Rheumatoid arthritis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayesha A. Khan, MD, Manpreet Kaur, MD [2]

Rheumatoid arthritis is a chronic inflammatory systemic disease which is found commonly in women and starts in mid 30’s to 40’s. Cause of rheumatoid arthritis is idiopathic but there are genetic factors such as HLA-DR4 cluster, environmental factors like smoking, hormonal factors like hyperprolactinemia, infectious factors like mycoplasma, epstein-Barr virus (EBV), rubella virus, porphyromonas gingivalis, socioeconomic, psychological, and lifestyle factors such as obesity play important role in the development of rheumatoid arthritis. There is no established system for the classification of rheumatoid arthritis. Depending on the presentation of rheumatoid arthritis, it is classified into typical classic rheumatoid arthritis and palindromic rheumatism. Common symptoms of rheumatoid arthritis are joint pain of small joints of the hands, wrist, and forefoot, joint swelling, morning joint stiffness classically lasting for more than an hour, decreased grip strength, generalized aching, and fatigue, weight loss, depression. Less common symptoms are tingling and numbness in the arm and weakness in the arm. Anti-CCP antibodies testing is the gold standard test for the diagnosis of rheumatoid arthritis.It has the specificity of about 81-100%, with the sensitivity of 39–94%. Hallmark of rheumatoid arthritis Xray findings are soft tissue swelling, joint space narrowing, and erosions but it involves small joints with multiple deformities. Findings on an ultrasound suggestive of rheumatoid arthritis are tenosynovitis, bursitis, baker’s cyst and inflammation of synovium. Therapeutic use of ultrasound is the guidance of corticosteroid injection in the joint and fluid aspiration from the joint effusion. MRI is helpful in the diagnosis of early and subacute rheumatoid arthritis. Findings on MRI diagnostic of rheumatoid arthritis are synovial hyperemia, synovial hyperplasia, pannus, subchondral cysts, erosions, effusion of joints and bone marrow edema. The mainstay of treatment of rheumatoid arthritis is pharmacotherapy. There are two types of therapies- non-pharmacological therapy and pharmacological therapy. There are different drug regimen depending upon the stage of the disease. In active stage, combined therapy include disease-modifying antirheumatic drugs (DMARDs) are used along with the anti-inflammatory drugs. Therapy for resistant disease and flares is the addition of oral glucocorticoids. In case of the flare, add another DMARDs with methotrexate or replace with another DMARDs. Surgery is usually reserved for patients with debilitating disease, failure of medical therapy and radiographic findings of end-stage arthritis. Various surgical options used for the treatment of RA are tenosynovectomy, arthroscopic or open synovectomy, joint fusion, small joint implant arthroplasty, total joint replacement of deformed joint. Effective measures for the primary prevention of rheumatoid arthritis are patient education, exercise, physical and occupational therapy and cognitive behavioral therapies. Effective measures for the secondary prevention of rheumatoid arthritis are calcium and vitamin D supplementation to prevent osteoporosis. To prevent cardiovascular complications and recurrent attacks of RA, effective methods are exercise, smoking cessation, and dietary control.

Rheumatoid arthritis signs and symptoms were first noticed by Augustin Jacob Landre-Beauvais, a resident physician at the Saltpetriere asylum in France, in 1800, He named it as Goutte Asthenique Primitive or Primary Asthenic Gout. The name Rheumatoid arthritis coined by Archibald Garrod in 1890. In 1970, human leukocyte antigen (HLA) was first implicated in the pathogenesis of rheumatoid arthritis.

There is no established system for the classification of rheumatoid arthritis. Depending on the presentation of rheumatoid arthritis, it is classified into typical classic rheumatoid arthritis and palindromic rheumatism. Rheumatoid arthritis is seropositive when ACPAs (anti-CCP) and/or rheumatoid factor are present. Seronegative disease is a distinct polyarthritis with less well-defined pathogenesis and typically less joint destruction, but the treatment approach is similar. The classification criterion for the diagnosis of rheumatoid arthritis according to American College of Rheumatology, uses 4 parameters including joint involvement, serology, duration of symptoms, and acute phase reactants. If the score is more than 6 according to this criteria, the disease is classified as definite rheumatoid arthritis.^[1]

Rheumatoid arthritis is mediated by the combination of a predisposing genotype upon which genetic factors, environmental and microorganism also contribute resulting in the inflammation and destruction of the synovial membrane. All the factors lead to citrullination or post-translational modifications, the altered peptides bind to MHC protein with shared epitopes which further lead to antigen presentation to T-cells. T-cells further stimulate B-cells and cytokines which leads to cartilage damage. Mutation of human leukocyte antigen (HLA) genes on chromosome 6 is involved in pathogenesis of rheumatoid arthritis. Conditions associated with RA are vasculitis, uveitis, scleritis, peripheral ulcerative keratitis, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, organizing pneumonia, venous thromboembolism, pericarditis, myocarditis, congestive heart failure, atrial fibrillation, sjogren’s syndrome, felty’s syndrome.

Rheumatoid arthritis follows a continuum from healthy to a preclinical at-risk stage, transition, early synovitis, and ultimately established destructive disease. This progression is not always unidirectional. ACPA positivity can revert to negative, and some ACPA-positive individuals never develop RA, creating opportunities for prevention and reflecting multiple possible pathogenic pathways in different patients. ^[1]

Rheumatoid arthritis occurs when your immune system attacks the synovium — the lining of the membranes that surround your joints.The resulting inflammation thickens the synovium, which can eventually destroy the cartilage and bone within the joint.The tendons and ligaments that hold the joint together weaken and stretch. Gradually, the joint loses its shape and alignment.Cause of rheumatoid arthritis is idiopathic but genetic like HLA-DR4 cluster, environmental like smoking, hormonal like hyperprolactinemia, immunologic, infectious factors like mycoplasma, epstein-Barr virus (EBV), rubella virus, porphyromonas gingivalis, socioeconomic, psychological, and lifestyle factors such as obesity play important role in the development of rheumatoid arthritis.

Only about 15% of identical twins both develop rheumatoid arthritis, so genes alone do not explain the disease. Epigenetic changes such as DNA methylation may increase risk, as shown in RA-discordant twins.^[2] In at-risk people with high RF or ACPA levels, abnormal DNA methylation in immune genes can appear years before symptoms.^[3] Later, T cells with these abnormal epigenetic marks build up in inflamed synovium, unlike in osteoarthritis.^[4]

Rheumatoid arthritis must be differentiated from osteoarthritis , septic arthritis, reactive arthritis, behcet’s disease and psoriatic arthritis.

The incidence of rheumatoid arthritis is approximately 40 per 100,000 individuals worldwide. The prevalence of rheumatoid arthritis is approximately 1 percent in Caucasians per 100,000 individuals worldwide.The peak onset of the disease is between the age of  50 and 75 years. Women are three times more commonly affected by rheumatoid arthritis than men. The mortality rate of rheumatoid arthritis is approximately 10%.

Environmental and behavioral exposures are major determinants of rheumatoid arthritis susceptibility and disease severity. Common risk factors in the development of rheumatoid arthritis are the family history of RA, cigarette smoking, race like more prevalent in Native Americans, strongly associated with major histocompatibility complex (MHC) class II antigen HLA-DR4 and patient with silica and asbestos exposure. Less common risk factors are obesity and high consumption of red meat.

Cigarette smoking and genetic risk can sometimes act together: in ACPA-positive smokers with two shared-epitope copies, RA risk is ~20 times higher than in nonsmokers.^[5]After quitting, the risk slowly falls and can approach that of nonsmokers within 2–3 decades.^[6]

According to the American College of Rheumatology Guideline, screening for rheumatoid arthritis is not recommended.

The symptoms of rheumatoid arthritis usually develop in the third to fourth decade of life and start with symptoms such as fatigue, small joints pain and morning stiffness which lasts more than 1 hour. Complication of rheumatoid arthritis involve all the systems. Cardiac complications are pericarditis, congestive heart failure, endocarditis and myocardial infarction. Pulmonary complications are pleurisy, alveolitis, pleural effusion and pulmonary fibrosis. Rheumatological complications are joint deformities, felty’s syndrome, sjögren’s syndrome, osteoporosis and atlantoaxial subluxation. Eye complications such as scleritis and keratitis. Renal complications are chronic renal failure from amyloidosis. Nervous system complications like peripheral neuropathy and mononeuritis multiplex. Prognosis is generally good with early diagnosis and treatment, and 10-year disability rate of patients with rheumatoid arthritis is approximately 40%.

Anti-CCP antibodies testing is the gold standard test for the diagnosis of rheumatoid arthritis.It has the specificity of about 81-100%, with the sensitivity of 39–94%.

Patients with rheumatoid arthritis may have a positive history of the family history of RA, history of smoking and other autoimmune disease. Common symptoms of rheumatoid arthritis are joint pain of small joints of the hands, wrist, and forefoot, joint swelling, morning joint stiffness classically lasting for more than an hour, decreased grip strength, generalized aching, and fatigue, weight loss, depression. Less common symptoms are tingling and numbness in the arm and weakness in the arm.

Patients with rheumatoid arthritis usually appear fatigued. On skin examination, rheumatoid nodules, erythema nodosum, atrophy of the digital skin, palmar erythema and diffuse thinning of the skin are found. If there is involvement of eyes, Scleritis and Scleromalacia are seen. On auscultation of lungs, there are decreased breath sounds on both sides and crackles may be present. On palpation of the abdomen, hepatomegaly and splenomegaly is usually found when it is associated with Felty’s syndrome. On examination of extremities, redness, and swelling of the affected joints, tenderness, pain on movement and decreased the range of movement is usually found.

Laboratory tests used to diagnose rheumatoid arthritis are complete blood count with differentials, erythrocyte sedimentation rate, CRP, Renal function test, LFT and antibodies such as rheumatoid factor, anti-CCP and anti MCV.

Hallmark of rheumatoid arthritis are soft tissue swelling, joint space narrowing and erosions. Hand and wrist findings on xray are subchondral cysts, ulnar deviation of the MCP joints, boutonniere and swan neck deformities, hitchhiker’s thumb deformity, scapholunate dissociation, ulnar translocation and ankylosis. Feet findings on xray are Subtalar joint involvement, posterior calcaneal tubercle erosion, hammer toe deformity and hallux valgus. Findings of shoulder such as distal clavicle erosions, erosions of the superolateral aspect of the head of the humerus, high riding shoulder due to subacromial-subdeltoid bursitis. Knee findigs are joint effusions, loss of joint space and prepatellar bursitis. Hip findings are concentric loss of joint space and acetabular protrusio. Spine findings are atlantoaxial subluxation, atlantoaxial impaction: cephalad migration of C2,osteoporosis and osteoporotic fractures and erosion of spinous processes.

There are no ECG findings associated with rheumatoid arthritis. An ECG may be helpful in the diagnosis of pericarditis associated with rheumatoid arthritis. Findings of pericarditis are diffuse ST-segment elevation and PR segment depression.

Ultrasound is helpful in the diagnosis of rheumatoid arthritis. Findings on an ultrasound suggestive of rheumatoid arthritis are tenosynovitis, bursitis, baker’s cyst and inflammation of synovium. Therapeutic use of ultrasound are guidance of corticosteroid injection in the joint and fluid aspiration from the joint effusion.

CT scan is a useful non-invasive test used to diagnose the complications of rheumatoid arthritis such as subluxation of the alanto-axial joint. It is also used in the presurgical assessment of neurological symptoms.

MRI is helpful in the diagnosis of early and subacute rheumatoid arthritis. Findings on MRI diagnostic of rheumatoid arthritis are synovial hyperemia, synovial hyperplasia, pannus, subchondral cysts, erosions, effusion of joints and bone marrow edema.

DEXA Scan is helpful in the diagnosis of the complication of rheumatoid arthritis such as osteoporosis and osteopenia.

There are no other diagnostic studies associated with rheumatoid arthritis.

The mainstay of treatment of rheumatoid arthritis is pharmacotherapy. Early diagnosis of rheumatoid arthritis is helpful in treatment. Choice of treatment depends on various factors such as stage of disease, comorbid conditions, stage of therapy and presence of severe prognostic signs. There are two types of therapies- non-pharmacological therapy and pharmacological therapy. There are different drug regimen depending upon the stage of the disease. In active stage, combined therapy include disease-modifying antirheumatic drugs (DMARDs) are used along with the anti-inflammatory drugs. Therapy for resistant disease and flares is the addition of oral glucocorticoids. In case of the flare, add another DMARDs with methotrexate or replace with another DMARDs.

• Traditional DMARDs

1. Methotrexate
2. Leflunomide
3. Sulfasalazine
4. Hydroxychloroquine

• Biologic DMARDs

1. TNF inhibitors: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab
2. IL-6 inhibitors: sarilumab, tocilizumab
3. IL-1 inhibitor: anakinra
4. T-cell costimulation modulator: abatacept
5. B-cell depletion: rituximab

• Targeted synthetic DMARDs (JAK inhibitors)

1. Baricitinib
2. Tofacitinib
3. Upadacitinib

---

• Cytokine pathways

1. GM-CSF
2. Interleukin-15
3. Interleukin-17A
4. Interleukin-18
5. Interleukin-23
6. Interferon-γ (ineffective)
7. Lymphotoxin alpha (ineffective)
8. RANKL (helped erosions, not synovitis)

• Signal transduction

1. p38 MAP kinase
2. Bruton’s tyrosine kinase
3. PI3 kinase γ or δ
4. Syk tyrosine kinase

• Cell-targeting

1. Cadherin-11 (ineffective)
2. CD4 (ineffective)
3. CD52 (ineffective)
4. CD5 (ineffective)

• Cell recruitment

1. ICAM-1 (ineffective)
2. Multiple chemokines/chemokine receptors (limited or no efficacy)

The mainstay of treatment for rheumatoid arthritis is medical therapy. Surgery is usually reserved for patients with debilitating disease, failure of medical therapy and radiographic findings of end-stage arthritis. Various surgical options used for the treatment of RA are tenosynovectomy, arthroscopic or open synovectomy, joint fusion, small joint implant arthroplasty, total joint replacement of deformed joint.

Effective measures for the primary prevention of rheumatoid arthritis are patient education, exercise, physical and occupational therapy and cognitive behavioral therapies.

Effective measures for the secondary prevention of rheumatoid arthritis are calcium and vitamin D supplementation to prevent osteoporosis. To prevent cardiovascular complications and recurrent attacks of RA, effective methods are exercise, smoking cessation, and dietary control.

Recently Identified Cell Lineages and Cell Phenotypes Contributing to Rheumatoid Arthritis (RA).^[1]

Cell class	Cell lineage / phenotype	Comments	Study
T cells	CD4+ PD1+ CXCR5− (Tph)	Located in lymphoid aggregates adjacent to B cells; produce interleukin-21, which supports B-cell proliferation and differentiation into plasma cells	Rao et al.[7]
T cells	CD8+ GZMK+	Located in RA synovial sublining; source of interferon-γ	Jonsson et al.[8]
B cells	Mucosal, circulating, and synovial B cells	Oligoclonal expansion with evidence of recirculation and ACPA affinity maturation due to somatic mutation	Kongpachith et al.[9]
B cells	NR4A+	Produces lymphotoxins and interleukin-6, which promote lymphoid aggregate formation	Meednu et al.[10]
Macrophages	MerTK−	Proinflammatory; found in active RA synovium; associated with interleukin-6 and TNF production	Alivernini et al.[11]
Macrophages	MerTK+	Antiinflammatory; associated with lipoxin and resolvin production	Cai et al.[12]
Macrophages	CX3CR1+	Resident cells in RA synovial lining with tight junctions that serve as immunologic barrier; disrupted in RA synovium	Culemann et al.[13]
Macrophages	Alternatively activated	Interleukin-33 reprogrammed with metabolic rewiring that uncouples respiratory chain and enhances inflammation resolution	Faas et al.[14]
Macrophages	HBEGF+	Promotes fibroblast aggressiveness and invasion	Kuo et al.[15]
Fibroblasts	FAP+ CD90+	Proinflammatory phenotype located in sublining; regulated by NOTCH3	Wei et al.[16]
Fibroblasts	FAP+ CD90−	Located in intimal lining; produce interleukin-6, metalloproteinases, and prostanoids in RA	Mizoguchi et al.[17]
Fibroblasts	ETS1	Regulates bone damage through production of RANKL by fibroblasts in synovium	Yan et al.[18]
Fibroblasts	PRIME cells	Present in circulation of patients with RA (transcriptome profile); increase in peripheral-blood PRIME cells precedes RA flares, possibly associated with B-cell activation	Orange et al.[19]
Neutrophils (synovium and lung mucosa)	–	Produce NETs, which bind citrullinated peptides to enhance ACPA production	Corsiero et al.[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Signs and symptoms associated with rheumatoid arthritis were noticed by Augustin Jacob Landre-Beauvais, a resident physician at the Saltpetriere asylum in France, in 1800. He named this disease as Goutte Asthenique Primitive or Primary Asthenic Gout. The name Rheumatoid arthritis was coined by Archibald Garrod in 1890. In 1970, human leukocyte antigen (HLA) was first implicated in the pathogenesis of rheumatoid arthritis.

• Rheumatoid arthritis associated signs and symptoms were noticed by Augustin Jacob Landre-Beauvais, a resident physician at the Saltpetriere asylum in France, in 1800. He named rheumatoid arthritis as Goutte Asthenique Primitive or Primary Asthenic Gout.^[1]
• In 1890, Archibald Garrod coined the name Rheumatoid arthritis.^[2]
• In 1970, human leukocyte antigen (HLA) was first implicated in the pathogenesis of rheumatoid arthritis.^[3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

There is no established system for the classification of rheumatoid arthritis. Depending on the presentation of rheumatoid arthritis, it is classified into typical classic rheumatoid arthritis and palindromic rheumatism. The classification criterion for the diagnosis of rheumatoid arthritis according to American College of Rheumatology, uses 4 parameters including joint involvement, serology, duration of symptoms, and acute phase reactants. If the score is more than 6 according to this criteria, the disease is classified as definite rheumatoid arthritis.

There is no established system for the classification of rheumatoid arthritis. Depending on the presentation of rheumatoid arthritis, it may be classified as follows:

• Typical/classic rheumatoid arthritis:
  • Disease onset is insidious and it involves early metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the fingers, the interphalangeal joints of the thumbs, the wrists, and the metatarsophalangeal (MTP) joints of the toes.^[1][2]
• Palindromic rheumatism:
  • The onset is episodic.
  • Different joints are affected at different times or sequentially.

The 2010 American College of Rheumatology classification criteria for diagnosis of rheumatoid arthritis:^[3][4]

The 2010 American College of Rheumatology criteria rates various variables on a scale from 0-10 points. The points are assigned in four separate domains of signs and symptoms:

1) Joint involvement

2) Serology

3) Duration of symptoms

4) Acute phase reactants

Patients are classified as definite RA if the score of 6 or more points is seen according to the following criteria. The details of the scoring criteria are discussed below:

The 2010 American College of Rheumatology classification criteria for rheumatoid arthritis.
Domains	Description	Number	Score
Joint Involvement	Median-large joint*	2-10	1
		1-3	2
	Small joints**	4-10	3
		>10***	5
Serology	No positive for either RF or anti-CCP		0
	At least one of these test positive at the high titer		2
	At least one of these test positive at low titer		3
Duration of synovitis	+/> six weeks		1
Acute phase reactants	Neither CRP or ESR is abnormal		0
	Abnormal CRP or ESR		1
*Distal interphalangeal,1st carpometacarpal and 1st tarsometatarsal joints are excluded from the assessment. Shoulder, elbow, knee, and ankle joints are included. ** Small joints refer to metacarpophalangeal, proximal interphalangeal, second through 5th metatarsophalangeal, thumb interphalangeal and wrist joints *** In this category, at least one of the involved joints must be a small joint; the other joints can include any combination of large additional small joint joins as well as other such as temporomandibular, acromioclavicular, sternoclavicular

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with which genetic factors, environmental factors, and microorganisms contribute, resulting in the inflammation and destruction of the synovial membrane. These factors lead to citrullination or post-translational modifications, resulting in the production of altered peptides. The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells. T-cells further stimulate B-cells and cytokines which results in cartilage damage. Mutation of human leukocyte antigen (HLA) genes on chromosome 6 is involved in pathogenesis of rheumatoid arthritis. Various conditions associated with RA include vasculitis, uveitis, scleritis, peripheral ulcerative keratitis, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, organizing pneumonia, venous thromboembolism, pericarditis, myocarditis, congestive heart failure, atrial fibrillation, sjogren’s syndrome, and felty’s syndrome.

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with genetic factors, environmental factors, and microorganisms, resulting in the inflammation and destruction of the synovial membrane.

Various factors involved are:

Environmental factors:

• Environmental factors lead to repeated activation of innate immunity at mucosal surfaces.

• Smoking effects the genes to increase susceptibility up to 20 to 40 fold.
  • Smoking causes increased expression of peptidyl arginine deiminase (PAD) in alveolar macrophages.
  • Peptidyl arginine deiminase converts arginine to citrulline, the process is known as citrullination, in the airway which further creates neoantigens that can be recognized by the adaptive immune system.^[1][2]

Genetic factors:

• Genetics factors such as human leukocyte antigen (HLA)-DR.
• These genes are involved in inducing immune response, matrix regulation, and inflammation.^[3]

Microrganisms:

• In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
• This can lead to citrullination and thereby promotes anti-citrullinated protein antibodies (ACPA)
• A. actinomycetemcomitans produces a toxin that increases calcium influx into neutrophils which further leads to citrullination of peptides and promotes APCA.

• All the above factors lead to citrullination or post-translational modifications.
• The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells.
• T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including rheumatoid factors and anti-citrullinated protein antibodies (ACPAs).
• Fibroblast-like synoviocytes, antigen presenting cells (APCs), and macrophages are activated locally and produce various inflammatory factors.
• The autoimmune response causes synovial inflammation resulting in immune complex formation and complement activation, leading to an increase in cytokine production and synovial vascular leakage.
• Cytokines lead to bone and cartilage destruction.

• The development of rheumatoid arthritis is the result of mutation of human leukocyte antigen (HLA) genes on chromosome 6.^[4][5]

Conditions associated with rheumatoid arthritis include:^[6][7]

• Osteopenia
• Myositis
• Vasculitis
• Uveitis
• Scleritis
• Peripheral ulcerative keratitis
• Interstitial fibrosis
• Pulmonary nodules
• Bronchiolitis obliterans
• Organizing pneumonia
• Venous thromboembolism
• Pericarditis
• Myocarditis
• Congestive heart failure
• Atrial fibrillation
• Sjogren’s syndrome
• Felty’s syndrome

On gross pathology of rheumatoid arthritis the following features may be noticed:^[8]

• Irregular surface, seen due to synovial hyperplasia.
• Subchondral cysts, usually present at the later stage of the disease.

On microscopic histopathological analysis:^[9][10]

• The earliest finding is the formation of the new synovial blood vessels.
• Hypertrophy of synovial lining layer and infiltration of mononuclear cells may be observed.
• Chronic inflammation with lymphocytic infiltration may be seen.
• There is pannus formation which consists of fibrovascular tissue or granulation tissue.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Rheumatoid arthritis is usually idiopathic but genetic factors like HLA-DR4 cluster, environmental like smoking, hormonal like hyperprolactinemia, immunologic, infectious factors like mycoplasma, epstein-Barr virus (EBV), rubella virus, porphyromonas gingivalis, socioeconomic, psychological, and lifestyle factors such as obesity also play an important role in the development of rheumatoid arthritis.

The cause of rheumatoid arthritis is idiopathic but genetic, environmental, hormonal, immunologic, infectious factors, socioeconomic, psychological, and lifestyle factors also play an important role in the development of rheumatoid arthritis.

Common causes of rheumatoid arthritis include:

• Genetic factors:^[1]
  • In United States, HLA-DR4 cluster (HLA-DR beta 0401, 0404, or 0405,) part of one of the peptide-binding sites of certain HLA-DR molecules associated with rheumatoid arthritis.
  • In European countries, HLA-DR1 (HLA-DR beta 0101) is associated with rheumatoid arthritis.
• Infectious agents:
  • Various infectious agents involved in rheumatoid arthritis include:^[2][3]
    • Mycoplasma
    • Epstein-Barr virus (EBV)
    • Rubella virus
    • Porphyromonas gingivalis

Less common causes of rheumatoid arthritis include:

• Hormonal factors:^[4]
  • Hyperprolactinemia
• Environmental factors:
  • Smoking
• Lifestyle factors:
  • Obesity
  • Poor health

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Rheumatoid arthritis must be differentiated from osteoarthritis , septic arthritis, reactive arthritis, behcet’s disease and psoriatic arthritis.

Abbreviations: ANA: Antinuclear antibody, RF: Rheumatoid factor, Anti-CCp: Anti-cyclic citrullinated protein antibody, Anti U1RNP: Anti-U1 ribonucleoprotein antibodies , Anti Sm : Anti-Sm antibodies, Anti Ro: Anti Ro antibody also called anti-Sjögren’s-syndrome-related antigen A antibody, Anti-dsDNA: Anti-double stranded DNA.

Disease		Arthritis					Auto-antibodies							Raynaud phenomenon	Rash pattern	Distinguishing/specific features
		Polyarthritis	Tenderness	Edema	Deformity /Erosion	Pattern	ANA	RF	Anti-CCp	Anti U1RNP	Anti Sm	Anti Ro	Anti-dsDNA
Behçet’s disease		+/-	+/-	+/-	–	Medium and large joints	–	–	–	–	–	–	–		Recurrent and usually painful mucocutaneous ulcers, acneiform lesions, papulo-vesiculo-pustular eruptions, superficial thrombophlebitis	Male dominancy
Systemic lupus erythematosus[1]		+	+	+	–	Small joints	↑	–	–	–	↑	↑	–	+	Malar rash and photosensitivity
Rheumatoid arthritis (RA)[2]		+	+	+	+	Small and large joints	–	↑↑	↑↑	–	–	–	–	+	Subcutaneous nodules	Erosive arthropathy
Rhupus[3]		+	+	+	+	Small and large joints	↑	↑	↑	↑	↑	–	↑	+	Malar rash and photosensitivity	Erosive arthropathy
Mixed connective tissue disease (MCTD)[4]		–	–	–	+	Small and large joints	–	↑↑	↑	–	–	–	–	+	Cutaneous eruptions, gottron’s papules, photodistributed erythema, poikiloderma, and calcinosis cutis	Overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM) that lead to more than one diagnosis
Undifferentiated connective tissue disease (UCTD)[5]		+	–	–	–	Lower extremity	↑	↑	–	–	↑	–	–	+	Erythematous macules, patches, or papules with delicate scale	Multiple connective tissue diseases with no enough criteria for a single diagnosis
Systemic sclerosis (SSc)[6]		+/-	+	+	+/-	Lower extremity	↑↑	–	–	–	↑	–	↑	+	Hyperkeratosis, edema, and erythema	Sclerodactyly, Telangiectasias, Calcinosis, Malignant hypertension, acute renal failure
Sjögren’s syndrome[7]		+/-	+/-	–	–	Lower extremity, axiallary creases	↑	–	–	–	↑	↑	–	–	Xerosis, scaly skin, annular erythema	Keratoconjunctivitis sicca
Vasculitis	Giant cell[8]	–	+	+	–	Distal extremity	–	–	–	–	–	–	–	–	Rare	Involvement of cranial branches of arteries, visual loss
	Takayasu[9]	–	+/-	+/-	–	Transient extremity	–	–	–	–	–	–	–		Erythema nodosum, pyoderma gangrenosum	Absent or weak peripheral pulse
	Poly-arteritis nodosa[10]	–	+/-	–	–	General and mild	–	–	–	–	–	–	–		Tender erythematous nodules, purpura, livedo reticularis, bullous or vesicular eruption	Testicular pain or tenderness and neuropathies
Kikuchi’s disease[11]		–	+/-	–	–	medium and large joints	↑/↓	–	–	–	–	–	–	–	Transient skin rashes, malar rash, erythematous macules, patches, papules, or plaques	May be associated with SLE
Serum sickness[12]		+	+	+/-	–	General	–	–	–	–	–	–	–	–	Pruritic rash, urticaria and/or serpiginous macular rash	Self-limited
Psoriatic arthritis[13]		–	–	–	–	Small and large joints	–	–	–	–	–	–	–	–	Psoriasis and onychodystrophy	Dactylitis (sausage digits)
Human parvovirus B19 infection[14]		+	+	–	–	Small joints	–	–	–	–	–	–	–	–	Erythematous rashes	Rare in adults, fifth’s disease in children

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

The incidence of rheumatoid arthritis is approximately 40 per 100,000 individuals worldwide. The prevalence of rheumatoid arthritis is approximately 1 percent in Caucasians per 100,000 individuals worldwide.The peak onset of the disease is between the age of 50 and 75 year. Women are three times more commonly affected by rheumatoid arthritis than men. Mortality rate of rheumatoid arthritis is approximately 10,000 per 100,000 individuals.

• The incidence of rheumatoid arthritis is approximately 40 per 100,000 individuals worldwide.^[1]

• The prevalence of rheumatoid arthritis is approximately 1000 Caucasians per 100,000 worldwide.^[2][3][4]

• The mortality rate of rheumatoid arthritis is approximately 10,000 per 100,000 individuals.

• Patients of all age groups may develop rheumatoid arthritis.
• The peak onset of the disease is between the age of 50 and 75 years.

• Rheumatoid arthritis usually affects Native Americans.
• African Americans and Caribbean region are less likely to develop rheumatoid arthritis .

• Women are three times more commonly affected by rheumatoid arthritis than men.^[5][6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Common risk factors in the development of rheumatoid arthritis are a positive family history of RA, cigarette smoking, Native American race, major histocompatibility complex (MHC) class II antigen HLA-DR4 and patient with silica and asbestos exposure. Less common risk factors include obesity and high consumption of red meat.

• Common risk factors in the development of rheumatoid arthritis include:
  • A positive family history of rheumatoid arthritis.
  • Cigarette smoking: The duration of smoking is co-related strongly with increased risk of RA.^[1]
  • Gender: Women have a higher risk as compared to men.^[2]
  • Race:
    • Native Americans have higher prevalence rates.
    • African american and Caribbean region have lower prevalence rates.
    • More common in monozygotic twins and diazygotic twins.^[3]
  • Genetic:
    • It is strongly associated with the inherited tissue type major histocompatibility complex (MHC) class II antigen HLA-DR4 (most specifically DR0401 and 0404), hence family history is an important risk factor.
  • Occupational factors:
    • Silica and asbestos exposure have been associated with development of RA.^{[4] [5]}

• Less common risk factors in the development of rheumatoid arthritis include:
  • Obesity and high consumption of red meat may lead to an increased disease severity.^[6][7]
  • Increased alcohol intake.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

There is insufficient evidence to recommend routine screening for rheumatoid arthritis is not recommended.

There is insufficient evidence to recommend routine screening for rheumatoid arthritis is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

The symptoms of rheumatoid arthritis usually develop in the third to fourth decade of life. Symptoms such as fatigue, small joint pain and morning stiffness are seen initially, the stiffness may last more than 1 hour. Complications of rheumatoid arthritis may involve various organ systems. Cardiac complications include pericarditis, congestive heart failure, endocarditis, and myocardial infarction. Pulmonary complications include pleurisy, alveolitis, pleural effusion, and pulmonary fibrosis. Rheumatological complications include joint deformities, Felty’s syndrome, sjögren’s syndrome, osteoporosis, and atlantoaxial subluxation. Ophthalmology complications include scleritis and keratitis. Renal complications include chronic renal failure from amyloidosis. Nervous system complications like peripheral neuropathy, quadriplegia, and mononeuritis multiplex may also be seen. Prognosis is generally good with early diagnosis and treatment. The 10-year disability rate of patients with rheumatoid arthritis is approximately 40%.

• The symptoms of rheumatoid arthritis usually develop in the third to fourth decade of life. Symptoms such as fatigue, small joint pain and morning stiffness lasting more than 1 hour may be seen.
• If left untreated, patients with rheumatoid arthritis may progress to develop extra-articular manifestation.

The complication of rheumatoid arthritis are given below:^[1][2]

The rheumatological complications of rheumatoid arthritis include:

• Joint deformitites
• Felty’s syndrome
• Sjögren’s syndrome

The cardiac complications of rheumatoid arthritis include:

• Pericarditis
• Congestive heart failure
• Endocarditis
• Myocardial infarction

Paitents with RA are at increased risk of vascular disease.^[3][4][5]

The degree of increase in risk is hard to estimate as meta-analyses of the cohorts note that many studies did not adjust for cardiovascular risk factors. This includes the meta-analysis by Dadoun^[6] cited by the EULAR guidelines^[7] and the meta-analysis by Aviña-Zubieta^[8] cited by the American Heart Association^[9].

Thus, while EULAR recommends multiplying cardiac risk in RA patients by 1.5, this does not seem supported by the analysis cited by EULAR.

The pulmonary complications of rheumatoid arthritis include:^[10][11][12]

• Pleurisy
• Alveolitis
• Pleural effusion
• Pulmonary fibrosis

The ocular complications of rheumatoid arthritis include:

• Scleritis
• Keratitis

The renal complications of rheumatoid arthritis include:

• Chronic renal failure from amyloidosis

The neurological complications of rheumatoid arthritis include:^[13][14]

• Peripheral neuropathy and mononeuritis multiplex
• Quadriplegia

The orthopedic complications of rheumatoid arthritis include:^[15]

• Erosion of the odontoid process and transverse ligaments in the cervical spine
• Osteoporosis
• Atlanto-axial subluxation

The hematologic complications of rheumatoid arthritis include:

• Lymphoma
• Anemia

The dermatological complications of rheumatoid arthritis include:^[16][17]

• Splinter haemorrhages
• Periungual infarcts
• Leg ulcers
• Digital gangrene
• Pyoderma gangrenosum

• Prognosis is generally good with early diagnosis and treatment, and 10-year disability rate of patients with rheumatoid arthritis is approximately 40%.

• Poor prognostic factors are:^[18][19]
  • Insidious onset of symptoms
  • Female sex
  • Age less than 30 years
  • HLA-DRB1*04/04 genotype
  • High serum levels of autoantibodies
  • Extra-articular symptoms
  • Systemic symptoms
  • Cigarette smoking
  • Lack of formal education
  • Lower socioeconomic status

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