Rheumatoid Arthritis (RA)

Subcutaneous rheumatoid nodules are not usually an early sign but eventually develop in up to 30% of patients, usually at sites of pressure and chronic irritation (eg, the extensor surface of the forearm, metacarpophalangeal joints, soles of feet). Paradoxically, rheumatoid nodules can increase in patients taking methotrexate, despite lessening of joint inflammation. Visceral nodules (eg, pulmonary) are usually asymptomatic and may occur in severe rheumatoid arthritis. Pulmonary nodules of rheumatoid arthritis cannot be distinguished from pulmonary nodules of other etiology without biopsy.

Other extra-articular signs include vasculitis Cutaneous Vasculitis Cutaneous vasculitis refers to vasculitis affecting small- or medium-sized vessels in the skin and subcutaneous tissue but not the internal organs. Cutaneous vasculitis may be limited to the... read more causing leg ulcers, digital ischemia, or multiple mononeuropathy (mononeuritis multiplex), pleural or pericardial effusions, obliterative bronchiolitis, interstitial lung disease Overview of Interstitial Lung Disease Interstitial lung diseases are a heterogeneous group of disorders characterized by alveolar septal thickening, fibroblast proliferation, collagen deposition, and, if the process remains unchecked... read more , pericarditis Pericarditis Pericarditis is inflammation of the pericardium, often with fluid accumulation in the pericardial space. Pericarditis may be caused by many disorders (eg, infection, myocardial infarction, trauma... read more , myocarditis Myocarditis Myocarditis is inflammation of the myocardium with necrosis of cardiac myocytes. Myocarditis may be caused by many disorders (eg, infection, cardiotoxins, drugs, and systemic disorders such... read more , lymphadenopathy Lymphadenopathy Lymphadenopathy is palpable enlargement of ≥ 1 lymph nodes. Diagnosis is clinical. Treatment is of the causative disorder. (See also Overview of the Lymphatic System.) Lymph nodes are present... read more , Felty syndrome, Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more , scleromalacia, and episcleritis Episcleritis Episcleritis is self-limiting, recurring, usually idiopathic inflammation of the episcleral tissue that does not threaten vision. Symptoms are a localized area of hyperemia of the globe, irritation... read more .

Involvement of the cervical spine can cause atlantoaxial subluxation Atlantoaxial Subluxation Atlantoaxial subluxation is misalignment of the 1st and 2nd cervical vertebrae, which may occur only with neck flexion. (See also Evaluation of Neck and Back Pain and Craniocervical Junction... read more and spinal cord compression Spinal Cord Compression Various lesions can compress the spinal cord, causing segmental sensory, motor, reflex, and sphincter deficits. Diagnosis is by MRI. Treatment is directed at relieving compression. (See also... read more ; subluxation may worsen with extension of the neck (eg, during endotracheal intubation). Importantly, cervical spine instability is usually asymptomatic.

Patients with rheumatoid arthritis are at increased risk for early coronary artery disease Overview of Coronary Artery Disease Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more , metabolic bone disease such as osteopenia and osteoporosis Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more , and various cancers (lung, lymphoproliferative disorders, and nonmelanoma skin cancers), which may be related to underlying, uncontrolled systemic inflammatory processes.

Many disorders can simulate rheumatoid arthritis:

Some patients with crystal-induced arthritis, especially calcium pyrophosphate arthritis Calcium Pyrophosphate Arthritis Calcium pyrophosphate arthritis (CPP arthritis) involves intra-articular and/or extra-articular deposition of calcium pyrophosphate dihydrate (CPPD) crystals. Manifestations are protean and... read more , may meet criteria for rheumatoid arthritis; however, synovial fluid examination should clarify the diagnosis. The presence of crystals makes rheumatoid arthritis unlikely, although calcium pyrophosphate crystal disease and rheumatoid arthritis may coexist in the same patient. Joint involvement and subcutaneous nodules can result from SLE, gout, cholesterol, and amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more as well as rheumatoid arthritis; aspiration or biopsy of the nodules may occasionally be needed.

SLE Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more usually can be distinguished if there are skin lesions on light-exposed areas, hair loss, oral and nasal mucosal lesions, absence of joint erosions in even long-standing arthritis, joint fluid that often has white blood cell counts < 2000/mcL (2.0 x10⁹/L) (predominantly mononuclear cells), antibodies to double-stranded DNA, renal disease, and low serum complement levels. In contrast to rheumatoid arthritis, swan neck and ulnar deviation deformities in SLE are usually reducible.

Arthritis similar to rheumatoid arthritis can also occur in other rheumatic disorders (eg, polyarteritis Polyarteritis Nodosa (PAN) Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular arteries, resulting in secondary tissue... read more , systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more , dermatomyositis Autoimmune Myositis Autoimmune myositis is characterized by inflammatory and degenerative changes in the muscles (polymyositis, necrotizing immune-mediated myopathy) or in the skin and muscles (dermatomyositis)... read more , or polymyositis Autoimmune Myositis Autoimmune myositis is characterized by inflammatory and degenerative changes in the muscles (polymyositis, necrotizing immune-mediated myopathy) or in the skin and muscles (dermatomyositis)... read more ), or there can be features of more than one disease, which suggests an overlap syndrome Mixed Connective Tissue Disease (MCTD) Mixed connective tissue disease is an uncommon, specifically defined syndrome characterized by clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with very... read more .

Sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more , Whipple disease Whipple Disease Whipple disease is a rare systemic illness caused by the bacterium Tropheryma whipplei. Main symptoms are arthritis, weight loss, abdominal pain, and diarrhea. Diagnosis is by small-bowel... read more , multicentric reticulohistiocytosis, and other systemic diseases may involve joints; other clinical features and tissue biopsy sometimes help differentiate these conditions. Acute rheumatic fever has a migratory pattern of joint involvement and evidence of antecedent streptococcal infection (culture or changing antistreptolysin O titer); in contrast, rheumatoid arthritis tends to involve additional joints over time.

Reactive arthritis Reactive Arthritis Reactive arthritis is an acute spondyloarthropathy that often seems precipitated by an infection, usually genitourinary or gastrointestinal. Common manifestations include asymmetric arthritis... read more can be differentiated by antecedent gastrointestinal or genitourinary symptoms; asymmetric involvement and pain at the Achilles insertion of the heel, sacroiliac joints, and large joints of the leg; conjunctivitis; iritis; painless buccal ulcers; balanitis circinata; or keratoderma blennorrhagicum on the soles and elsewhere.

Psoriatic arthritis Psoriatic Arthritis Psoriatic arthritis is a seronegative spondyloarthropathy and chronic inflammatory arthritis that occurs in people with psoriasis of the skin or nails. The arthritis is often asymmetric, and... read more tends to be asymmetric and is not usually associated with RF, but clinical differentiation may be difficult in the absence of nail or skin lesions. Distal interphalangeal joint involvement and severely mutilating arthritis (arthritis mutilans) is strongly suggestive, as is the presence of a diffusely swollen (sausage) digit. Psoriatic arthritis may involve the sacroiliac joints and lower spine. Distinguishing between psoriatic arthritis and rheumatoid arthritis is important because response to some specific drugs differs.

Ankylosing spondylitis Ankylosing Spondylitis Ankylosing spondylitis is the prototypical spondyloarthropathy and a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back... read more may be differentiated by spinal and axial joint involvement, absence of subcutaneous nodules, and a negative RF test. The HLA-B27 allele is present in 90% of White patients with ankylosing spondylitis.

Osteoarthritis Osteoarthritis (OA) Osteoarthritis is a chronic arthropathy characterized by disruption and potential loss of joint cartilage along with other joint changes, including bone hypertrophy (osteophyte formation). Symptoms... read more can be differentiated by the joints involved; the absence of rheumatoid nodules, systemic manifestations, or significant amounts of RF; and by synovial fluid white blood cell counts < 2000/mcL (2.0 x10⁹/L). Osteoarthritis of the hands most typically involves the DIP joints, bases of the thumbs, and proximal interphalangeal joints and may involve the metacarpophalangeal joints, but typically spares the wrist. Rheumatoid arthritis does not affect the DIP joints. Rheumatoid arthritis is characterized by clinically apparent, symmetric, small joint inflammation with frequent wrist involvement.

Complete bed rest is rarely indicated, even for a short time; however, a program including judicious rest should be encouraged. Quality sleep should be encouraged, because poor sleep increases pain.

An ordinary nutritious diet is appropriate. Rarely, patients have food-associated exacerbations; no specific foods have reproducibly been shown to exacerbate or lessen the symptoms of rheumatoid arthritis. Substituting omega-3 fatty acids (in fish oils) for dietary omega-6 fatty acids (in meats) partially relieves symptoms in some patients by transiently decreasing production of inflammatory prostaglandins and possibly by modifying the gut microbiome. Smoking cessation can increase life expectancy.

Food and diet misinformation targeting rheumatoid arthritis patients is common, and patients should be directed to reliable sources of information.

Joint splinting reduces local inflammation and may relieve severe symptoms of pain or compressive neuropathies. Cold may be applied to reduce joint pain and swelling. Orthopedic or athletic shoes with good heel and arch support are frequently helpful; metatarsal supports placed posteriorly (proximal) to painful metatarsophalangeal joints decrease the pain of weight bearing. Molded shoes may be needed for severe deformities. Occupational therapy and self-help devices enable many patients with debilitating rheumatoid arthritis to perform activities of daily living.

Exercise should proceed as tolerated. During acute inflammation, passive range-of-motion exercise helps prevent flexion contractures. Heat therapy can be applied to help alleviate stiffness. Range-of-motion exercises done in warm water are helpful because heat improves muscle function by reducing stiffness and muscle spasm. However, contractures can be prevented and muscle strength can be restored more successfully after inflammation begins to subside; active exercise (including walking and specific exercises for involved joints) to restore muscle mass and preserve range of joint motion are recommended. Flexion contractures may require intensive exercise, casting, or immobilization (eg, splinting) in progressively more stretched-open positions. Paraffin baths can warm digits and facilitate finger exercise.

Massage Massage Treatment of pain and inflammation aims to facilitate movement and improve coordination of muscles and joints. Nondrug treatments include therapeutic exercise, heat, cold, electrical stimulation... read more by trained therapists, traction Cervical traction Treatment of pain and inflammation aims to facilitate movement and improve coordination of muscles and joints. Nondrug treatments include therapeutic exercise, heat, cold, electrical stimulation... read more , and deep heat treatment Heat Treatment of pain and inflammation aims to facilitate movement and improve coordination of muscles and joints. Nondrug treatments include therapeutic exercise, heat, cold, electrical stimulation... read more with diathermy or ultrasonography may be useful adjunctive therapies to anti-inflammatory drugs.

Surgery may be considered if drug therapy is unsuccessful. Surgery must always be considered in terms of the total disease and patient expectations. For example, deformed hands and arms limit crutch use during rehabilitation; seriously affected knees and feet limit benefit from hip surgery. Reasonable objectives for each patient must be determined, and function must be considered; straightening ulnar-deviated fingers may not improve hand function. Surgery may be done while the disease is active.

Arthroplasty with prosthetic joint replacement is indicated if damage severely limits function; total hip and knee replacements are most consistently successful. Prosthetic hips and knees may limit vigorous activity (eg, competitive athletics). Excision of subluxed painful metatarsophalangeal joints may greatly aid walking. Thumb fusions may provide stability for pinch. Neck fusion may be needed for C1-2 subluxation with severe pain or potential for spinal cord compression. Arthroscopic or open synovectomy can relieve joint inflammation but only temporarily unless disease activity can be controlled. Withholding some immunosuppressive medications at the time of arthroplasty should be considered to limit the risk of infection. Even low-dose prednisone (< 7.5 mg a day) may increase infectious risk.

Aspirin is no longer used for rheumatoid arthritis because effective doses are often toxic. Only one NSAID should be given at a time (see table NSAID Treatment of Rheumatoid Arthritis Nonsteroidal Anti-inflammatory Drug (NSAID) Treatment of Rheumatoid Arthritis ), although patients may also take aspirin at ≤ 325 mg/day for its antiplatelet cardioprotective effect. Because the maximal response for NSAIDs can take up to 2 weeks, doses should be increased no more frequently than this. Doses of drugs with flexible dosing can be increased until response is maximal or maximum dosage is reached. All NSAIDs treat the symptoms of rheumatoid arthritis and decrease inflammation but do not alter the course of the disease; thus, they are only used adjunctively.

NSAIDs inhibit cyclooxygenase (COX) enzymes and thus decrease production of prostaglandins. Some prostaglandins under COX-1 control have important effects in many parts of the body (ie, they protect gastric mucosa and inhibit platelet adhesiveness). Other prostaglandins are induced by inflammation and are produced by COX-2. Selective COX-2 inhibitors, also called coxibs (eg, celecoxib), seem to have efficacy similar to nonselective NSAIDs and are slightly less likely to cause gastrointestinal toxicity; however, they are not less likely to cause renal toxicity. Celecoxib 200 mg orally once/day has a comparable cardiovascular safety profile to nonselective NSAIDs. It remains unclear whether full-dose celecoxib (200 mg orally 2 times a day ) has cardiovascular risks comparable to the nonselective NSAIDs.

NSAIDs should generally be avoided in patients with previous peptic ulcer disease or dyspepsia; gastric acid suppressive therapy should be provided in these patients if an NSAID is used (eg, short term). Other possible adverse effects of all NSAIDs include headache, confusion and other central nervous system symptoms, increased blood pressure, worsening of hypertension, edema, and decreased platelet function; however, celecoxib has no significant antiplatelet effect. NSAIDs may increase cardiovascular risk (see Treatment of Pain/Nonopioid Analgesics Nonopioid Analgesics ). Creatinine levels can rise reversibly because of inhibited renal prostaglandins and reduced renal blood flow; rarely, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma caused by aspirin can have the same problems with these other NSAIDs, but celecoxib may not cause these problems.

NSAIDs should be used at the lowest possible dose needed to mitigate their adverse effects.

(See table Other Drugs Used to Treat Rheumatoid Arthritis Other Drugs Used to Treat Rheumatoid Arthritis for specific dosage information and adverse effects of other drugs used to treat rheumatoid arthritis.)

DMARDs seem to slow the progression of rheumatoid arthritis and are indicated for nearly all patients with rheumatoid arthritis. They differ from each other chemically and pharmacologically. Many take weeks or months to have an effect. About two thirds of patients improve overall, and complete remissions are becoming more common. Many DMARDs result in evidence of decreased damage on imaging studies, presumably reflecting decreased disease activity. Patients should be fully apprised of the risks of DMARDs and monitored closely for evidence of toxicity.

When choosing DMARDs, the following principles should be considered:

Methotrexate is a folate antagonist with immunosuppressive effects at high dose. It is anti-inflammatory at doses used in rheumatoid arthritis. It is very effective and has a relatively rapid onset (clinical benefit often within 3 to 4 weeks). Methotrexate should be used with caution, if at all, in patients with hepatic dysfunction or renal failure. Alcohol should be avoided. Supplemental folate, 1 mg orally once/day, reduces the likelihood of adverse effects. Complete blood count (CBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin and creatinine level should be determined about every 8 to 12 weeks. When used early in the course of rheumatoid arthritis, efficacy may equal the biologic agents. Rarely, a liver biopsy is needed if liver test findings are persistently twice the upper limit of normal or more and the patient needs to continue to use methotrexate. Severe relapses of arthritis can occur after withdrawal of methotrexate. Paradoxically, rheumatoid nodules may enlarge with methotrexate therapy. In rheumatoid arthritis patients with stable parenchymal lung disease, methotrexate can be continued with close monitoring of their respiratory status, if the methotrexate is controlling joint inflammation.

Hydroxychloroquine can also control symptoms of mild rheumatoid arthritis. Funduscopic examination should be done and visual fields should be assessed before and every 12 months during treatment. The drug should be stopped if no joint improvement occurs after 9 months.

Sulfasalazine can alleviate symptoms and slow development of joint damage. It is usually given as enteric-coated tablets. Benefit should occur within 3 months. Enteric coating or dose reduction may increase tolerability. Because neutropenia may occur early, CBCs should be obtained after 1 to 2 weeks and then about every 12 weeks during therapy. AST and ALT should be obtained at about 6-month intervals and whenever the dose is increased. In male patients, sulfasalazine may cause reversible oligospermia.

Leflunomide interferes with an enzyme involved with pyrimidine metabolism. It is about as effective as methotrexate but is less likely to suppress bone marrow, cause abnormal liver function, or cause pneumonitis. Alopecia and diarrhea are fairly common at the onset of therapy but may resolve with continuation of therapy.

Systemic corticosteroids decrease inflammation and other symptoms more rapidly and to a greater degree than other drugs. They may not prevent joint destruction, and their clinical benefit often diminishes with time. Furthermore, rebound often follows the withdrawal of corticosteroids in active disease. Because of their long-term adverse effects, some doctors recommend that corticosteroids are given only for short periods of time to maintain function until a DMARD has taken effect.

Corticosteroids may be used for severe joint or systemic manifestations of rheumatoid arthritis (eg, vasculitis, pleurisy, pericarditis). Relative contraindications include peptic ulcer disease, hypertension, untreated infections, diabetes mellitus, and glaucoma. The risk of latent tuberculosis should be considered before corticosteroid therapy is begun.

Intra-articular injections of depot corticosteroids may temporarily help control pain and swelling in particularly painful joints. Triamcinolone hexacetonide may suppress inflammation for the longest time. Triamcinolone acetonide and methylprednisolone acetate are also effective. No single joint should be injected with a corticosteroid more than 3 to 4 times a year, as too-frequent injections may accelerate joint destruction (although there are no specific data from humans to support this effect). Because injectable corticosteroid esters are crystalline, local inflammation transiently increases within a few hours in < 2% of patients receiving injections. Although infection occurs in only < 1:40,000 patients, it must be considered if pain occurs > 24 hours after injection.

Treatment with azathioprine or cyclosporine (an immunomodulatory drug) may provide efficacy similar to DMARDs. However, these drugs are more toxic and less well studied. Thus, they are used only for patients in whom treatment with more traditional DMARDs has failed. They are used infrequently unless there are extra-articular complications.

Tumor necrosis factor (TNF)-alpha antagonists (eg, adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, and their biosimilars) reduce the progression of erosions and reduce the number of new erosions. Although not all patients respond, many have a prompt, dramatic feeling of well being, sometimes with the first injection. Inflammation is often dramatically reduced. These drugs are often added to methotrexate therapy to increase the effect and possibly prevent the development of drug-neutralizing antibodies.

Recent information suggests safety during pregnancy with TNF inhibitors and anakinra (3 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more ). TNF-alpha antagonists should probably be stopped before major surgery to decrease the risk of perioperative infection (4 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more ). Etanercept, infliximab, and adalimumab can be used with or without methotrexate. TNF inhibitors may predispose to heart failure and thus are relatively contraindicated in stage 3 and stage 4 heart failure. There is a minimal risk of lymphoma in rheumatoid arthritis patients who are being treated with TNF inhibitors. 2015 ACR guidelines conditionally recommended using DMARDs, rituximab, or abatacept instead of TNF inhibitors in patients with history of lymphoma (5 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more ). Evidence regarding solid tumors in TNF inhibitors is mixed. Other possible adverse events of TNF inhibitors include injection site reaction, acute and delayed infusion reaction, demyelinating disease, granulomatous diseases such as sarcoidosis, cytopenias (especially neutropenia), cutaneous vasculitis, and rarely antineutrophilic cytoplasmic associated vasculitis.

Sarilumab is an interleukin-6 (IL-6) inhibitor. It is available for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to or are intolerant of one or more DMARDs.

Tocilizumab is an IL-6 inhibitor and has clinical efficacy in patients who have responded incompletely to other biologic agents.

Abatacept, a soluble fusion cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) Ig, is indicated for patients with rheumatoid arthritis with an inadequate response to other DMARDs, and conditionally recommended over other biologic DMARDs in patients with rheumatoid arthritis and non-tuberculous mycobacterial lung disease.

Anakinra is a recombinant interleukin-1 (IL-1) receptor. IL-1 is heavily involved in the pathogenesis of rheumatoid arthritis. Infection and leukopenia can be problems. It is used less often because it must be given every day.

Rituximab is an anti-CD 20 antibody that depletes B cells. It can be used in patients refractory to other treatments. Response is often delayed but may last 6 months. The course can be repeated after 6 months. Mild adverse effects are common, and analgesia, corticosteroids, diphenhydramine, or a combination may need to be given concomitantly. Rituximab therapy has been associated with progressive multifocal leukoencephalopathy (as have other immunosuppressive drugs), mucocutaneous reactions, delayed leukopenia, and hepatitis B reactivation with hepatic necrosis. Patients on rituximab may have a blunted immune response to the COVID-19 vaccine COVID-19 Vaccine COVID-19 vaccines provide protection against COVID-19, the disease caused by infection with the SARS-CoV-2 virus. Vaccination is the most effective strategy to prevent severe illness and death... read more and have poorer outcomes if infected with SARS-CoV-2. Therefore, rituximab is now generally reserved for patients who did not respond to other biologic DMARDs (including a combined TNF-alpha inhibitor and methotrexate) and to those with lymphoproliferative disorders.

Rituximab therapy might be gradually discontinued if the patient has had low disease activity or been in remission for at least 6 months.

Although there are some differences among agents, the most serious concern with the biologics and targeted DMARDs is infection, particularly with reactivated tuberculosis. Patients should be screened for tuberculosis Screening for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more with purified protein derivative (PPD) or an interferon-gamma release assay. Other serious infections can occur, including sepsis, invasive fungal infections, and infections due to other opportunistic organisms. Patients should be up to date on vaccinations Overview of Immunization Immunity can be achieved Actively by using antigens (eg, vaccines, toxoids) Passively by using antibodies (eg, immune globulins, antitoxins) A toxoid is a bacterial toxin that has been modified... read more prior to treatment with a biologic agent.

Janus kinase (JAK) inhibitors are small molecule agents that interfere with the communication between cells that coordinate inflammation by inhibiting the enzyme JAK. JAK inhibitors include tofacitinib, baricitinib, and upadacitinib. (See also table .) JAK inhibitors carry an increased incidence of herpes zoster, thus vaccination against zoster Herpes Zoster Vaccine Chickenpox (varicella) and shingles ( herpes zoster) are caused by the varicella-zoster virus; chickenpox is the acute invasive phase of the virus, and shingles represents reactivation of the... read more is strongly suggested prior to use of these medications.

Baricitinib is an oral Janus kinase (JAK) inhibitor. It is indicated for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonists.

Tofacitinib is a JAK inhibitor that is given orally with or without concomitant methotrexate to patients who do not respond to methotrexate alone or other biologic agents.

Upadacitinib is a JAK inhibitor that is given orally to adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Other JAK inhibitors that may soon become available in the US include filgotinib and peficitinib.

A prospective, randomized, open-label study compared the JAK inhibitor tofacitinib (5 and 10 mg doses) with TNF-alpha antagonists. After a median follow-up of 4 years, the results showed a higher risk of major adverse cardiovascular events (MACEs) and cancer with tofacitinib than with TNF-alpha antagonists, especially in patients over age 50 years and with at least 1 risk factor for cardiovascular disease (6 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more ).