|Ahead of print publication
The impact of obesity on disease activity and other health outcome measures in rheumatoid arthritis
Ankur Dalal1, Rizwan Rajak2
1 Department of Medicine, The Sarvajanik Medical Trust Hospital; Wellness Clinic for Rheumatic and Musculoskeletal Medicine, Surat, Gujarat, India
2 Division of Rheumatology, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, Wales; Department of Rheumatology, Croydon University and Purley Memorial Hospital, Croydon Health Services, NHS Trust, UK
|Date of Submission||08-Mar-2020|
|Date of Acceptance||16-May-2020|
Wellness Clinic for Rheumatic and Musculoskeletal Medicine, 6 and 7, 4th Floor, Jash Point, Opposite Kshetrapal Temple, Sagarampura, Surat - 395 003, Gujarat
Source of Support: None, Conflict of Interest: None
Obesity is a common risk factor for noncommunicable diseases such as hypertension and diabetes. It is believed to be a state of low-grade inflammation. Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory arthritis, and obesity is thought to influence its development through adipokines. However, the exact impact of obesity on the disease course of RA is not well understood. This nonsystematic literature review is, therefore, carried out in an effort to understand about how do the obesity affects disease activity (DA) and other health outcome measures in patients with RA. The reviewed evidences suggest that obesity if at all predispose than mostly to the sero-negative RA. Overall, the reviewed data show that obesity may increase DA, but not the radiological joint damage and mortality in patients with RA. However, few evidences also suggest that obesity by itself may actually increase the level of inflammatory markers rather than underlying disease process. These contradictory observations show a definite requirement of further research in this regard and until then weight reduction through reducing fat over lean body mass can be recommended in patients with RA to improve their DA, disability, quality of life, and general cardiovascular status.
Keywords: Disease activity, mortality, obesity, radiological joint damage, rheumatoid arthritis
| Introduction|| |
Overweight and obesity are defined as excessive or abnormal accumulation of fat in the body that presents a risk to health. The terms “overweight” and “obesity” refer to body weight that is greater than what is considered normal or healthy for a certain height. Overweight is generally due to extra body fat, but may also be related to extra muscle, bone, or water. Obesity is usually due to too much body fat. Obesity is one of the most prevalent risk factors for hypertension, diabetes, heart diseases, and osteoarthritis.
Rheumatoid arthritis (RA) is a most prevalent chronic systemic inflammatory rheumatic disease of unknown etiology. It is manifested predominantly by articular involvement. Extensive research has been done so far on how to control the inflammation in RA. Even though, a sizeable number of RA patients does not respond to the primary line of management and continue to have persistent disease activity (DA). Some of the predictors for poor outcome in RA are well known, which include female sex, cigarette smoking, and positive auto-antibody status. However, these factors may even sometime fail in predicting the prognosis.
The connection between obesity and risk of inflammatory rheumatic diseases has been suggested recently, with obese people are suspected at a high risk of developing RA. Thus, clinical impact of obesity on RA disease course is also become an important issue. This evidence-based review is, therefore, carried out to understand the impact of obesity on DA and other health outcome measures in RA.
| Search Strategy|| |
The articles were searched through PubMed and Google Scholar web search engines. Articles of more than 20 years old were excluded. The search terms included were “Obesity,” “Disease activity,” “Disability,” “Quality of life,” “Radiological joint damage,” “Mortality,” and “Rheumatoid arthritis;” however, relevant keyword variations were also tried. All types of articles restricted to human and adult population were screened. Search of the articles was limited to those published in English. Bibliography screening of primary articles was done. Additional articles of critical importance were included based on the authors' personal knowledge. Out of these, a narrative review meant to be an informative rather than all-encompassing was synthesized, largely based on a knowledgeable selection of recent high-quality articles on the topic of interest.
| Obesity and Rheumatoid Arthritis|| |
Common genetics of obesity and rheumatoid arthritis
The obesity is actually considered as one of the environmental risk factors for the development of RA. Genetically, obesity has two forms, syndromic (chromosomal rearrangement) and nonsyndromic (monogenic or polygenic). The study of polygenic obesity (common and individually different) is more complex than monogenic obesity (rare, severe, and early onset). A number of obesity and RA susceptible gene loci have been identified in different populations by the genome-wide association study approach. Mutation that leads to monogenic obesity are in pro-opiomelanocortin/ prohormone convertase (PC) 1, leptin (LEP)/leptin receptor (LEPR), neuropeptide Y (NPY), Ghrelin receptor, melanocortin receptors (MC3R/MC4R) or fat mass and obesity-associated (FTO) genes, whereas to polygenic obesity are in β- adrenergic receptors (ADRBs), uncoupling proteins(UCPs), or SLC6A14 genes. The genes associated with high risk of developing RA are human leucocyte antigen (HLA) DR4 (shared epitope region of DRβ1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), or peptidyl arginine deiminase 4 (PADI4). However, both the conditions are thought to be developing through complex interaction between multiple genetic and environmental factors. Obesity-related genes (such as FTO, MC4R, and LEP) have been linked with this interaction and epigenome. β-adrenergic receptor, leptin, and leptin receptors (encoded by ADRB1–3, LEP, and LEPR genes, respectively) play an important role in immunometabolism among the obese persons by regulating the inflammatory cytokines., A variant of FTO gene locus was found to be associated with response to infliximab in RA recently. However, data on common genetics between obesity and RA are very scarce till today.
Common pathogenesis factors of obesity and rheumatoid arthritis
It is difficult to answer that whether obesity comes first or the underlying process that cause RA is already set up when obesity develops. The mechanism by which obesity may lead to RA is not known, whereas there are many plausible interactions between obesity and RA [Figure 1], further research is needed to understand these complex connections whereby obesity influences the development of RA.,
|Figure 1: Common plausible factors in the pathogenesis of obesity and rheumatoid arthritis. These factors either single or in combination may act through direct or indirect complex interactions in pathogenesis of obesity and rheumatoid arthritis. SCFA: Short chain fatty acid, LPS: Lipopolysaccharides, B Reg: Regulatory B, : Increase,: Decrease, Fiaf: Fasting-induced adipocyte factor, TG: Triglyceride, IL: Interleukin, T Reg: Regulatory T cells, NF-kB: Nuclear factor kappa B, TNF: Tumor necrosis factor, CRP: C-reactive protein. Microbiota is to be considered gut related|
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The impact of obesity on the risk of developing RA, DA, and joint protection can be explained by adipokines such as leptin (pro-inflammatory), visfatin (pro-inflammatory), resistin (pro-inflammatory), and adiponectin (anti-inflammatory), one of the most studied plausible pathogenesis factor so far. They are thought to have role in RA immunopathology. Many studies have shown that the blood level of adiponectin and leptin may reflect DA and predict the radiographic progression in RA. However, how these or other newly identified adipokines may affect RA activity is not yet understood completely.
Obesity and risk of developing rheumatoid arthritis
Many case–control studies,, and longitudinal studies, have already shown that the obesity is associated with increased risk of developing RA, with more compatible results are related to sero-negative RA. However, in contrast, few studies repeatedly suggest that obesity is not a predisposing factor for RA.,,
The reasons for this discrepancy are not usually discussed. However, it seems that methodological or classification differences, misdiagnosis, or strict adjustment for possible co-variables in more recent studies may eliminate the previously noted positive correlation between obesity and RA development.,
Controversies in obesity definition in rheumatoid arthritis
Overall obesity is assessed by calculating body mass index (BMI) (>30 kg/m2 as per height and weight) and central adiposity by waist circumference and waist-to-hip ratio, whereas relative adiposity can be assessed by using dual X-ray absorptiometry (DXA) in the general population., However, BMI or its standard cutoff value may not be a reliable tool for the assessment of obesity in patients with RA. This may be due to the decrease in lean and increase in fat mass. Therefore, lower thresholds of BMI have been proposed to define obesity in RA population with the help of bioelectrical impedance (BMI >28 kg/m2) or DXA (≥26.1 kg/m2 for women and ≥24.7 kg/m2 for men) by some researchers., However, it is not used in most of the clinical studies conducted so far!
| Impact of Obesity on Disease Activity in Rheumatoid Arthritis|| |
Impact of obesity on disease activity score
Many prospective,, and few retrospective, cohort studies were done during the past 10 years in an attempt to assess the impact of obesity on DA in RA either as a primary or a secondary objective. Most of these studies had observed the changes in DA score (DAS) 28 for a specific period of time in relation to BMI to see the overall impact of obesity on DA in RA [Table 1]. Mirpourian et al. did not report any association between BMI and change in DAS28 as well as any correlation between BMI and change in tender joint count (TJC) during follow-up. Ajeganova et al. reported higher crude mean DAS28 in obese patients group throughout their study period till the last follow-up. Klaasen et al. reported that BMI notably negatively influence the decreased change in both DAS28 and TJC on follow-up at 4 months in their study. Ottaviani et al. also reported that obese participants had markedly reduced odds of a decrease in DAS28 on follow-up at 6 months. Pers et al. did not report any association between BMI and baseline DAS28 as well as change in DAS28 on follow-up at 6 months.
|Table 1: Studies assessing the impact of obesity on different disease activity parameters in rheumatoid arthritis|
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Heimans et al. studied the patients sample from the BeSt cohort, a study basically conducted to compare four various treatment strategies in early RA patients. They utilized the data to assess the impact of obesity on DA by using DAS in patients with RA [Table 1]. They reported that overweight/obese participants had higher DAS44 on follow-up at 1 year. They also found that participants in the overweight/obese groups had higher TJC after adjusting for covariates, but overweight/obesity was not correlated with higher swollen joint count (SJC) or systemic inflammation.
None of the above studies had examined longitudinal changes in simplified diseases activity index or clinical diseases activity index measures. Most of these studies did not find any significant relationship between BMI and change in SJC.
Liu et al. recently conducted a systematic review and meta-analysis to estimate the impact of obesity on DA in RA, which also included most of the above-mentioned studies. They concluded that obesity negatively affects expected improvements in DA measures and patient reported outcomes during the course of RA management.
Impact of obesity on minimal disease activity or remission
Lupoli et al. conducted a meta-analysis in near past with intention to find the impact of body weight on achieving minimal DA (MDA) in patients with rheumatic diseases. Overall, ten studies were included on patients with RA in their meta-analysis. Despite some limitations mentioned such as differed inclusion/exclusion criteria, significant heterogeneity, lack of data on BMI changes over study period, and variability in MDA definition, by using sensitivity analyses and meta-regression analysis, the researchers had found that MDA achievement rate was remarkably higher in those who had a normal body weight compared to obese RA patients.
Liu et al. also studied the impact of obesity on remission in RA in their systematic review and meta-analysis and concluded that obesity decreases odds of achieving remission in RA.
They both have recommended on investigating the role of intervention to reduce BMI for their ability to improve DA outcome.,
Impact of obesity on inflammatory markers versus actual disease activity
Obesity is considered a state of low-grade inflammation. A retrospective observational study by Maheshwari et al. after doing multiple regression analysis concluded that obese patients had significantly elevated erythrocyte sedimentation rate (ESR), and therefore, had elevated DAS28 ESR score, without changes in any other patient or physician reported outcome measures. One other study involving two large cohorts by George et al. tested the hypothesis and concluded that inflammatory markers were higher among obese individuals with RA (especially C-reactive protein (CRP) in women compared to what just seen in the general obese population) and correlated it with excess adiposity, independent of other measures of DA in RA. However, they also found that low BMI was associated with high CRP in men with RA, which was just opposite to what seen in the general population. Similar observations were also reported by Sharma et al. in the recent past. They recruited the patients of RA with remission or low DA as well as implied strict exclusion criteria to eliminate DA and other potential contributors as the cause of raised ESR or CRP.
Thus, recent evidences are actually in contradiction to the previous findings and suggest that obesity by itself may actually increases the level of inflammatory markers rather than the underlying disease process or activity! However, the discrepancy between two sex remains incompletely understood.
| Impact of Obesity on Other Health Outcome Measures in Rheumatoid Arthritis|| |
Impact of obesity on disability
Stavropoulos-Kalinoglou et al. found that obese patients with established RA (mean duration of disease >10 years) had significantly higher functional disability in comparison to its normal counterpart.
A very recent cohort study carried out by Baker et al. evaluated the connections between obesity, weight loss, and worsening of disability in RA patients from two large registry studies, who especially were followed for a long duration. The results of the health assessment questionnaire (HAQ) or multidimensional-HAQ were prospectively noted during the follow-up period. They concluded that severe obesity is associated with disability in RA along with rapid progression. Out of these two registries, the results from one cohort were found to be independent of other clinical factors, CRP, and SJC. They also observed that weight loss is actually correlated with worsening of disability, which might actually be due to underlying chronic illness and age- or disease-related comorbidities.
Two of the studies, mentioned in previous sections, which actually tested the impact of obesity on DA in patients with RA had also reported the results on reduced physical function by using HAQ score in obese RA patients.
Impact of obesity on quality of life
García-Poma et al. had tested the hypothesis and concluded many years before that obesity is independently correlated with poor quality of life (QoL) in patients with RA. They utilized the medical outcomes study short form-36 to quantify QoL and the association was tested by use of multiple linear regression models.
However, above-mentioned studies who looked in to the impact of obesity on DA in RA did not report any longitudinal changes in fatigue, wellness, or QoL.
Impact of obesity on radiographic joint damage
A case–control study conducted by Rho et al. had examined the hypothesis and concluded that levels of adipokines were higher in patients with RA and might drive the radiographic joint damage (RJD). Visfatin might related with increased, while leptin with decreased RJD.
However, on the other hand, a study by Baker et al., which was actually secondary analysis of GO-BEFORE trial, a multicenter, double-blind, placebo-controlled trial that compared the efficacy of methotrexate or golimumab in the treatment of RA had confirmed that higher BMI was independently associated with less RJD. This observation was seen consistent in both sero-positive and sero-negative RA patients. They also suggested that adipokines level (adiponectin or leptin) did not appear to mediate this association in observed subset.
Similarly, recently published systematic review and meta-analysis by Vidal et al. had just concluded that obese patients with RA may generally have lower RJD. They also suggested that the higher adiponectin level seen in obese patients may actually have a protective role on joints. They emphasized on further studies to better understand underlying mechanisms in this regard.
Impact of obesity on mortality
Despite the known adverse effects of obesity, patients with RA and high BMI seems to have a low long-term risk of untimely death including all-cause mortality from cancer, cardiovascular, and lung diseases. This is called obesity paradox. The patient who loses weight may actually lose lean body mass, leading to rise in mortality risk (from ongoing adiposity and underlying diseases process). It has been hypothesized that disease (or age)-related weight loss may actually responsible for this paradox and not the loss of beneficial biologic effect of obesity.,
| Limitations of Review|| |
There are several limitations to our review. We did not perform a systematic review nor did a meta-analysis and so actual clinically significant effect of obesity on DA and other health outcome measures in RA could not be estimated. The analysis mentioned herein does not claim to be exhaustive. For instance, data on obesity and risk of developing RA, including genetics and pathogenesis mechanisms, were highlighted only superficially. The limitations related to data searching were restriction of search engine to two, nonavailability of free full-text of some studies, and the review question for which pertinent evidences are not so easy to find. The articles published only in the English language were selected. All these might lead to omission of few relevant studies.
Obesity and RA link is proposed to be related to an inflammatory effect of adipokines. However, this is not yet completely understood. Obesity may not predispose to RA, except some compatible results regarding sero-negative RA. The basis behind these observations still needs to be evaluated by further research. The World Health Organization definition of obesity may not be reliable for RA patients. Therefore, lower thresholds of BMI, which was proposed by some researchers, should be tested by further studies. More prospective studies on the impact of obesity on inflammatory markers versus actual DA are definitely warranted. Until then, weight loss reducing the fat over lean body mass by the way of diet and exercise can be recommended to improve DA, disability, and QoL as well as general cardiovascular status of obese patients with RA.
| Conclusion|| |
Overall, it seems that the impact of obesity on RA correlates with increase DA, decrease rate of remission, higher debility and lower QoL, but not with increase in joint damage and mortality. However, increase in inflammatory markers due to the effect of obesity cause false elevation of DAS as well as DA in RA, which may lead to overtreatment. This should be kept in mind while managing obese RA patients according to treat-to-target strategy.
The work was completed in partial fulfilment of MSc in Rheumatology from the University of South Wales, Pontypridd, UK.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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