What are the treatments, doses, and side effects, including effects on body weight, for rheumatoid arthritis, specifically conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs), biologic DMARDs (bDMARDs), and Janus kinase (JAK) inhibitors?

Treatment of Rheumatoid Arthritis: DMARDs, Doses, and Side Effects

First-Line Treatment Strategy

Methotrexate should be initiated immediately upon RA diagnosis as the anchor DMARD, starting at 7.5-10 mg weekly and rapidly escalating to 20-25 mg weekly within 4-6 weeks, combined with folic acid supplementation and short-term low-dose glucocorticoids (≤10 mg/day prednisone equivalent) for up to 6 months. 1, 2

Methotrexate (MTX) - First-Line csDMARD

Dosing:

• Start: 7.5-10 mg weekly orally 2
• Target: Rapidly escalate to 20-25 mg weekly (or 16 mg in Asian populations) within 4-6 weeks 2
• Consider subcutaneous administration if higher doses needed or GI side effects occur (85% ACR20 response vs 77% oral) 2
• Always prescribe folic acid supplementation 2

Common Side Effects:

• Gastrointestinal intolerance (nausea, diarrhea)
• Hepatotoxicity (requires regular liver enzyme monitoring)
• Bone marrow suppression
• Alopecia
• Stomatitis 3, 4

Black Box Warnings:

• Hepatotoxicity with potential for fibrosis and cirrhosis
• Bone marrow suppression
• Fetal death and congenital abnormalities (pregnancy category X)
• Pulmonary toxicity including pneumonitis 3

Monitoring Requirements:

• Liver enzymes regularly
• Complete blood count
• Renal function 3

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Alternative First-Line csDMARDs (When MTX Contraindicated)

Leflunomide

Dosing:

• Loading dose: 100 mg daily for 3 days 3
• Maintenance: 20 mg daily (can reduce to 10 mg if not tolerated) 3
• Note: Loading dose may be eliminated to decrease risk of adverse events, especially in patients at increased risk of hematologic/hepatic toxicity 3

Common Side Effects:

• Diarrhea
• Alopecia
• Weight loss
• Liver enzyme elevations
• Hypertension 3

Black Box Warnings:

• Hepatotoxicity
• Teratogenicity (pregnancy category X)
• Requires drug elimination procedure if pregnancy desired 3

Monitoring:

• Liver enzymes must be monitored regularly
• Blood pressure
• Complete blood count 3

Sulfasalazine

Dosing:

• Start: 500 mg daily
• Escalate to 2-3 g daily in divided doses 1

Common Side Effects:

• Gastrointestinal upset
• Rash
• Hepatotoxicity
• Bone marrow suppression
• Oligospermia (reversible) 4

Monitoring:

• Liver enzymes
• Complete blood count 4

Hydroxychloroquine

Dosing:

• 200-400 mg daily (≤5 mg/kg/day based on ideal body weight) 5, 2

Common Side Effects:

• Retinal toxicity (rare but serious)
• Gastrointestinal upset
• Skin rash 4

Monitoring:

• Ophthalmologic examination at baseline and annually after 5 years of use 4

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Treatment Escalation Algorithm

If no improvement by 3 months or target not reached by 6 months on MTX monotherapy, add a biologic DMARD or targeted synthetic DMARD for patients with poor prognostic factors (positive RF/anti-CCP, high disease activity, early erosions). 1, 2

Poor Prognostic Factors Requiring Early Escalation:

• Positive rheumatoid factor or anti-CCP antibodies (especially high titers >250)
• High disease activity
• Early erosions
• Failure of two csDMARDs 1, 5

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Biologic DMARDs (bDMARDs)

bDMARDs should be combined with MTX for optimal efficacy; IL-6 pathway inhibitors and JAK inhibitors may have advantages as monotherapy if csDMARDs cannot be used as comedication. 1

TNF Inhibitors

Adalimumab (Humira)

Dosing:

• 40 mg subcutaneously every other week 6
• Can increase to 40 mg weekly if inadequate response 6

Efficacy:

• ACR20 response: 46-65% (vs 13-30% placebo)
• ACR50 response: 22-52% (vs 7-10% placebo)
• ACR70 response: 12-24% (vs 3-5% placebo) 6

Common Side Effects:

• Injection site reactions
• Upper respiratory infections
• Headache
• Rash 6

Black Box Warnings:

• Serious infections including tuberculosis, invasive fungal infections, and other opportunistic infections
• Malignancy including lymphoma and other cancers
• Requires TB screening before initiation 6

Etanercept

Dosing:

• 50 mg subcutaneously weekly OR 25 mg twice weekly 1

Side Effects/BBW: Similar to adalimumab 1

Infliximab

Dosing:

• 3 mg/kg IV at weeks 0,2,6, then every 8 weeks
• Can increase to 10 mg/kg or shorten interval to every 4 weeks 1

Side Effects/BBW: Similar to adalimumab, plus infusion reactions 1

Golimumab

Dosing:

• 50 mg subcutaneously monthly (can increase to 100 mg in patients ≥100 kg) 1, 2

Side Effects/BBW: Similar to other TNF inhibitors 1, 2

Certolizumab Pegol

Dosing:

• 400 mg subcutaneously at weeks 0,2,4
• Maintenance: 200 mg every other week OR 400 mg every 4 weeks 1, 5

Side Effects/BBW: Similar to other TNF inhibitors 1, 5

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Non-TNF Biologic DMARDs

Abatacept (T-cell costimulation inhibitor)

Dosing:

• IV: Weight-based dosing (<60 kg: 500 mg; 60-100 kg: 750 mg; >100 kg: 1000 mg) at weeks 0,2,4, then every 4 weeks
• Subcutaneous: 125 mg weekly 1

Common Side Effects:

• Infusion reactions (IV formulation)
• Upper respiratory infections
• Headache
• Nausea 1

Black Box Warning:

• Serious infections 1

Special Consideration:

• Conditionally recommended over other bDMARDs for patients with nontuberculous mycobacterial lung disease 1, 2

Rituximab (B-cell depleting agent)

Dosing:

• 1000 mg IV at weeks 0 and 2
• Repeat course every 6 months or based on disease activity 1

Common Side Effects:

• Infusion reactions
• Infections
• Hypogammaglobulinemia 1

Black Box Warnings:

• Severe infusion reactions
• Tumor lysis syndrome
• Progressive multifocal leukoencephalopathy (PML)
• Hepatitis B reactivation 1

Special Considerations:

• Requires prophylactic antiviral therapy in hepatitis B core antibody positive patients 2
• Conditionally recommended for patients with previous lymphoproliferative disorder 2
• In persistent hypogammaglobulinemia without infection, continuation is conditionally recommended over switching 1

Tocilizumab (IL-6 receptor inhibitor)

Dosing:

• IV: 4 mg/kg every 4 weeks, can increase to 8 mg/kg (max 800 mg)
• Subcutaneous: 162 mg weekly or every other week 1

Common Side Effects:

• Upper respiratory infections
• Nasopharyngitis
• Headache
• Hypertension
• Elevated liver enzymes
• Lipid abnormalities
• Neutropenia
• Thrombocytopenia 1

Black Box Warnings:

• Serious infections including tuberculosis
• GI perforation (rare but serious) 1

Monitoring:

• Liver enzymes
• Lipid panel
• Complete blood count 1

Sarilumab (IL-6 receptor inhibitor)

Dosing:

• 200 mg subcutaneously every 2 weeks
• Can reduce to 150 mg every 2 weeks for management of neutropenia, thrombocytopenia, or liver enzyme elevations 1

Side Effects/Monitoring: Similar to tocilizumab 1

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Targeted Synthetic DMARDs (tsDMARDs) - JAK Inhibitors

JAK inhibitors may be considered after biologic treatment has failed, or as an alternative to biologics when poor prognostic factors are present; they have advantages as monotherapy similar to IL-6 inhibitors. 1

Tofacitinib

Dosing:

• 5 mg orally twice daily 1

Common Side Effects:

• Upper respiratory infections
• Headache
• Diarrhea
• Nasopharyngitis
• Elevated liver enzymes
• Lipid abnormalities
• Anemia 1

Black Box Warnings:

• Serious infections including tuberculosis and opportunistic infections
• Malignancy including lymphoma
• Thrombosis including pulmonary embolism, deep vein thrombosis, and arterial thrombosis
• Major adverse cardiovascular events (MACE) - increased risk in patients ≥50 years with ≥1 cardiovascular risk factor
• Death - increased risk in patients ≥50 years with ≥1 cardiovascular risk factor 1

Monitoring:

• Complete blood count
• Liver enzymes
• Lipid panel
• TB screening 1

Baricitinib

Dosing:

• 2 mg orally once daily (can use 4 mg in selected patients) 1

Side Effects/BBW/Monitoring: Similar to tofacitinib 1

Upadacitinib

Dosing:

• 15 mg orally once daily 1

Side Effects/BBW/Monitoring: Similar to tofacitinib 1

Filgotinib

Dosing:

• 200 mg orally once daily (100 mg in patients with renal impairment) 1

Side Effects/BBW/Monitoring: Similar to tofacitinib 1

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Glucocorticoid Bridging Therapy

Short-term glucocorticoids (≤10 mg/day prednisone equivalent) should be added when initiating or changing csDMARDs, in different dose regimens and routes, but must be tapered as rapidly as clinically feasible. 1

Dosing:

• Low-dose: ≤10 mg/day prednisone equivalent
• Duration: Up to 6 months maximum
• Taper as rapidly as clinically feasible 1, 2

Rationale:

• Provides rapid symptom relief while waiting for DMARD effect
• Should not be used as monotherapy or long-term maintenance 1

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Treatment Monitoring and Adjustment

Monitor disease activity every 1-3 months during active disease; if no improvement by 3 months or target not reached by 6 months, therapy must be adjusted. 1, 2

Treatment Targets:

• Primary goal: Clinical remission
• Alternative goal: Low disease activity 1

Switching Strategy After bDMARD/tsDMARD Failure:

If a first bDMARD or tsDMARD has failed, switch to another bDMARD or tsDMARD; if a TNF inhibitor has failed, can use another TNF inhibitor or an agent with a different mode of action. 1, 3

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Special Population Considerations

Patients with Recent Serious Infection (within 12 months):

• Addition of csDMARDs conditionally recommended over bDMARD/tsDMARD 1, 2
• Addition/switching to DMARDs conditionally recommended over glucocorticoid escalation 1, 2

Patients with Nontuberculous Mycobacterial Lung Disease:

• Use lowest possible glucocorticoid dose (discontinue if possible) 1
• Addition of csDMARDs conditionally recommended over bDMARD/tsDMARD 1, 2
• If bDMARD needed, abatacept conditionally recommended over other options 1, 2

Patients with Heart Failure (NYHA Class III or IV):

• Use non-TNF inhibitor bDMARDs or tsDMARDs instead of TNF inhibitors 2

Patients with Previous Lymphoproliferative Disorder:

• Rituximab conditionally recommended over other DMARDs 2

Patients with Hepatitis B:

• Prophylactic antiviral therapy strongly recommended when initiating rituximab or other b/tsDMARDs in hepatitis B core antibody positive patients 2

Patients with Nonalcoholic Fatty Liver Disease:

• Methotrexate conditionally recommended over alternative DMARDs in patients with normal liver enzymes, liver function tests, and no evidence of advanced liver fibrosis 1

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Drug Tapering in Sustained Remission

If a patient achieves persistent remission after tapering glucocorticoids, consider tapering bDMARDs or tsDMARDs, especially if combined with a csDMARD; if sustained long-term remission continues, cautious csDMARD dose reduction can be considered. 1

Tapering Sequence:

1. First: Taper and discontinue glucocorticoids 1
2. Second: Consider tapering bDMARDs/tsDMARDs (dose reduction or interval prolongation) if in persistent remission on csDMARD combination 1, 4
3. Third: Consider tapering csDMARD only after sustained long-term remission 1

Important Caveat: Most data on tapering are available for TNF inhibitors; rates of maintaining remission after stopping bDMARDs are relatively low 7, 8

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Common Pitfalls to Avoid

• Failing to prescribe folic acid with methotrexate - leads to unnecessary side effects 2
• Inadequate MTX dosing - not escalating to 20-25 mg weekly reduces efficacy 2, 9
• Delaying treatment escalation - waiting beyond 3-6 months without improvement leads to worse outcomes 1, 2
• Using glucocorticoids as long-term monotherapy - increases toxicity without addressing disease modification 1
• Failing to screen for tuberculosis before TNF inhibitor or JAK inhibitor initiation - increases risk of reactivation 2, 6
• Not monitoring liver enzymes and blood counts regularly - misses early toxicity signals 3
• Stopping DMARDs completely in remission - high risk of disease flare 1, 7