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The use of hydroxychloroquine showed benefits for metabolic profiles among patients with rheumatoid arthritis, a systematic review and meta-analysis found, although whether the drug should be widely used for this reason is unclear.

In seven studies that compared lipid profiles between patients who did or did not use hydroxychloroquine, the pooled mean differences for total cholesterol and low-density lipoprotein (LDL) cholesterol, respectively, were -9.8 (95% CI -14 to -5.6) mg/dL and -10.6 (95% CI -14.2 to -7) mg/dL, favoring users, according to Charlotte Hua, MD, of Montpellier University in France, and colleagues.

In addition, the pooled differences for high-density lipoprotein (HDL) cholesterol and triglycerides were +4.1 (95% CI 2.2 to 6) mg/dL and -19.1 (95% CI -27.2 to -11.1) mg/dL, again favoring those who used the drug, the researchers reported online in.

"Hydroxychloroquine improves symptoms of rheumatoid arthritis in some patients. It also appears to have benefits for some common comorbidities, like diabetes and hyperlipidemia," Daniel H. Solomon, MD, chief of the Section of Clinical Sciences in the Division of Rheumatology at Brigham and Women's Hospital and Harvard Medical School in Boston, told MedPage Today.

"However, it is not clear whether this translates into reduced cardiovascular risk. These potential benefits need to be weighed against the real risk of macular toxicity among patients using hydroxychloroquine for extended periods."

Antimalarial agents such as hydroxychloroquine have been used in inflammatory diseases for decades -- most notably systemic lupus erythematosus. Possible mechanisms of action include interference with toll-like receptor signaling and antigen presentation, along with inhibition of lysosomal activity, which may decrease insulin degradation and interfere with cholesterol formation.

The efficacy of hydroxychloroquine in rheumatoid arthritis is only moderate, and is a component of so-called , along with methotrexate and sulfasalazine, a treatment option currently chosen by few patients.

Nonetheless, because of the potential ameliorating effects on metabolic and cardiovascular comorbidities -- major contributors to the increased mortality in RA -- Hua and colleagues said they conducted a systematic literature search, looking for evidence of the potential impact of hydroxychloroquine treatment for patients at risk.

Nine studies were identified, seven of which were cohort studies and two that were clinical trials. The systematic review included 35,213 patients, with 12,245 hydroxychloroquine users and the remainder nonusers.

The specific analyses included:

• For lipid levels, 6,536 users and 9,760 nonusers
• For diabetes incidence, 4,811 users and 12,074 nonusers
• For insulin resistance, 80 users and 243 nonusers
• For glycated hemoglobin (Hb)A1c analyses, 33 users and 31 nonusers
• For cardiovascular disease, 824 users and 1,029 nonusers

In two studies that assessed lipid levels after 2 to 3 months of hydroxychloroquine treatment, mean changes in total cholesterol, LDL, and triglycerides were -13.1 (95% CI -20.9 to -5.3) mg/dL, -12.3 (95% CI -20.2 to -4.6) mg/dL, and -12.5 (95% CI -28.9 to 3.9) mg/dL, respectively. The mean increase in HDL was 1.6 (95% CI -0.96 to 4.3) mg/dL.

For diabetes, hydroxychloroquine users had a lower incidence than nonusers, with a pooled hazard ratio of 0.59 (95% CI 0.49-0.70), while changes in HbA1c levels from baseline to 3 months were -0.19 in hydroxychloroquine users versus -0.08 in methotrexate users. As to insulin resistance, there were no significant differences between users and nonusers on homeostatic models of insulin resistance or beta-cell function.

For cardiovascular disease risk and incidence, three studies were included. In one retrospective study (presented as an abstract), cardiovascular morbidity declined with use (OR 0.27, 95% CI 0.16-0.46), and in a case-control study, cardiovascular disease risk was lower among users (OR 0.45, 95% CI 0.10-2). In a retrospective study, hydroxychloroquine use was associated with a decreased incidence of cardiovascular disease (HR 0.60, 95% CI 0.41-0.94, P=0.02) and lower incidence of a composite endpoint including coronary artery disease, stroke, and transient ischemic attack (HR 0.67, 95% CI 0.42-1.070, P=0.09).

"This meta-analysis confirms prior work that has suggested improvement in diabetes control, reduced diabetes risk, and improved lipid profiles among people using hydroxychloroquine," Solomon said. "It is important to organize these data in one systematic review as the authors have done."

However, he continued, "their supplementary data regarding observational studies of hydroxychloroquine and reduced cardiovascular risk is much weaker. The several studies that they included are weak methodologically, so any conclusions must be very tentative."

The authors of the systematic review conceded that their analysis may have been influenced by confounding bias, in that hydroxychloroquine might be more likely to be used by patients with milder disease, who are also less likely to have cardiovascular disease. "Consequently, the lower cardiovascular risk noted for the patients using hydroxychloroquine is perhaps linked to the characteristics of these patients' disease and not to the hydroxychloroquine treatment in itself."

The researchers concluded that use of this "safe and inexpensive treatment" may be a useful adjunct in the prevention of metabolic and cardiovascular events for patients with rheumatoid arthritis.

But adherence can be less when treatment regimens are more complicated, Solomon pointed out. "This dampens my enthusiasm for keeping patients on hydroxychloroquine when they require additional treatments and triple therapy is not their choice."

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