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Rheumatoid Arthritis

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Other Names

  • Rheumatoid Arthritis (RA)


  • This page refers to Rheumatoid Arthritis (RA), a chronic, systemic, autoimmune inflammatory joint disease



  • Worldwide prevalence is about 0.24%[1]
  • Incidence of 0.5% to 1%[2]
    • Incidence appears to decrease from north to south in northern hemisphere
    • Incidence decreases from urban to rural areas
  • Annual incidence in United States/ Western countries
    • 40 per 100,000 persons[3]
  • Lifetime risk
    • 3.6% in women, 1.7% in men[4]


Swan neck deformity in a patient with rheumatoid arthritis
Clinical Example of Boutonniere Deformity[5]
  • General
    • Chronic inflammatory joint disease which can cause bone and cartilage damage, disability
    • Early diagnosis is key to optimizing treatment
    • Treatment involves a combination of conventional, biological and new non-biological disease-modifying antirheumatic drugs
    • Frequent relapses and remissions
  • Definition
    • Early RA: Symptoms present for fewer than 6 months
    • Established RA: Symptoms present for more than 6 months
  • Joint involvement
    • Typically involves small joints of hands
    • Typically symmetric
    • Starts peripherally in small joints, can involve proximal joints if left untreated[6]
  • Extra-articular manifestations
    • Primarily involves joints
    • Can be considered a syndrome that has extra-articular manifestations
    • Vasculitis
    • Interstitial lung disease
    • Amyloidosis
    • Lymphoma
    • Cardiovascular Disease
  • Disease burden associated with[7]
    • Decline in physical function
    • Decline in quality of life
    • Cumulative comorbid risk
  • Felty syndrome
    • Rare, extra-articular manifestation
    • Characterized by RA, neutropenia, and splenomegaly.


  • General
    • Pathologically heterogenous
    • Etiology remains unknown
    • Presence of autoantibodies (seropositive) associated with more severe symptoms, joint disease, mortality[8]
  • Immune complexes
    • Formed by autoantibodies against citrullinated peptides (ACPA), binding rheumatoid factor (RF)
    • Subsequent leads to abundant complement activation
    • ACPAs can be IgG, IgA or IgM
    • Anti-carbamylated and acetylated peptide autoantibodies also implicated
  • Inflammation
    • Joint swelling reflects synovial membrane inflammation (aka synovitis)
    • Characterized by leukocyte infiltration into the normally sparsely populated synovial compartment
    • Cellular composition includes:
      • Innate immune cells (eg, monocytes, dendritic cells, mast cells, and innate lymphoid cells)
      • Adaptive immune cells (eg, T-helper-1 and T-helper-17 cells, B cells, plasma blasts, and plasma cells)
    • Subsequently, there is enhanced chondrocyte catabolism, synovial osteoclastogenesis
    • Regulated by a complex cytokine and chemokine network
  • Histopathology
    • New synovial blood vessel growth, leads to migration of leukocytes
    • Angiogenesis leads to endothelial activation, adhesion molecules, cell migration into the synovium
    • Increase in cyclooxygenase (COX) 2-derived nociceptive eicosanoids, matrix metalloproteinases (MMPs)[9]
    • Granulomatous phase can occur after treatment with development of rheumatoid nodules

Risk Factors

  • Demographic
    • Female > Male
    • Risk increases with age, peak incidence 65 to 80[10]
  • Obesity
    • 30% increased risk in patients with BMI greater than 30[11]
  • Family history
    • Increases risk 3-5 times
    • Increase rate in concordance twins[12]
  • Heritability[13]
    • Seropositive: Estimated to be 40-65%
    • Seronegative: estimated to be about 20%
  • Genetic associations
    • HLA system maintains a strong, dominant association (HLA-DR4 & HLA-DW4)
    • Less well understood: CD28, CD40, cytokine signaling, etc
  • Tobacco Use Disorder[14]
    • Strongest environmental risk factor associated with RA[15]
  • Low socioeconomic status[16]
  • Low educational attainment
  • Periodontal disease
    • Hypothesized to be due to abnormal immune response to Porphyromonas gingivalis
  • Infectious agents, association not well characterized
    • Proteus mirabilis
    • Escherichia coli
    • EpsteinBarr virus
  • Gut microbiome
    • Alterations in common microbial populations have been implicated[17]
    • Gastrointestinal dysbiosis implicated in one study

Differential Diagnosis

Clinical Features

Severe rheumatoid arthritis of hands with multiple nodules, ulnar deviation, MCP joint subluxation[18]
  • History
    • Patients report painful, swollen joints
    • Most commonly affected joints are the hands
    • Axial involvement is uncommon; cervical involvement is seen in lon gstanding RA
    • Onset is often recent, slow and insidious
    • Episodic pattern can be seen but is less common (palindromic rheumatism)
    • Morning stiffness
  • Physical Exam
    • Affected joints are painful to palpation or with movement
    • Swelling may not always be apparent
    • Synovial thickening may feel "boggy"
    • There is typically no erythema or warmth to affected joints
    • If the wrist is involved, patients may have symptoms of carpal tunnel
    • Reduced grip strength
    • Hands: Ulnar deviation, metacarpophalangeal joint subluxation
    • Feet: hallux valgus, claw toes, metatarsophlanageal (MTP) subluxation
    • Rheumatoid nodules are the most common cutaneous manifestation, seen on olecranon
    • Ulcerative skin lesions (due to venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis)
  • Special Tests


Rheumatoid arthritis of hands with erosive subluxation of MCP joints, ulnar deviation, prominent ulnar-carpal degeneration.[19]
Boutonierre deformity (yellow arrows) and hitch hiker deformity (thumb)[20]


  • General
    • There is is no pathognomonic laboratory test for RA
    • This makes diagnosis challenging
  • Complete Blood Count
    • Anemia of chronic disease
    • Thrombocytosis
    • Neutropenia may be present (felty syndrome)
  • Rheumatoid Factor (RF)
    • 75% to 85% of patients with RA will test positive for RF, ACPA or both
    • 45% to 75% of patients with RA test positive for RF
    • Not specific to RA, can be seen in other connective tissue diseases, chronic infections, and healthy individuals
  • Anti-citrullinated protein antibodies (ACPA)
    • Found in about 50% of patients with early arthritis
  • C-reactive protein
    • Typically elevated in patients with active disease, not specific
  • Erythrocyte Sedimentation Rate (ESR)
    • Typically elevated in patients with active disease, not specific
  • Anti-MCV (mutated citrullinated vimentin)

Synovial Fluid

  • Findings[21]
    • Leukocyte count between 1500 to 25,000/cubic mm, predominantly polymorphonuclear cells
    • Low C3, low C4


  • Findings
    • Periarticular osteopenia
    • Joint space narrowing
    • Bony erosions
  • Bone and cartilage erosions are pathognomonic finding[22]
    • Seen more commonly in patients with advanced disease
  • Protrusio Acetabuli
    • Medial migration of femoral head past the radiographic teardrop
    • Also seen in Marfan's syndrome, Paget's disease, Otto's pelvis and other metabolic bone conditions


  • Clinical utility, incorporation into diagnostic criteria remains undefined
  • Potential findings
    • Decreased signal from the bone marrow on T1-weighted images
    • Gadolinium-enhanced images indicates bone marrow edema
    • Synovial thickening, can be used to predict presence of bony erosions[23]


2010 ACR/EULAR Diagnostic Criteria[24]

  • Number and site of involved joints
    • 2 to 10 large joints = 1 point (shoulders, elbows, hips, knees, and ankles)
    • 1 to 3 small joints = 2 points (metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists)
    • 4 to 10 small joints = 3 points
    • Greater than 10 joints (including at least 1 small joint) = 5 points
  • Serological testing for rheumatoid factor or anti-citrullinated peptide/protein antibody
    • Low positive = 2 points
    • High positive = 3 points
  • Elevated acute phase reactant (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) = 1 point
  • Symptom duration at least six weeks = 1 point
  • Interpretation
    • Total score of 6+ classifies as having RA

Radiographic Staging[25]

  • Stage 1
    • No destructive changes on x-rays
  • Stage 2
    • Presence of x-ray evidence of periarticular osteoporosis, subchondral bone destruction but no joint deformity
  • Stage 3
    • X-ray evidence of cartilage and bone destruction
    • Seen in addition to joint deformity and periarticular osteoporosis
  • Stage 4
    • Presence of bony or fibrous ankylosis along with stage 3 features

Disease Classification of Rheumatoid Arthritis

Laine Stages Range of Movement Stage Pain Imaging Neer Approximate Stages
Stage 1 Slight limitation Mild-to-moderate pain, tenderness Generalized osteopenia Dry
Stage 2 Moderate limitation Moderate-to-severe pain, crepitus Osteopenia, erosions, jonit space narrowing Wet
Stage 3 Severe functional deficits Severe pain, limits ADLs Advanced erosive changes Resorptive



  • Goals[26]
    • Early diagnosis, early initiation of treatment
    • Prevent irreversible joint damage
    • Achieve long term clinical remission, optimize quality of low
    • Frequency of monitoring based on severity of disease activity
  • General
    • Early initiate of DMARDs
  • Physical Therapy
  • Counseling
  • Patient education
  • Corticosteroids


  • Disease-modifying antirheumatic drugs (DMARDs)
    • Target inflammation, reduce structural disease progression
    • Note: NSAIDS are not considered DMARD
    • Can be broken down into synthetic and biologic
  • Conventional DMARDS
    • Methotrexate
    • Sulfasalazine
    • Lefulonomide
    • Hydroxychloroquine
  • Biological DMARDS
    • Adalimumab
    • Certolizumab pegol
    • Etanercept
    • Golimumab
    • Infliximab
    • Anti-B-cell: Rituximab
    • Anti-T-cell co-stimulation: Abatacept
    • Anti-IL 6R: Tocilizumab
  • Targeted synthetic DMARDS
    • Janus kinase inhibitors: Tofacitinib


  • Operative treatment dictated by specific clinical condition
    • With DMARDS, surgical indications have been dramatically reduced


  • Rheumatoid Nodules
    • Primarily a cosmetic concern, can be painful
    • Can be injected with steroids
    • Less commonly, surgical excision
  • Boutonniere deformity
    • Nonsurgical: Splint for flexible PIP
    • Surgical: extensor tendon reconstruction, PIP arthrodesis or arthroplasty
  • Swan neck deformity
    • Nonsurgical: splinting PIP to prevent hyperextension
    • Surgical: FDS tenodesis, fowler tenotomy, dorsal capsule release, etc
  • Flexor Tendon Conditions
  • Extensor Tendon Conditions

Rehab and Return to Play


  • No widely accepted rehabilitation guidelines

Return to Play/ Work

  • No clear guidelines

Complications and Prognosis


  • General
    • RA has no cure, considered a progressive disease
    • All individuals will have multiple exacerbations
  • Despite treatment
    • Many patients progress to disability
    • Suffer significant morbidity over time
  • Early treatment (within 6 months of symptom onset)
    • Improved functional capacity
    • Decreased disease activity
  • Mortality[27]
    • Similar in early vs late treatment
    • Higher in patients receiving no treatment


  • Functional disability[28]
    • About 40% of patients develop functional disability within 10 years of diagnosis
    • Affects ability to work, complete activities of daily living
  • Osteopenia, Osteoporosis
    • Complications of disease and some of the treatments
    • 60-100% increased risk of fracture compared to general population
  • Pulmonary manifestations
    • Pleuritis, bronchiolitis, and interstitial fibrosis
  • Coronary Artery Disease
    • Independent risk factor, CAD is accelerated in RA patients
  • Diabetes Mellitus
    • Increased risk of insulin resistance and DM
  • Rheumatoid vasculitis
    • Rarely seen
  • Deep Vein Thrombosis
    • Risk from disease and some of the treatment agents including TNF inhibitors, JAK inhibitors
    • Pulmonary Embolism can be seen
  • Sjogren Syndrome
    • Seen in up to 10% of patients with RA and pulmonary disease
  • Depression
    • Seen in patients with long term active disease, debilitating physical function
    • Estimated to affect between 17 and 39% of patients with RA[29]
  • Anemia of chronic disease
  • Felty syndrome
    • Rare, extra-articular manifestation
    • Characterized by RA, neutropenia, and splenomegaly.
  • Lymphoma
  • Stills Disease
    • Acute onset RA with fever, rash and splenomegaly
  • Cervical spondylitis

See Also


  1. Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1316-22.
  2. Silman AJ, Pearson JE, Pincus T, et al. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 2002; 4 (suppl 3): S265–72.
  3. 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 Rheum. 2010 Jun;62(6):1576-82.
  4. Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, Davis JM, Hunder GG, Therneau TM, Gabriel SE. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011 Mar;63(3):633-9.
  5. Image courtesy of verywellhealth.com, "Boutonniere Deformity"
  6. Bullock J, Rizvi SAA, Saleh AM, Ahmed SS, Do DP, Ansari RA, Ahmed J. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med Princ Pract. 2018;27(6):501-507.
  7. Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 2011; 70: 8–14.
  8. van Gaalen FA, van Aken J, Huizinga TW, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) infl uences the severity of rheumatoid arthritis. Arthritis Rheum 2004; 50: 2113–21.
  9. Demasi M, Cleland LG, Cook-Johnson RJ, James MJ. Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast-like synoviocytes: interactions with monocyte-derived soluble mediators. Arthritis Rheum. 2004 Aug;50(8):2441-9.
  10. Eriksson JK, Neovius M, Ernestam S, Lindblad S, Simard JF, Askling J. Incidence of rheumatoid arthritis in Sweden: a nationwide population-based assessment of incidence, its determinants, and treatment penetration. Arthritis Care Res (Hoboken). 2013 Jun;65(6):870-8.
  11. Qin B, Yang M, Fu H, Ma N, Wei T, Tang Q, Hu Z, Liang Y, Yang Z, Zhong R. Body mass index and the risk of rheumatoid arthritis: a systematic review and dose-response meta-analysis. Arthritis Res Ther. 2015 Mar 29;17:86.
  12. Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903-7.
  13. Jiang X, Frisell T, Askling J, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheumatol 2015; 67: 352–62.
  14. Klareskog L, Malmstrom V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol 2011; 23: 92–98
  15. Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017 Jun;39(4):437-446.
  16. Millar K, Lloyd SM, McLean JS, et al. Personality, socio-economic status and infl ammation: cross-sectional, population-based study. PLoS One 2013; 8: e58256.
  17. Scher JU, Littman DR, Abramson SB. Review: microbiome in infl ammatory arthritis and human rheumatic diseases. Arthritis Rheumatol 2016; 68: 35–45.
  18. Image courtesy of orthobullets.com, "Rheumatoid Arthritis"
  19. Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 7245
  20. Case courtesy of Dr Aditya Shetty, Radiopaedia.org, rID: 28018
  21. Kortekangas P, Aro HT, Tuominen J, Toivanen A. Synovial fluid leukocytosis in bacterial arthritis vs. reactive arthritis and rheumatoid arthritis in the adult knee. Scand J Rheumatol. 1992;21(6):283-8.
  22. Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol. 1989 May;16(5):585-91.
  23. McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan PL, McLean L. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann Rheum Dis. 1999 Mar;58(3):156-63.
  24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81.
  25. Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1-26.
  26. Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compán MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin-Mola E, Nash P, Ostergaard M, Östör A, Richards P, Sokka-Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016 Jan;75(1):3-15.
  27. Gwinnutt JM, Symmons DPM, MacGregor AJ, Chipping JR, Marshall T, Lunt M, Verstappen SMM. Twenty-Year Outcome and Association Between Early Treatment and Mortality and Disability in an Inception Cohort of Patients With Rheumatoid Arthritis: Results From the Norfolk Arthritis Register. Arthritis Rheumatol. 2017 Aug;69(8):1566-1575.
  28. Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol. 2017 Jun;4(2):161-165.
  29. Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). 2013 Dec;52(12):2136-48.
Created by:
John Kiel on 14 June 2019 08:14:46
Last edited:
9 November 2022 19:51:48