Over the last decades outcome has greatly improved for rheumatoid arthritis (RA) and spondyloarthritis (SpA). This is in sharp contrast to the situation for polymyalgia rheumatica (PMR), with a lifetime prevalence of 2.4% for women and 1.7% for men, PMR is the commonest auto-inflammatory musculoskeletal disease in adults aged ≥50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS). Glucocorticoids (GC) are the mainstay of treatment. However, there is an unmet medical need of alternatives in the treatment of PMR as 50% of patients will relapse or have difficulties to reduce the corticosteroid doses. Also, there is increasing awareness of steroid related toxicity and in addition, long-term toxicity is a well-known side-effect of glucocorticoids in PMR.

Low dose methotrexate (< 10 mg per week) has been tested in two blinded randomized control trials and 4 open label studies and has shown low to moderate efficacy as corticosteroid-sparing agent. Studies on tumor necrosis factor (TNF) blockers yielded negative results. The effectiveness of leflunomide has only been convincingly demonstrated in case series.

The high rate of relapses and adverse events in steroid treated patients indicate that alternative adjuvant agents are needed.

There is evidence that leflunomide could serve as steroid sparing agent and that leflunomide can be used to prevent relapses in the clinical management of polymyalgia rheumatica.

We will perform a randomized placebo controlled trial. Eligible patients will be randomly assigned in a 1:1 ratio receiving either leflunomide 20 mg once daily + glucocorticoids , or placebo + glucocorticoids.

Over the last decades outcome has greatly improved for rheumatoid arthritis (RA) and spondyloarthritis (SpA). This is in sharp contrast to the situation for polymyalgia rheumatica (PMR), with a lifetime prevalence of 2.4% for women and 1.7% for men, PMR is the commonest auto-inflammatory musculoskeletal disease in adults aged ≥50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS). Glucocorticoids (GC) are the mainstay of treatment. However, there is an unmet medical need of alternatives in the treatment of PMR as 50% of patients will relapse or have difficulties to reduce the corticosteroid doses. Also, there is increasing awareness of steroid related toxicity and in addition, long-term toxicity is a well-known side-effect of glucocorticoids in PMR.

Low dose methotrexate (< 10 mg per week) has been tested in two blinded randomized control trials and 4 open label studies and has shown low to moderate efficacy as corticosteroid-sparing agent. Studies on TNF blockers yielded negative results. The effectiveness of leflunomide has only been convincingly demonstrated in case series.

The high rate of relapses and adverse events in steroid treated patients indicate that alternative adjuvant agents are needed.

There is evidence that leflunomide could serve as steroid sparing agent and that leflunomide can be used to prevent relapses in the clinical management of polymyalgia rheumatica.

We will perform a randomized placebo controlled trial. Eligible patients will be randomly assigned in a 1:1 ratio receiving either leflunomide 20 mg once daily + glucocorticoids , or placebo + glucocorticoids.

Primary endpoint The clinically relevant lower total number of relapses in leflunomide treated PMR patients as compared to placebo treated patients at 18 months.

Secondary endpoints

1. Steroid sparing capacity of leflunomide in patients with newly diagnosed PMR. Glucocorticoid sparing is expressed as a reduction of the cumulative glucocorticoid dose in the first 2 years of treatment.
2. Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
3. Less GC side effects in leflunomide PMR patient group

The first 2 weeks patients will receive leflunomide 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks leflunomide will be increased to 20 mg per day.

In case leflunomide has to be stopped due to side effects or inefficacy methotrexate will be used as rescue therapy 10 mg per week open label, based on the evidence that 10 mg methotrexate per week is steroid sparing. Those patients will be classified as non-responder.

Randomization will be stratified by age, gender and weight. Therefore, blocked randomization with variable block size will be performed.

Patients in both groups will be started on prednisolone 15 mg once daily and will be randomized within 2 weeks of the start of steroid therapy. The steroids will be tapered according to a short fixed protocol starting with 15 mg a day with a slow gradual taper till 0 in week 27.

Criteria for relapse or recurrence of PMR Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR.

Relapse / recurrence Patient global higher than 3/ 10 and Physician global higher than 1/10 and An increased C reactive protein (CRP) ( > 5 mg/L) Is called a relapse if it was observed during steroid tapering, and is called a Recurrence if it was observed after steroid withdrawal.

Criteria for remission Patient global 3/ 10 or less and Physician global 1/10 or less and A normal CRP ( < 5 mg/L)

Secondary outcome measure PMR-AS The PMR-AS (Leeb and Bird) is a composite score with the following items: Physician global, Pt global, CRP, ability to raise the shoulders on examination, and duration of morning stiffness in minutes.

This randomized controlled trial (RCT) will assess:

1. Time to relapse and steroid-sparing capacity of leflunomide
2. PMR disease activity including patient reported outcome
3. Treatment related complications of steroids
4. Safety and tolerability of leflunomide

This blinded RCT in PMR is a unique study involving 5 centres in 4 different countries. It is the first study to use the recently developed consensus and outcome criteria in PMR which were developed by multidisciplinary groups including patients input. It is both timely and needed to fund a study in PMR since due to ageing in especially Western Europe the expectancy is that the incidence and prevalence of PMR will increase in the coming years. In brief: It is time to take PMR seriously and treat the patients with steroid sparing agents in order to prevent co-morbidities like diabetes, hypertension and osteoporosis in an ageing population.

The 5 centres (Department of Rheumatology and Immunology, Medical University Graz, Department of Rheumatology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, The Department of Rheumatology, Southend University Hospital, Westcliff-on-sea, Chapel Allerton Hospital and St James's University Hospital Leeds and the University Medical Centre Groningen) participating in this study also set up an immediate early access outpatient clinic for PMR patients.

We will keep close contact with patients and their organizations to check whether our aims are in line with their expectations.

The relevance and gain for patients will be a different approach to PMR on the level of

• Early recognition/ making an appropriate diagnosis
• Starting steroid sparing treatment in an adequate dose at baseline
• Better outcome and earlier control of PMR with less relapses and cumulative dosis of steroids (benefit of thight control).

Our study can provide substantial benefit to the society. We seek to demonstrate that relatively cheap drug like leflunomide can improve the treatment of these PMR patients and limit the occurrence of relapses and GC-related side effects. Since leflunomide is an old and cheap drug the pharmaceutical companies are not interested in funding, we hope therefore that the Dutch Arthritis Association will fund our study.

Inclusion Criteria:

1. Signed written informed consent
2. Female or male aged ≥ 50 years
3. PMR according to the American College of Rheumatology (ACR)/European league Against Rheumatism (EULAR) 2012 PMR core (essential) classification criteria
4. Newly diagnosed PMR being on glucocorticoids for less than 4 weeks

Exclusion Criteria:

1. Presence of any other connective tissue disease, including vasculitis/giant-cell arteritis

2. PMR on glucocorticoids for >4 week or >25 mg/day

3. History of alcohol or drug abuse or current alcohol or drug abuse

4. Transplanted organ (except corneal transplant performed more than 3 months prior to screening)

5. Evidence (as assessed by the investigator) of active infection, presence of hepatitis B surface antigen or hepatitis C antibody in blood, HIV positivity.

6. Malignancy within 5 years prior to screening, except for non-melanoma skin cancer

7. Exposure to DMARD/biological in the last 5 years

8. Pain syndromes, e.g. fibromyalgia, drug-induced myalgia

9. Active thyroid disease

10. Neurological diseases, e.g. Parkinson's disease

11. Contraindications for Leflunomide (serious immunodeficiency, e.g. AIDS, cytopenia as defined under 12, moderate to severe kidney failure (as defined under 12), liver test abnormality (as defined under 12)

12. Laboratory abnormalities:

    • Glomerular filtration rate <50 ml/min
    • Alanine-aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5x upper limit of normal
    • Platelet count <100 x 109/L (100,000/mm3)
    • Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L)
    • White blood cells <3.0 x 109/L (3,000/mm3)Absolute neutrophil count <2.0 x 109/L (2,000/mm3)
    • Absolute lymphocyte count <0.5 x 109/L (500/mm3)

13. Uncontrolled or poorly controlled hypertension

14. Major surgery or hospitalization within 3 month prior to screening

15. Any medical condition that could interfere with the implementation or interpretation of the study or with the safety of the patient during the study.

Manuscript after publication

Within 2 years after study termination, study data will be available and published

Study data will be available upon request to the principal investigator