DMARD & Biologic Therapy: Screening, Monitoring & Toxicity

Before starting immunosuppression

The screen. Before a biologic or JAK inhibitor, and as a baseline for conventional DMARDs, every patient needs a TB test, hepatitis B and C serologies, a CBC, a metabolic panel with liver enzymes and creatinine, and a pregnancy test or contraception plan. Lipids are added before IL-6 or JAK inhibitors.

Latent tuberculosis. A positive IGRA with a normal chest radiograph and no symptoms is latent infection. Start latent TB therapy (for example 4 months of rifampin or 9 months of isoniazid) and begin the TNF inhibitor after about a month; active TB must be fully treated first. TNF-α maintains granulomas, so TB that reactivates during anti-TNF therapy is often extrapulmonary or disseminated. Patients with ongoing exposure risk are rescreened yearly.

Hepatitis B. HBsAg-positive patients receive antiviral prophylaxis with entecavir or tenofovir before rituximab, TNF or JAK inhibitors or high-dose glucocorticoids. Resolved infection (HBsAg negative, anti-HBc positive) can still reactivate, especially with B-cell depletion, so rituximab calls for prophylaxis or close monitoring of HBV DNA and ALT. Reactivation can cause fulminant hepatitis.

Vaccines. Live vaccines (MMR, varicella, yellow fever, intranasal influenza) are given at least 4 weeks before biologics, JAK inhibitors or high-dose steroids and avoided during therapy. Non-live vaccines are safe at any time: recombinant zoster (important before JAK inhibitors), pneumococcal conjugate vaccine (PCV20 or PCV21), yearly inactivated influenza, COVID-19 and hepatitis B if nonimmune. Rituximab blunts antibody responses, so vaccines are best given before the first infusion.

Methotrexate

Mechanism and dosing. Methotrexate is the anchor DMARD for RA. It inhibits dihydrofolate reductase, and at low doses much of its anti-inflammatory effect comes from adenosine release. It is taken once weekly, orally or subcutaneously, usually 7.5–25 mg. Folic acid reduces mucositis, GI upset and transaminase elevation without reducing efficacy.

Accidental daily dosing of weekly methotrexate is a recurring cause of fatal toxicity; prescriptions and counseling must state once-weekly dosing explicitly.

Monitoring. Baseline CBC, liver tests, creatinine, hepatitis B and C serologies and a chest radiograph are obtained. CBC, liver tests and creatinine are repeated every 2–4 weeks for the first 3 months, every 8–12 weeks between months 3 and 6, and every 12 weeks thereafter.

Liver. Hepatic fibrosis is the long-term concern. Alcohol should be limited, and fatty liver, obesity, diabetes and preexisting liver disease increase risk; significant liver disease is a contraindication.

Marrow and kidneys. Methotrexate is cleared by the kidneys, so CKD, dehydration or acute kidney injury raises drug levels, and severe renal impairment is a contraindication. TMP-SMX adds antifolate activity and reduces excretion, precipitating pancytopenia. Painful mouth ulcers are often the first sign. Toxicity is treated by stopping the drug and giving leucovorin (folinic acid), a reduced folate that bypasses the DHFR block; ordinary folic acid cannot.

Lung. Methotrexate pneumonitis is a hypersensitivity reaction, usually in the first year, with subacute dry cough, dyspnea, fever, hypoxemia and bilateral infiltrates. The drug is stopped permanently, infection including Pneumocystis is excluded, and glucocorticoids are given.

Pregnancy. Methotrexate is a teratogen and abortifacient. Contraception is required, and it is stopped 1–3 months before a planned conception.

Other conventional DMARDs

Hydroxychloroquine. This antimalarial is used for mild RA, in combination regimens and as the backbone of SLE therapy. It needs no routine blood monitoring, but it causes dose-related retinopathy (bull's-eye maculopathy). A baseline eye exam is followed by annual screening after 5 years, sooner with risk factors: dose above 5 mg/kg/day of actual body weight, CKD, tamoxifen use or preexisting macular disease. It is safe in pregnancy and breastfeeding.

Sulfasalazine. Split into sulfapyridine and 5-ASA by colonic bacteria, it causes GI upset, sulfa rash, hemolysis in G6PD deficiency, agranulocytosis (CBC monitoring, especially early), hepatotoxicity, orange discoloration of urine and reversible oligospermia. It impairs folate absorption, so folic acid is added, and it is pregnancy-compatible.

Leflunomide. Leflunomide inhibits dihydroorotate dehydrogenase and pyrimidine synthesis. Adverse effects include hepatotoxicity, cytopenias, diarrhea, hypertension and peripheral neuropathy. It is teratogenic, and enterohepatic recirculation keeps its metabolite in the body for up to 2 years, so a woman planning pregnancy needs a washout: cholestyramine 8 g three times daily for 11 days, then two plasma levels below 0.02 mg/L at least 14 days apart.

Azathioprine. This prodrug of 6-mercaptopurine is inactivated by TPMT and by xanthine oxidase. Low TPMT activity causes severe myelosuppression, so TPMT genotype or activity is checked first. Allopurinol and febuxostat block xanthine oxidase and cause life-threatening pancytopenia; the combination is avoided, or the azathioprine dose is sharply reduced. Other risks are hepatotoxicity, pancreatitis, skin cancer and lymphoma. Azathioprine is pregnancy-compatible.

Biologic and targeted synthetic DMARDs

TNF inhibitors. Adalimumab, infliximab, etanercept (a soluble receptor), golimumab and certolizumab increase the risk of TB reactivation, serious bacterial infection and opportunistic infection with Listeria, Legionella, histoplasmosis and other endemic fungi. They are held during active serious infection. They are avoided in NYHA class III–IV heart failure, which they can worsen, and in demyelinating disease such as MS or optic neuritis, which they can trigger. Drug-induced lupus, which often carries anti-dsDNA as well as anti-histone antibodies, is usually mild (rash, arthritis, serositis), usually spares the kidneys and brain (anti-TNF lupus may also have low complement) and resolves when the drug is stopped. Paradoxical psoriasiform rash, injection or infusion reactions and nonmelanoma skin cancer also occur.

Rituximab. This anti-CD20 antibody depletes B cells. Infusion reactions are reduced by premedication. HBV reactivation can occur even after resolved infection, repeated courses cause hypogammaglobulinemia (IgG is checked before redosing), and progressive multifocal leukoencephalopathy from JC virus presents with subacute focal deficits and nonenhancing white-matter lesions.

IL-6 receptor blockade. Tocilizumab and sarilumab cause lower GI perforation (avoid with a history of diverticulitis), neutropenia, transaminase elevation and hyperlipidemia; lipids are checked 4–8 weeks after starting. Because IL-6 drives CRP and fever, infection or perforation can present with a normal CRP and no fever, and abdominal pain warrants CT.

JAK inhibitors. Oral tofacitinib, baricitinib and upadacitinib increase the risk of herpes zoster, venous thromboembolism, major adverse cardiovascular events and malignancy, particularly in patients aged 50 or older with cardiovascular risk factors and in smokers. They are reserved for patients who have not responded to a TNF inhibitor and are avoided after prior VTE. CBC, liver tests and lipids are monitored, and recombinant zoster vaccine is given beforehand.

Pregnancy and reproduction

Compatible. Hydroxychloroquine (continued in lupus because stopping it provokes flares), sulfasalazine with folic acid, azathioprine, TNF inhibitors and low-dose prednisone can be used in pregnancy. Certolizumab is preferred when a TNF inhibitor is needed late in pregnancy: it is a PEGylated Fab′ fragment without an Fc region, so the neonatal Fc receptor does not transport it across the placenta.

Avoid. Methotrexate is stopped 1–3 months before conception, leflunomide requires a cholestyramine washout, and mycophenolate is stopped at least 6 weeks before conception. Sulfasalazine can reduce sperm counts, which recover after the drug is stopped.