Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis (RA PLUS)

• Total cholesterol [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  We will examine the effect of HCQ on total cholesterol during the active treatment phase compared with placebo phase.
• Insulin Sensitivity Index [ Time Frame: Week 16 ] [ Designated as safety issue: No ]

  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)

• Insulin Sensitivity Index [ Time Frame: Baseline ] [ Designated as safety issue: No ]

  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)

• Total Cholesterol [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  We will examine the effect of HCQ on total cholesterol during the active treatment phase compared with placebo phase.
• Total Cholesterol [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
  We will examine the effect of HCQ on total cholesterol during the active treatment phase compared with placebo phase.

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.

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.

• Rheumatoid Arthritis
• Insulin Resistance

• Placebo then HCQ
  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.
  Intervention: Drug: Hydroxychloroquine
• HCQ then Placebo
  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.
  Intervention: Drug: Hydroxychloroquine

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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