Rheumatoid Arthritis: Worse Disease Control With Higher BMI

Janis C. Kelly

May 21, 2014

Extra pounds cost overweight patients with rheumatoid arthritis half their chance at early disease control and more than 40% of their chance at prompt pain remission, according to a study published online May 12 in the Annals of the Rheumatic Diseases.

"I believe that the time has come for studies investigating if the effect we see in this and similar studies can be countered by voluntary decrease of fat mass after diagnosis," lead author Maria E.C. Sandberg, PhD, from the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News. "It may be tempting to jump to that conclusion straight ahead, but this is something that needs to be investigated carefully, perhaps in a [randomized controlled trial]. If that is the case, then I think these findings can have a great clinical impact. Until then, maybe it can be helpful for patients at increased risk of RA or with early arthritis."

Large Study Confirms Effect of Obesity in RA

The researchers used data for 495 patients newly diagnosed with RA from the Epidemiological Investigation of Risk Factors for Rheumatoid Arthritis (EIRA) study, a population-based, case-control study. Patients were recruited between 2006 and 2009, and none had taken disease-modifying antirheumatic drugs (DMARDs) at baseline. Body mass index (BMI) was calculated at diagnosis and investigated both as a dichotomized variable and using World Health Organization categories for normal weight (BMI, <25 kg/m2), overweight (BMI, 25 - 30 kg/m2), and obesity (BMI, ≥30 kg/m2).

The main outcome variables were changes in 28-joint disease activity score (DAS28)-based measures and in visual-analog pain scale at 3-month and 6-month follow-up visits after diagnosis. The researchers defined low disease activity as a DAS28 score of 3.2 or lower, and remission as a DAS28 score lower than 2.6. They defined DAS28 decrease as a change greater than the median decrease in the population. The researchers adjusted analyses for sex, calendar period of diagnosis, age at diagnosis, smoking, socioeconomic status, physical activity, physically demanding work, DAS28/pain at diagnosis, vegetable intake, anti-citrullinated protein antibody status, and treatment at diagnosis.

At diagnosis, 86% of patients began methotrexate, and 6% began other DMARDs.

Dr. Sandberg and colleagues report that patients with early RA who were overweight or obese at diagnosis had 51% lower odds (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.31 - 0.78) of achieving low disease activity after either 3 or 6 months of DMARD treatment. Overweight or obese patients had 42% (OR, 0.58; 95% CI, 0.37 - 0.92) lower odds of remission at 6 months, and 43% (OR, 0.57; 95% CI, 0.37 - 0.88) lower odds of pain remission at 3 months compared with normal-weight patients with early RA. DAS28 at diagnosis, sex, prednisolone treatment, and anti-citrullinated protein antibody status had no effect on response to treatment.

Dose–Response Relationship Between BMI, RA Treatment Effect

"A statistically significant dose-response relationship was found between BMI (normal weight, overweight and obesity) and low-disease activity, good response, remission and above-median decrease, at the 6-month visit (p for each <0.01)," the authors write.

The effect of higher BMI was significant for subjective components of the DAS28 (tender joint count, patient global assessment), but not for objective components (C-reactive protein, erythrocyte sedimentation rate, 28-swollen joint count).

The authors conclude that this population-based study showed that patients who are overweight at the time of RA diagnosis have a statistically significant decreased chance of achieving good disease control during the initial phase of disease. "Whether these results are due to an effect of BMI on the natural progression of RA or that BMI affects the response to methotrexate, is not possible to answer due to the large proportion of patients treated with methotrexate (86%). If BMI is affecting the methotrexate response, possible mechanisms are, for example, due to intolerance or to decreased effect. The clinical implication would, however, be the same, irrespective of the underlying reason for the effect of BMI," they write.

Experts Call for Studies on Weight Loss and RA Response

Whether subsequent weight loss might improve RA outcomes is the key unanswered question, but the authors note that these data "provide evidence for efforts to address overweight in individuals at increased risk for RA, and also in the general population."

Dr. Sandberg said the available data did not include information on the body weight of the patients at 6 months but that 1-year and 3-year follow-up questionnaires being sent to all EIRA participants will provide that information.

"Long-term weight decrease in RA is a complicated subject," Dr. Sandberg pointed out. "It may, for example, be a marker of an active and aggressive disease or an effect of a voluntary change to healthier lifestyle, but it is something that we look forward to investigating more in the future."

Effect Might Be Partly a Result of the Inflammatory Effect of Adipose Tissue

Kaleb Michaud, PhD, codirector of the National Data Bank for Rheumatic Diseases and assistant professor of medicine, University of Nebraska Medical Center, Omaha, told Medscape Medical News that the data "are consistent with what we are starting to expect from the inflammatory aspects of extra adipose tissue."

Dr. Michaud, who was not involved in the study, would like to see a subgroup analysis of outcomes in underweight patients because data from the National Data Bank for Rheumatic Diseases have shown worse outcomes for BMI of 18.5 kg/m2 or lower.

"There is no 'magical' transition between healthy and obese at 25 kg/m2, and so comparing those who are more obese (≥30 kg/m2) vs healthy (19 - 25 kg/m2) might be a better comparison," Dr. Michaud said.

Should Treatment Be Adjusted Earlier in Obese Patients With RA?

Dr. Michaud also noted that methotrexate bioavailability might also be a factor to consider. "It would be good to see if increasing the dosage of [methotrexate] in early RA would result in similar outcomes after 6 months and that those with higher BMI required greater doses. At that point, rheumatologists may have a better starting dose ahead of time based on the patient's BMI," he said.

Gianfranco Ferraccioli, MD, who was not involved in this study but had previously reported that obesity reduced the response to TNF inhibitors of patients with RA, told Medscape Medical News that the data are convincing because these patients with early RA were not biased by different treatments.

Dr. Ferraccioli said, "In practice, the authors do not give us any clue on whether body weight led to changes of drug ([methotrexate] or other DMARDs) dosages or not. The second major issue is the lack of pharmacokinetic data in obese people." Dr. Ferraccioli is professor of rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.

Dr. Ferraccioli advised clinicians to consider earlier adjustments to therapy for patients with RA who are obese at baseline. "Instead of waiting for more than 3 months before changing therapy, modify the therapeutic program. We know that some biologics are equally effective in obese and nonobese people," Dr. Ferraccioli said.

This study was supported by the Swedish Medical Research Council; the Swedish Research Council for Health, Working Life and Welfare; the AFA foundation; Vinnova; King Gustaf V’s 80-year foundation; the Swedish Rheumatic Foundation; and the Swedish Foundation for Strategic Research. The authors, Dr. Michaud, and Dr. Ferraccioli have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online May 12, 2014. Abstract

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