A Randomized Controlled Trial Comparing the Efficacy and Safety Profile of Oral Versus Subcutaneous Route of Methotrexate Administration in Moderate to Severe Psoriasis

Introduction:

Methotrexate is one of the oldest and most commonly used systemic drugs for the treatment of psoriasis.[1] Even with the advent of other treatment modalities like systemic retinoids and biologics, methotrexate remains a popular modality for treatment of psoriasis owing to its cost-effectiveness, ease of administration and greater experience among practitioners regarding its use.[2] Despite long-term experience in the use of methotrexate in psoriasis, robust evidence and consensus regarding the ideal dosing schedule and route of administration is still lacking.[3] Oral route of methotrexate has been found to have unpredictable and non-linear bioavailability especially at doses greater than 15 mg/kg.[4] Subcutaneous route of methotrexate on the other hand is associated with better and more linear bioavailability at higher doses.4 Methotrexate by subcutaneous route has also been known to better tolerability and lesser gastrointestinal side effects as compared to oral route. [5] Recently conducted METOP study, which was a randomized controlled study comparing subcutaneous route of methotrexate administration and placebo in control of moderate to severe plaque psoriasis concluded that subcutaneous methotrexate is an efficient and safe modality of treatment of psoriasis. The study also suggested that the pace and longevity of response by subcutaneous route of methotrexate administration may be better than seen with oral route.[6] A recent retrospective study also concluded that subcutaneous route of methotrexate is an effective modality of treatment in patients of psoriasis who have failed oral methotrexate.[7] This study will be the first randomized controlled trial comparing oral versus subcutaneous route of administration of methotrexate in its efficacy in clearance of psoriasis and side effect profile. The study will help in clarification of dilemma of clinicians regarding the ideal route of administration of methotrexate in psoriasis. It will also further strengthen the evidence regarding the adverse effects and tolerability of subcutaneous route of methotrexate administration.

Methodology:

Aim of the study : To compare the effectiveness and safety profile of oral versus subcutaneous route of administration of methotrexate in patients with moderate to severe psoriasis.

This study will be an intention to treat single blinded randomized controlled trial. The participants will be patients with moderate to severe psoriasis fulfilling the inclusion and exclusion criteria . They will be randomly allocated to the two treatment arms in the beginning of the study. Participants in one treatment arm will receive methotrexate by oral route while participants in second treatment arm will receive methotrexate by subcutaneous route. Baseline PASI, percentage of body surface area involvement(BSA) and DLQI will be calculated for each patient at the start of study. Any systemic treatment will be stopped for a duration of at least 5 times their half lives before the start of methotrexate in each patient. The participants in first treatment arm will receive 0.3 mg/kg (upto a maximum of 25 mg/week ) of weekly oral methotrexate for 12 weeks or achievement of PASI 90 whichever is earlier while the patients in second treatment arm will receive subcutaneous methotrexate at 0.3 mg/kg/week for the same duration. The participants will be followed at regular intervals and monitored adequately for hematological, hepatotoxic and other adverse effects both clinically and through laboratory investigations according to methotrexate consensus guidelines during the treatment period. PASI, Body surface area (BSA) involvement and DLQI will be assessed at each follow up visit and at the end of 12 weeks. The treatment will be tapered at the rate of 5 mg/2 weeks and stopped after 12 weeks or achievement of PASI 90 whichever is earlier. The participants will be followed up for a period of 24 weeks after stopping methotrexate to observe the relapse free period.