type : Full Length Weight change in the early rheumatoid arthritis period and risk for subsequent mortality among women with RA and matched comparators

Objective: We investigated whether weight change during the early RA period was associated with subsequent mortality and evaluated for an RA-specific effect. Methods: We identified incident RA during the Nurses’ Health Study (1976-2016) and created a comparison cohort, matching each RA case with up to 10 non-RA comparators by age and year of RA diagnosis (index date). To capture weight change around the early RA period (“periRA/index”), we used weight measures 2-4 years before and after index date. Cox regression estimated HRs for mortality by peri-RA/index weight change categories separately in each cohort and combined, evaluating for an RA-specific effect. Results: Among 121,701 women, 902 developed incident RA, matched to 7,884 non-RA comparators. There were 371(41.1%) deaths in the RA cohort during mean 17.0 years follow-up after the early RA period and 2,303(29.2%) deaths among comparators during mean 18.4 years follow-up. Peri-RA weight loss >30 lb had HR of 2.78 (95%CI1.58-4.89) for mortality compared to stable weight; the comparison cohort had similar results (HR 2.16, 95%CI1.61-2.88). Weight gain >30 lb had no association with mortality among RA (HR 1.45, 95%CI0.69-3.07) or comparators (HR 1.19, 95%CI0.89-1.59). There was no interaction between RA/comparator status and weight change for mortality (pinteraction=0.68). A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Conclusion: Severe weight loss during the early RA period was associated with increased subsequent mortality risk for women with and without RA. These results extend prior observations by including non-RA comparators and finding no protective association between weight gain and mortality, arguing against an RA-specific obesity paradox for mortality. The increased mortality risk for patients with rheumatoid arthritis (RA) compared to the general population may be due to altered immunity, medication side effects, systemic effects of inflammation, worsened physical function, accumulation of multimorbid conditions, and excess unhealthy behaviors such as smoking(1-5). The contribution of metabolic and inflammatory factors (such as obesity) to RA etiology and outcomes has received increased attention recently(6, 7). Several studies have investigated the effect of body mass index (BMI) on mortality among patients with RA. In RA cohorts, obesity has been associated with 34-67% decreased mortality compared to those with normal BMI(8-11). Follow-up studies suggested that this “obesity paradox” for mortality in RA may be explained by pathologic unintentional weight loss in the few years preceding death, rather than a biologic protective effect of obesity. According to this explanation, patients with longstanding RA who reached normal or underweight BMI have higher observed mortality and are relatively less healthy than RA patients that maintained obesity or overweight(11, 12). In other chronic diseases and the general population, similar findings of a paradoxical protective effect for overweight or obesity, as well as increased mortality risk with unintentional weight loss, have been reported(13-16). Studies in RA evaluating obesity, weight change, and mortality have typically consisted of long duration and relatively short follow-up prior to death. Therefore, prior associations may not have been specifically related to RA, but rather may have been detecting a general phenomenon related to multimorbidities, aging, or frailty(13, 17). We hypothesized that the early RA period is the window of time most likely to specifically contribute to weight change in RA due to systemic inflammation prior to treatment, and changes A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. in physical activity and diet with active symptoms(18, 19). Therefore, to investigate the specific effect of weight change on mortality in RA, weight measures are needed before RA diagnosis and at the end of the early RA period to effectively capture weight changes that might occur during the entire early RA period. Furthermore, a non-RA population is required to establish that observed effects are specifically related to RA and not multimorbidities, aging, or frailty. Since weight loss often immediately precedes death, lengthy follow-up between the weight change measurement and death assessment enhances the ability to associate weight loss with an underlying chronic disease such as RA rather than as the proximal cause of death. Within the Nurses’ Health Study (NHS), we investigated the effect of weight change during the early RA period on subsequent mortality, including a non-RA group to evaluate for the specific effect of RA. We hypothesized that severe weight loss and gain during the early RA period would be associated with increased risk of mortality compared to stable weight, but that there would be similar effects among those with and without RA. METHODS Study population. In 1976, 121,701 female registered nurses in the U.S. aged 30-55 enrolled in the NHS. Women in the NHS completed questionnaires at baseline and every two years, providing data on anthropometrics, behaviors, sociodemographics, diet, medications, and diseases. Follow-up in the NHS has been high, with >90% returning questionnaires each cycle(1). All aspects of this study were approved by the Partners HealthCare IRB. Incident RA cohort. We excluded participants with prevalent RA or other connective tissue disease (CTD) prior to the NHS baseline in 1976. Women who self-reported a diagnosis of RA or other CTD after the initial questionnaire were mailed a screening questionnaire(20). For those who screened positive, medical records were obtained and reviewed by two rheumatologists to confirm RA meeting the 1987 American College of Rheumatology classification criteria(21). Details on RA characteristics at diagnosis, including date of diagnosis, A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. serologic status, radiographic changes/erosions, and nodules, were obtained from medical record review. Seropositivity was defined as positive rheumatoid factor (RF) or cyclic citrullinated peptide (CCP) antibodies per tests sent through routine medical care. Women diagnosed with RA prior to the clinical use of CCP would not have had this tested during clinical care, so CCP was generally only available on women diagnosed later during follow-up. We only analyzed RA cases who had weight measures available at two questionnaire cycles before as well as two cycles after the date of RA diagnosis (Figure 1). Matched non-RA comparison cohort. To evaluate for an RA-specific effect between weight change and mortality, we created a comparison cohort without RA within the NHS. To control for age and temporal trends, we matched each RA case with up to ten non-RA comparators based on age and calendar year. We defined the index date for matching as the date of RA diagnosis, as previously described(5). Participants in the NHS were eligible to be a comparator if they had never reported RA or other CTD prior to or on the index date and had weight measures at two follow-up cycles before as well as two cycles after index date. Since we matched women on the same age in years and same calendar year, exactly ten comparators with complete exposure data may not have been available for every woman with incident RA. Weight change in the early RA/index period. All weight measures were prospectively self-reported in pounds (lb), previously validated in the NHS as highly accurate compared to measured weight (r=0.98)(22). We investigated weight change during the early RA period since this is the window when weight change is most likely to be related to RA-specific processes (Figure 1). We chose the initial weight (Weight 1) as reported two cycles (minimum of 2 and maximum of 4 years) prior to the date of RA diagnosis since the weight measure immediately preceding RA diagnosis might have been affected by RA symptoms prior to definitive clinical diagnosis. We chose the subsequent weight (Weight 2) as reported two cycles after the date of RA diagnosis (minimum of 2 and maximum of 4 years) to capture the early RA period, which is A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. often defined as the first two years after diagnosis(23-25). Therefore, we captured weight change in the “peri-RA” period which encompassed the entire early RA period. For comparators, we used a parallel strategy to identify weights before and after the index date to define analogous “early index” and “peri-index” periods even though these women were not diagnosed with any disease at the index date. In this study, the entire peri-RA/index period typically encompassed 6 years (Figure 1). We created categories of weight change based on the absolute weight gained or lost comparing the initial and subsequent weights (ΔWeight=Weight 2–Weight 1). We defined stable weight as |ΔWeight| ≤10 lb, mild loss as ΔWeight <-10 to -20 lb, moderate loss as ΔWeight <-20 to -30 lb, severe loss as ΔWeight <-30 lb, mild gain as ΔWeight >10 to 20 lb, moderate gain as ΔWeight >20 to 30 lb, severe gain as ΔWeight >30 lb. Identification of deaths. As previously described in detail, deaths were identified by systematic searches of the National Death Index and state vital records(26). This search is supplemented by family and postal authority reports. These methods ascertain >98% of deaths in the NHS(27). Women who died during the peri-RA or peri-index periods were not included in the analysis since ΔWeight could not be calculated. Complete death data were available until May 31, 2016 which was the end of the analysis. Covariates. We considered covariates as confounders based on their association with both RA risk and mortality in prior literature. All covariates except for RA disease characteristics were assessed at the same questionnaire as Weight 1. BMI was categorized as underwei