Randomised comparative trial comparing oral tofacitinib with oral methotrexate in nail lichen planus and trachyonychia: an investigator blinded trial.

Lichen planus is a chronic inflammatory disease affecting mucosae, skin, scalp, nails, with nail involvement seen in 10-15% of cases, termed nail lichen planus (NLP). NLP manifests in three forms: typical NLP, idiopathic nail atrophy, and trachyonychia. NLP is marked by the thinning of the nail plate, accompanied by longitudinal ridges and fissures. These symptoms can occur with or without the presence of pterygium. Twenty-nail dystrophy, also known as trachyonychia, is marked by nail roughness caused by excessive longitudinal ridging, without pterygium, presenting a monomorphic appearance. Idiopathic nail atrophy involves atrophy in multiple nails with or without the nail plate and pterygium, and presents with an acute course,

scarring of most nails, and nail absence due to pterygium formation or nail plate destruction. Histopathological examination is preferred for diagnosing these forms of NLP.

NLP is notoriously difficult to treat due to its resistance and the lack of long-term, prospective studies. This makes treatment outcomes unpredictable and challenging to manage effectively. Intralesional/ intramuscular steroid like triamcinolone acetonide is recommended as the firstline treatment. Oral steroids are discouraged due to side effects. Effective alternatives include oral retinoids like acitretin and alitretinoin. Severe cases might need immunosuppressants such as azathioprine, methotrexate or cyclosporine. Hydroxychloroquine and biologics aren’t recommended, but tofacitinib shows promise, pending further research. Trachyonychia treatment focuses on symptom management and addressing underlying conditions, though it

can be challenging and may not always be effective, often requiring a tailored approach based on the patient’s specific needs. Despite the significant functional and cosmetic impact of NLP, there is a notable scarcity of evidence-based treatments. The primary aim is to prevent or reduce permanent scarring and to halt the inflammatory process as early as possible to ensure the best possible outcome. This RCT seeks to address the lack of established treatment modalities for nail lichen planus and trachyonychia, which can be distressing for patients and challenging for healthcare providers. It aims to assess the safety and efficacy of using oral tofacitinib v/s oral methotrexate as a treatment for nail lichen planus and trachyonychia.

Methotrexate has been adopted as the standard of care for patients with nail lichen planus and trachyonychia in the department of dermatology at PGIMER, Chandigarh, due to its efficacy.

It ‘operates through distinct mechanisms depending on its application in immunosuppression and chemotherapy for autoimmune diseases. It enters cells via human reduced folate carriers

(SLC19A1) and then transforms into methotrexate-polyglutamate. The enzyme DHFR, which is essential for converting dihydrofolate into tetrahydrofolate, the active form of folic acid, gets

inhibited by both methotrexate-polyglutamate and methotrexate. Tetrahydrofolate is essential for synthesizing DNA and RNA nucleotides. Additionally, methotrexate-polyglutamate

hinders the de novo synthesis of thymidylate synthase and purines, further blocking DNA synthesis. In autoimmune diseases, methotrexate works differently. It inhibits the enzyme

AICAR transformylase, which disrupts guanine and adenosine metabolism, leading to adenosine buildup. Adenosine has anti-inflammatory properties, which represses

methyltransferase activity, down-regulates B-cells, increases the sensitivity of activated CD95 T-cells, and suppresses T-cell activation. It also hinders the binding of IL-1 beta to the cell surface receptor. Tofacitinib functions as a JAK inhibitor, targeting specific signalling pathways involved in immune and inflammatory responses. By modulating these pathways, it has shown promise in various autoimmune and inflammatory conditions. This mechanism of action suggests its potential in mitigating immune-mediated diseases like lichen planus and trachyonychia

associated with the discussed conditions. The RCT will include 60 patients aged 12 to 60 years with nail lichen planus or trachyonychia requiring systemic treatment. Thirty participants will receive oral tofacitinib, and the other 30 participants will receive oral methotrexate. The study will extend over 24 months with regular follow-up visits. Assessments will include both objective (typical Nail Lichen Planus Severity Index) and subjective (physician global assessment) tools of target nails and monitoring for adverse events. The research acknowledges the potential risks of tofacitinib and methotrexate, such as severe infections and haematological derangement, transaminitis and dyslipidemia. The patient will be kept on regular follow-ups to monitor for the adverse events.