Bisphosphonates for the Treatment of Seropositive Musculoskeletal Complaints

Study Overview
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Brief Summary
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Seropositive Rheumatoid arthritis (RA) is characterized by autoantibodies that develop prior to clinical onset, allowing identification of individuals at risk for disease development. In a unique program in Stockholm, seropositive individuals presenting with musculoskeletal complains are currently identified and followed-up in a dedicated outpatient clinical program. Despite significant disease burden and increased sick leave among these individuals, we lack today any therapeutic and preventive measures. We aim to (1). establish a nation-wide health program, (2). develop an algorithm for disease risk estimation and (3). test a novel strategy to delay and/or prevent disease onset in seropositive at risk individuals with musculoskeletal complains. We will perform a multicentre randomised study to treat autoantibody-positive individuals at risk for developing RA presenting with pain (Population), by repurposing of bisphosphonates (Intervention) as compared to placebo (Control) to treat pain (primary Outcome) and delay/prevent RA development during 1-year follow-up (secondary Outcome)

Detailed Description
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we have recently identified a novel disease-triggering pathogenic mechanism in autoantibody-positive individuals consisting in a bone-mediated induction of pain by autoantibodies. We hypothesize that specific targeting of this new mechanism, rather than using therapies developed for already established disease (where other mechanisms are active), will be able to treat pain with arthralgia and halt disease progression in seropositive at-risk individuals. We will address this hypothesis by repurposing of bisphosphonates, currently used in clinical practice in both RA patients as well as in many individuals at risk for RA (mainly women in post-menopausal age). We will perform a multi centre, prospective, randomised, double-blind and placebo-controlled study with 2 parallel groups. Patients will be randomised 1:1 to receive either one infusion aclasta (5 mg zolendronic acid, n=40) or placebo (n=40). The primary outcome is the VAS pain score and the study is powered to detect a 20% difference in the primary endpoint between the active and the control arm. The study is powered to detect a 20-percentage point difference in proportions between the control and the treated group. Subjects may withdraw from the trial at any time at their own or the investigators request for safety reasons.

Official Title
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Towards Efficient Prediction and Prevention of Rheumatoid Arthritis

Conditions
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Seropositive Muskuloskeletal Complaints

Intervention / Treatment
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* Drug: Zoledronic Acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age older than 18 years Lack of arthritis as estimated by clinical and ultrasound examination of the joints ACPA positive Intermediate or high risk for RA (according to the algorithm described above) VAS score of at least 20 mm Exclusion Criteria: A previous diagnosis of arthritis Intolerance/contraindication to any of the study medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bisphophonate<br>Zolendronic acid, one infusion iv | Drug: Zoledronic Acid<br>* Treating seropositive individuals with musculoskeletal symptoms with one infusion zolendronic acid as compared to placebo<br>|
| Placebo Comparator: Placebo<br>Placebo, one infusion iv | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VAS pain | PAin on a visual analogue scale | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HAQ | Health assessment questionnaire | 3 months | 
| MRI | MRI investigation of the symptomatic joints in the hands | 6 months | 
| Rheumatoid Arthritis (RA ) diagnosis | Getting a diagnosis of RA | 1 year |