Conventional & Biologic DMARDs

Overview: Three Families of DMARDs

Disease modification. NSAIDs and glucocorticoids relieve pain and swelling, but only disease-modifying antirheumatic drugs (DMARDs) slow the synovitis that erodes cartilage and bone. They form three families: conventional synthetic DMARDs (methotrexate, hydroxychloroquine, sulfasalazine, leflunomide), biologics (monoclonal antibodies and receptor fusion proteins), and oral targeted synthetic DMARDs (JAK inhibitors, apremilast). Conventional agents take weeks to months to work, so a short glucocorticoid course often bridges the gap.

Reading the names. -ximab is chimeric (infliximab, rituximab), -zumab humanized (tocilizumab, certolizumab, ixekizumab), -umab fully human (adalimumab, golimumab, secukinumab, ustekinumab, guselkumab), and -cept a receptor fused to an IgG Fc (etanercept, abatacept). Chimeric proteins are the most immunogenic, provoking infusion reactions and neutralizing anti-drug antibodies.

Conventional Synthetic DMARDs

Methotrexate. This folate analog inhibits dihydrofolate reductase (DHFR), depleting the tetrahydrofolate needed for purine and thymidylate synthesis. At low once-weekly rheumatologic doses (roughly 7.5–25 mg), retained methotrexate polyglutamates also inhibit AICAR transformylase; accumulating AICAR increases adenosine release, and adenosine acting on A2A receptors damps neutrophil and lymphocyte activation. It is the anchor drug for RA and also treats psoriasis and the peripheral arthritis of PsA.

Methotrexate toxicity. Expect stomatitis and mucositis, cytopenias, hepatic fibrosis or cirrhosis (worse with alcohol, obesity, and diabetes), hypersensitivity pneumonitis (fever, dry cough, interstitial infiltrates), and teratogenicity (an abortifacient, stopped before conception). Daily folic acid prevents much of the mucosal, GI, and liver toxicity without reducing efficacy; CBC, liver enzymes, and creatinine are monitored. Because it is renally cleared, toxicity climbs in kidney failure and with trimethoprim-sulfamethoxazole, which adds a second antifolate and slows excretion. Leucovorin (folinic acid) bypasses DHFR to rescue overdose.

Methotrexate for RA is taken once a WEEK; mistaken daily dosing causes fatal pancytopenia and mucositis.

Hydroxychloroquine. A weak base trapped in acidic lysosomes and endosomes, it raises their pH, impairing peptide processing for MHC class II and blunting the endosomal TLR7 and TLR9 signals that drive type I interferon. It treats mild RA, joins methotrexate and sulfasalazine in "triple therapy," and is the backbone of SLE treatment. It is minimally immunosuppressive and continued through pregnancy and breastfeeding. Bull's-eye maculopathy depends on cumulative dose: keep the dose at or below 5 mg/kg/day of actual body weight, examine the retina at baseline, and screen yearly after 5 years (sooner with kidney disease or tamoxifen).

Sulfasalazine. Colonic bacteria cleave its azo bond into sulfapyridine, which is absorbed and supplies the antirheumatic effect and most toxicity, and 5-aminosalicylic acid (mesalamine), which acts locally in ulcerative colitis. It treats RA, peripheral (not axial) spondyloarthritis, and IBD-associated arthritis. Adverse effects: nausea, reversible oligospermia, hemolysis in G6PD deficiency, agranulocytosis, sulfonamide rashes (rarely Stevens-Johnson syndrome), orange-yellow urine, and reduced folate absorption. It is compatible with pregnancy when folate is supplemented.

Leflunomide. Its active metabolite teriflunomide inhibits dihydroorotate dehydrogenase (DHODH), the mitochondrial enzyme of de novo pyrimidine synthesis, so activated lymphocytes arrest in G1. It substitutes for methotrexate in RA and PsA. Toxicities: diarrhea, hepatotoxicity, hypertension, alopecia, cytopenias, and teratogenicity. Enterohepatic recycling keeps it in the body for up to 2 years, so pregnancy planning requires a cholestyramine washout with confirmed undetectable levels. Compare mycophenolate, which inhibits IMP dehydrogenase in guanine nucleotide synthesis.

TNF-α Inhibitors

Agents. Four monoclonal antibodies neutralize TNF-α: infliximab (chimeric, IV, usually combined with methotrexate to limit anti-drug antibodies), adalimumab and golimumab (fully human), and certolizumab pegol (a PEGylated Fab′ fragment without an Fc region). Etanercept is instead the p75 TNF receptor fused to IgG1 Fc, a soluble decoy that captures TNF-α and lymphotoxin-α. The class treats RA, PsA, psoriasis, and ankylosing spondylitis; the monoclonals also treat Crohn disease and ulcerative colitis, but etanercept is ineffective in IBD.

Certolizumab lacks an Fc region, so the neonatal Fc receptor barely carries it across the placenta; it is the TNF inhibitor favored in pregnancy.

Infection risk. TNF-α activates macrophages and holds granulomas together. Blocking it reactivates latent tuberculosis, often extrapulmonary or disseminated, and unmasks endemic mycoses (histoplasmosis, coccidioidomycosis) and intracellular bacteria such as Listeria and Legionella. Hepatitis B can also reactivate.

Noninfectious effects. TNF inhibitors can induce a lupus-like syndrome in which anti-dsDNA is often positive (classic drug-induced lupus is anti-histone positive), provoke demyelination (MS, optic neuritis), worsen NYHA class III–IV heart failure, trigger paradoxical psoriasiform eruptions, and slightly raise lymphoma and non-melanoma skin cancer risk. MS and advanced heart failure are contraindications; infliximab also causes infusion reactions.

Before any biologic or JAK inhibitor:

Other Biologics: Cytokine and Cell Targets

IL-6 receptor. Tocilizumab (and sarilumab) block soluble and membrane IL-6 receptors, which signal through gp130. Uses: RA, giant cell arteritis (glucocorticoid-sparing), systemic JIA, and cytokine release syndrome after CAR-T therapy. IL-6 drives hepatic CRP synthesis, so CRP and fever stay low and can hide serious infection. Other risks: lower GI perforation (especially with diverticulitis), rising LDL and transaminases, and neutropenia.

IL-17A. Secukinumab and ixekizumab neutralize IL-17A; brodalumab blocks IL-17 receptor A. They are among the most effective drugs for plaque psoriasis and also treat PsA and ankylosing spondylitis. IL-17 recruits neutrophils and induces epithelial antimicrobial peptides, so blockade predisposes to mucocutaneous candidiasis and can trigger or worsen IBD.

IL-12/23 and IL-23. IL-12 (p35 + p40) drives Th1 cells and IFN-γ, whereas IL-23 (p19 + p40) sustains IL-17- and IL-22-producing Th17 cells. Ustekinumab binds the shared p40 subunit and blocks both; guselkumab, risankizumab, and tildrakizumab bind p19 and block IL-23 alone. They treat psoriasis and PsA, and ustekinumab and several p19 inhibitors treat Crohn disease and ulcerative colitis, but IL-23-pathway blockers do not help axial spondyloarthritis.

IL-1. Anakinra is recombinant IL-1 receptor antagonist (daily subcutaneous injection); canakinumab (anti-IL-1β antibody) and rilonacept (an IL-1 "trap" fusion protein) act on the same pathway. Benefit in RA is modest, but IL-1 blockade excels in autoinflammatory disease: cryopyrin-associated periodic syndromes (gain-of-function NLRP3 mutations → excess caspase-1 cleavage of pro-IL-1β, with fevers, urticaria-like rash, and AA amyloidosis risk), colchicine-resistant familial Mediterranean fever, systemic JIA and adult-onset Still disease, and gout flares.

Abatacept. Naive T cells need signal 1 (TCR with peptide–MHC) and signal 2 (CD28 binding B7 molecules CD80/CD86 on antigen-presenting cells). Abatacept, CTLA-4 fused to IgG1 Fc, binds CD80/CD86 more avidly than CD28, so T cells receive signal 1 alone and become anergic. It treats RA, PsA, and JIA; combining it with a TNF inhibitor adds serious infections, and COPD may worsen. Belatacept, a relative, prevents kidney-transplant rejection.

Rituximab. This chimeric anti-CD20 antibody depletes pre-B through memory B cells by antibody-dependent cellular cytotoxicity, complement, and apoptosis. It treats seropositive RA after TNF-inhibitor failure, GPA and MPA, pemphigus vulgaris, and B-cell lymphomas. Plasma cells lack CD20, so existing antibody levels fall slowly, but new vaccine responses are blunted. Risks: first-infusion reactions, hepatitis B reactivation, progressive multifocal leukoencephalopathy (JC virus), and hypogammaglobulinemia.

Targeted Synthetic DMARDs

JAK inhibitors. Many cytokine receptors signal through associated Janus kinases, which phosphorylate STAT proteins that dimerize and enter the nucleus to switch on inflammatory genes. Oral tofacitinib (JAK1/JAK3), baricitinib (JAK1/JAK2), and upadacitinib (JAK1) interrupt signaling from IL-6, interferons, and common γ-chain cytokines (IL-2, IL-7, IL-15, IL-21), treating RA, PsA, ankylosing spondylitis, and ulcerative colitis. Herpes zoster is the signature infection, so recombinant zoster vaccine is given first. In older RA patients with cardiovascular risk, tofacitinib caused more cardiovascular events, venous thromboembolism, and malignancy than TNF inhibitors, prompting boxed warnings and use after TNF-inhibitor failure. LDL rises and cytopenias occur.

Apremilast. Inhibiting phosphodiesterase-4 raises cAMP in immune cells, lowering TNF-α, IL-17, and IL-23 while increasing IL-10. It is a modest oral option for plaque psoriasis, PsA, and Behçet oral ulcers, causing diarrhea, nausea, headache, weight loss, and depressed mood; no routine laboratory monitoring or TB screening is needed.

Matching the Drug to the Disease

Rheumatoid arthritis. Start methotrexate early, often with a brief glucocorticoid bridge, and treat to a target of remission or low disease activity. If disease stays active after about 3–6 months, add a biologic (TNF inhibitor, abatacept, tocilizumab, or rituximab if seropositive) or a JAK inhibitor, or escalate to triple therapy. Leflunomide replaces methotrexate when it is contraindicated; hydroxychloroquine or sulfasalazine alone suits mild disease.

Pregnancy rule of thumb: hydroxychloroquine, sulfasalazine, and certolizumab are compatible; methotrexate and leflunomide are not.