Category:DMARDs

A DMARD (disease-modifying antirheumatic medicine) is a medicine that slows or arrests the underlying joint destruction of rheumatoid arthritis and the other inflammatory arthritides, rather than only relieving the pain and stiffness of the active disease. The term was coined to draw a contrast with the symptomatic treatments (the non-steroidal anti-inflammatory medicines and the systemic glucocorticoids) that produced rapid symptom relief but did not preserve the joint over time. The category includes the conventional synthetic DMARDs (methotrexate, hydroxychloroquine, sulfasalazine, leflunomide), the biologic DMARDs (the TNF inhibitors and the medicines targeting other cytokines and lymphocyte populations), and the targeted synthetic DMARDs (the Janus kinase inhibitors).

The first effective DMARD was, by accident, a metal. In 1929 the French rheumatologist Jacques Forestier, working at the spa town of Aix-les-Bains on the hypothesis that rheumatoid arthritis might be a chronic infection by Mycobacterium tuberculosis (a common but ultimately incorrect hypothesis of the era), administered injectable gold salts on the precedent of Koch's earlier observation that gold cyanide inhibited mycobacterial growth in vitro.^[1] The TB hypothesis was wrong, but the patients improved. Forestier's gold sodium thiomalate became, and remained for sixty years, the standard slow-acting antirheumatic medicine, even after it was clear that the mechanism had nothing to do with tuberculosis. Gold has since been retired in favour of more effective and better-tolerated medicines, but it established the principle that a slow-acting medicine could modify the disease.

The antimalarials hydroxychloroquine and chloroquine entered rheumatology by a similarly indirect route. During the Second World War, American servicemen taking quinacrine and chloroquine for malaria prophylaxis in the Pacific theatre were noted to have improvement in pre-existing rheumatoid arthritis and lupus; postwar trials confirmed the effect, and hydroxychloroquine (the better-tolerated 4-aminoquinoline derivative) became standard combination therapy for systemic lupus and a backbone medicine for mild rheumatoid arthritis. Sulfasalazine, originally synthesised by Nanna Svartz in Stockholm in 1942 as a combination of sulfapyridine (an antibacterial) and 5-aminosalicylate (an anti-inflammatory) on the same now-discredited infectious-cause hypothesis, has retained a place in seronegative arthritis and inflammatory bowel disease.

The pivotal modern conventional DMARD is methotrexate. The medicine had been used for psoriasis since 1958 (Edmundson and Guy), but its use in rheumatoid arthritis depended on a series of controlled trials in the 1980s led by Michael Weinblatt at the Brigham and Women's Hospital. Weinblatt showed in 1985 that low-dose (7.5-to-25 mg) once-weekly oral methotrexate produced substantial clinical improvement in rheumatoid arthritis that persisted at long-term follow-up, with toxicity (transaminitis, oral ulcers, cytopenias) that was manageable in routine clinical practice.^[2] The medicine has since become the anchor of essentially every modern combination regimen and is the comparator against which every new DMARD is tested.

The transformative event of contemporary rheumatology was the introduction of the biologic DMARDs. The London immunologists Marc Feldmann and Ravinder Maini at the Kennedy Institute, working in the late 1980s on cytokines in rheumatoid synovium, had shown that tumour necrosis factor alpha was the upstream cytokine of the inflammatory cascade in rheumatoid arthritis. Their 1992 trial of the chimeric anti-TNF monoclonal antibody cA2 (infliximab) in 20 patients with refractory disease produced dramatic improvement that motivated the broader programme; Centocor's infliximab was approved in 1998, Immunex's etanercept (a soluble TNF-receptor decoy fusion protein) the same year, and Abbott's fully human adalimumab in 2002.^[3] The TNF inhibitors were the prototype for a class that has since included the IL-6 receptor antagonist tocilizumab (2010), the costimulation modulator abatacept (CTLA-4-Ig fusion, 2005), the anti-CD20 monoclonal rituximab (2006 for RA after long use in lymphoma), the IL-1 receptor antagonist anakinra (2001), and an expanding list of cytokine- and lymphocyte-targeted biologics.

The most recent class of DMARD is the targeted synthetic group: the oral Janus kinase (JAK) inhibitors. JAK1, JAK2, JAK3, and TYK2 are the intracellular kinases that transduce signals from many of the cytokine receptors blocked by the biologics; inhibiting them with a small molecule reproduces, in part, the effect of multiple biologic medicines at once. Tofacitinib (Pfizer, 2012) was the first; baricitinib (Lilly, 2018) and upadacitinib (AbbVie, 2019) followed. The class has produced efficacy comparable to the TNF inhibitors but with a different safety profile, dominated by herpes zoster reactivation, lipid elevation, venous thromboembolism, and, in the ORAL Surveillance postmarketing trial of tofacitinib in older smokers, a small excess of major adverse cardiovascular events and malignancy that has led to restrictions in older or higher-risk patients.

The contemporary practice of rheumatology is built on a "treat-to-target" strategy: the DMARDs are escalated until a measurable target of low disease activity or remission is reached, monitored by composite disease-activity indices (DAS28, CDAI, SDAI) every three months. Early aggressive treatment (initiation of DMARDs within the first three to six months of disease) preserves joint function in a way that delayed treatment does not, and a substantial fraction of patients with rheumatoid arthritis now achieve sustained clinical remission on combination therapy. The therapeutic transformation in rheumatology between 1985 and 2020 is comparable, in magnitude and in clinical impact, to the transformations in HIV medicine and in oncology of the same period.

By category:

• Conventional synthetic DMARDs:
  • Methotrexate (the anchor medicine; also indexed under antifolates and antimetabolites)
  • Hydroxychloroquine and chloroquine (4-aminoquinolines, also indexed under antimalarials)
  • Sulfasalazine
  • Leflunomide (pyrimidine synthesis inhibitor)
  • Azathioprine, cyclosporine, mycophenolate (cross-listed under immunosuppressants)
• Biologic DMARDs (cross-indexed under biologics):
  • TNF inhibitors: adalimumab, infliximab, etanercept, golimumab, certolizumab pegol
  • IL-6 receptor antagonist: tocilizumab, sarilumab
  • Costimulation modulator: abatacept
  • B-cell depleting: rituximab
  • IL-1 receptor antagonist: anakinra, canakinumab
  • IL-17 inhibitor (axial spondyloarthritis, psoriatic arthritis): secukinumab, ixekizumab
  • IL-12/23 inhibitor: ustekinumab, guselkumab, risankizumab
• Targeted synthetic DMARDs (oral JAK inhibitors): tofacitinib, baricitinib, upadacitinib, filgotinib
• Largely retired: gold salts (gold sodium thiomalate, auranofin), penicillamine

The boundary of this category is "medicine that modifies the underlying disease course of an inflammatory arthritis." The NSAIDs and the systemic glucocorticoids are symptomatic medicines used adjunctively in inflammatory arthritis but are not DMARDs; they are listed under their own categories. The biologics for non-arthritic conditions (the anti-IL-5 medicines for severe asthma, the anti-IL-23 medicines for psoriasis without joint involvement, the anti-CD20 in oncologic indications) are not DMARDs in this category sense and are listed under their primary indication. The medicines used for the systemic-autoimmune conditions adjacent to the inflammatory arthritides (the cyclophosphamide- and mycophenolate-based regimens for lupus nephritis and vasculitis, the belimumab and anifrolumab for SLE) are conventionally collected under immunosuppressants and cross-indexed where they have an articular indication.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.