Can leflunomide alone be a solid treatment for overlapping syndrome and Sjögren's syndrome?

From the Guidelines

Leflunomide alone is not typically considered a first-line or complete treatment for overlapping syndrome and Sjögren's syndrome, though it may be used as part of a comprehensive treatment plan. For overlapping syndromes (which involve features of multiple autoimmune conditions) and Sjögren's syndrome specifically, treatment usually requires a multi-faceted approach tailored to the specific manifestations present. Leflunomide, a disease-modifying antirheumatic drug (DMARD) that inhibits pyrimidine synthesis and has immunomodulatory effects, can help control joint inflammation and systemic manifestations in some patients, as suggested by the EULAR recommendations for the management of Sjögren's syndrome 1. The typical dosage is 10-20 mg daily, often with a loading dose of 100 mg daily for three days in some protocols. However, most rheumatologists would combine leflunomide with other treatments such as hydroxychloroquine, low-dose corticosteroids, or other immunosuppressants depending on organ involvement.

Some key points to consider in the treatment of overlapping syndrome and Sjögren's syndrome include:

• The use of systemic therapies should be restricted to patients with active systemic disease, as defined by the ESSDAI definitions 1.
• The management of systemic features must be tailored to the specific organ involved and the severity evaluated by the ESSDAI 1.
• Leflunomide may be considered as part of a treatment plan, but its use as monotherapy is limited due to its mechanism of action, which primarily targets T-cell proliferation and doesn't address all the immunological pathways involved in these complex autoimmune conditions.
• Patients require monitoring for potential side effects including liver function abnormalities, bone marrow suppression, and gastrointestinal disturbances.
• For Sjögren's-specific symptoms like dry eyes and dry mouth, additional treatments such as artificial tears, saliva substitutes, pilocarpine, or cevimeline would be necessary.

It's also important to note that leflunomide has been associated with drug-induced lung disease, including interstitial lung disease (ILD), and should be used with caution in patients with a history of lung disease 1. Overall, a comprehensive treatment plan that takes into account the specific manifestations of the disease and the potential risks and benefits of each treatment option is necessary to optimize outcomes for patients with overlapping syndrome and Sjögren's syndrome.

From the Research

Overlapping Syndrome and Sjögren's Syndrome Treatment

• Leflunomide alone may not be a solid treatment for overlapping syndrome and Sjögren's syndrome, as most studies suggest combination therapy with hydroxychloroquine is more effective 2, 3, 4.
• A study published in 2020 found that leflunomide-hydroxychloroquine combination therapy resulted in a clinical response in patients with primary Sjögren's syndrome, with a mean difference in ESSDAI score of -4·35 points compared to the placebo group 2.
• Another study published in 2019 found that the combination of leflunomide and hydroxychloroquine additively inhibited immune activation, supporting the potential implementation of this drug combination in Sjögren's syndrome treatment 3.
• However, a phase II pilot study published in 2007 found that leflunomide alone had a modest effect on primary Sjögren's syndrome, with some patients experiencing adverse events such as gastrointestinal discomfort and hair loss 5.

Combination Therapy

• The combination of leflunomide and hydroxychloroquine has been shown to target type I IFN-associated proteins in patients with Sjögren's syndrome, which may predict and monitor clinical response 4.
• A study published in 2023 found that early changes in serum Galectin-9 levels were robustly associated with clinical response to leflunomide-hydroxychloroquine combination therapy 4.
• Another study published in 2020 found that leflunomide-hydroxychloroquine combination therapy was safe and resulted in a clinical response in patients with primary Sjögren's syndrome, with no serious adverse events occurring in the treatment group 2.

Adverse Events

• Leflunomide alone has been associated with adverse events such as gastrointestinal discomfort, hair loss, and lupus-like skin lesions 6, 5.
• The combination of leflunomide and hydroxychloroquine has been associated with adverse events such as gastrointestinal discomfort, modest transient increases in alanine aminotransferase, and short episodes of general malaise and shivering 2.