A placebo-controlled randomized controlled trial exploring the effect of methotrexate on pain, function and structural outcomes in erosive inflammatory hand osteoarthritis.

The trial will include Norwegian adult males and females with symptomatic erosive inflammatory hand osteoarthritis.

Participants will be randomized 1:1 to either:

1. Methotrexate oral x 1/week; weekly starting dose 15 mg for two weeks, followed by 20 mg the remaining weeks (intervention group). Dosage can be reduced to as low as 10 mg if higher doses are not tolerated.
2. Placebo (control group).

Both arms will receive folic acid 1mg daily.

The treatment duration for both groups is 52 weeks.

Inclusion Criteria:

• Finger joint pain 40-80 on 0-100 visual analog scale (VAS) with insufficient pain relief from, inability to tolerate or contra-indications to oral paracetamol and/or NSAIDs, and hand symptoms (pain, aching, or stiffness) on most days the previous 6 weeks before randomization.
• Hand OA according to the American College of Rheumatology (ACR) criteria, at least 1 distal (DIP) or proximal interphalangeal (PIP) joint of the 2nd-5th finger with radiographic pre-erosive (J-phase) or erosive disease (E-phase) according to the Verbruggen-Veys anatomical phase system, and at least two DIP/PIP joints with power Doppler signal of at least grade 1 or grey-scale synovitis of at least grade 2 on ultrasound.

Exclusion Criteria:

A full list of the exclusion criteria for this study comprised the following:

• Contraindications to methotrexate:

  • Abnormal renal function, defined as serum creatinine >142 µmol/L in women and >168 µmol/L in men, or a glomeruli filtration rate (GFR) <40 mL/min/1.73 m2.
  • Abnormal liver function, defined as transaminases above the upper normal limit, active or previous hepatitis B or C infection, or known cirrhosis
  • Lung fibrosis (maximum 6 months old x-ray), active infection, or reduced hematopoiesis (i.e. anemia, leukopenia and/or thrombocytopenia).
  • Planned pregnancy within 18 months after screening (men/women), and pregnancy, breastfeeding, or insufficient anti-conception therapy for female fertile participants. Contraception should be maintained during treatment and until the end of systemic exposure, i.e. 3 months after methotrexate discontinuation. Sufficient anti-conception therapy consists of intra-uterine device (coil) or hormonal anti-conception (birth control pills, implant, intra-uterine system, dermal patch, vaginal ring, or injections).
  • Alcohol or other drug abuse in the last year.
  • Intolerance to lactose.

• Chronic inflammatory rheumatic diseases (such as rheumatoid arthritis and psoriatic arthritis or gout), active inflammatory bowel disease, or positive rheumatoid factor or anti-CCP antibodies.

• Other severe co-morbidities such as hemochromatosis, fibromyalgia, psoriasis, blood dyscrasias, and coagulation disorders, history of malignancy (except successfully treated squamous or basal cell skin carcinoma), uncontrolled diabetes mellitus, severe hypertension, unstable ischemic heart disease, severe heart failure, severe pulmonary disease, severe and/or opportunistic infections and/or chronic infections, active tuberculosis, positive human immunodeficiency virus (HIV) status, recent stroke, bone marrow hypoplasia, or demyelinating diseases of the central nervous system.

• Other likely causes of hand symptoms: thoracic outlet syndrome, carpal tunnel disease, diabetic cheiropathy, injury in finger joints previous 6 months, or palmar tenosynovitis/trigger finger.

• Oral or intra-muscular steroids in the previous month

• Intra-articular treatments or aspirations of any kind of any joint in the hands 3 months before inclusion

• Analgesics or NSAIDs, unless stable dosage for ≥1 month.

• Symptomatic slow-acting drugs for OA (SYSADOA), unless stable dose for ≥3 months and require stable dose throughout the study.

• Disease-modifying osteoarthritis drugs (DMOADs) previous three months.

• Scheduled hand surgery during study participation.

• Planning to start other treatments for hand OA in the study participation period.

• Not able to adhere to the study visit schedule and protocol requirements.

The trialists and other study personnel that conceive of the study, and then plan, manage, monitor, analyze and publish it, will have access to IPD. Participants' identification code numbers are de-identified by replacing the original code number with a new random code number. Only the PI and project coordinator have access to this code.

The protocol, SAP, ICF, and CSR will be shared with regulatory agents as required.

Identical placebo cannot be produced due to text, color and shape of methotrexate tablets. Thus, both placebo and methotrexate will be encapsulated to ensure blinding.