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

• Insulin Sensitivity Index [ Time Frame: Baseline and Week 8 ] [ 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)

  
  

• HOMA-IR [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]

  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

  
  
• HOMA-B [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  HOMA-B = (360 x Insulin)/(Glucose - 63)
  
  
• Total Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  mg/dL
  
  
• LDL Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  mg/dL
  
  
• HDL Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  mg/dL
  
  
• Triglycerides [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  mg/dL
  
  

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.