Rheumatoid Arthritis

General Principles

Rheumatoid arthritis (RA) is a systemic disease of unknown etiology that is characterized by a symmetric inflammatory polyarthritis, extra-articular manifestations (rheumatoid nodules, pulmonary fibrosis, serositis, scleritis, vasculitis), and serum rheumatoid factor (RF). The course of RA is variable but tends to be chronic and progressive.


Clinical Presentation

  • Most patients describe the insidious onset of pain, swelling, and morning stiffness in the hands and/or wrists or feet. Synovitis may be evident on examination of the metacarpophalangeal (MCP), proximal interphalangeal (PIP), wrist, or other joints. Suspect the diagnosis in patients presenting with symmetric arthritis in three or more joints, especially involving small joints and associated with morning stiffness lasting more than 30 minutes.
  • Joint deformities include ulnar deviation, swan neck (MCP flexion, PIP hyperextension, and DIP [distal interphalangeal] flexion), boutonniere (PIP flexion, DIP hyperextension), and cock-up deformities in feet.
  • Less commonly affects C1-C2, but it is important to recognize since it can lead to myelopathy.
  • Extra-articular manifestations occur in up to 40% of the patients, especially if they are seropositive.1 Some of these include rheumatoid nodules (most commonly on extensor surfaces), Raynaud phenomenon (RP), cutaneous vasculitis, interstitial lung disease (ILD), pericarditis, mononeuritis multiplex, CNS (central nervous system) vasculitis, scleritis, episcleritis, keratoconjunctivitis sicca (secondary Sjogren syndrome), neutropenia (1% develop Felty syndrome), among others. Gastrointestinal or renal manifestations are exceedingly rare.

Diagnostic Testing

RF may be positive in 80% of patients. Cyclic citrullinated peptide (CCP) antibodies may be detected in 50%–60% of patients with early RA.2

  • CCP antibodies are more specific (>90%) for RA than RF.2 RF can be positive in other conditions, which can be remembered by the mnemonic CHRONIC. It stands for CHronic disease (primary biliary cirrhosis, silicosis, asbestosis), Rheumatoid arthritis, Other CTDs (systemic lupus erythematosus [SLE], Sjogren syndrome, systemic sclerosis, etc.), Neoplasms (lymphoma), Infections (hepatitis C, subacute bacterial endocarditis, tuberculosis), and Cryoglobulinemia. RF can also be positive in healthy population.3
  • Hand and wrist radiographs may show early changes of erosions or periarticular osteopenia.
  • Musculoskeletal MRI and ultrasonography are more sensitive than plain radiographs and may be used in equivocal cases to demonstrate clinically inapparent synovitis or erosions.


  • The treatment strategy for RA is based on a treat-to-target approach, the target being remission or low disease activity at the least. This translates into pain control, suppression of inflammation, prevention of progressive joint destruction, and maintenance of joint and muscle function.
  • Disease-Modifying Anti-Rheumatic Drugs (DMARDs) appear to alter the natural history of RA by retarding the progression of bony erosions and cartilage loss. Because RA may lead to substantial long-term disability (and is associated with increased mortality), the standard of care is to initiate therapy with such agents early in the course of RA.
  • Symptomatic treatment alone with NSAIDs is not appropriate since it does not modify the course of the disease.
  • Glucocorticoids have some disease-modifying activity, but their toxicity precludes the long-term use.
  • Since DMARDs typically take 1–3 months to have their maximal effect, NSAIDs or glucocorticoids can be given as “bridging” therapy while allowing enough time to DMARDs to achieve their maximal effect.

Disease-Modifying Anti-Rheumatic Drugs

  • Multiple synthetic and biologic DMARDs are approved for the treatment of RA, but they also have significant potential toxicities. Selection of DMARDs should be based on patient comorbidities, and careful monitoring for side effects is imperative.
    • Typically, methotrexate is the initial choice for moderate to severe RA.
    • Leflunomide is also an alternative.
    • Hydroxychloroquine or sulfasalazine can be used as the initial choice in mild RA.
    • Combinations of DMARDs can be used if the patient has a partial response to the initial agent. Combination therapy with methotrexate, hydroxychloroquine, and sulfasalazine, known as triple therapy, is felt to have efficacy similar to biologics in the treatment of RA.4 Methotrexate and leflunomide may have additive hepatotoxicity, and this combination should be used cautiously.
  • If response to monotherapy or combination of conventional DMARD agents is unsatisfactory after an adequate trial (or if limiting toxicity supervenes), addition of a biologic DMARD should be considered.
  • Available biologic DMARDs for RA include:
    • Anti-TNF: adalimumab, etanercept, infliximab, golimumab, certolizumab pegol
    • JAK inhibitors (technically molecule-targeted DMARD): tofacitinib, baricitinib, upadacitinib
    • Anti-IL-1: anakinra
    • Anti-IL-6: tocilizumab, sarilumab
    • Costimulation inhibitor: abatacept
    • B cell–depleting therapy (anti-CD20): rituximab
  • Combinations of synthetic DMARDs plus targeted or biologic DMARDs are increasingly used treatment regimens. Methotrexate is commonly combined with tumor necrosis factor (TNF) antagonists because there is evidence for additive efficacy and for a decrease in the formation of human antichimeric antibodies against the TNF blocker. Methotrexate is often used in combination with rituximab or abatacept. But it is important to note that combination therapy with two biologic DMARDs is contraindicated because of increased infectious complications.
  • For dosing, side effects, and contraindications please see theMedications in Rheumatologysection at the end of the chapter.

NSAIDs and Glucocorticoids

  • NSAIDs or glucocorticoids may be used as an adjunct to DMARD therapy. Indications for glucocorticoids include symptomatic relief while awaiting response to a slow-acting immunosuppressive or immunomodulatory agent, persistent synovitis despite adequate trials of DMARDs and NSAIDs, severe constitutional symptoms (e.g., fever and weight loss), or extra-articular disease (vasculitis, episcleritis, or pleurisy).
  • Oral administration of prednisone 5–20 mg daily usually is sufficient for the treatment of synovitis, whereas severe constitutional symptoms or extra-articular disease may require up to 1 mg/kg PO daily.
  • Intra-articular administration may provide temporary symptomatic relief when only a few joints are inflamed. The beneficial effects of intra-articular steroids may persist for days to months and may delay or negate the need for systemic glucocorticoid therapy.


  • Patients with RA and a single joint inflamed out of proportion to the rest of the joints must be evaluated for coexistent septic arthritis.
  • Felty syndrome: The triad of RA, splenomegaly, and granulocytopenia also occurs in a small subset of patients, and these patients are at risk for recurrent bacterial infections and nonhealing leg ulcers.
  • Approximately 70% of patients show irreversible joint damage on radiography within the first 3 years of disease.5 Work disability is common, and life span may be shortened.

Cardiovascular Risk

Cardiovascular disease (CVD) is accelerated in patients with RA and is the most common cause of death. CVD risk in RA is similar to that in diabetes. Traditional CAD risk factors do not explain this increased risk which is felt to be due to underlying chronic inflammation, and side effects from medications like NSAIDs and glucocorticoids. EULAR recommends calculating cardiovascular risk every 5 years, but it should be noted that traditional risk calculators are not accurate to predict cardiovascular risk in RA.6,7 Aggressive primary prevention, minimizing exposure to glucocorticoids and NSAIDs, and control of RA disease activity are recommended to reduce cardiovascular risk.


  1. Turesson C, O’Fallon WM, Crowson CS, et al. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722.  [PMID:12860726]
  2. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis. 2003;62(9):870.  [PMID:12922961]
  3. Nielsen SF, Bojeson SE, Schnohr P, et al. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ 2012;345:e5244.  [PMID:22956589]
  4. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum. 1992; 35(1):26.
  5. van Vollenhoven RF, Geborek P, Forslind K, et al. Swefot trial. Lancet. 2009;374(9688):459-466.  [PMID:19665644]
  6. Rowson CS, Matteson EL, Roger VL, et al. Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. Am J Cardiol. 2012;110(3):420-424.
  7. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76:17-28.  [PMID:27697765]


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