Rheumatoid Arthritis Medication
- Author: Howard R Smith, MD; Chief Editor: Herbert S Diamond, MD more...
Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach that includes both nonpharmacologic therapies and pharmacologic agents such as nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids.
DMARDs represent the most important measure in the successful treatment of rheumatoid arthritis. These agents can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.
Leflunomide is indicated for the treatment of active RA to reduce signs and symptoms, inhibit structural damage and improve physical function. Corticosteroids, aspirin, or other NSAIDs may be continued during leflunomide use. Leflunomide is contraindicated in women who are or may become pregnant.
Leflunomide is a pyrimidine synthesis inhibitor that blocks autoimmune antibodies and reduces inflammation. It also inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidine synthesis pathway and has antiproliferative activity. Complete blood counts (CBCs) and liver enzymes must be monitored.
Sulfasalazine (SSZ) is indicated for the treatment of patients with RA who have had an inadequate response to salicylates or other NSAIDs. It acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.
SSZ delayed-release tablets do not have an immediate response; therefore, concurrent treatment with NSAIDs or other analgesics is recommended at least until the effect of the delayed-release tablets is apparent. The initial dosage is 0.5-1 g/day. The dosage can be adjusted to a dose of 3 g/day after 12 weeks if an adequate clinical response is not seen.
Hydroxychloroquine (HCQ) is approved for the treatment of acute or chronic RA. The initial dosage is 400-600 mg/day; dosages should be computed on the basis of patient body weight. If a good clinical response is seen over a period of 4 to 12 weeks, the dosage can be reduced by 50% and continued at a level of 200-400 mg/day. The risk of retinopathy is greater when this dosage is exceeded. It should be noted that each 200 mg tablet contains only 155 mg of active drug.
Patients must have a baseline eye examination (including color and vision testing, funduscopic examination, and visual-field testing) performed before starting HCQ therapy. Most rheumatologists recommend an HCQ eye examination every 6-12 months.
Rituximab is most often used in combination with methotrexate (MTX). It has been shown to be effective at reducing signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to therapy with 1 or more tumor necrosis factor (TNF) antagonists. Treatment with rituximab may deplete CD20+ B cells. The usual regimen consists of 2 intravenous (IV) infusions of 1000 mg, separated by 2 weeks, in combination with MTX.
DMARDs represent the most important measure in the successful treatment of RA.
Although azathioprine is not a first-line agent, it is sometimes used in the treatment of active RA to reduce signs and symptoms, particularly in patients who may have coinciding connective tissue diseases, such as systemic lupus erythematosus. Aspirin, NSAIDs, or low-dose glucocorticoids may be continued during treatment with azathioprine. The mechanism whereby azathioprine affects autoimmune diseases is unknown; however, it works primarily on T cells.
The initial dosage is 1 mg/kg/day (50-100 mg/day) given as a single dose or in divided doses twice daily. The dosage may be increased by 0.5 mg/kg/day at 6-8 weeks and thereafter at 4-week intervals, up to a maximum dosage of 2.5 mg/kg/day. Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.
Tocilizumab is an IL-6 receptor inhibitor. It is indicated for moderate to severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. It has been approved as an IV infusion or SC injection that may be used alone or in combination with MTX or other DMARDs. The usual dosage for IV infusion is 4 mg/kg once every 4 weeks, with a maximum dose of 800 mg per infusion. The usual dose for SC injection is 162 mg given every other week, then increased to every week for patients < 100 kg, or 162 mg given every week for patients≥100 kg.
Tofacitinib is an oral Janus kinase (JAK) pathways inhibitor. It is indicated as second-line treatment for moderate to severe active RA in patients with an inadequate response to or intolerance of MTX. Tofacitinib may be used as monotherapy or in combination with MTX or other nonbiologic DMARDs, but it should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine and cyclosporine).
Although cyclosporine is approved for the treatment of patients with severe active RA in which the disease has not adequately responded to MTX, it is not commonly used to treat RA, because of its nephrotoxicity. When cyclosporine is used, patients' renal function must be closely monitored.
Cyclosporine can be used in combination with MTX in RA patients who do not have an adequate response to MTX alone. The initial dosage is 2.5 mg/kg/day divided twice daily. The onset of action generally occurs between 4 and 8 weeks. The dosage may be titrated to a maximum of 4 mg/kg/day.
MTX is a folic acid antagonist that is approved for the management of severe active RA in patients who have had an insufficient therapeutic response to or are intolerant of an adequate trial of first-line therapy, including full-dose NSAIDs. MTX is started at lower doses and increased to full doses within approximately 4-6 weeks. The initial dosage is 7.5 mg/wk PO in a single dose; alternatively, the weekly regimen may be administered in divided doses of 2.5 mg PO at 12-hour intervals for 3 doses. A self- administered subcutaneous injection is also available (Otrexup), and may improve bioavailability and avoid GI effects for patients who need higher doses.
The CBC should be monitored monthly and liver and renal function every 1-3 months during therapy (though American College of Rheumatology [ACR] guidelines indicate that it may be safe to monitor liver function every 3-4 months).
MTX is contraindicated in pregnancy, because it is an abortifacient and has teratogenic effects, including craniofacial abnormalities, limb defects, and central nervous system (CNS) defects such as anencephaly, hydrocephaly, and meningomyelopathy, especially with first-trimester exposure.
Anakinra is a recombinant, nonglycosylated form of the human interleukin (IL)-1 receptor antagonist (IL-1Ra) that is indicated for reducing signs and symptoms and slowing the progression of structural damage of moderately to severely active RA that has failed treatment with 1 or more DMARDs. Anakinra can be used alone or in combination with DMARDs other than TNF-blocking agents.
The initial dosage is 100 mg/day subcutaneous (SC) injection. However, anakinra is not commonly used to treat RA, because of its relative inefficacy. It is more often used to treat juvenile idiopathic arthritis (JIA) and periodic fever syndromes.
Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for the full T-cell activation that is implicated in RA pathogenesis.
This agent is approved for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA. Abatacept can be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.
Abatacept is dosed according to body weight; after the initial IV infusion, it is repeated at week 2 and week 4 and then every 4 weeks. Maintenance doses may be administered as a monthly IV infusion or by the patient as a weekly SC injection.
DMARDs, TNF Inhibitors
The recognition of TNF-α and IL-1 as central proinflammatory cytokines has led to the development of agents that block either these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions.
The TNF inhibitors, which bind TNF and thus prevent its interaction with its receptors, include etanercept, infliximab, golimumab, certolizumab, and adalimumab. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually MTX, has been administered without sufficient success.
Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, the emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections. Rarely, demyelinating disorders and bone marrow suppression occur.
Acute and chronic infections, demyelinating disorders, New York Heart Association (NYHA) class III or IV heart failure, and recent malignancies are contraindications for the use of TNF inhibitors. A thorough search for latent tuberculosis using chest radiography or purified protein derivative (PPD) testing is recommended before these agents are started. Patients taking anti-TNF agents must avoid live-virus vaccines to avoid the risk of serious infection.
Infliximab, a chimeric monoclonal antibody against TNF-α, is approved for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA, in combination with MTX. This agent binds to cells that express membrane TNF. Infliximab is administered at doses of 3 mg/kg IV at weeks 0, 2, and 6 and then every 4-8 weeks, usually with MTX.
Etanercept, a bivalent p75–TNF receptor linked to the Fc portion of human immunoglobulin G (IgG), is approved for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA. It can be given alone or in combination with MTX. This agent binds lymphotoxin (formerly termed TNF-β) in addition to soluble TNF-α. The usual dosage is 25 mg SC twice weekly or 50 mg SC weekly, with or without concomitant MTX.
Golimumab, a human monoclonal antibody to TNF-α, inhibits TNF-α bioactivity, thereby modulating immune activity in patients with RA. It is approved for the treatment of adults with moderately to severely active RA, in combination with MTX. It may be administered as either a SC injection every month, or as an IV infusion every 2 months following 2 once monthly doses. Golimumab should be given in combination with MTX.
Certolizumab is a pegylated anti−TNF-α agent, which results in disruption of the inflammatory process in RA. It is indicated for the treatment of adults with moderately to severely active RA. The standard regimen consists of an initial dose of 400 mg and 2 subsequent doses of 400 mg at weeks 2 and 4 (given as 2 SC injections of 200 mg), followed by 200 mg every other week.
Adalimumab is indicated to reduce inflammation and inhibit progression of structural damage in moderate to severe RA, alone or in combination with MTX or other nonbiologic DMARDs. This agent is reserved for those who experience an inadequate response to 1 or more DMARDs. Adalimumab can be used alone or in combination with MTX or other DMARDs.
Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human TNF. It binds specifically to TNF-α and blocks interaction with p55 and p75 cell-surface TNF receptors.
Although tetracyclines are not typically used to treat RA, the ACR recommends minocycline monotherapy in patients with a disease duration shorter than 24 months who have low disease activity and no poor prognostic factors.[68, 4]
The minocycline regimen that is most commonly used in RA is 100 mg twice daily for up to 2 years. The anti-inflammatory effects of minocycline may result from inhibition of inflammatory cell migration and transformation of lymphocytes.
Nonsteroidal Anti-inflammatory Drugs
NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and therefore are not sufficient to treat RA when used alone. Like corticosteroids, NSAIDs can be reduced in dose or discontinued with successful DMARD therapy. These agents decrease intraglomerular pressure and decrease proteinuria.
The several dozen NSAIDs available can be classified into several different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, celecoxib, and diclofenac.
Ibuprofen is indicated for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Naproxen is used to relieve mild to moderate pain. This agent inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Diclofenac is one of a series of phenylacetic acids that have demonstrated anti-inflammatory and analgesic properties in pharmacologic studies. It is believed to inhibit COX, which is essential in the biosynthesis of prostaglandins.
Diclofenac can cause hepatotoxicity; therefore, liver enzymes should be monitored in the first 8 weeks of treatment. This agent is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.
Ketoprofen is used to relieve mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses higher than 75 mg do not yield increased therapeutic effects. Administer high doses with caution, and closely observe the patient for response.
Celecoxib is approved for the relief of signs and symptoms of RA. It primarily inhibits COX-2, which is considered an inducible isoenzyme (induced during pain and inflammatory stimuli). Inhibition of COX-1 may contribute to NSAID gastrointestinal (GI) toxicity. At therapeutic concentrations, celecoxib does not inhibit COX-1, thus potentially resulting in decreased GI toxicity. Administer the lowest possible dose for each patient. Use of celecoxib has been associated with an increased risk of cardiovascular toxicity.
Analgesics such as acetaminophen may be used in patients with RA.
Acetaminophen is used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, those with upper GI disease, and those who are taking oral anticoagulants. This agent does not have anti-inflammatory properties.
Tramadol has been used to reduce pain in patients with RA. However, this agent only provides analgesic effects and does not have anti-inflammatory properties.
The immediate-release formulation of tramadol is approved for the management of moderate to moderately severe pain in adults. The extended-release formulation is used for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of pain for an extended period of time.
Topical Skin Products
Topical agents such as diclofenac can provide analgesia for patients with RA. This agent is commonly used in patients who experience acute pain.
Diclofenac topical gel is approved in patients with osteoarthritis at a dosage of 32 g/day applied over all affected joints. It has also been used to provide analgesic effects in patients with RA.
Corticosteroids are potent anti-inflammatory drugs commonly used in patients with RA to bridge the time until DMARDs become effective. Prednisone dosages as high as 10 mg/day are typically used, but some patients may require even higher dosages. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.
Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Circadian (ie, bedtime) administration of modified-release prednisone (Rayos) has been shown shown to decrease morning stiffness with RA.
Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.
Prednisolone controls or prevents inflammation by controlling the rate of protein synthesis, suppressing the migration of PMNs and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at the cellular level.
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|Early RA (<6 months)||
|(Notable change from 2012 to 2015 guidelines: The 2015 guidelines do not recommend initial combination DMARD therapy in early RA with moderate to high disease activity)|
|Established RA (=6 month or meets 1987 ACR RA classification criteria)||If disease activity remains moderate or high despite DMARD monotherapy, ACR guidelines recommend one of the following:
|If disease activity remains moderate or high despite use of a single anti-TNF biologic:
|If disease activity remains moderate or high despite use of one anti-TNF biologic and one non-TNF biologic:
|(Notable change from 2012 to 2015 guidelines: Instead of switching from one anti-TNF biologic to another anti-TNF biologic because of continued activity, it is recommended to change first to a non-TNF biologic)|
|Result of Initial/Repeat TST or IGRA||Recommendation|
|Negative||In patients with RA but without risk factors or clinical suspicion for TB
|In patients with RA and immunosuppression plus LTBI risk factors
|ACR = American College of Rheumatology; IGRA = interferon gamma release assay; LBTI = latent tuberculosis infection; RA = rheumatoid arthritis; TB = tuberculosis; TST = tuberculin skin test.
Source: Singh JA, Saag KG, et al2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research http://dx.doi.org/10.1002/art.39480 (2015).