approaches in RA are concerned with early aggressive intervention with one or more conventional or traditional synthetic DMARDs (cs/tsDMARDs) and/ or biologic DMARDs (bDMARDs) either as mono or combination therapy, in addition to symptomatic anti-inflammatory therapy (NSAIDs, low-dose prednisone). This tight control policy aims to; normalize, sustain or maximize physical functionality via retardation or arrest of joint damage. The treat-to-target is the currently established management approach in the international recommendations provided by ACR, EULAR and the Asia Pacific League of Associations for Rheumatology [31, 32], **Figure 3**.

Recent update on the guidelines of management of rheumatoid arthritis as provided by the EULAR European League Against Rheumatism in 2019 announcing the following overarching principles [33]:

**Figure 3.** *Identified synthetic and biologic disease modifying anti-rheumatic drugs in rheumatoid arthritis.*


### **8.1 EULAR 2019 recommendations**

In 2019 the EULAR taskforce stated a number of updated recommendations emphasizing the strategy to start DMARDs therapy as soon as the diagnosis of RA is made. These recommendations included [33]:


**11**

**Author details**

Reem H.A. Mohammed

ties and costs.

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies*

comedication, IL-6 pathway inhibitors and tsDMARDs may have some advan-

• If a bDMARDs or tsDMARDs has failed, treatment with another bDMARD† or a tsDMARD‡ should be considered; if one TNF inhibitor therapy has failed, patients may receive an agent with another mode of action or a second TNF

• If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs or tsDMARDs, especially if this treatment is

• If a patient is in persistent remission, tapering the csDMARD could be

• Apply standardized measures for assessment of disease activity, functional

• Tailoring of therapy with potential consideration of patient safety, comorbidi-

Rheumatology and Clinical Immunology, Department of Rheumatology and

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

Rehabilitation, School of Medicine, Cairo University, Egypt

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

provided the original work is properly cited.

*DOI: http://dx.doi.org/10.5772/intechopen.92771*

combined with a csDMARD.

inhibitor.

considered.

**9. Summary**

tages compared with other bDMARDs.

• Establish early diagnosis of rheumatoid arthritis.

• Arrange for evidence-based management.

• Apply aggressive measures to target disease.

• Identify patients with arthritis in need for treatment.

assessment, patient and physician global assessment.

comedication, IL-6 pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs.


## **9. Summary**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

while prescribing therapy by the rheumatologist.

treatment.

edge of comorbidities.

mechanisms of action.

**8.1 EULAR 2019 recommendations**

made. These recommendations included [33]:

• Treatment of patients with RA should target the best care and must be based on a shared decision between the RA patient and the rheumatologist.

• Disease activity, structural damage, patient safety, and other comorbidities, including the risk for thromboembolism must be considered when prescribing

• Rheumatologists are responsible for the primary care of the patient as they possess the optimal depth and breadth of experience regarding the use of all types of DMARDs, including efficacy, outcomes, risk assessment and knowl-

• The heterogeneous nature of rheumatoid arthritis mandates patients' access to effective disease modifying anti-rheumatic drugs with successful multiple

• RA incurs high individual, medical and societal costs, should be considered

In 2019 the EULAR taskforce stated a number of updated recommendations emphasizing the strategy to start DMARDs therapy as soon as the diagnosis of RA is

• Treatment should be aimed at reaching a target of sustained remission or low disease activity in every patient. Adopted definitions for disease activity states assessment and therapy include: (a) remission ACR-EULAR remission definition—Boolean or index based, (b) low disease activity state according to any of the validated composite disease activity measures that include joint counts moderate and high disease activity, and (c) respective disease activity state according to any of the validated composite disease activity measures that include joint counts.

• Monitoring should be frequent in active disease (every 1–3 months); if there is no improvement by at most 3 months after the start of treatment or the target

• Methotrexate MTX should be part of the first treatment strategy—the anchor

• In patients with a contraindication to MTX (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy.

• If the treatment target is not achieved with the first csDMARD strategy, in the absence of poor prognostic factors, other csDMARDs should be considered.

• If the treatment target is not achieved with the first csDMARD strategy, when and poor prognostic factors are present, a bDMARD or a tsDMARD should be added.

• Biologic DMARDs and traditional synthetic DMARDs (tsDMARDs) should be combined with a csDMARD; in patients who cannot use csDMARDs as

• Short-term glucocorticoids should be considered when initiating or changing csDMARDs, in different dose regimens and routes of administration, but

has not been reached by 6 months, therapy should be adjusted.

should be tapered as rapidly as clinically feasible.

**10**

drug.


## **Author details**

Reem H.A. Mohammed Rheumatology and Clinical Immunology, Department of Rheumatology and Rehabilitation, School of Medicine, Cairo University, Egypt

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

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

### **References**

[1] Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016;**388**(10055):2023-2038

[2] Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: Results from Olmsted County, Minnesota, 1955-2007. Arthritis and Rheumatism. 2010;**62**(6):1576-1582

[3] Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis. Journal of Autoimmunity. 2010;**35**(1):10-14

[4] Malemba JJ, Mbuyi-Muamba JM, Mukaya J, Bossuyt X, Verschueren P, Westhovens R. The epidemiology of rheumatoid arthritis in Kinshasa, Democratic Republic of Congo—A population-based study. Rheumatology (Oxford, England). 2012;**51**(9):1644-1647

[5] Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nature Reviews. Immunology. 2017;**17**(1):60-75

[6] Albano SA, Santana-Sahagun E, Weisman MH. Cigarette smoking and rheumatoid arthritis. Seminars in Arthritis and Rheumatism. 2001;**31**(3):146-159

[7] Harrison BJ, Silman AJ, Wiles NJ, Scott DG, Symmons DP. The association of cigarette smoking with disease outcome in patients with early inflammatory polyarthritis. Arthritis and Rheumatism. 2001;**44**(2):323-330

[8] Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Annals of the Rheumatic Diseases. 2001;**60**(3):223-227

[9] Bodkhe R, Balakrishnan B, Taneja V. The role of microbiome in rheumatoid arthritis treatment. Therapeutic Advances in Musculoskeletal Disease. 2019;**11**:1759720X19844632

[10] du Teil Espina M, Gabarrini G, Harmsen HJM, Westra J, van Winkelhoff AJ, van Dijl JM. Talk to your gut: The oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis. FEMS Microbiology Reviews. 2019;**43**(1):1-18

[11] Citera G, Padulo LA, Fernandez G, Lazaro MA, Rosemffet MG, Maldonado Cocco JA. Influence of HLA-DR alleles on rheumatoid arthritis: Susceptibility and severity in Argentine patients. The Journal of Rheumatology. 2001;**28**(7):1486-1491

[12] Wakitani S, Murata N, Toda Y, Ogawa R, Kaneshige T, Nishimura Y, et al. The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese. British Journal of Rheumatology. 1997;**36**(6):630-636

[13] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;**46**(2):183-196

[14] Klareskog L, Amara K, Malmstrom V. Adaptive immunity in rheumatoid arthritis: Anticitrulline and other antibodies in the pathogenesis of rheumatoid arthritis. Current Opinion in Rheumatology. 2014;**26**(1):72-79

[15] Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse

**13**

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies*

League Against Rheumatism collaborative initiative. Annals of the Rheumatic Diseases. 2010;**69**(9):1580-1588

[23] Schoels M, Alasti F, Smolen JS, Aletaha D. Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition.

Arthritis Research & Therapy.

[24] Studenic P, Smolen JS, Aletaha D. Near misses of ACR/EULAR criteria for remission: Effects of patient global assessment in Boolean and index-based definitions. Annals of the Rheumatic Diseases. 2012;**71**(10):1702-1705

[25] Aletaha D, Martinez-Avila J, Kvien TK, Smolen JS. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Annals of the Rheumatic Diseases.

[26] Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis and Rheumatism. 1981;**24**(10):1308-1315

[27] Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: Agreement of the Disease Activity Score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford, England).

2012;**71**(7):1190-1196

2004;**43**(10):1252-1255

[28] Smolen JS, Breedveld FC,

Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology

(Oxford, England). 2003;**42**(2):244-257

[29] Aletaha D, Ward MM, Machold KP, Nell VP, Stamm T, Smolen JS. Remission

2017;**19**(1):155

*DOI: http://dx.doi.org/10.5772/intechopen.92771*

inflammatory diseases. PLOS Genetics.

[16] Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis and Rheumatism.

[17] Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the United States of America. 1997;**94**(20):10895-10900

[18] Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis?: II. T cellindependent mechanisms from beginning to end. Arthritis and Rheumatism. 2002;**46**(2):298-308

[19] Firestein GS. Evolving concepts of rheumatoid arthritis. Nature.

[20] Villeneuve E, Nam JL, Bell MJ, Deighton CM, Felson DT, Hazes JM, et al. A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis. Annals of the Rheumatic Diseases.

2003;**423**(6937):356-361

2013;**72**(1):13-22

[21] Smolen JS, Landewe R,

of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs. Annals of the Rheumatic Diseases.

2010;**69**(6):964-975

Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR

recommendations for the management

[22] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European

2013;**9**(4):e1003444

1996;**39**(11):1781-1790

*Introductory Chapter: Rheumatoid Arthritis - Overview of Current Facts and Strategies DOI: http://dx.doi.org/10.5772/intechopen.92771*

inflammatory diseases. PLOS Genetics. 2013;**9**(4):e1003444

[16] Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis and Rheumatism. 1996;**39**(11):1781-1790

[17] Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the United States of America. 1997;**94**(20):10895-10900

[18] Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis?: II. T cellindependent mechanisms from beginning to end. Arthritis and Rheumatism. 2002;**46**(2):298-308

[19] Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;**423**(6937):356-361

[20] Villeneuve E, Nam JL, Bell MJ, Deighton CM, Felson DT, Hazes JM, et al. A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis. Annals of the Rheumatic Diseases. 2013;**72**(1):13-22

[21] Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs. Annals of the Rheumatic Diseases. 2010;**69**(6):964-975

[22] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Annals of the Rheumatic Diseases. 2010;**69**(9):1580-1588

[23] Schoels M, Alasti F, Smolen JS, Aletaha D. Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition. Arthritis Research & Therapy. 2017;**19**(1):155

[24] Studenic P, Smolen JS, Aletaha D. Near misses of ACR/EULAR criteria for remission: Effects of patient global assessment in Boolean and index-based definitions. Annals of the Rheumatic Diseases. 2012;**71**(10):1702-1705

[25] Aletaha D, Martinez-Avila J, Kvien TK, Smolen JS. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Annals of the Rheumatic Diseases. 2012;**71**(7):1190-1196

[26] Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis and Rheumatism. 1981;**24**(10):1308-1315

[27] Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: Agreement of the Disease Activity Score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford, England). 2004;**43**(10):1252-1255

[28] Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford, England). 2003;**42**(2):244-257

[29] Aletaha D, Ward MM, Machold KP, Nell VP, Stamm T, Smolen JS. Remission

**12**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

history of RA. Annals of the Rheumatic

Diseases. 2001;**60**(3):223-227

[9] Bodkhe R, Balakrishnan B, Taneja V. The role of microbiome

treatment. Therapeutic Advances in Musculoskeletal Disease. 2019;**11**:1759720X19844632

[10] du Teil Espina M, Gabarrini G, Harmsen HJM, Westra J, van Winkelhoff AJ, van Dijl JM. Talk to your gut: The oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis. FEMS Microbiology Reviews. 2019;**43**(1):1-18

[11] Citera G, Padulo LA, Fernandez G, Lazaro MA, Rosemffet MG, Maldonado Cocco JA. Influence of HLA-DR alleles on rheumatoid arthritis: Susceptibility and severity in Argentine patients. The Journal of Rheumatology.

[12] Wakitani S, Murata N, Toda Y, Ogawa R, Kaneshige T, Nishimura Y, et al. The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese. British Journal of Rheumatology.

in rheumatoid arthritis

2001;**28**(7):1486-1491

1997;**36**(6):630-636

[13] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;**46**(2):183-196

[14] Klareskog L, Amara K,

Malmstrom V. Adaptive immunity in rheumatoid arthritis: Anticitrulline and other antibodies in the pathogenesis of rheumatoid arthritis. Current Opinion in Rheumatology. 2014;**26**(1):72-79

[15] Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor

signaling and influences risk of diverse

[1] Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016;**388**(10055):2023-2038

Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: Results from Olmsted County, Minnesota, 1955-2007. Arthritis and Rheumatism. 2010;**62**(6):1576-1582

[3] Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis. Journal of Autoimmunity.

[4] Malemba JJ, Mbuyi-Muamba JM, Mukaya J, Bossuyt X, Verschueren P, Westhovens R. The epidemiology

Kinshasa, Democratic Republic of Congo—A population-based study. Rheumatology (Oxford, England).

of rheumatoid arthritis in

[5] Malmstrom V, Catrina AI,

Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nature Reviews. Immunology. 2017;**17**(1):60-75

[6] Albano SA, Santana-Sahagun E, Weisman MH. Cigarette smoking and rheumatoid arthritis. Seminars in Arthritis and Rheumatism.

[7] Harrison BJ, Silman AJ, Wiles NJ, Scott DG, Symmons DP. The association of cigarette smoking with disease outcome in patients with early inflammatory polyarthritis. Arthritis and Rheumatism. 2001;**44**(2):323-330

[8] Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA),

particularly in patients without a family

2012;**51**(9):1644-1647

2001;**31**(3):146-159

2010;**35**(1):10-14

**References**

[2] Myasoedova E, Crowson CS,

and active disease in rheumatoid arthritis: Defining criteria for disease activity states. Arthritis and Rheumatism. 2005;**52**(9):2625-2636

[30] Aletaha D, Alasti F, Smolen JS. Rheumatoid arthritis near remission: Clinical rather than laboratory inflammation is associated with radiographic progression. Annals of the Rheumatic Diseases. 2011;**70**(11):1975-1980

[31] Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care & Research (Hoboken). 2016;**68**(1):1-25

[32] Lau CS, Chia F, Harrison A, Hsieh TY, Jain R, Jung SM, et al. APLAR rheumatoid arthritis treatment recommendations. International Journal of Rheumatic Diseases. 2015;**18**(7):685-713

Section 2

Pathophysiologic Challenges

in Rheumatoid Arthritis

**15**

[33] Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2019 update. Annals of the Rheumatic Diseases. June 2020;**79**(6):685-699. DOI: 10.1136/annrheumdis-2019-216655. [Epub 2020 Jan 22]

## Section 2
