Published October 31, 2023
A brief refresher with useful tables, figures, and research summaries
Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease characterized by chronic, symmetric, inflammatory arthritis that classically affects multiple joints, particularly of the hands, wrists, and feet. Although inflammatory arthritis is the prototypical presentation of RA, extra-articular manifestations are common and may precede the onset of inflammatory arthritis. RA is more common among women than men, although both sexes are affected. If left untreated, RA may lead to irreversible destruction of affected joints and tendons. Although RA is currently incurable, advances in management have led to substantial improvement in prognosis such that people with RA can live with remission or low disease activity for decades without developing deformities.
family history of RA or other autoimmune diseases
prior or current cigarette smoking
exposure to airborne inhalants
genetic susceptibility (particularly human leukocyte antigen DR4)
presence of anticitrullinated protein antibodies (ACPA), particularly anti–cyclic citrullinated peptides (anti-CCP) antibodies
presence of rheumatoid factor (RF)
The joint disease of RA typically manifests as a symmetric, distal, chronic inflammatory arthritis. As with other causes of inflammatory arthritis, patients typically report prolonged morning stiffness that improves with activity. While symmetric inflammatory arthritis is characteristic, some cases of RA may have one or a few joints that are more affected than others, particularly early in the disease course.
Joints typically affected by RA include the metacarpophalangeal joints (MCPs) and proximal interphalangeal joints (PIPs) of the hands, wrists, metatarsophalangeal joints (MTPs) of the feet, and ankles. The distal interphalangeal joints (DIPs) of the hands are typically spared. Larger joints such as the elbows, shoulders, and knees may be involved, as well. While the cervical spine is commonly affected, RA typically spares the thoracic and lumbar spine as well as the sacroiliac (SI) joints and hips.
Extra-articular manifestations: In addition to inflammatory arthritis, RA frequently affects other organ systems. Occasionally, extra-articular manifestations can precede the onset of joint disease, and extra-articular disease activity may or may not track with articular disease activity. In addition, RA frequently overlaps with other systemic autoimmune diseases, particularly Sjögren syndrome. Examples of extra-articular manifestations are listed below:
skin: rheumatoid nodules, cutaneous small-vessel vasculitis
lungs: interstitial lung disease (typically usual interstitial pneumonia [UIP] pattern), rheumatoid nodules, exudative pleural effusions
eyes: sicca syndrome (frequent overlap with Sjögren syndrome), episcleritis, scleritis, peripheral ulcerative keratitis
heart: pericarditis, myocarditis
nervous system: compressive neuropathies (most commonly carpal tunnel syndrome secondary to wrist synovitis), polyneuropathy, mononeuritis multiplex (typically secondary to rheumatoid vasculitis)
hematologic: anemia of chronic inflammation, Felty syndrome (neutropenia, splenomegaly), large granular lymphocyte (LGL) leukemia (neutropenia, splenomegaly, frequent infections, LGL proliferation)
RA is a clinical diagnosis that requires the clinician to incorporate elements of the history, physical examination, laboratory tests, and imaging. RA is considered in patients with any chronic inflammatory arthritis, particularly in the distribution described above (see Clinical Presentation) or in patients with extra-articular manifestations and serologic evidence of rheumatoid arthritis (e.g., UIP pattern of interstitial lung disease with a high-titer anti–cyclic citrullinated peptide [CCP] antibody).
Early diagnosis of RA is important, as early treatment leads to better patient outcomes related to joint damage and disease control. Diagnosis in the initial stages can be difficult, as the clinical findings may not be obvious. In some cases, the clinical picture/serologic status will evolve, and the diagnosis will be revealed with time. Giving consideration to a broad list of differential diagnoses will minimize the chance of misdiagnosis.
Laboratory evaluation: In addition to a complete blood count, basic metabolic profile, and liver function tests, laboratory testing in patients with suspected RA includes:
Erythrocyte sedimentation rate and C-reactive protein: While these may be elevated in RA in many cases, the specificity and sensitivity are low, so normal values do not rule out RA, and joint pain with elevated acute phase reactants may be observed in noninflammatory causes of joint pain.
Rheumatoid factor (RF) and anti-CCP antibodies: Most patients with RA are positive for either or both antibodies, although seronegative RA can occur. Low-titer RF has low specificity and can be associated with numerous other conditions. Anti-CCP positivity, especially at high titers, has high specificity and positive predictive value for RA. Seropositivity (RF or anti-CCP) is associated with increased risk of erosive disease, extra-articular involvement, and responsiveness to different medication options.
Patients with features of RA who are seronegative may have a syndrome quite similar to RA or may actually have another type of inflammatory arthritis (e.g., psoriatic arthritis, lupus-associated inflammatory arthritis, dermatomyositis-associated arthritis, pseudo-RA such as in calcium pyrophosphate dihydrate [CPPD] arthritis). Therefore, other diagnostic possibilities should be considered in long-term management. Classifying such patients as having “seronegative inflammatory arthritis” may reduce the risk of misdiagnosis.
Antinuclear antibody (ANA): Although patients with RA can have positive ANA, ANA positivity may indicate an overlap with an ANA-associated systemic autoimmune disease (e.g., systemic lupus erythematosus, Sjögren syndrome, inflammatory myopathy, mixed connective tissue disease, or systemic sclerosis). Other specific autoantibodies should be checked as guided by patient presentation.
Imaging: When rheumatoid arthritis is suspected, clinicians should obtain radiographs of the hands and feet, as well as other affected joints as indicated. Radiographic findings in RA include symmetric joint-space narrowing of affected joints, periarticular osteopenia, and marginal erosions (i.e., those located at the edge where the joint capsule meets the articular cartilage). Early in the disease course, plain radiographs may be normal. In cases where history and physical exam are equivocal for the presence of inflammatory arthritis or synovitis, a musculoskeletal ultrasound or MRI can be used to identify more-subtle synovitis, but these imaging modalities need not be routinely performed.
(Source: Bone Changes in Rheumatoid Arthritis. N Engl J Med 2005.)
Treatment of RA has advanced considerably in the past 30 years. The gold standard of treatment currently is to aim for remission or low disease activity as quickly as possible after diagnosis, as this leads to the best long-term outcomes.
Drugs that have demonstrated the ability to reduce the degree of synovitis or the amount of bone erosion on plain radiographs are known collectively as disease-modifying antirheumatic drugs (DMARDs). The original drugs in this group are called conventional synthetic DMARDs (csDMARDs), the newest monoclonal antibodies are biologic DMARDs (bDMARDs), and the medications that target intracellular enzymes or molecules are referred to as targeted synthetic DMARDs (tsDMARDs).
Rarely used in current practice:
Janus kinase inhibitors:
Tumor necrosis factor inhibitors:
Methotrexate (up to a usual maximal dose of 25 mg weekly) is considered an “anchor” drug to which other DMARDs are added. Methotrexate works synergistically with almost all other DMARDs to prevent joint damage and reduce disease activity. For example, in the case of tumor necrosis factor (TNF) inhibitors, combination therapy with methotrexate and a TNF inhibitor has been shown in clinical trials to be more effective than either medication alone. Therefore, if methotrexate alone is insufficient, adding other agents to methotrexate is preferred over switching from methotrexate monotherapy to monotherapy with another DMARD.
The aim of treatment is to reduce disease activity to as low as possible to achieve remission or low disease activity based on validated assessment tools (known as a treat-to-target approach).
Infection is the most significant risk associated with nearly all DMARDs. The index of suspicion for infection must be high for all patients on DMARDs, and the threshold for treating suspected infections should be low.
Reactivation of herpes simplex virus, varicella zoster virus, hepatitis B virus, and Mycobacterium tuberculosis are particularly important potential complications. In addition, some of these medications confer an increased risk for severe Covid-19.
Development of almost any infection, regardless of the microorganism, can be atypical in patients taking DMARDs. Some patients may not have a fever or may have a low/normal C-reactive protein level in peripheral blood (especially with anti–interleukin-6 agents such as tocilizumab and sarilumab, which lead to an artifactual lowering of acute phase reactants).
Adjunctive treatments to manage pain, such as nonsteroidal anti-inflammatory drugs, acetaminophen, and fish oil, are also used in RA, although these analgesics do not modify the progression of disease.
The 2021 American College of Rheumatology (ACR) recommendations for the initiation of DMARDs are described in the following table:
(Source: 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheum 2021. Reproduced with permission.)
Landmark clinical trials and other important studies
Barkhane Z et al. Cureus 2023.
This meta-analysis of observational studies emphasized the increased cardiovascular risk in patients with rheumatoid arthritis.
Tuttle J et al. N Engl J Med 2023
Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis.
Ytterberg SR et al. N Engl J Med 2022.
The ORAL Surveillance study, a phase 3b-4 safety trial, demonstrated that in a cardiovascular risk–enriched population with rheumatoid arthritis, the risks of major adverse cardiovascular risk and malignancy were higher in patients treated with the janus kinase (JAK) inhibitor tofacitinib than with the tumor necrosis factor (TNF) inhibitor adalimumab. The findings led the FDA to add a black box warning for JAK inhibitors.
Orange DE et al. N Engl J Med 2020.
In this landmark study, longitudinal genomic analysis of rheumatoid arthritis flares revealed pre-inflammatory mesenchymal (PRIME) cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium.
Stoffer MA et al. Ann Rheum Dis 2016.
An updated literature review showing that targeted RA therapy is associated with better outcomes than routine care
Emery P et al. N Engl J Med 2014.
In this randomized controlled trial of maintenance therapy in patients with early RA who achieved remission with etanercept-plus-methotrexate therapy, patients maintained on reduced-dose etanercept-plus-methotrexate therapy had better disease control than those who switched to methotrexate alone or placebo.
O’Dell JR et al. Arthritis Rheum 2002.
Randomized, double-blind, placebo-controlled trial evaluating the effects of three pharmacologic combinations with methotrexate on symptom response in DMARD-naive patients with rheumatoid arthritis
The best overviews of the literature on this topic
Gravallese EM and Gary S. Firestein GS. N Engl J Med 2023.
Cush JJ. Med Clin North Am 2021.
Burmester GR and Pope JE. Lancet 2017.
Smolen JS et al. Lancet 2016.
McInnes IB and Schett G. N Engl J Med 2011.
Turner B et al. Ann Intern Med 2010.
The current guidelines from the major specialty associations in the field
Fraenkel L et al. Arthritis Rheumatol 2021.
Smolen JS et al. Ann Rheum Dis 2020.
Videos, cases, and other links for more interactive learning
Gibson E. The Curbsiders 2019.
Interview with Dr. Robert McLean