Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether hydroxychloroquine (HCQ) reduces insulin resistance in non-diabetic subjects with rheumatoid arthritis (RA). The investigators will conduct a double-blind randomized crossover trial in subjects with RA to test the hypothesis that HCQ improves insulin sensitivity. The investigators will also use data from the trial to identify determinants of insulin resistance in RA. The investigators hypothesize that RA will be associated with an increased risk of insulin resistance and that independent risk factors for increased insulin resistance in RA include higher BMI, elevated acute phase reactants, greater fat to muscle ratio, and less physical activity.

Detailed Description
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Our ability to better control the pain and disability of rheumatoid arthritis (RA) now focuses attention on reducing the impact of RA-associated comorbidities. The most common cause of death in RA is cardiovascular (CV) disease, and the risk of myocardial infarction and stroke are approximately doubled in RA. The determinants of CV risk in RA include traditional CV risk factors as well as aspects of the inflammatory process defining RA. It is likely that RA-associated inflammation accelerates atherosclerosis through direct effects on the endothelium as well as indirect effects on insulin metabolism. Several studies report an increased prevalence of insulin resistance among persons with RA. However, it is not clear whether the inflammation of RA causes insulin resistance. Corticosteroids and abnormalities in the hypothalamic-pituitary axis may also contribute to abnormal glucose metabolism. Little information is available to guide management of a pre-diabetic insulin resistance state in RA. Hydroxychloroquine (HCQ), a commonly used medicine early in RA, may play a role in improving insulin resistance. Several previous trials demonstrated the ability of HCQ to reduce blood glucose levels in diabetics, and a large epidemiologic study found that subjects with RA using HCQ were less likely to develop diabetes. In animal models, anti-malarials lower blood glucose through slowing insulin metabolism. With CV disease a major comorbidity in RA and insulin resistance possibly a major determinant of CV risk, intervention studies need to begin to translate prior work into clinical therapeutics. Relevance: If this study demonstrates a beneficial effect of HCQ on insulin resistance among the randomized subjects, this would provide strong evidence that HCQ has benefits beyond RA and SLE disease activity. Currently, HCQ is stopped in many patients as they step-up to more aggressive DMARD treatments, or HCQ may never be tried in some patients who present with RA carrying with poor prognosis. If HCQ improves insulin sensitivity, there may be rationale for continuing HCQ chronically in patients with RA. As well, a larger clinical endpoint study would be strongly considered.

Official Title
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Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis, Insulin Resistance

Intervention / Treatment
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* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older Able to provide informed consent and comply with study visits Hemoglobin ≥ 10 g/dL (within last two months) WBC ≥ 4 K/uL (within last two months) Platelet count ≥ 150 ≤ 450 K/uL (within last two months) (GFR) Creatinine clearance ≥ 70 ml/min (MDRD) (within last two months) SGOT, SGPT ≤ 1.5 times upper limits of normal (within last two months) Normal eye exam within 12 months of study entry (copy of letter from subject's ophthalmologist or optometrist stating that the subject has no evidence of macular pathology) Diagnosis of rheumatoid arthritis Exclusion Criteria: History of any neuromuscular disease including muscular dystrophy, metabolic myopathies, peripheral neuropathy, multiple sclerosis, and other myopathies or myositides History of diabetes or fasting plasma glucose of 126 mg/dl or greater History of any untoward reaction to antimalarials Uncontrolled hypertension (>140/90) History of any ophthalmologic disease except for glaucoma or cataracts Planned elective surgery during the study period Digoxin therapy Treatment with corticosteroids (> 5 mg) for any disorder History of psoriasis Any chronic disease that in the opinion of the investigator warrants exclusion (e.g. inflammatory bowel disease, malignancy other than basal cell carcinoma, chronic liver disease) History of chronic intestinal disorders (Crohn's disease, ulcerative colitis, celiac sprue, collagenous colitis, eosinophilic enteritis) Creatinine clearance ≤ 60 ml/min (MDRD) (within last two months) Hemoglobin ≤ 10 g/dL (within last two months) WBC ≤ 4 K/uL (within last two months) Platelet count ≤ 150 ≥ 450 K/uL (within last two months) SGOT, SGPT ≥ 1.5 times upper limits of normal (within last two months) Women who are pregnant or breastfeeding

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Placebo then HCQ<br>This arm of the study will contain half the study population after randomization. The participants in this arm will receive hydroxychloroquine for 8 weeks and then crossover to a placebo for 8 weeks. Study staff will be blinded to which order they are taking the hydroxychloroquine and placebo in. | Drug: Hydroxychloroquine<br>* Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject's weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg.<br>* Other names: Plaquenil;|
| Other: HCQ then Placebo<br>This arm of the study will contain half the study population after randomization. The participants in this arm will receive hydroxychloroquine for 8 weeks and then crossover to a placebo for 8 weeks. Study staff will be blinded to which order they are taking the hydroxychloroquine and placebo in. | Drug: Hydroxychloroquine<br>* Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject's weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg.<br>* Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity Index | We will examine the effect of HCQ on the Matsuda Insulin Sensitivity Index (ISI) during the active treatment phase compared with placebo phase. ISI is based on insulin and glucose levels in a fasting state during an oral glucose tolerance test (OGTT) and is calculated as follows: ISI (Matsuda) = 10000/√ G0 X I0 X Gmean X Imean G0 - fasting plasma glucose (mg/dL) I0 - fasting plasma insulin (mIU/L) Gmean - mean plasma glucose during OGTT (mg/dL) Imean - mean plasma insulin during OGTT (mIU/L) | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HOMA-IR | We will examine the effect of HCQ on HOMA-IR during the active treatment phase compared with placebo phase. HOMA-IR = (Glucose x insulin)/405 | Baseline and Week 8 | 
| HOMA-B | HOMA-B = (360 x Insulin)/(Glucose - 63) | Baseline and Week 8 | 
| Total Cholesterol | mg/dL | Baseline and Week 8 | 
| LDL Cholesterol | mg/dL | Baseline and Week 8 | 
| HDL Cholesterol | mg/dL | Baseline and Week 8 | 
| Triglycerides | mg/dL | Baseline and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholesterol, rheumatoid arthritis, insulin resistance, hydroxychloroquine