Short summary

Methotrexate (MTX) is an effective and inexpensive immunomodulating drug with well-described toxicity. Common adverse effects (AE) of MTX are nausea, hepatotoxicity and cytopenia. Our goal is to investigate the side effects profile and if it differs depending on the way of administration by a prospective trial.

Primary endpoint: Do patients experience less nausea and discomfort after switching from oral MTX to injection MTX treatment?

Secondary: Do patients with psoriasis who are treated with methotrexate experience more nausea and discomfort than patients with eczema or rheumatoid arthritis?

Rationale

Methotrexate (MTX) is an effective and inexpensive immunomodulation drug with well-described toxicity. It is a commonly used disease modifying anti-rheumatic drug (DMARD) in treating various forms of skin diseases and rheumatic conditions. MTX has been used for as much as 50 years and is currently first-line systemic therapy in moderate-to-severe psoriasis, psoriatic arthritis and rheumatoid arthritis (RA).

MTX is a folic acid antagonist and its proposed mode of action is anti-inflammatory due to moderate immunosuppression and anti-proliferation. However, the mechanisms are not fully understood and will not be subject to further description in the protocol.

Best evidence suggests to commence treatment with MTX with an oral dose of 12.5-15 mg/once weekly and dose escalation of 5mg/week up to 25-30 mg/once weekly to quickly control disease activity.

Common adverse effects (AE) of MTX are gastrointestinal (nausea appr. 15%, stomach ache appr. 10%,  diarrhea appr. 5%, dyspepsia appr. 10%, loss of appetite appr. 10%, vomiting appr. 5% and stomatitis appr. 5%), hepatotoxicity (increased alanine-transferase appr. 2% ), haemocytopenia appr. 2%, mucocutaneous or pulmonal infections appr. 5%. The most frequent reported AE are gastrointestinal (GI) with nausea as the most common AE with about 10-20% incidence in any MTX treated population.

If lack of effect, hepatotoxicity or intolerable AE of oral MTX occur, one solution is to switch to subcutaneous (SC) or intramuscular (IM) administration. SC MTX has higher bioavailability than oral MTX as SC MTX does not undergo first pass metabolism, thus dosage can often be reduced without reducing efficacy. The lower SC dosage could result in less perceived AE. It is also a common belief that oral administration of MTX predisposes to more intense GI AE, as MTX can act directly on the GI system. This belief is based on small case series. A recent review describes the research on the subject of changes GI AE in oral vs. SC/IM administration as inconsistent. Interestingly and contrary to clinical experience, a recent randomized controlled blinded trial (RCT) failed to identify overall differences in perceived AE comparing SC MTX to oral MTX treatment.  However, our own recent retrospective questionnaire-based study examining patient reported outcome measures (PROM) of GI AE in oral MTX vs. SC MTX showed a significant reduction in both frequency and intensity of nausea and discomfort after switching to SC MTX. It is clear that better quality studies are needed and we decided to set up a prospective study to examine this highly relevant clinical conundrum further.

Description of the cohort

We wish to include patients of all ages who switch from treatment with methotrexate orally to methotrexate by injection. There are no limitations such as age, gender or ethnicity. We recruit patients who as part of their regular follow-up are deemed fit to switch as per usual standard of care (see rationale). Inclusion in the study will take place at the Departments of Dermatology in Aarhus, Odense, Roskilde and Bispebjerg and the Department of Rheumatology, Odense.

Data and biological material

Questionnaire, chart data and clinical databases DANBio and Dermbio.

Collaborating researchers and departments

Department of Dermato-venerology and Allergy Centre, Odense University Hospital and Department of Dermatology, Aarhus University Hospital, Denmark

• Jon Erik Fraes Diernaes

Department of Dermato-venerology and Allergy Centre, Odense University Hospital

• Anette Bygum

Department of Dermato-venerology, Roskilde Hospital

• Charles Kromann
• Gregor Borut Ernst Jemec

Department of Rheumatology, Odense University Hospital

• Philip Rask Lage-Hansen
• Torkell Ellingsen