LOS ANGELES, California—Rheumatoid arthritis (RA) disease flares sometimes reported by patients following exposure to psychological stress may occur because stress can stimulate monocyte production of TNFα (tumor necrosis factor α) in RA patients, according to Sarosh J. Motivala, PhD, and colleagues at the UCLA Semel Institute for Neuroscience and Human Behavior. Dr. Motivala reports in Arthritis & Rheumatism that monocytes from patients who have been taking TNFα antagonists seem immune to this stress response.¹

"[B]rief psychological stress, lasting as little as 15 minutes, can trigger increased monocyte production of TNFα in RA patients who are not receiving treatment with TNFα antagonists. Subsequent work examining how psychological stress affects signal transduction of TNFα would help to explain why RA patients may be particularly prone to flares in disease activity following stress," Dr. Motivala said.

TNF inhibitors blunt the effects of stress in RA patients

The researchers hypothesized that a short period of experimental stress would increase TNFα levels, which were measured by lipopolysaccharide (LPS)-stimulated monocyte production, in patients with RA compared with healthy controls. They further hypothesized that the stress stimulation would not greatly increase TNFα production in RA patients taking TNF inhibitors than in those not taking these drugs.

The study included 21 RA patients (11 of whom were taking TNFα antagonists) and 20 age- and sex-matched healthy controls. About 70% of the RA patients were taking nonbiologic DMARDs, and nearly 40% took NSAIDs, but none took >10 mg/day of oral prednisone.

The subjects performed the Trier Social Stress Task, in which subjects are evaluated on public speaking performance and on serial subtraction math tasks. Subjects rated their level of subjective stress on a scale of 0-100; blood pressure and heart rate were measured during the task. Blood was collected at baseline, immediately following the task, and at 30 and 60 minutes after the task. The blood samples were analyzed for plasma ACTH, cortisol, and interleukin-6 (IL-6). Heparinized samples were used to measure stimulated production of IL-6 and TNFα.

The task increased self-reported psychological stress in all three groups, but members of both RA groups (with vs without TNF inhibitors) had stress levels higher than controls (P <.05). LPS-stimulated monocyte production of TNFα was similar at baseline and immediately after the task for all three groups. At 30 and 60 minutes, however, the RA patients taking TNFα antagonists continued to have TNFα production levels similar to those of the healthy controls, but the RA patients not taking TNF inhibitors had significantly higher TNFα levels (P <.05 at both time points).

Translating research into practice

"Among RA patients not taking TNFα antagonists, stress produced a marked increase in stimulate monocyte production of TNFα compared with responses in age- and sex-matched controls. In contrast, RA patients taking TNFα antagonists (infliximab, etanercept, or adalimumab) were protected from stress-related increases in TNFα production, with unchanged production throughout the laboratory session similar to that in healthy controls," Dr. Motivala said.

The researchers suggest that this difference may reflect altered TNFα regulation at the cellular level in the RA patients compared with normal controls. "[W]e speculate that TNFα antagonists may block stress-induced increases in TNFα production by altering the NF-κB signaling pathway," they write. They suggest that the use of TNFα antagonists might be particularly helpful in RA patients who are especially vulnerable to stress.

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