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
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.
Less time needed to reach both remission on glucocorticoids and glucocorticoid free
remission
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:
Time to relapse and steroid-sparing capacity of leflunomide
PMR disease activity including patient reported outcome
Treatment related complications of steroids
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.