What are alternative treatments for Sjogrens syndrome (Sjogren's syndrome) in patients who cannot tolerate or have not responded to Hydroxychloroquine (HCQ)?

Treatment for Sjögren's Syndrome Beyond Hydroxychloroquine

For Sjögren's syndrome patients who cannot tolerate or have not responded to hydroxychloroquine, treatment should be stratified by disease severity: symptomatic management with topical therapies and muscarinic agonists for sicca features alone, immunosuppressive agents (methotrexate, azathioprine, mycophenolate, or cyclophosphamide) combined with glucocorticoids for moderate systemic disease, and rituximab for severe refractory systemic manifestations. 1, 2

Sicca Symptoms Without Systemic Disease

Ocular Dryness

• Topical cyclosporine A or topical corticosteroids are recommended for refractory dry eyes requiring more intensive ophthalmological management 1
• Serum tear drops may be considered for severe cases, though evidence remains limited 1
• Oral muscarinic agonists (pilocarpine or cevimeline) improve subjective (but not objective) ocular outcomes and can be added to topical therapy 1
• Punctal plugs show inconclusive evidence with no significant differences versus artificial tears in primary Sjögren's patients 1

Oral Dryness

• Muscarinic agonists (pilocarpine or cevimeline) are the therapy of choice for patients with residual salivary gland function 3, 4
• Saliva substitutes provide transient relief and should be used frequently 4, 5
• Bromhexine may help change saliva consistency 4, 5

Critical caveat: HCQ, immunosuppressive agents, and rituximab are not recommended for treating sicca symptoms alone, as pivotal RCTs showed no placebo-differences for subjective and objective ocular/oral outcomes with overwhelmingly negative results and excess side effects 1

Musculoskeletal Pain and Fatigue

Inflammatory Articular Pain

• Short-term NSAIDs (no longer than 7-10 days) for acute episodes 1
• Consider continuing or initiating HCQ specifically for frequent episodes of articular pain, despite limited evidence for other manifestations 1

Chronic Non-Inflammatory Pain

• Avoid repeated NSAIDs or glucocorticoids for chronic daily pain 1
• Physical activity and aerobic exercise should be the first-line intervention, with demonstrated improvement in fatigue, depression, and aerobic capacity 1
• Gabapentin, pregabalin, or amitriptyline for chronic neuropathic pain 1
• Antidepressants and anticonvulsants may be considered for chronic musculoskeletal pain 1

Important pitfall: Biological agents (rituximab, anakinra, epratuzumab, abatacept) showed no significant placebo-differences for pain and fatigue in pivotal RCTs, with rituximab having a fivefold greater economic cost without quality-of-life benefit—therefore, off-label biologics are not warranted for treating only musculoskeletal pain or fatigue 1

Moderate Systemic Disease

First-Line Immunosuppression

When glucocorticoids alone are insufficient or cannot be tapered below acceptable doses, add immunosuppressive agents: 1, 2

• Methotrexate (evidence level 1b) 1
• Azathioprine (requires TPMT testing before initiation; monitor for drug-induced pneumonitis, GI upset, hepatotoxicity, and bone marrow suppression) 2
• Mycophenolate mofetil (750-1000 mg twice daily; monitor for nausea, diarrhea, hepatotoxicity, and bone marrow suppression) 2
• Leflunomide 1

No head-to-head comparisons exist between these agents, preventing definitive recommendations of one over another except based on patient-specific characteristics, comorbidities, and safety profiles 1, 2

Glucocorticoid Use

• Doses and routes depend on organ involvement severity 1
• Minimize to <7.5 mg/day prednisone equivalent for chronic maintenance and withdraw when possible 1
• Prompt initiation of immunosuppressive agents expedites glucocorticoid tapering 1

Critical caveat: Over 95% of reported cases using immunosuppressive agents received concomitant glucocorticoids, making monotherapy efficacy assessment difficult 1, 2

Severe, Refractory Systemic Disease

Rituximab Indications

Rituximab (1 g IV every 15 days x2) should be considered for: 1, 2, 6

• Severe organ-threatening disease refractory to standard immunosuppressive agents 1
• Vasculitis 2
• Cryoglobulinemia-associated MALT lymphoma 2
• Other marginal zone lymphomas 2
• Diffuse large B-cell lymphoma 2

Studies of >400 patients demonstrated rituximab efficacy in reducing ESSDAI scores, achieving organ-specific responses, and reducing glucocorticoid doses 1, 2

Rituximab Safety Monitoring

Before initiating rituximab: 6

• Screen for hepatitis B (HBsAg and anti-HBc) in all patients
• Consult hepatology for patients with evidence of prior HBV infection regarding monitoring and antiviral therapy
• Monitor for HBV reactivation during and for up to 24 months following therapy
• Discontinue immediately if HBV reactivation occurs

During treatment, monitor for: 6

• Progressive multifocal leukoencephalopathy (PML)—most cases diagnosed within 12 months
• Serious infections (bacterial, fungal, viral)
• Cardiac arrhythmias
• Infusion reactions

Alternative Second-Line Options

• Calcineurin inhibitors (cyclosporine or tacrolimus) 2
• Cyclophosphamide for severe organ-threatening disease or as rescue therapy (IV route preferred to reduce bladder cancer risk; requires Pneumocystis jirovecii prophylaxis) 1, 2

Organ-Specific Systemic Involvement

Interstitial Lung Disease

For symptomatic ILD with moderate-to-severe impairment: 2

• Initial treatment: Systemic corticosteroids (0.5-1.0 mg/kg) for symptomatic ILD, especially organizing pneumonia
• Maintenance therapy: Mycophenolate mofetil or azathioprine as first-line steroid-sparing agents

For rapidly progressive ILD or acute respiratory failure: 2

• High-dose IV methylprednisolone
• Add cyclophosphamide or rituximab if inadequate response to initial therapies

Drug-induced lung disease warning: Methotrexate, leflunomide, rituximab, cyclophosphamide, sulfasalazine, and TNF-alpha inhibitors can cause pulmonary toxicity—consider bronchoscopy/biopsy and medication withdrawal if patients are progressive or refractory 2

Key Limitations and Caveats

• Lack of licensing for biologics significantly limits their clinical use despite having the highest level of evidence among tested drugs 2
• Several immunomodulatory agents tested in Sjögren's showed only marginal benefits or unacceptable adverse event rates 2
• The average duration of diagnosis in clinical trials was long (up to 9.2 years), potentially limiting treatment responsiveness 7
• Meta-analysis found increased withdrawals from adverse events with active treatment (risk ratio 2.33) 7
• Concomitant fibromyalgia or chronic fatigue syndrome should be identified using standardized tools, as these influence treatment decisions and outcomes 1