Rheumatoid Arthritis

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Rheumatoid arthritis (RA) is an autoimmune disease that has an unknown aetiology. It is characterised by symmetrical erosive synovitis and sometimes multisystem disease. Typically patients have a chronic fluctuating disease course, that if left untreated results in progressive joint destruction, deformity, disability, and premature death.

Epidemiology

There is an annual incidence of around 0.4 per 1000 in female and 0.2 per 1000 in males. The prevalence is 0.4-1% with geographical variation, and is ~1% in New Zealand. The strongest risk factor is smoking and this also confers a worse prognosis. Females are more commonly affected than males at a 3-4:1 ratio. Peak onset is 4th and 5th decades but it can occur at any age. 12% of females with RA develop it post-partum.

Aetiology

The aetiology remains unknown. It has a multi-factorial origin, that includes a genetic predisposition.

Pathology

The disease is characterised by immune-driven, chronic inflammation. In the synovial tissue, there is recruitment and retention of inflammatory cells, the formation of villous projections, and the generation of pannus tissue that invades and destroys cartilage and bone. The pathology occurs in stages. Mechanisms that initiate disease are distinct from those that perpetuate disease. In chronic synovitis there are interactions of cell types native to the joint and inflammatory cells are recruited. Cytokine "networks" are established. Angiogenesis occurs and this is promoted by mediators that include growth factors, proinflammatory cytokines, chemokines, matrix components, cell adhesion molecules, proteases, and others. Enzymatic destruction of the cartilage matrix occurs. Osteoclasts contribute to articular bone resorption.

Clinical Assessment

History is used to assess for inflammatory rhythm and extraarticular features, examination is used to detect swelling and tenderness, blood tests are used to detect inflammation (CRP, ESR) and autoantibodies (RF, anti-CCP), and imaging is used to detect radiographic signs of disease (XR, US, MRI).

The preclinical phase is defined by an RA-related autoimmunity without clinically apparent inflammatory arthritis. This RA-related autoimmunity can be triggered initially outside the joints in a mucosal site. The RA-related autoantibodies that include RF and anti-CCF can be used to identify those at risk of developing RA in the future.

In clinically apparent disease, the typical features are morning stiffness along with swelling in the wrists, PIPJs and MCPJs. The early diagnosis is critical, however many cases of early arthritis are not RA.

Extra-articular features may occur including constitutional symptoms, distinct organ manifestations, and severe multiorgan disease. Systemic features may have a poor prognosis, especially the presence of vasculitis and rheumatoid lung disease.

Examination findings are synovitis, nodules, tenosynovitis, and bursitis. see Joint Assessment Video for examination method.

Clinical disease activity using composite measures is of at least similar validity to ultrasonographic assessment without any clinical benefit.

Function can be assessed with the Health Assessment Questionnaire or direct functional performance tests. Function is influenced by disease activity as well as joint damage. Any functional disability from joint damage is irreversible.

Antibodies

Most autoantibodies are not joint-specific. Autoantibodies are present in the earliest stages of disease, and there may be years before clinical disease manifestation.

Rheumatoid factors (RFs) are autoantibodies to the Fc portion of IgG. High-titre IgM-RF and IgA-RF are associated with erosive and more severe disease. RF is positive in ~80% with longstanding disease, but is also found in post vaccination, viral infection, malignancy, healthy elderly, and others.

Anti-citrullinated citrullinated protein antibodies (anti-CCPs) are autoantibodies to atigens containing the unusual amino acid citrulline. They are more specific (~96%) than RF but less sensitive (~75%). Similar to high-titre RF are associated with erosive RA with a poor prognosis.

Imaging

Symmetric bilateral RA is commonly seen in the hands and feet, but asymmetric disease is frequently found in large joints.

The typical change seen on plain films is erosion. The earliest radiographic changes occur in the hands and feet: tissue swelling, erosions, and diffuse joint space narrowing. Radiographic evidence of disease in the large joints is most common in the elbow, shoulder, and knee. Sacroiliac joint disease is uncommon.

Rare late-term complications are atlantoaxial subluxation and basilar invagination. The best view for atlantoaxial subluxation is a lateral film of the cervical spine in flexion. For basilar invagination MRI and CT are best. Ultrasound and MRI are increasingly commonly used to detect subclinical disease.

Diagnostic Criteria

2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis
Target population (those who should be tested): Patients
  1. Who have at least 1 joint with definite clinical synovitis (swelling)[Note 1]
  2. Whose synovitis is not better explained by another disease[Note 2]

Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of ≥6/10 is needed to classify a patient as having definite RA)[Note 3]

A. Joint involvement[Note 4] Score
1 large joint[Note 5] 0
2–10 large joints 1
1–3 small joints (with or without involvement of large joints)[Note 6] 2
4–10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint)[Note 7] 5
B. Serologic results (at least 1 test result is needed for classification[Note 8] Score
Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C. Acute-phase reactants (≥1 test result is needed for classification)[Note 9] Score
Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
D. Duration of symptoms[Note 10] Score
<6/wk 0
≥6/wk 1

ACPA, Anti–citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
From Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.

Criteria Notes

  1. The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with long-standing disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.
  2. Differential diagnoses vary among patients with different presentations but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.
  3. Although patients with a score of <6 of 10 are not classifiable as having RA, their status can be reassessed, and the criteria might be fulfilled cumulatively over time.
  4. Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.
  5. “Large joints” refers to shoulders, elbows, hips, knees, and ankles.
  6. ∥“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
  7. In this category, at least one of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular).
  8. “Negative” refers to international unit (IU) values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; “low-positive” refers to IU values that are higher than the ULN but three times or less the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is available only as positive or negative, a positive result should be scored as low positive for RF.
  9. Normal and abnormal is determined by local laboratory standards.
  10. “Duration of symptoms” refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment regardless of treatment status.

Management

Early diagnosis and treatment are critical for optimal outcomes.

Disease activity is the immediate target of therapeutic intervention. The ultimate goal is optimal disease outcome which encompasses health-related quality of life. The proxy measure for disease outcome is radiographic damage.

NSAIDs can reduce joint pain and swelling, but have no effect on disease progression. They can however be a useful first line analgesic.

DMARDs should be used at the earliest opportunity (within 6-12 weeks of diagnosis). The disease activity is monitored regularly until a target is reached, which is ideally remission. A proportion of patients can achieve remission in early RA without medication, however DMARDs are effective in slowing or stopping RA progression and are the mainstays of treatment. Effective management also reduces the risk of complications including cardiovascular disease and cancers. Eventual withdrawal of DMARDs is potentially possible in some patients but there is a high risk of relapse.

The most commonly used DMARDs are methotrexate and sulfasalazine at initiation. Leflunomide is a second or third line agent. Other DMARDs include hydroxychloroquine, IM gold, cyclosporin, and azathioprine. Most agents require regular monitoring (FBC, LFTs, UECs). Methotrexate has the best continuation rate. Combinations of DMARDs may be used.

the biological DMARDs include anti-TNFα therapies (adalimumab, etanercept, infliximab), anti-B cell therapy (rituximab), and anti-IL6 therapy (tociluzumab).

Glucocorticoids are used for local intra-articular injections. Prednisone is only used for those who are resistant or unable to tolerate NSAIDs. They can also be useful for short term flares.

Surgery is indicated in the setting of uncontrolled pain and functional limitation secondary to joint damage.

Prognosis

The median years of life lost for men is 10, and for women is 11.

Core Reading

  • Smolen et al.. Rheumatoid arthritis. Lancet (London, England) 2016. 388:2023-2038. PMID: 27156434. DOI.
  • Singh et al.. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) 2016. 68:1-26. PMID: 26545940. DOI.
  • Østensen & Förger. Management of RA medications in pregnant patients. Nature reviews. Rheumatology 2009. 5:382-90. PMID: 19506586. DOI.
  • Richards et al.. How to use biologic agents in patients with rheumatoid arthritis who have comorbid disease. BMJ (Clinical research ed.) 2015. 351:h3658. PMID: 26282936. DOI.
  • McInnes & Schett. The pathogenesis of rheumatoid arthritis. The New England journal of medicine 2011. 365:2205-19. PMID: 22150039. DOI.