The outcomes of bariatric surgery on rheumatoid arthritis disease activity: a prospective cohort study

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. Overweight and obesity can aggravate disease activity and clinical outcome in patients with RA. However, the role of bariatric surgery in inducing weight loss in the treatment of RA has not been confirmed. In this 12-month prospective cohort study, RA patients with obesity who were referred to our hospital were included. Thirty-two patients were classified into the bariatric surgery group according to the patient’s decision after a comprehensive assessment of surgery indications, and 33 patients received only pharmacotherapy for RA. At the 12-month follow-up, the response rates of ACR20, ACR50 and ACR70 were 75.0% vs. 51.5%, 53.1% vs. 39.4% and 31.3% vs. 21.2% in the bariatric surgery and non-surgery groups, respectively (all p < 0.05); the mean DAS28-ESR, DAS28-CRP and cDAI scores were 1.5 ± 0.9 vs. 2.4 ± 1.4, 1.2 ± 0.9 vs. 2.2 ± 1.7 and 9.5 ± 6.8 vs. 15.8 ± 12.5, respectively, in surgical patients compared to non-surgical patients (all p < 0.05). Compared to baseline, after 12 months, a significant reduction was observed in the use of leflunomide, biological agents, combination treatments, and NSAIDs in both groups (p < 0.05 or p < 0.01). However, there was no difference in medication use between the 2 groups either at baseline or at the 12-month follow-up (all p > 0.05). Compared to non-surgical patients, in RA patients with obesity, weight loss after bariatric surgery was associated with lower disease activity. Medication tapering for RA in patients who underwent bariatric surgery was not superior to that in non-surgical patients.


Discussion
Obesity, with a higher prevalence, is one of the described risk factors for the onset of RA, and it negatively affects disease activity and treatment outcomes 4,17 . The benefits of bariatric surgery beyond the weight loss effect on disease and prognosis continue to be reported in other autoimmune or inflammatory diseases, including systemic lupus erythaematosus, inflammatory bowel disease, autoimmune thyroiditis and autoimmune liver diseases [18][19][20][21] . The association between obesity and RA might present a strategy for the prevention or control of RA activity 22,23 . Although it has been shown that substantial weight loss from bariatric surgery results in lower disease activity and improved response to treatment 14 , the effect of bariatric surgery on the treatment of RA was unconfirmed in a prior cohort study. Our study demonstrated that compared with non-surgical patients who were followed for up to 12 months, RA patients with obesity who underwent bariatric surgery had significant weight loss and a better response to treatment. RA-related medication usage, on the other hand, had no difference between the surgical and non-surgical patients at baseline or at the 12-month follow-up.
However, studies from Baker et al. 15,16 showed that both severe obesity and weight loss were associated with worsening disability, and weight loss was a risk factor for death in patients with RA. Mounting studies have shown that obesity augments RA disease activity and decreases the likelihood of achieving sustained remission despite intensive treatment 24,25 . Non-surgical weight loss interventions contributed to a weight loss of 4.5 kg and significantly improved physical function in 19 overweight RA patients 26 . Furthermore, a more substantial strategy for weight loss, such as surgery, also has an impact on the levels of various inflammatory markers induced by obesity [27][28][29][30] . Santos et al. 31 enrolled 46 patients with obesity-related metabolic dysfunction and showed that gastric banding surgery resulted in a significant decrease in the inflammation process associated with adipose tissue loss. Interestingly, in a Swedish study followed up for 29 years, there was no association between bariatric surgery and the incidence of RA in obese patients 32 , which might demonstrate that bariatric surgery has no preventive effect on the occurrence of RA.
Few prior studies have specifically focused on the effects of more substantial weight loss on RA severity before and after bariatric surgery. To the authors' knowledge, the only report is a retrospective cohort study 14 of bariatric surgery in 53 RA patients with moderate to high RA disease and a BMI of 47.8 ± 7.7 kg/m 2 . This study concluded that bariatric surgery resulted in a significant disease remission rate of 74% at a follow-up of 5.8 ± 3.2 years after surgery compared to a rate of 26% at baseline 14 . This study design was an uncontrolled cohort without a control group. It is therefore unclear whether the observed improvement in RA activity after bariatric surgery is related to RA-related medications or to surgery-specific effects. In the present study, both surgical and non-surgical patients had significantly decreased disease activity at 12 months compared to baseline, which was consistent with the abovementioned study. More importantly, after 12 months of follow-up, compared with the non-surgery group, the surgical patients also had a better response rate to RA-related medication in terms of ACRs, DAS28, and cDAI scores, providing powerful evidence to support the potential role of bariatric surgery in the treatment of RA.
The study of bariatric surgery's efficacy on 31 patients with systemic lupus erythaematosus demonstrated that 42% of patients showed a reduction in the number of immunosuppressive medications and that 19.3% were off steroids completely at a mean follow-up of 3 years 33 . These findings suggest that surgery-induced weight loss is associated with decreased SLE immunosuppression medication requirements 33 . The study has the same issue that, due to the lack of comparison group data, it is uncertain whether the medication reduction is attributable to bariatric surgery or SLE-related treatment. A study of bariatric surgery in RA patients showed a significantly decreased usage of RA-related medication after bariatric surgery (66% at 1 year after surgery compared to 98% at baseline) 14 . In our study, there was a significant reduction in the use of leflunomide, biological agents,   Table 3. Patients' medication at baseline and 12 months of follow-up. *P < 0.05 and **P < 0.01 compared between patients in the same group at the 12-month follow-up and baseline. † Biological agents including TNFα inhibitors or JAK inhibitors. ‡ Combination treatment including 2 or more immunosuppressive medications. csDMARDs, conventional synthetic disease modifying antirheumatic drugs; NSAIDs, nonsteroidal antiinflammatory drugs. (2020) 10:3167 | https://doi.org/10.1038/s41598-020-59723-8 www.nature.com/scientificreports www.nature.com/scientificreports/ combination treatment, and NSAIDs in both surgical and non-surgical patients after 12 months compared to the baseline (p < 0.05 or p < 0.01). However, there were no differences in medication use between the 2 groups either at baseline or after 12 months of follow-up. Our data suggested that medication tapering for RA patients who underwent bariatric surgery was not superior to that in non-surgical patients.
There are some limitations to our study. First, the study was an open-label clinical study, and the treating doctors and patients were not blinded to the therapeutic strategy. Even so, the disease activity measurements were performed by different trained evaluators who were unaware of the specific therapeutic regimen to make the study more objective. Second, previous studies demonstrated that metabolic factors, including dietary intake and physical activity, were associated with the occurrence and disease activity [34][35][36] . However, as the setup of the parameters was mainly focused on the change in RA disease activity before and after treatment, data on these metabolic factors were not collected in this study. The deficiency of these metabolic factors might confound the treatment efficacy of bariatric surgery on RA disease activity. Finally, other limitations, including a lower case number, nonrandomized design, and short-term follow-up, need to be perfected in future studies.
To the best of our knowledge, this is the first cohort study to evaluate the treatment efficacy of bariatric surgery on RA patients with obesity compared with non-surgical patients. Our data demonstrated that bariatric surgery appears to be feasible in RA patients with obesity. The activity-improving effects of bariatric surgery were evident 4 months after surgery and persisted for at least 12 months. In conclusion, the present results suggest that weight loss may have an important role in the nonpharmacologic management of RA patients. These findings warrant further study concerning the treatment of RA patients, especially those with obesity.

Methods
Design overview. Approval for this retrospective study was granted by the ethics review board of the First Affiliated Hospital of Anhui Medical University (AHEC2013-015), and all methods were performed in accordance with the relevant ethical guidelines and regulations. Prior written informed consent was obtained from all patients. This 12-month cohort study was conducted between May 2016 and August 2018. RA patients with obesity who were referred to our hospital for surgical treatment of obesity and pharmacotherapy for RA were included. participants and interventions. The eligible patients for this study had to meet the following criteria: (1) RA diagnosis determined by 2010 ACR/EULAR classification criteria 37 ; (2) age of 18-65 years; (3) BMI ≥30 kg/m 2 in 3 continuous years; (4) no abuse of alcohol or psychotropic drugs, and no serious behaviour disorder or mental retardation; (5) TJCs ≥5 and SJCs ≥3; and (6) ESR ≥20 mm/h or CRP ≥20 mg/L. Patients were excluded if they had (1) a history or current infection or any type of malignant cancer; (2) secondary obesity, such as Cushing syndrome, hypothyroidism, polycystic ovary syndrome, hypopituitarism, hypothalamic obesity, or prolactinoma; and (3) intolerance to surgery due to serious organ diseases. During the study, nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose glucocorticoids of ≤50 mg prednisone or equivalent/day were allowed when necessary.
All patients with RA were classified into either a bariatric surgery group or a non-surgery group after the comprehensive assessment of surgery indications according to the patient's decision. Bariatric surgery was defined as Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG). The RA-related treatment regimen was determined by rheumatologists. The disease activity measurements were performed by different trained evaluators who were unaware of the specific therapeutic regimen. Data collection. Data collected included baseline demographic characteristics, clinical parameters, operative data, RA activity index scores, and postoperative and follow-up outcomes. The demographic characteristics of the recruited patients included age, sex, height, weight, BMI, comorbidities, and the disease duration of RA. The clinical parameters included rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (Anti-CCP), ESR, and CRP. Operative data included surgery type and time, estimated blood loss, and intraoperative complications. The RA activity index included the patient's global assessment of overall well-being (PtGA), the physician's global assessment (PyGA) at baseline, the 28-joint count disease activity score (DAS28), and the clinical disease activity index (cDAI) at baseline and at the 4-, 8-, and 12-month follow-up. The postoperative and follow-up outcomes assessed were the percentage of patients who achieved the American College of Rheumatology criteria (ACR20, ACR50, and ACR70 represent ≥20%, 50% and 70% improvement, respectively), weight loss and excess weight loss (percentage of baseline weight above BMI 25 kg/m 2 lost) 14 at the 4-, 8-, and 12-month follow-up, and complications and changes in immunosuppressive medication at the 12-month follow-up.
Statistical analysis. Data are presented as the mean and standard deviation (SD) for measurement variables and frequency percentages for categorical variables. Parameters were analysed using the unpaired Student's t test (or the Mann-Whitney U test) for measurement variables and the χ 2 test (or Fisher's exact test) for categorical variables. Covariance analysis was used to compare the difference in disease activity over time in surgical and non-surgical patients. Patients with missing end points were considered to be nonresponders. Values of p < 0.05 were considered statistically significant. Statistical analysis and plotting were performed using SPSS 23 (IBM Corporation, Armonk, New York, NY, United States) and GraphPad Prism 7 (GraphPad, San Diego, CA, United States).
Institutional review board statement. The study was reviewed and approved by the Medical Science Ethics Committee of First Affiliated Hospital of Anhui Medical University.
informed consent statement. All study participants, or their legal guardian, provided informed written consent prior to study enrollment.