Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

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.

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