Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project

Study Overview
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Brief Summary
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Inflammatory rheumatic diseases (IRD), such as rheumatoid arthritis, are characterized by adverse changes in body composition. Lean mass and bone mineral density are usually reduced while adiposity (total fat mass, visceral adiposity…) is increased in comparison with healthy controls. Many factors may influence the body composition of those patients such as aging, Disease Modifying Anti-Rheumatic Drugs (DMARDs), nutrition and physical activity. However, data on body composition and adverse changes under DMARDs in patients with rheumatoid arthritis (RA) are actually scarce. This is the case with tofacitinib (targeted synthetic DMARD or tsDMARD) while preliminary data let us think that this treatment may influence body composition and bone mineral density. This study is going to be the first to focus on changes in body composition (fat mass and lean mass), bone mineral density and bone marrow adiposity under tofacitinib.

Official Title
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Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tofacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient's ≥18 years old with moderately to severely active Rheumatoid Arthritis (RA) (ACR/EULAR criteria ) Previously untreated with Janus Kinase (JAK) inhibitors With an indication for tofacitinib will be eligible. All patients will have to be treated with tofacitinib either alone or with methotrexate. -Healthy volunteers should be ≥18 years old. Exclusion Criteria: • treatment with more than three anti-Tumor Necrosis Factor alpha (TNFα). Patients who were receiving anti-TNFα will be required a washout period lasting at least five-half-lives before to start tofacitinib, previously exposed to JAK inhibitors, patients who were receiving non-anti-TNFα biologics (abatacept, tocilizumab, sarilumab or rituximab) will be required a washout period lasting at least five-half-lives before to start tofacitinib Concomitant methotrexate (MTX) will be permitted if started ≥3 months prior to study start and at a stable dose (≤25 mg/week) for ≥4 weeks. history or discovery of an osteoporotic fracture AND/OR T-score≤-3 if ≥50 years AND/OR Z-score ≤-3 if <50 years during the screening phase, current treatment with oral corticosteroids higher than 10 mg prednisone/day, pathologies or treatments that could affect the bone metabolism (breast cancer with aromatase inhibitors, gastrointestinal malabsorption, stomach cancer, primary hyperparathyroidism, uncontrolled hyperthyroidism…), weight> 160 kg, patients on restrictive diets or considering such a diet during the study period, patients with an intense exercise program or planning to benefit from it during the study period,

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with rheumatoid arthritis<br>Patients with rheumatoid arthritis with an indication for tofacitinib: 5mgx2 per day | Drug: Tofacitinib<br>* Patients will be treated with tofacitinib<br>|
| Healthy subjects<br>Healthy subjects matched to cases (1:1) on age (±5 years), sex, and menopausal status for women and body mass index (BMI, ±3 kg/m²) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation in visceral adiposity (VAT or Visceral Adipose Tissue) in cm² | Variation in visceral adiposity (VAT or Visceral Adipose Tissue) in cm² | Between the measurement before and after 6 months of tofacitinib treatment (difference before/after). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurements of VAT in cm². | Measurements of VAT in cm² | at baseline | 
| Measurements of total fat mass (TBF) in kg, total lean mass (TLM) in kg, appendicular lean mass (aLM) in kg | Measurements of total fat mass (TBF) in kg, total lean mass (TLM) in kg, appendicular lean mass (aLM) in kg | at baseline | 
| Measurements of body fat percentage (%) | Measurements of body fat percentage (%) | at baseline | 
| Measurements of fat mass index (FMI) in kg/m² and skeletal muscle mass index (SMI) in kg/m² | Measurements of fat mass index (FMI) in kg/m² and skeletal muscle mass index (SMI) in kg/m² | at baseline | 
| Measurements of Bone mineral Density (BMD) in g/cm². | Measurements of Bone mineral Density (BMD) in g/cm². | at baseline | 
| Change in body fat percentage (% between measurement | Change in body fat percentage (%) between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Change in total fat mass (TBF) between measurement | Change in total fat mass (TBF) in kg between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Change in fat mass index (FMI) in kg/m², between measurement | Change in fat mass index (FMI) in kg/m², between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Change in total lean mass (TLM, kg) and appendicular lean mass (aLM) in kg between measurement | Change in total lean mass (TLM, kg) and appendicular lean mass (aLM) in kg between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Change in skeletal muscle mass index (SMI) in kg/m² between measurement | Change in skeletal muscle mass index (SMI) in kg/m² between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Change in BMD (in g/cm²) at the lumbar spine (L1-L4) and non-dominant total hip between measurement | Change in BMD (in g/cm²) at the lumbar spine (L1-L4) and non-dominant total hip between measurement | Before and after 6 months of tofacitinib treatment (difference before/after). | 
| Variation of bone remodelling markers (Cross-laps (CTX) and Type I procollagen N-terminal propeptide (P1NP)) between measurement | Variation of bone remodelling markers (Cross-laps (CTX) and Type I procollagen N-terminal propeptide (P1NP)) between measurement | Before and after 6 months of tofacitinib treatment. | 
| Variation in leptin (ng/ml) between measurement. | Variation in leptin (ng/ml) between measurement. | Before and after 6 months of tofacitinib treatment | 
| Change in bone marrow adiposity (%) at the lumbar spine between measurement | Change in bone marrow adiposity (%) at the lumbar spine between measurement | Before and after 6 months of tofacitinib treatment. | 
| Variation in Short Physical Performance Battery Protocol (SPPB) between measurement | Variation in Short Physical Performance Battery Protocol (SPPB) between measurement | Before and after 6 months of tofacitinib treatment. | 
| Changes in the parameters of the primary outcome and the secondary outcomes (n°2 to 8) | Changes in the parameters of the primary outcome and the secondary outcomes (n°2 to 8) | Before and after 12 months of tofacitinib treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, tofacitinib, body composition, bone marrow adiposity, bone marrow density