Can patients with overlapping syndrome and Sjögren's be treated with leflunomide (LEF) or methotrexate (MTX) in combination with Plaquenil (hydroxychloroquine)?

From the Guidelines

Yes, patients with overlapping syndrome and Sjögren's can be treated with leflunomide (LEF) or methotrexate (MTX) in combination with Plaquenil (hydroxychloroquine), with hydroxychloroquine being conditionally recommended over other csDMARDs due to its better tolerability and favorable risk profile 1. When considering treatment options for patients with overlapping syndrome and Sjögren's, combination therapy with LEF or MTX and Plaquenil may be beneficial for achieving better disease control.

• Hydroxychloroquine is typically prescribed at 200-400 mg daily,
• methotrexate dosing ranges from 7.5-25 mg weekly (with folate supplementation),
• and leflunomide at 10-20 mg daily. These combination regimens target different inflammatory pathways simultaneously, potentially offering better disease control. However, according to the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis, methotrexate is conditionally recommended over leflunomide due to its greater dosing flexibility and lower cost 1. Regular monitoring is essential, including blood counts, liver function tests, and kidney function every 1-3 months. Additionally, patients on hydroxychloroquine require baseline and periodic eye examinations to monitor for retinal toxicity. The specific combination and dosing should be individualized based on the patient's symptom severity, organ involvement, comorbidities, and previous treatment responses, as overlapping autoimmune syndromes often present with variable manifestations requiring tailored approaches. Key considerations include the patient's disease activity, potential side effects, and the need for close monitoring to minimize risks associated with these medications. In clinical practice, the choice between LEF and MTX in combination with Plaquenil should prioritize the patient's overall health status, disease severity, and potential for drug interactions or adverse effects, with a preference for methotrexate over leflunomide when possible, as suggested by the guideline 1.

From the FDA Drug Label

7.5 Methotrexate Concomitant use of hydroxychloroquine sulfate and methotrexate may increase the incidence of adverse reactions.

Liver Enzyme Monitoring ALT (SGPT) must be performed at baseline and monitored at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month.

Combination Therapy with Plaquenil

• Patients with overlapping syndrome and Sjögren's can be treated with leflunomide (LEF) or methotrexate (MTX) in combination with Plaquenil (hydroxychloroquine), but with caution.
• Concomitant use of hydroxychloroquine sulfate and methotrexate may increase the incidence of adverse reactions 2.
• When leflunomide and methotrexate are given concomitantly, liver enzyme monitoring should be performed according to ACR guidelines 3.
• Close monitoring of patients is necessary to minimize the risk of adverse reactions.
• The decision to use combination therapy should be made on a case-by-case basis, considering the individual patient's risk factors and medical history. 2 3

From the Research

Treatment Options for Overlapping Syndrome and Sjögren's

• Patients with overlapping syndrome and Sjögren's can be treated with various medications, including leflunomide (LEF) and methotrexate (MTX) in combination with Plaquenil (hydroxychloroquine) 4, 5, 6.
• The use of LEF and hydroxychloroquine in combination has shown promising results in reducing disease activity and improving symptoms in patients with primary Sjögren's syndrome 5, 6.

Efficacy of Leflunomide and Hydroxychloroquine Combination Therapy

• A study published in 2020 found that LEF and hydroxychloroquine combination therapy resulted in a significant reduction in disease activity, as measured by the ESSDAI score, compared to placebo 6.
• Another study published in 2019 found that the combination of LEF and hydroxychloroquine had an additive immunosuppressive effect, supporting the rationale for combination therapy in Sjögren's syndrome 5.

Biomarkers for Predicting and Monitoring Treatment Response

• Research has identified several interferon-associated biomarkers, including Galectin-9, that may be useful in predicting and monitoring treatment response to LEF and hydroxychloroquine combination therapy 7.
• Early changes in serum Galectin-9 levels have been found to be a robust predictor of clinical response at 24 weeks 7.

Safety and Tolerability of Combination Therapy

• The combination of LEF and hydroxychloroquine has been found to be safe and well-tolerated, with no serious adverse events reported in one study 6.
• Common adverse events associated with LEF and hydroxychloroquine combination therapy include gastrointestinal discomfort, modest transient increases in alanine aminotransferase, and short episodes of general malaise and shivering 6.