|Year : 2019 | Volume
| Issue : 4 | Page : 225-228
Impact of obesity on disease activity and other health outcome measures in ankylosing spondylitis
Akshat Pandey1, Harmeet Singh Saluja2, Arvind Mittal3
1 Department of Rheumatology, Apollo Hospitals, Indore, Madhya Pradesh, India
2 Department of Medicine, SAMC and PGI, Indore, Madhya Pradesh, India
3 Department of Medicine, GMC, Bhopal, Madhya Pradesh, India
|Date of Submission||19-Oct-2019|
|Date of Acceptance||30-Oct-2019|
|Date of Web Publication||12-Dec-2019|
Department of Rheumatology, Apollo Hospitals, Indore, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Obesity is a rapidly increasing pandemic, with almost one-third of the world population being affected. It has its impact on various systems, of which musculoskeletal system is also majorly affected. Its impact on rheumatoid arthritis and psoriatic arthritis are already known, but its association with ankylosing spondylitis is debatable and very few studies are being conducted to support its impact. The below article is a review of the association and impact of obesity on the disease activity, factors involved in its pathogenesis, impact on others underlying diseases, and therapeutic affections. This article also urges the need for the physicians to treat obesity as a separate disease condition which requires treatment like any other disease to improve the quality of life of individuals and to limit the progress of other diseases.
Keywords: Ankylosing spondylitis, disease activity, obesity
|How to cite this article:|
Pandey A, Saluja HS, Mittal A. Impact of obesity on disease activity and other health outcome measures in ankylosing spondylitis. Apollo Med 2019;16:225-8
| Introduction|| |
According to the World Health Organization (WHO), obesity is like a global epidemic, which is ever increasing and a major health concern for society. They have reported that presently more than 1.9 billion adults are overweight, whereas more than 650 million are obese. It has a major impact on the individual's physical, social, and psychological aspects of life. It is also responsible for the development and progress of other comorbidities affecting systems such as cardiovascular, metabolic, rheumatic, and musculoskeletal systems. It is even observed that the number of deaths globally due to obesity is more as compared to deaths due to underweight.
Overweight and obesity are defined as abnormal or excessive accumulation of fat that may cause health impairment. Body mass index (BMI) is a tool used to measure and classify overweight and obesity. It is expressed as weight in kilograms divided by square of the height of the person in meters. As per the WHO, a BMI of ≥25 is termed as overweight, while if the BMI is ≥30, it is termed as obese.
| Ankylosing Spondylitis and Its Disease Activity Index|| |
Of the various systems affected, the impact of obesity on the musculoskeletal system involving ankylosing spondylitis (AS) is debatable. AS is a type of spondyloarthropathy presenting with inflammation of the axial skeleton, peripheral arthritis, and enthesitis which is the site of insertion of bone to tendons or ligaments or joint capsules. The patient presents clinically in their twenties. AS has a strong genetic association with (human leukocyte antigen [HLA]) HLA-B27 antigen. The prevalence of AS is seen in 0.5% of the population, with males being relatively more affected than females roughly around 2:1.
This inflammatory condition of the spine causes some of the vertebras to fuse, leading to reduced flexibility, stiffness, and deranged posture. Most commonly, the patient complains of pain and stiffness in the neck or lower back region, which is more in the morning on waking up or after a period of inactivity. On radiography, there is the presence of sacroiliitis, which confirms the diagnosis, but this develops in the later stage of disease. Initials such patients are treated with nonsteroidal anti-inflammatory drugs, which temporarily relieve the pain but fail to control or modify the course of the disease. The delay in diagnosis may be up to 7–10 years by which the treatments options become limited. Since its onset is early, it has a major impact on the quality of life (QoL) of the patients as it not only reduces the physical functioning but also causes an economic burden on the individual.
In AS, certain standard indexes are used to determine the severity of the disease and its impact on patient's activity. Here, the Bath Ankylosing Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) are the most widely used tools to assess the disease activity in AS. The BASDAI completely uses the patient-related outcomes (PROs) to measure the disease activity; hence, it has some limitations, whereas the ASDAS is dependent on both PROs and the C-reactive protein (CRP) levels. And as is known adipose tissue is related to producing certain pro-inflammatory cytokines, of which CRP is one.,
| Obesity and Inflammatory Mechanism|| |
Obesity is also referred as a low-grade inflammatory condition due to the increased production of pro-inflammatory mediators. Adipose tissue has immune-modulatory properties since it produces several pro-inflammatory cytokines such as tumor necrosis factor-a (TNFa), interleukin 6 (IL-6), and adipose tissue-specific pro-inflammatory cytokines called adipocytokines.
There are a variety of adipocytokines of which adiponectin, resistin, and leptin are the most abundantly produced. Leptin is a cytokine that is a product of the obese (ob) gene, which has an impact on the body weight homeostasis by interfering with the food intake and the amount of energy burnt at the level of the hypothalamus. Another factor named resistin is known to be a pro-inflammatory factor, which is found to be more in the synovial fluid in rheumatoid arthritis (RA) patients. Even some studies support that the resistin levels will be higher in the serum of AS patients and even demonstrate a positive association with the radiological progression of the diseases.
These findings suggest that obesity is a low-grade inflammatory condition owing to the pro-inflammatory and immune-modulatory features of the adipose tissue. Furthermore, it proves that obesity is one of the major risk factors in the development and progression of rheumatic diseases such as RA, though its relation in AS is still debatable.,,
It is also observed that in an individual with a normal or lean body, these immune cells are at absolute equilibrium with the adipocytes  and maintain an anti-inflammatory condition within the body by producing products such as IL (IL-10, IL-4, and IL-13). Whereas in obese individuals, there is an increase in the T-helper cells (TH1, TH17) and decrease in the regulatory T-cells (Th2), which causes the production of inflammatory cytokines such as TNFa and IL-6, which favors the inflammatory condition. Although in AS, it is observed that there is not an increase in the fat mass, the adiposity favors reduced treatment response and favors the disease progression.
| Effect of Obesity on the Therapeutic Effects of Drugs and the Disease Activity in Ankylosing Spondylitis|| |
For the treatment of AS, patients are started with anti-TNF drugs such as infliximab or adalimumab, to which they respond well. However, it has been observed that in some cases, they stop responding after a certain time., Being obese and overweight has a reduced response to TNFi. Researchers have observed that obesity is associated with 60% chance of failure of response to TNFi drugs in rheumatic and musculoskeletal diseases (RMDs). To the extent that more severe be obesity, more are the chances of failure of response.
It was observed in a study on patients with normal weight, overweight, and obese after treatment for 1 year with a similar dose of TNFi therapy that they achieved Assessment in SpondyloArthritis International Society 40% response (ASAS40) of 44%, 34%, and 29%, respectively. This could prove that obese people are either underdosed with TNFi or since obese patients release more adipokines, which is a pro-inflammatory element that might increase inflammatory arthritis. This study also revealed that in inflammatory arthritis or rheumatic arthropathies the weight of the patient must be considered as it could be a probable reason for decreased results of TNFi medications. Since obesity is also associated with increased adiposity and thus more production of CRP. The increased CRP state also explains the increase complaint of pain and reduced function, which affects the PROs. There are reports of strong association between higher PROs in obese persons with AS. Targeting an ASDAS improvement seems difficult in obese patients.
In another retrospective study with infliximab similar findings of reduced BASDAI 50 was achieved after a duration of 6 and 12 months, which means obese patients failed to show a ≥50% improvement. Here, of the 155 patients, obese patients (26.5%) showed a reduced therapeutic response to the drug infliximab after 6 months as compared to patients with normal body weight.
Similar findings were seen in another study with 170 patients, where the BASDAI 50 scores were less in overweight (54.5%) and obese patients (30.4%) as compared to normal-weight patients (72.8%) after 1 year. This difference was specifically observed in patients with infliximab as compared to other anti-TNF agents, whereas it is the only anti-TNF agent, which is administered on weight basis. In another study, infliximab showed better ASAS40 response as compared to other TNFi drugs. This could suggest the need to analyze the dosage of other TNFi in relation to treating obese AS patients. Even with the drug adalimumab, in a study by Rosas et al., AS patients showed a reduced clinical response according to the BASDAI scale.
Various studies have been conducted to see the association between anti-TNF drugs levels and the clinical benefits in AS patients. It has been observed that certain patients develop anti-drug antibodies which could cause the loss in the efficiency of the drugs. In a study done by Durcan et al. in Ireland, it was revealed that obese patients have higher disease activity score and functional limitation score, while worse patient global score. While in another study by Rubio Vargas et al. on 428 patients, BMI had no significant association with PRO. Both studies were done on the Caucasian population where the standard BMI is different. In a study done by Lee et al. on the Asian population, there was no association between the two components. These differences might prove the probability that there might be a difference in the association between PROs and obesity in different races.
Even after analyzing the inflammatory mechanisms in obesity, which is also observed in other RMDs, yet in some studies, obesity has shown a negative impact on criteria such as disease activity, functions, QoL, impact on other comorbid conditions, and the prognosis of the disease. However, still with the ever-increasing ratios of RMDs, there is also a more so increase in the prevalent cases of obesity. Yet, it is dealt poorly by the routine clinical practitioners.
The accentuated inflammatory state due to low adiponectin levels in obese patients which might give a poor pain and BAS-G score. Furthermore, in obese individuals, the load on the weight-bearing joints is more causing more pain, leading to poorer pain scores. In patient with AS, apart from medications; spinal mobility and physical activity are recommended, but due to obesity, there might be reduced activity. Thus, more pain which would further precipitate lack of physical activity. Thus, this vicious cycle causes the disease condition to worsen which manifests with poor QoL and PROs.
While planning the management of AS, the required lifestyle modifications, nutritional assessment, the required changes in diet and the emphasis on physical activity should be made. Since obesity is preventable, maximum emphasis should be given to maintain the standard BMI. Apart from the general lifestyle changes, in AS more specific lifestyle modifications should be made as maintain to maintain a correct posture, advice physical exercise regime, and healthy diet. As these shall not only help in immediate effect by favoring the action of treatment but also, in the long run, might help in preventing or controlling other comorbid conditions such as cardiovascular diseases. Recent research has proven that weight loss by any means (diet, physical activity, or surgery) decreases the disease activity in RMDs, which was seen in the reduction of serum inflammatory cytokines and better action of medications.,
There are various factors which interfere with the drug response, such as the genetics, pharmacokinetics of the drugs, interaction with other drugs such as disease-modifying anti-rheumatic drugs especially with methotrexate and severity of the disease. In certain studies, a negative relationship was seen between obesity and blood serum values of anti-TNF drugs. Obesity is known to not only modify the pharmacokinetics of the TNFi drugs but also increase the drug clearance shorten the half-life, thus causing lower drug concentrations and thus reduced effects. This justifies the assumption of reduced response despite prescribing dose corresponding to the body weight.
Drug distribution is mainly affected by the body composition, blood flow, and affinity of drugs for the tissue proteins. Since in obese patients, there is a larger quantity of body fat mass, which reduces the absolute drug distribution and reduce its pharmacologically effect.
| Existence and Impact on Other Comorbidities|| |
According to a retrospective study from the Mayo Clinic, Minnesota, of the 9827 patients who came for a general medical examination; 2543 were found to be obese. Moreover of these, only 19.9% of these obese individuals were diagnosed with obesity.
Obesity is known to be associated with increased morbidity and mortality. It is also known to cause several complications, such as Type II diabetes, hypertension, and hyperlipidemia. Its association in causing Type II diabetes mellitus has been well established. Similarly, this excess body weight is responsible for almost 25% of the cases of essential adult hypertension.
Obese individuals are at higher risk of abnormal lipid metabolism causing high serum cholesterol, low-density lipoproteins, and very low-density lipoproteins, and triglycerides. Ischemic heart disease, stroke, and several types of cancers are known to have an association with obesity.
Thus, obesity is linked with increased mortality and decreased life expectancy.
| Management of Obesity With Ankylosing Spondylitis|| |
AS has no known cause; hence, its prevention is difficult. The only management is restricting the progress of the disease. As observed obesity has an association with the progress on the disease, it is vital to manage weight first for better treatment efficacy.
Treating obesity as disease condition will make physicians keen to diagnose and treat it at the earliest and help in minimizing and preventing its potential complications on other systems. Obesity is by large preventable. It is the individual and communities' responsibility in choosing and providing healthier food options and regular physical activity.
We urge the physicians to act in controlling this preventable health concern while managing patients with RMDs. Patients should be made aware of the benefits of losing weight for treatment efficacy.
| Conclusion|| |
The above article has emphasized on the inflammatory mechanism associated with obesity, which favors the worsening of AS by affecting the QoL, reducing physical functioning, and reducing the treatment efficacy. Hence while diagnosing and treating patients with AS, the physician should urge the patient to lose weight for better prognosis and limiting the progress of AS. Obesity should be considered as any disease condition which if diagnosed early and controlled can help prevent several other conditions and keep control of other RMDs.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ryan DH, Kahan S. Guideline recommendations for obesity management. Med Clin North Am 2018;102:49-63.
van der Linden SM, Valkenburg HA, de Jongh BM, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984;27:241-9.
Bednarek-Tupikowska G, Zdrojowy-Wełna A, Stachowska B, Kuliczkowska-Płaksej J, Matczak-Giemza M, Kubicka E, et al.
Accumulation of abdominal fat in relation to selected proinflammatory cytokines concentrations in non-obese wrocław inhabitants. Endokrynol Pol 2014;65:449-55.
Calabro P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: Linking obesity to vascular inflammation. J Am Coll Cardiol 2005;46:1112-3.
Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-83.
Hutcheson J. Adipokines influence the inflammatory balance in autoimmunity. Cytokine 2015;75:272-9.
Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol 2005;174:5789-95.
Syrbe U, Callhoff J, Conrad K, Poddubnyy D, Haibel H, Junker S, et al.
Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression. Arthritis Rheumatol 2015;67:678-85.
Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al.
The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: Implications and effects of weight loss. Obes Surg 2004;14:589-600.
Crowson CS, Matteson EL, Davis JM 3rd
, Gabriel SE. Contribution of obesity to the rise in incidence of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2013;65:71-7.
de Hair MJ, Landewé RB, van de Sande MG, van Schaardenburg D, van Baarsen LG, Gerlag DM, et al.
Smoking and overweight determine the likelihood of developing rheumatoid arthritis. Ann Rheum Dis 2013;72:1654-8.
Lu B, Hiraki LT, Sparks JA, Malspeis S, Chen CY, Awosogba JA, et al.
Being overweight or obese and risk of developing rheumatoid arthritis among women: A prospective cohort study. Ann Rheum Dis 2014;73:1914-22.
Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, et al.
Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 2013;17:411-22.
Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012;18:363-74.
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008;57:3239-46.
Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: Not a passive bystander. Autoimmun Rev 2014;13:981-1000.
Kneepkens EL, Wei JC, Nurmohamed MT, Yeo KJ, Chen CY, van der Horst-Bruinsma IE, et al.
Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up. Ann Rheum Dis 2015;74:396-401.
van der Heijde D, Schiff MH, Sieper J, Kivitz AJ, Wong RL, Kupper H, et al.
Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: Long-term results from the ATLAS trial. Ann Rheum Dis 2009;68:922-9.
Micheroli R, Hebeisen M, Wildi LM, Exer P, Tamborrini G, Bernhard J, et al.
Impact of obesity on the response to tumor necrosis factor inhibitors in axial spondyloarthritis. Arthritis Res Ther 2017;19:164.
Vincent HK, Seay AN, Montero C, Conrad BP, Hurley RW, Vincent KR. Functional pain severity and mobility in overweight older men and women with chronic low-back pain – Part I. Am J Phys Med Rehabil 2013;92:430-8.
Ottaviani S, Allanore Y, Tubach F, Forien M, Gardette A, Pasquet B, et al.
Body mass index influences the response to infliximab in ankylosing spondylitis. Arthritis Res Ther 2012;14:R115.
Gremese E, Bernardi S, Bonazza S, Nowik M, Peluso G, Massara A, et al.
Body weight, gender and response to TNF-α blockers in axial spondyloarthritis. Rheumatology (Oxford) 2014;53:875-81.
Rosas J, Llinares-Tello F, Senabre-Gallego JM, Barber-Vallés X, Santos-Soler G, Salas-Heredia E, et al.
Obesity decreases clinical efficacy and levels of adalimumab in patients with ankylosing spondylitis. Clin Exp Rheumatol 2017;35:145-8.
Durcan L, Wilson F, Conway R, Cunnane G, O'Shea FD. Increased body mass index in ankylosing spondylitis is associated with greater burden of symptoms and poor perceptions of the benefits of exercise. J Rheumatol 2012;39:2310-4.
Rubio Vargas R, van den Berg R, van Lunteren M, Ez-Zaitouni Z, Bakker PA, Dagfinrud H, et al.
Does body mass index (BMI) influence the ankylosing spondylitis disease activity score in axial spondyloarthritis? Data from the SPACE cohort. RMD Open 2016;2:e000283.
Lee YX, Kwan YH, Png WY, Lim KK, Tan CS, Lui NL, et al.
Association of obesity with patient-reported outcomes in patients with axial spondyloarthritis: A cross-sectional study in an urban Asian population. Clin Rheumatol 2017;36:2365-70.
Gallo G, Candilio G, De Luca E, Iannicelli A, Sciaudone G, Pellino G, et al.
Bariatric surgery and rheumatic diseases: A Literature review. Rev Recent Clin Trials 2018;13:176-83.
Sparks JA, Halperin F, Karlson JC, Karlson EW, Bermas BL. Impact of bariatric surgery on patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2015;67:1619-26.
Singh S, Facciorusso A, Singh AG, Vande Casteele N, Zarrinpar A, Prokop LJ, et al.
Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: A systematic review and meta-analysis. PLoS One 2018;13:e0195123.
Bardia A, Holtan SG, Slezak JM, Thompson WG. Diagnosis of obesity by primary care physicians and impact on obesity management. Mayo Clin Proc 2007;82:927-32.
Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: Findings from the national health and nutrition examination survey, 1999 to 2004. J Am Coll Surg 2008;207:928-34.
Wilson PW, D'Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk: The framingham experience. Arch Intern Med 2002;162:1867-72.