What is the recommended first-line Disease-Modifying Antirheumatic Drug (DMARD) for patients with Sjögren's syndrome?

DMARD Selection in Sjögren's Syndrome

There is no universally recommended first-line DMARD for Sjögren's syndrome, as the choice depends entirely on disease manifestations and severity; hydroxychloroquine (HCQ) 200-400 mg/day is commonly used for mild systemic disease despite limited efficacy evidence, while mycophenolate mofetil (MMF) or azathioprine are preferred as first-line steroid-sparing agents for moderate-to-severe systemic involvement, particularly interstitial lung disease. 1

Disease Severity-Based Approach

Mild-to-Moderate Systemic Disease

• Hydroxychloroquine 200-400 mg/day may be considered for patients with mild systemic manifestations, though evidence for clinical efficacy is weak 1
• The 2020 EULAR guidelines note that several immunomodulatory agents tested in Sjögren's showed marginal benefits or unacceptable adverse event rates 1
• A large 2014 RCT (JOQUER trial) demonstrated that HCQ provided no significant improvement in dryness, pain, or fatigue compared to placebo at 24 weeks (17.9% vs 17.2% response rate, OR 1.01,95% CI 0.37-2.78) 2
• Despite negative RCT data, a 2025 real-world study suggested HCQ at doses of 300-400 mg daily or >5 mg/kg may reduce disease activity (ESSDAI scores), particularly in patients ≤50 years, with SSA/RF seropositivity, baseline ESSDAI 5-13, or when combined with glucocorticoids >20 mg/day 3

Moderate-to-Severe Systemic Disease (Including ILD)

For patients with symptomatic interstitial lung disease (ILD) with moderate-to-severe impairment:

• First-line maintenance therapy: MMF or azathioprine when long-term steroid use is contemplated and steroid-sparing immunosuppression is required 1
• Initial treatment typically includes systemic corticosteroids (0.5-1.0 mg/kg) for symptomatic ILD, especially organizing pneumonia 1
• Following initial corticosteroid treatment, MMF or azathioprine should be used as first-line maintenance drugs 1

Important safety considerations:

• Azathioprine: Test for thiopurine methyltransferase (TPMT) activity/genotype before initiating to reduce risk of life-threatening leukopenia; monitor for drug-induced pneumonitis, GI upset, hepatotoxicity, bone marrow suppression 1
• MMF: Monitor for nausea, diarrhea, hepatotoxicity, and bone marrow suppression 1

Severe, Refractory Systemic Disease

Second-line options when MMF or azathioprine are insufficient or not tolerated:

• Rituximab (1 g IV every 15 days x2) may be considered for severe, refractory systemic disease 1
• Best indications for rituximab include vasculitis, cryoglobulinemia-associated MALT lymphoma, other marginal zone lymphomas, and diffuse large B-cell lymphoma 1
• Studies of >400 patients showed rituximab efficacy in reducing ESSDAI scores, achieving organ-specific responses, and reducing glucocorticoid doses 1
• Calcineurin inhibitors (cyclosporine or tacrolimus) are alternative second-line options 1
• The combination of glucocorticoids, cyclosporin A, and HCQ showed numerically higher response rates (OR 3.73,95% CI 1.19-11.72) 3

Rapidly Progressive or Life-Threatening Disease

• High-dose IV methylprednisolone for acute respiratory failure or rapidly progressive ILD 1
• Cyclophosphamide or rituximab should be considered in addition to high-dose corticosteroids for patients with acute/subacute hypoxic respiratory failure despite initial therapies 1
• Provide Pneumocystis jirovecii prophylaxis with cyclophosphamide; use IV route to reduce bladder cancer risk 1

Critical Caveats

No head-to-head comparisons exist between immunosuppressive agents in Sjögren's syndrome, preventing definitive recommendations of one agent over another except based on patient-specific factors and safety profiles 1

Lack of licensing for biologics significantly limits their use in clinical practice despite having the highest level of evidence among tested drugs 1

Drug-induced lung disease risk: Be aware that methotrexate, leflunomide, rituximab, cyclophosphamide, sulfasalazine, and TNF-alpha inhibitors can cause drug-induced ILD; consider bronchoscopy/biopsy and medication withdrawal if patients are progressive or refractory 1

Over 95% of reported cases using immunosuppressive agents in primary Sjögren's received concomitant glucocorticoids, making assessment of monotherapy efficacy difficult 1