Rheumatoid Arthritis

Rheumatoid arthritis is a chronic systemic inflammatory disease whose major manifestation is synovitis of multiple joints.

It has a prevalence of 1% and is more common in women than men (female:male ratio of 3:1). Rheumatoid arthritis can begin at any age, but the peak onset is in the fourth or fifth decade for women and the sixth to eighth decades for men.

The cause is not known. Susceptibility to rheumatoid arthritis is genetically determined with multiple genes contributing. Inheritance of HLA-DRB1 alleles encoding a distinctive five-amino-acid sequence known as the “shared epitope” is the best characterized genetic risk factor.

Untreated, rheumatoid arthritis causes joint destruction with consequent disability and shortens life expectancy.

Early, aggressive treatment is the standard of care.

The pathologic findings in the joint include chronic synovitis with formation of a pannus, which erodes cartilage, bone, ligaments, and tendons.

Effusion and other manifestations of inflammation are common.

Diagnostic Essentials

• Usually insidious onset with morning stiffness and joint pain.
• Symmetric polyarthritis with predilection for small joints of the hands and feet; deformities common with progressive disease.
• Radiographic findings: juxta-articular osteoporosis, joint erosions, and joint space narrowing.
• Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) are present in 70–80%.
• Extra-articular disease: subcutaneous nodules, interstitial lung disease, pleural effusion, pericarditis, splenomegaly, scleritis, and vasculitis.

Clinical Findings

Symptoms and Signs

Joint Symptoms

The clinical manifestations of rheumatoid arthritis are highly variable, but joint symptoms usually predominate.

Although acute presentations may occur, the onset of articular signs of inflammation is usually insidious, with prodromal symptoms of vague periarticular pain or stiffness.

Symmetric swelling of multiple joints with tenderness and pain is characteristic.

Monoarticular disease is occasionally seen initially.

Stiffness persisting for > 30 minutes (and usually many hours) is prominent in the morning. Stiffness may recur after daytime inactivity and be much more severe after strenuous activity.

Although any diarthrodial joint may be affected, PIP joints of the fingers, MCP joints, wrists, knees, ankles, and MTP joints are most often involved.

Synovial cysts and tendon ruptures may occur.

Entrapment syndromes are common—particularly of the median nerve at the carpal tunnel of the wrist. Rheumatoid arthritis can affect the neck but spares the other components of the spine and does not involve the sacroiliac joints. In advanced disease, atlantoaxial (C1–C2) subluxation can lead to myelopathy.

Rheumatoid Nodules

Twenty percent of patients have subcutaneous rheumatoid nodules, most commonly situated over bony prominences but also observed in the bursae and tendon sheaths.

Nodules are occasionally seen in the lungs, the sclerae, and other tissues.

Nodules correlate with the presence of rheumatoid factor in serum (“seropositivity”), as do most other extra-articular manifestations.

Ocular Symptoms

Dryness of the eyes, mouth, and other mucous membranes is found especially in advanced disease (see Sjögren syndrome).

Other ocular manifestations include episcleritis, scleritis, scleromalacia due to scleral nodules, and peripheral ulcerative keratitis.

Other Symptoms

Interstitial lung disease is not uncommon (estimates of prevalence vary widely according to method of detection) and manifests clinically as cough and progressive dyspnea.

Pericarditis and pleural disease are usually silent clinically, but symptomatic effusions can occur.

Occasionally, a small-vessel vasculitis develops and manifests as tiny hemorrhagic infarcts in the nail folds or finger pulps.

Necrotizing arteritis is well reported but rare.

A small subset of patients with rheumatoid arthritis has Felty syndrome, the occurrence of splenomegaly and neutropenia, usually in the setting of severe, destructive arthritis.

Felty syndrome must be distinguished from large granular lymphoproliferative disorder, with which it shares many features.

Laboratory Findings

Anti-CCP antibodies and rheumatoid factor, an IgM antibody directed against the Fc region of IgG, are present in 70–80% of patients with established rheumatoid arthritis.

Rheumatoid factor has a sensitivity of only 50% in early disease.

Anti-CCP antibodies are the most specific blood test for rheumatoid arthritis (specificity ~95%).

Rheumatoid factor can occur in other autoimmune diseases and in chronic infections, including hepatitis C, syphilis, subacute bacterial endocarditis, and tuberculosis. The prevalence of rheumatoid factor positivity also rises with age in healthy individuals.

Approximately 20% of rheumatoid arthritis patients have antinuclear antibodies.

The ESR and levels of CRP are typically elevated in proportion to disease activity.

Anemia of chronic disease is common.

The platelet count is often elevated, roughly in proportion to the severity of overall joint inflammation.

Initial joint fluid examination confirms the inflammatory nature of the arthritis (see Table).

Arthrocentesis is needed to diagnose superimposed septic arthritis, which is a common complication of rheumatoid arthritis and should be considered whenever a patient with rheumatoid arthritis has one joint inflamed out of proportion to the rest.

Imaging

Of all the laboratory tests, radiographic changes are the most specific for rheumatoid arthritis.

Radiographs obtained during the first 6 months of symptoms, however, are usually normal.

The earliest changes occur in the hands or feet and consist of soft tissue swelling and juxta-articular demineralization.

Later, diagnostic changes of uniform joint space narrowing and erosions develop. The erosions are often first evident at the ulnar styloid and at the juxta-articular margin, where the bony surface is not protected by cartilage.

Characteristic changes also occur in the cervical spine, with C1–2 subluxation, but these changes usually take many years to develop.

Although both MRI and ultrasonography are more sensitive than radiographs in detecting bony and soft tissue changes in rheumatoid arthritis, their value in early diagnosis relative to that of plain radiographs has not been established.

Differential Diagnosis

The differentiation of rheumatoid arthritis from other joint conditions and immune-mediated disorders can be difficult.

Osteoarthritis

In contrast to rheumatoid arthritis, osteoarthritis spares the wrists and the MCP joints. Osteoarthritis is not associated with constitutional manifestations, and the joint pain is characteristically relieved by rest, unlike the morning stiffness of rheumatoid arthritis. Signs of articular inflammation, prominent in rheumatoid arthritis, are usually minimal in degenerative joint disease.

CPPD

CPPD disease can cause a degenerative arthropathy of the MCPs and wrists; radiographs are usually diagnostic.

Gout

Although gouty arthritis is almost always intermittent and monoarticular in the early years, it may evolve with time into a chronic polyarticular process that mimics rheumatoid arthritis. Gouty tophi can resemble rheumatoid nodules but are not associated with rheumatoid factor, whose sensitivity for rheumatoid nodules approaches 100%. The early history of intermittent monoarthritis and the presence of synovial urate crystals are distinctive features of gout.

Spondyloarthropathies

Spondyloarthropathies, particularly earlier in their course, can be a source of diagnostic uncertainty; predilection for lower extremities and involvement of the spine and sacroiliac joints point to the correct diagnosis.

Lyme Disease

Chronic Lyme arthritis typically involves only one joint, most commonly the knee, and is associated with positive serologic tests.

Acute Viral Infections

Acute viral infections, most notably with Chikungunya virus and parvovirus B19, can cause a polyarthritis that mimics early-onset rheumatoid arthritis. However, fever is common, the arthritis usually resolves within weeks, and serologic studies confirm recent infection.

Hepatitis C

Chronic infection with hepatitis C can cause a chronic nonerosive polyarthritis associated with rheumatoid factor; tests for anti-CCP antibodies are negative.

SLE

Malar rash, photosensitivity, discoid skin lesions, alopecia, high titer antibodies to double-stranded DNA or Smith, glomerulonephritis, and CNS abnormalities point to the diagnosis of SLE.

Polymyalgia Rheumatica

Polymyalgia rheumatica occasionally causes polyarthralgias in patients > age 50, but these patients remain rheumatoid factor–negative and have chiefly proximal muscle pain and stiffness, centered on the shoulder and hip girdles.

Granulomatosis with Polyangiitis

Joint pain that can be confused with rheumatoid arthritis presents in a substantial minority of patients with granulomatosis with polyangiitis. This diagnostic error can be avoided by recognizing that, in contrast to rheumatoid arthritis, the arthritis of granulomatosis with polyangiitis preferentially involves larger joints (eg, hips, ankles, wrists) and usually spares the small joints of the hand.

Rheumatic Fever

Rheumatic fever is characterized by the migratory nature of the arthritis, an elevated antistreptolysin titer, and a more dramatic and prompt response to aspirin; carditis and erythema marginatum may occur in adults, but chorea and subcutaneous nodules occur only in children.

Cancers

Finally, a variety of cancers produce paraneoplastic syndromes, including polyarthritis.

One form is hypertrophic pulmonary osteoarthropathy most often produced by lung and GI carcinomas, characterized by a rheumatoid-like arthritis associated with clubbing, periosteal new bone formation, and a negative rheumatoid factor.

Diffuse swelling of the hands with palmar fasciitis occurs in a variety of cancers, especially ovarian carcinoma.

Treatment

The primary objectives in treating rheumatoid arthritis are reduction of inflammation and pain, preservation of function, and prevention of deformity.

Disease-modifying antirheumatic drugs (DMARDs) should be started as soon as the diagnosis of rheumatoid disease is certain and then adjusted with the aim of suppressing disease activity.

NSAIDs provide some symptomatic relief in rheumatoid arthritis but do not prevent erosions or alter disease progression. They are not appropriate for monotherapy and should only be used in conjunction with DMARDs, if at all.

The American College of Rheumatology recommends using standardized assessments, such as the Disease Activity Score 28 Joints or the Clinical Disease Activity Index, to gauge therapeutic responses, with the target of low disease activity or remission by these measures.

Corticosteroids

Low-dose corticosteroids (eg, oral prednisone 5–10 mg daily) produce a prompt anti-inflammatory effect and slow the rate of articular erosion. These are often used as a “bridge” to reduce disease activity until the slower acting DMARDs take effect or as adjunctive therapy for active disease that persists despite treatment with DMARDs. No more than 10 mg of prednisone or equivalent per day is appropriate for articular disease. Higher doses are used to manage serious extra-articular manifestations (eg, pericarditis, necrotizing scleritis).

When corticosteroids are to be discontinued, they should be tapered gradually on a planned schedule appropriate to the duration of treatment.

All patients receiving long-term corticosteroid therapy should take measures to prevent osteoporosis.

Intra-articular corticosteroids may be helpful for symptom control if one or two joints are the chief source of difficulty. Intra-articular triamcinolone, 10–40 mg depending on the size of the joint to be injected, may be given but not more than four times a year.

DMARDs

Synthetic DMARDs

Methotrexate

Methotrexate is the initial synthetic DMARD of choice for patients with rheumatoid arthritis.

It is generally well tolerated and often produces a beneficial effect in 2–6 weeks. The usual initial dose is 7.5 or 10 mg of methotrexate orally once weekly. If the patient has tolerated methotrexate but has not responded in 1 month, the dose can be increased to 15 mg orally weekly. The maximal oral dose is usually 20 mg weekly.

The most frequent side effects are gastric irritation and stomatitis.

Cytopenia, most commonly leukopenia or thrombocytopenia but rarely pancytopenia due to bone marrow suppression, is another important potential problem of methotrexate therapy. The risk of developing pancytopenia is much higher in patients whose serum creatinine is > 2 mg/dL (176.8 mcmol/L).

Hepatotoxicity with fibrosis and cirrhosis is an important toxic effect that correlates with cumulative dose and is uncommon with appropriate monitoring of liver biochemical tests.

Methotrexate is contraindicated in a patient with any form of chronic hepatitis, in pregnant women, and in any patient with significant kidney dysfunction (estimated GFR < 30 mL/minute/1.73 m2).

Heavy alcohol use increases hepatotoxicity, so patients should be advised to drink alcohol in extreme moderation, if at all.

Diabetes mellitus, obesity, and kidney disease also increase the risk of hepatotoxicity.

Liver biochemical tests should be monitored at least every 12 weeks, along with a CBC. The dose of methotrexate should be reduced if aminotransferase levels are elevated, and the drug should be discontinued if abnormalities persist despite dosage reduction.

All patients should be prescribed either daily folate (1 mg orally) or weekly leucovorin calcium (2.5–5 mg taken orally 24 hours after the dose of methotrexate) to reduce gastric irritation, stomatitis, cytopenias, and hepatotoxicity.

Hypersensitivity to methotrexate can cause an acute or subacute interstitial pneumonitis that can be life-threatening but which usually responds to cessation of the drug and institution of corticosteroids.

Because methotrexate is teratogenic, women of childbearing age must use effective contraception while taking the medication.

Methotrexate is associated with an increased risk of B-cell lymphomas, some of which resolve following the discontinuation of the medication as well as all types of skin cancer.

The combination of methotrexate and other folate antagonists, such as trimethoprim-sulfamethoxazole, should be used cautiously since pancytopenia can result.

Amoxicillin can decrease renal clearance of methotrexate, leading to toxicity.

Probenecid also increases methotrexate drug levels and toxicity and should be avoided.

Sulfasalazine

This drug is a second-line agent for rheumatoid arthritis.

It is usually introduced at a dosage of 500 mg orally twice daily and then increased each week by 500 mg until the patient improves or the daily dose reaches 3000 mg.

Side effects, particularly neutropenia and thrombocytopenia, occur in 10–25% and are serious in 2–5%.

Sulfasalazine also causes hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, so a G6PD level should be checked before initiation.

Patients with aspirin sensitivity should not be given sulfasalazine.

Patients taking sulfasalazine should have CBC monitored every 2–4 weeks for the first 3 months, then every 3 months.

Leflunomide

Leflunomide, a pyrimidine synthesis inhibitor, is administered orally as a single daily dose of 20 mg.

The most frequent side effects are diarrhea, rash, reversible alopecia, and hepatotoxicity.

Some patients experience dramatic unexplained weight loss.

The drug is teratogenic and has a half-life of 2 weeks, but active metabolites can be detected for up to 2 years. Thus, it is contraindicated in premenopausal women who wish to bear children.

Antimalarials

Hydroxychloroquine sulfate is the antimalarial agent most often used in rheumatoid arthritis.

Monotherapy with hydroxychloroquine should be reserved for patients with very mild disease because only a small percentage will respond and often only after 3–6 months of therapy.

Hydroxychloroquine is often used in combination with other conventional DMARDs, particularly methotrexate and sulfasalazine (so-called “triple therapy”).

The advantage of hydroxychloroquine is its comparatively low toxicity, especially at a dosage of 200–400 mg/day orally (not to exceed 5 mg/kg/day).

The prevalence of the most important adverse effect, retinal toxicity that can lead to visual loss, is a function of duration of therapy, occurring in < 2% of patients (dosed properly) during the first 10 years of use but rising to 20% after 20 years of treatment. Ophthalmologic examinations every 12 months are required.

Rare reactions include neuropathies and myopathies of both skeletal and cardiac muscle, which usually improve when the drug is withdrawn.

Janus Kinase Inhibitors

Tofacitinib, baricitinib, and upadacitinib, inhibitors of Janus kinase, are used to manage severe rheumatoid arthritis that is refractory to methotrexate or other agents.

Janus kinase inhibitors are oral agents that can be used either as monotherapy or in combination with methotrexate.

Tofacitinib is administered in a dose of 5 mg twice daily; baricitinib is 2 mg or 4 mg daily, and upadacitinib is 15 mg daily.

Janus kinase inhibitors can increase the risk of infections. Patients should be screened and treated for latent tuberculosis prior to receiving these drugs. Vaccination against varicella is also recommended.

There is an FDA black box warning for Janus kinase inhibitors about slightly higher risks of serious heart-related events, cancer, blood clots, and death based on data from a large, randomized, controlled trial comparing tofacitinib with tumor necrosis factor (TNF) inhibitors in patients taking methotrexate.

Biologic DMARDs

Tumor Necrosis Factor Inhibitors

Inhibitors of TNF—a proinflammatory cytokine—are frequently added to the treatment of patients who have not responded adequately to methotrexate and can be used as initial therapy in combination with methotrexate for patients with poor prognostic factors.

Five TNF inhibitors are in use: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

Etanercept, a soluble recombinant TNF receptor:Fc fusion protein, is usually administered at a dosage of 50 mg subcutaneously once per week.

Infliximab, a chimeric monoclonal antibody, is administered at a dosage of 3–10 mg/kg intravenously; infusions are repeated after 2, 6, 10, and 14 weeks and then are administered every 8 weeks.

Adalimumab, a human monoclonal antibody that binds to TNF, is given at a dosage of 40 mg subcutaneously every other week.

The dose for golimumab, a human anti-TNF monoclonal antibody, is 50 mg subcutaneously once monthly.

Certolizumab pegol is a PEGylated Fab fragment of an anti-TNF monoclonal antibody; the dose is 200–400 mg subcutaneously every 2 to 4 weeks.

Each drug produces substantial improvement in more than 60% of patients and is usually well tolerated.

Minor irritation at injection sites is the most common side effect of etanercept and adalimumab.

Rarely, nonrecurrent leukopenia develops in patients.

TNF inhibitors have been associated with a several-fold increased risk of serious bacterial infections and a striking increase in granulomatous infections, particularly reactivation of tuberculosis.

Screening for latent tuberculosis is mandatory before initiating TNF blockers.

It is prudent to suspend TNF blockers when a fever or other manifestations of a clinically important infection develops.

Demyelinating neurologic complications that resemble multiple sclerosis have been reported rarely in patients taking TNF inhibitors, but the true magnitude of this risk—likely small—has not been determined with precision.

Most observational studies have not found a higher risk of malignancy with TNF inhibitors, but the FDA has issued a safety alert about case reports of malignancies, including leukemias.

Infliximab was associated with increased morbidity in a heart failure trial; therefore, TNF inhibitors should be used with extreme caution in patients with heart failure.

Infliximab can rarely cause anaphylaxis and induce anti-DNA antibodies (but rarely clinically evident SLE).

Abatacept

Abatacept, a recombinant protein made by fusing a fragment of the Fc domain of human IgG with the extracellular domain of a T-cell inhibitory receptor (CTLA4), blocks T-cell costimulation and produces clinically meaningful responses in approximately 50% of individuals whose disease does not respond to the combination of methotrexate and a TNF inhibitor.

Rituximab

Rituximab, a humanized mouse monoclonal antibody that depletes B cells, can be used in combination with methotrexate or leflunomide for patients whose disease has been refractory to treatment with a TNF inhibitor.

Because rituximab reduces the humoral immune response, it should be used with caution during the COVID-19 pandemic as multiple studies suggest a higher risk of mortality from COVID-19 in patients using this drug.

Tocilizumab and Sarilumab

Tocilizumab and sarilumab are monoclonal antibodies that block the receptor for IL-6, an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis.

They are used most often in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.

These drugs have been associated with GI perforations, although this adverse event is rare.

Combination DMARDs

As a general rule, DMARDs have greater efficacy when administered in combination than when used individually. The most commonly used combination is methotrexate with a TNF inhibitor.

Still, most patients who require DMARD therapy are given methotrexate monotherapy initially because this regimen is effective in up to one-third of patients and is less expensive and less toxic than combination therapy.

The combination of methotrexate, sulfasalazine, and hydroxychloroquine (“triple therapy”) is economical, effective, and not inferior to the combination of methotrexate plus etanercept for those who have not responded to methotrexate monotherapy.

The choice of a second-line biologic agent for patients who have not responded to TNF inhibitors is often based on patient and provider preference and insurance coverage since comparative effectiveness data are sparse.

Biologic DMARDs should not be combined.

Course and Prognosis

After months or years, deformities may occur; the most common are ulnar deviation of the fingers, boutonniére deformity (hyperextension of the DIP joint with flexion of the PIP joint), “swan-neck” deformity (flexion of the DIP joint with extension of the PIP joint), valgus deformity of the knee, and volar subluxation of the MTP joints.

The excess mortality associated with rheumatoid arthritis is largely due to CVD that is unexplained by traditional risk factors and that appears to result from deleterious effects of chronic systemic inflammation on the vascular system.

When to Refer

Early referral to a rheumatologist is essential for diagnosis and the timely introduction of effective therapy.