musculoskeletal and connective tissue disorders
Rheumatoid Arthritis (RA)
Drugs for Rheumatoid Arthritis
The goal is to reduce inflammation to prevent erosions, progressive deformity, and loss of joint function. A treat-to-target approach to achieve full disease remission or minimal disease activity has been suggested ( Drugs for rheumatoid arthritis references , The optimal combinations of drugs are not yet clear. However, some data suggest that certain combinations of drugs from different classes (eg,methotrexateplus other DMARDs, a rapidly tapered corticosteroid plus a DMARD,methotrexateplus a TNF-alpha antagonist, or a TNF-alpha antagonist plus a DMARD) are more effective than using DMARDs alone sequentially or in combination with other DMARDs. In general, biologic agents are not given in combination with each other due to increased frequency of infections. The following is an example of initial therapy: Methotrexate10 to 15 mg orally once/week (withfolic acid1 mg orally once/day) is given. If tolerated and not adequate, the dosage of weeklymethotrexateis increased at 3- to 5-week intervals to a maximum of 25 mg orally or by injection (oral bioavailability decreases above 15 mg in a single dose). If response is not adequate, a biologic agent is usually added. Alternatively, triple therapy withmethotrexate,hydroxychloroquine, andsulfasalazineis a cost-effective option, but long-term tolerability is challenging. Leflunomidemay be used instead ofmethotrexateor added tomethotrexatewith close monitoring of serum transaminase levels and complete blood count. Methotrexateandleflunomide(and some other medications) must be avoided if pregnancy is anticipated. is no longer used for rheumatoid arthritis because effective doses are often toxic. Only one NSAID should be given at a time (see table Nonsteroidal Anti-inflammatory Drug (NSAID) Treatment of Rheumatoid Arthritis ), although patients may also take 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.Celecoxib200 mg orally once/day has a comparable cardiovascular safety profile to nonselective NSAIDs. It remains unclear whether full-dosecelecoxib(200 mg orally 2 times a day ) has cardiovascular risks comparable to the nonselective NSAIDs. has no significant antiplatelet effect. NSAIDs may increase cardiovascular risk (see 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 NSAIDs should be used at the lowest possible dose needed to mitigate their adverse effects. (See table 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: Combinations of DMARDs may be more effective than single drugs. For example,hydroxychloroquine,sulfasalazine, andmethotrexatetogether are more effective thanmethotrexatealone or the other two together. Combining a DMARD with another drug, such asmethotrexateplus a tumor necrosis factor (TNF)-alpha antagonist or a rapidly tapered corticosteroid, may be more effective than using DMARDs alone. Methotrexateis 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).Methotrexateshould 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), andalbuminand 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 usemethotrexate. Severe relapses of arthritis can occur after withdrawal ofmethotrexate. Paradoxically, rheumatoid nodules may enlarge withmethotrexatetherapy. In rheumatoid arthritis patients with stable parenchymal lung disease,methotrexatecan be continued with close monitoring of their respiratory status, if themethotrexateis controlling joint inflammation. Hydroxychloroquinecan 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. Sulfasalazinecan 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,sulfasalazinemay cause reversible oligospermia. Leflunomideinterferes with an enzyme involved with pyrimidine metabolism. It is about as effective asmethotrexatebut 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 injectionsof depot corticosteroids may temporarily help control pain and swelling in particularly painful joints.Triamcinolonehexacetonide may suppress inflammation for the longest time.Triamcinoloneacetonide andmethylprednisoloneacetate 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 withazathioprineorcyclosporine(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 tomethotrexatetherapy to increase the effect and possibly prevent the development of drug-neutralizing antibodies. ( Drugs for rheumatoid arthritis references ). TNF-alpha antagonists should probably be stopped before major surgery to decrease the risk of perioperative infection ( Sarilumabis 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. Tocilizumabis 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. Anakinrais 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. may have a blunted immune response to the COVID-19 Vaccine and have poorer outcomes if infected with SARS-CoV-2. Therefore, Rituximabtherapy 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 Screening for TB 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 .) JAK inhibitors carry an increased incidence of herpes zoster, thus Herpes Zoster Vaccine is strongly suggested prior to use of these medications. Baricitinibis 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. Tofacitinibis a JAK inhibitor that is given orally with or without concomitantmethotrexateto patients who do not respond tomethotrexatealone or other biologic agents. Upadacitinibis a JAK inhibitor that is given orally to adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance tomethotrexate. Other JAK inhibitors that may soon become available in the US include filgotinib and peficitinib. than with TNF-alpha antagonists, especially in patients over age 50 years and with at least 1 risk factor for cardiovascular disease ( Drugs for rheumatoid arthritis references ). 1.Fraenkel L, Bathon JM, England BR, et al: 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.Arthritis Rheumatol73(7):1108-1123, 2021. doi:10.1002/art.41752 2.Smolen JS, Landewé RBM, Bijlsma JWJ, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.Ann Rheum Dis79(6):685-699, 2020. doi:10.1136/annrheumdis-2019-216655 3.Sammaritano LR, Bermas BL, Chakravarty EE, et al: 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases.Arthritis Care Res (Hoboken)72(4):461-488, 2020. doi:10.1002/acr.24130 4.Goodman SM, Springer BD, Chen AF, et al: 2022 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty.Arthritis Care Res (Hoboken)74(9):1399-1408, 2022. doi:10.1002/acr.24893 5.Singh JA, Saag KG, Bridges SL Jr, et al: 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.Arthritis Rheumatol68(1):1-26, 2016. doi:10.1002/art.39480 6.Ytterberg SR, Bhatt DL, Mikuls TR, et al: Cardiovascular and cancer risk withtofacitinibin rheumatoid arthritis.N Engl J Med386(4):316-326, 2022. doi:10.1056/NEJMoa2109927 