Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis

The PREDMETH Trial: Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis - A Randomized Controlled Trial

This is a prospective, randomized, non-blinded, multi-center, non-inferiority trial designed to compare effectiveness and side-effects of methotrexate versus prednisone as first-line therapy for pulmonary sarcoidosis.

Sarcoidosis is a multisystem, granulomatous disorder, most commonly affecting the lungs. Symptom burden is high, and quality of life (QoL) and social participation are negatively affected. In patients with pulmonary sarcoidosis, treatment is recommended in case of significant symptoms and/or impaired or deteriorating lung function. Evidence-based treatment recommendations are limited, outdated and largely based on expert opinion.

Prednisone is currently the first-choice therapy in pulmonary sarcoidosis and leads to short-term improvement of lung function. Unfortunately, prednisone has major side-effects and is associated with impaired QoL. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects. The investigators hypothesize that first-line treatment with methotrexate is as effective as prednisone, with fewer side-effects and better QoL.

Inclusion Criteria:

• Diagnosis of sarcoidosis according to the ATS/ERS/WASOG criteria, in case of absent histology a diagnosis of sarcoidosis can also be established in a multidisciplinary team meeting in a sarcoidosis expert center based on a highly suggestive clinical and radiological picture.
• Age ≥18 years.
• A pulmonary indication for treatment and parenchymal involvement on X-ray or CT-scan conducted within three months before inclusion (determined by the treating physician and conform current guidelines).
• A forced vital capacity (FVC) of ≤90% of predicted, or a diffusion capacity of the lung for carbon monoxide (DLCO) ≤70% of predicted, or ≥5% FVC absolute decline/≥10% DLCO absolute decline in the past year. For pulmonary functions tests GLI reference values are used.

Exclusion Criteria:

• Any condition or circumstance that, in the opinion of the investigator, may make a subject unlikely or unable to complete the study or comply with study procedures.

• Previous immunosuppressive treatment for sarcoidosis

• Use of systemic immunosuppressive therapy within the preceding three months for another disease than sarcoidosis

• Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study treatment or within 90 days after the last dose in the randomized study phase. For males; planning to pro-create during the study or within 90 days after the last dose of the randomized study phase.

• Primary systemic treatment indication being an extra pulmonary location of sarcoidosis (e.g. cardiac of neurological)

• Contra-indication for methotrexate or corticosteroids:

  • severely impaired renal function (creatinine clearance <30 ml/min)
  • impaired hepatic function (serum bilirubin-value >5 mg/dl or 85,5 micromole/l)
  • bone marrow insufficiency with severe leukopenia, thrombocytopenia, or anaemia
  • severe acute or chronic infections, such as tuberculosis, HIV, parasitic infections or other immunodeficiency syndromes
  • mouth, stomach or duodenal ulcers