Drug

Dosage

Contraindications

Adverse reactions

Monitoring

Hydroxychloroquine

200 mg PO once daily or bid

Retinal diseases; visual impairment; renal failure; porphyria; psoriasis; G6PD deficiency; untreated chronic hepatitis B or C with Child-Pugh class C

Retinal (macular) damage reversible after drug discontinuation; rash; abdominal pain, diarrhea, appetite loss, nausea; other (very rare): myopathy, blurred vision, visual impairment, abnormal cutaneous/mucosal pigmentation, peripheral neuropathy

Ophthalmic exam (fundoscopy and visual fields): before starting treatment, then after 5 years (or 1 year if there are risk factors for retinopathy: macular disease, low eGFR, tamoxifen use, and hydroxychloroquine dose >5 mg/kg/d or chloroquine dose >2.3 mg/kg/d), with further follow-up every 12 months. There is a maximum lifetime dose of 1000 g, which is reached after 7 years on 400 mg/d

Leflunomide

10-20 mg PO once daily

Infectiona; leukopenia <3×109/L; thrombocytopenia <50×109/L; myelodysplasia; lymphoproliferative disorder treated in last ≤5 years; liver diseaseb,c,d; pregnancy and breastfeeding; severe or moderate renal impairment

Diarrhea, abdominal pain, nausea; rash; alopecia; liver damage; kidney damage; hypertension; teratogenicity (effective contraception necessary). In case of complications, drug has to be discontinued; elimination may be accelerated using cholestyramine (8 g tid for 11 days) or activated charcoal (50 g qid for 11 days). In women planning pregnancy and men planning to become fathers, levels of metabolite of leflunomide should be measured several times following accelerated elimination

CBC: before starting treatment, then every 2-4 weeks in initial 3 months of treatment, then every 2-3 months; after 6 months of treatment repeat every 3 months or less frequently. Serum creatinine: every 2 weeks until target drug dose is established, then every month. Serum ALT and AST: as above; in case of sustained increase in AST/ALT >3 × ULN, drug should be discontinued and liver biopsy considered to assess liver damage

Methotrexate

15-25 mg PO, IM, or SC once weekly; titrate dose to a max 25 mg; folic acid (5 mg/wk) or leucovorin (INN folinic acid) to be used concomitantly to prevent adverse effects (cytopenia, mouth ulceration, nausea)

As above + interstitial pneumonitis/pulmonary fibrosis; CrCl <30 mL/min

Elevated serum liver enzyme levels, liver fibrosis and cirrhosis (very rare); risk factors: alcohol consumption, obesity, diabetes, hepatitis B and C; pancytopenia due to bone marrow suppression and complications (dose-dependent); oral ulcers (in 30% of patients); nausea within 24-48 h of drug administration; interstitial lung disease (2%-6% regardless of dose and treatment duration); teratogenicity (effective contraception necessary); methotrexate should be discontinued (in both women and men) 3 months before planned conception; milder adverse effects (due to folic acid deficiency): mucositis, alopecia, GI disturbances

As above + chest x-ray before starting treatment (results of studies performed in the previous year are acceptable) and in course of treatment if cough or dyspnea develop

Sulfasalazine

1.5 g PO bid (dose should be titrated up)

Hypersensitivity to sulfonamides and salicylate; after ileostomy; liver diseaseb,c,e; renal failure; porphyria; G6PD deficiency; breastfeeding; considered safe in pregnancy

Majority of adverse effects occur within first few months of treatment and can be avoided by starting with low dose and titrating up gradually: loss of appetite, dyspepsia, nausea, vomiting, abdominal pain (30%); headache, vertigo/dizziness; fever; allergic skin (urticaria, photosensitivity) and joint reactions; hemolytic anemia (in patients with G6PD deficiency), very rarely aplastic anemia; granulocytopenia (1%-3%) may occur at any time of treatment (most commonly in first 3 months); elevated serum ALT/AST; interstitial lung disease (rare)

CBC, serum ALT, AST, and creatinine: as above

Adalimumab

20-40 mg SC every 1-2 weeks

Infectiona; viral hepatitisc,e; pregnancy, breastfeeding; heart failure (NYHA class III/IV and EF ≤50%); multiple sclerosis or other demyelinating disease; lymphoproliferative disease treated in last ≤5 yearsf

Severe infections (including opportunistic infections); positive autoantibodies including ANAs, anti-dsDNA, anticardiolipin, and antichimeric; rarely drug-induced lupus (in which case treatment should be discontinued); cytopenias (mainly leukopenia); demyelination syndromes, optic neuritis (very rare) with symptoms resolving after drug discontinuation; reactivation of HBV infection; elevated serum ALT/AST

Before starting: chest x-ray and tuberculin skin test/IGRA test, CBC, serum ALT/AST and creatinine, tests for viral hepatitis; pneumococcal (periodic), influenza (annual), and hepatitis B (in patients at risk of infection) vaccinations recommended; live vaccines contraindicated but could be administered prior to starting DMARD or biologic treatment; in course of treatment patients should be monitored for symptoms of infection; in women mammography is recommended before starting treatment

Etanercept

25 mg SC twice a week or 50 mg/wk

As above

As above

Infliximab

3-10 mg/kg IV, repeated after 2 and 6 weeks, then every 8 weeks, or 3-5 mg/kg every 4 weeks

As above

As above

Certolizumab

200 mg SC bid, repeated after 2 and 4 weeks, followed by maintenance dose 200 mg every 2 weeks

As above

As above

As above

Golimumab

50 mg SC once a month

As above

As above

As above

Abatacept

IV infusion over 30 min; body weight <60 kg: 500 mg, 60-100 kg: 750 mg, >100 kg: 1 g; subsequent doses to be administered 2 and 4 weeks after first infusion, then every 4 weeks

Infectiona; viral hepatitisc,e; pregnancy and breastfeeding

Severe infections; probably causes progressive multifocal leukoencephalopathy (very rare)

Before starting: chest x-ray and tuberculin skin test/IGRA test, CBC, serum ALT/AST and creatinine, tests for viral hepatitis; pneumococcal (periodic), influenza (annual), and hepatitis B (in patients at risk of infection) vaccinations recommended; live vaccines contraindicated; in course of treatment patients should be monitored for symptoms of infection; in women mammography is recommended before starting treatment

Rituximab

1g IV, 2 doses at 14-day interval; can be repeated every 6 months

Infectiona; viral hepatitisc,e; pregnancy and breastfeeding

Allergic reactions, infections, probably causes progressive multifocal leukoencephalopathy (very rare), reactivation of HBV infection

As above + plasma immunoglobulin levels

Tocilizumab

8 mg/kg IV every 4 weeks or 162 mg SC weekly

Infectiona; ALT/AST >5 × ULN; viral hepatitisc,g; neutropenia
<0.5×109/L and thrombocytopenia <50×109/L; pregnancy and breastfeeding

Infections, neutropenia, and thrombocytopenia, elevated ALT/AST (in particular during concomitant use of potentially hepatotoxic drugs, eg, DMARDs), dyslipidemia, intestinal perforation in patients with diverticulitis (infrequent)

As above (drug may suppress acute-phase reaction so patients should be very carefully monitored for features of infection) + ALT/AST every 4-8 weeks for first 6 months of treatment, then every 3 months; CBC after 4-8 weeks of treatment, then repeat when necessary

Tofacitinib

5 mg PO bid

Malignancy, current infection, pregnancy and breastfeeding

Headache, diarrhea, bacterial infections, herpes zoster infection

TB skin prick test and chest x-ray; CBC, ALT, AST, creatinine, and lipids; monitor for infection and malignancy

Baricitinib

2 mg PO daily

As tofacitinib

 As tofacitinib

As tofacitinib

a Active bacterial infection, TB (active or latent in patients not receiving anti-TB prophylaxis), active infection with varicella zoster or herpes simplex virus, active severe fungal infection (in the case of biologic agents probably also febrile viral upper respiratory tract infection and poorly healing infected skin ulcers).

b ALT and/or AST levels >2 × ULN.

c Acute hepatitis B or C.

d Chronic hepatitis B or C (regardless of treatment status and severity of liver disease).

e Chronic hepatitis B (unless treated and with Child-Pugh class A; sulfasalazine can be used in both class A and B) or chronic hepatitis C associated with Child-Pugh class B or C (etanercept is recommended as potentially safe in patients with chronic hepatitis C).

f Rituximab is recommended in patients with RA qualifying for a biologic agent and a history of treated lymphoproliferative malignancy or skin melanoma (anytime), as well as treated within the last 5 years nonmelanoma skin cancers or solid malignancies.

g Evidence is scarce regarding safety of tocilizumab in chronic viral hepatitis.

h Loading dose may be used to speed up the onset of effect; however, it is common practice to avoid it because of the risk of diarrhea and adherence issues. It is not recommended when leflunomide is used in combination therapy.