Malaria Drug Has Utility in RA

Hydroxychloroquine less likely to cause hyperlipidemia than

methotrexate.
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 by Diana Swift, Contributing Writer April 11, 2015

 This article is a collaboration between MedPage Today® and:
Action Points

 In early rheumatoid arthritis, treatment with the antimalarial hydroxychloroquine may

reduce the risk of hyperlipidemia, when compared with methotrexate.
 Note that the study suggests that more research is needed on the effect of TNF alpha
inhibition on hyperlipidemia.

In early rheumatoid arthritis (RA), treatment with the antimalarial hydroxychloroquine may
reduce the risk of hyperlipidemia, when compared with methotrexate (MTX), according to a
large retrospective study from Brigham and Women's Hospital, Boston.

The study of disease-modifying antirheumatic drug (DMARD) use also noted a possible increase
in hyperlipidemia risk in some initiating treatment with tumor necrosis factor alpha (TNF alpha
inhibitors). The investigation was led by Rishi J. Desai, PhD, a postdoctoral research fellow in
the hospital's Division of Pharmacoepidemiology and Pharmacoeconomics.

Although RA patients have a generally higher risk of cardiovascular disease (CVD), several
studies have suggested that RA patients may have lower total and low-density lipoprotein (LDL)
cholesterol than persons without RA. "Reports of inverse association between inflammatory
markers and lipid parameters may explain this phenomenon," Desai and associates wrote.

The study examined two large commercial insurance organizations' claims data from 2001 to
2012 and was reported in the April 2015 issue of Arthritis Care and Research. The primary
outcome was incident hyperlipidemia, defined by a diagnosis and a prescription for a lipid-
lowering agent.

For the subgroup of patients with available pre-study laboratory results, changes in lipid levels
were also assessed.

Excluding those diagnosed with a range of CVDs, or hyperlipidemia, or prescribed lipid-

lowering drugs, the investigators identified 17,145 eligible new RA patients from a larger cohort
of 30,831.

Patients -- more than 70% female and on average in their mid to late 40s -- were categorized into
one of four mutually exclusive groups based on their DMARD of initiation on the index date:
TNF alpha inhibitors, with or without other nonbiologic DMARDs; MTX without
hydroxychloroquine or TNF alpha inhibitors; hydroxychloroquine without MTX or TNF alpha
inhibitors; and other nonbiologic agents without MTX, hydroxychloroquine, or TNF alpha
inhibitors.

The largest proportion (46.32%) initiated treatment with MTX (the reference treatment),
followed by hydroxychloroquine (35.75%), other nonbiologic agents (12.04%), and TNF alpha
inhibitors (5.89%). In the other-nonbiologics group, the majority of the patients initiated
treatment with sulfasalazine (75.6%), leflunomide (15.4%), or azathioprine (6.8%).

The four exposure groups had similar distributions of age, hypertension, and diabetes mellitus.
The frequency of obesity, smoking, CVD drug, and analgesic use was lower in TNF alpha
inhibitor initiators, while hydroxychloroquine initiators had the highest proportion of females
(84.06%). In a subgroup with available pre-index outpatient C-reactive protein (CRP) results,
hydroxychloroquine initiators had a lower proportion of patients with high CRP levels (defined
as >3 mg/dL). The distribution of CRP levels was similar in the remaining three subgroups.

Of the 17,145 early-RA patients, 364 developed hyperlipidemia. Compared with MTX, in the
full cohort the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for
hyperlipidemia were 1.41 (95% CI 0.99-2.00) for TNF alpha inhibitors; 0.81 (95% CI 0.63-1.04)
for hydroxychloroquine; and 1.33 (95% CI 0.95-1.84) for other nonbiologic DMARDs. HRs for
the propensity score-trimmed cohort were 1.18 (95% CI 0.80-1.73), 0.75 (95% CI 0.58-0.98),
and 1.41 (95% CI 1.01-1.98), respectively.

In the subgroup analysis, hydroxychloroquine use showed significant reductions in lipids from
baseline compared with MTX. For LDL cholesterol the decrease was -8.9 mg/dL (95% CI -15.8
to -2.0); for total cholesterol it was -12.3 mg/dL (95% CI -19.8 to -4.8); and for triglycerides it
was -19.5 mg/dL (95% CI -38.7 to -0.3).

Based on its possible role in cholesterol metabolism, the lipid-lowering potential of

hydroxychloroquine has been evaluated in several studies of RA and systemic lupus
erythematosus patients that also reported reductions in LDL and total cholesterol. Although the
effect of inflammation has garnered the most attention over the past decade, traditional factors
continue to play a crucial role in the development of CVD in RA patients. "Therefore,
understanding RA treatments associated with favorable changes in traditional cardiovascular risk
factors can inform cardiovascular risk management in RA," the authors wrote.

Primary analysis noted increased hyperlipidemia risk in patients starting treatment with anti-TNF
alpha versus MTX, but the association was attenuated in the analysis stratifying by propensity
score (PS), so that ultimately TNF alpha inhibition was not associated with risk elevation. "The
discrepancy in the effect of TNF alpha inhibitors on the risk of hyperlipidemia between the full
cohort and the PS trimmed cohort deserves discussion," the authors wrote.

According to Desai and associates, previous meta-analyses have observed increased total
cholesterol levels after anti-TNF alpha. The thinking is that higher levels of inflammation may
reduce total cholesterol, whereas inflammation control via anti-TNF alpha may "normalize" lipid
levels, while conferring other important CV benefits such as improved endothelial function.

Addressing the study's limitations, the authors noted its retrospective observational nature and
the potential for confounding by indication as well as by variables not captured in insurance-
claims data such as weight, physical activity, and/or dietary habits.

They called for more research on the effect of TNF alpha inhibition on hyperlipidemia.