The Prospect of Rheumatoid Arthritis Prevention

Rheumatoid arthritis (RA) is treatable, and for that, we should be grateful. But wouldn’t it be better if we could prevent it from even happening? Recent data from a study in China demonstrated some interesting results. Could an older type of diabetes medication be the answer we’ve been looking for?

Background

Preclinical studies have suggested that thiazolidinediones (TZDs) have a protective effect against RA, but evidence from population-based studies to support this is scarce. TZDs are agonists of peroxisome proliferator-activated receptor gamma (PPARgamma), which is involved in the regulation of glucose homeostasis and lipid metabolism. PPARgamma also plays an important role in the control of inflammation, immune regulation and inhibition of apoptosis and oxidative stress, all of which have been shown to be associated with the pathogenesis of RA in animal models.^1-3

Researchers in China conducted a retrospective, population-based cohort study to assess the association between the use of TZDs and the incidence of RA in patients with type 2 diabetes mellitus (DM).⁴ The study was published online ahead of print in December 2023.

The primary outcome of the trial was incident cases of RA. This was defined as an RA diagnosis code followed by a second RA diagnosis code or a prescription of a disease-modifying anti-rheumatic drug (DMARD) within one year of the first diagnosis. This approach has been validated by previous research, demonstrating a positive predictive value of 89 to 97% for a true RA diagnosis.^5,6

Summary of Research

Zhao et al. used data from an electronic healthcare database in the Yinzhou District, Ningbo City, China, a highly urbanized region. The database integrates longitudinal information from electronic medical records, disease surveillance and management systems (including a diabetes registry and follow-up system), death registry and other healthcare services.

The final cohort included about 72,000 patients with type 2 DM who were either new TZD users or new alpha-glucosidase inhibitor (AGI) users (control group). TZDs included pioglitazone and rosiglitazone. AGIs included acarbose, miglitol and voglibose. TZDs and AGIs are among the top four most commonly prescribed medications for people with type 2 DM in China; only metformin and insulin secretagogues are prescribed more frequently.⁷

Patients were Chinese, aged 18 years or older with type 2 DM. The majority were around 60 years of age, with equal representation of men and women. Patients were excluded if they initiated combination therapy with TZDs and AGIs, or if they had received a diagnosis of arthritis or spondylitis prior to the index date of the study.

During a median follow-up time of 5.6 years, the incidence of RA was 187.4 and 135.2 per 100,000 person-years in AGI users and TZD users, respectively. TZD use was associated with a reduction in RA incidence, with a hazard ratio of 0.72 (95% CI, 0.59–0.89). Various subgroup analyses and sensitivity analyses were consistent with the results of the primary analysis.⁴

Implications for Clinical Practice

Houyu Zhao, PhD, Xiaowei Chen, BS, and Siyan Zhan, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China, were kind enough to share their take on the clinical implications of their fascinating research.

The Rheumatologist (TR): What can practicing rheumatologists take away from your findings?

Zhao et al.: Our study demonstrated that use of TZDs was associated with a lower incidence of RA in the Chinese population with type 2 DM, and had a greater protective effect on RA in female patients. Our findings could provide some evidence for the clinical application of glucose-lowering agents in the prevention of RA among patients with type 2 DM, as well as for the issue of drug safety in TZD. Rheumatologists could collaborate with endocrinologists or primary care physicians to optimize diabetes management strategies in patients with concurrent RA risk factors, taking into account the potential impact of TZD therapy on RA prevention. However, our results have not been confirmed by randomized clinical trials yet. More studies are needed before our results can be applied to clinical practice.

TR: What can’t this study tell us?

Zhao et al.: The study’s observational design, even with robust statistical adjustments, cannot establish causality. While it suggests an association between TZD use and reduced RA incidence, it cannot definitively prove that TZDs directly prevent the development of RA, so the results of this study cannot directly guide [clinical practice]. Moreover, the enrolled patients were from a single municipal district in China, so the conclusions of the study should not be generalized to other ethnic populations without caution. Despite efforts to adjust for potential confounders using statistical methods, other confounding factors, such as lifestyle factors (e.g., dietary habits) were not considered, [and these] have been shown to be associated with the risk of RA. Finally, the study’s follow-up period may not capture long-term outcomes, such as delayed onset of RA or potential adverse effects of prolonged TZD use.

TR: What would be your next steps in terms of future research?

Zhao et al.: We intend to conduct large-scale, multi-center, longitudinal, real-world, cohort studies with extended follow-up periods to assess the longterm effects of TZD use on RA incidence and other relevant outcomes in Ningbo City and other cities. We may conduct the RCT DUPLICATE (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) Initiative, which can simulate randomized clinical trials of TZD and other disease-modifying anti-rheumatic drugs using non-randomized real-world evidence studies.

TR: What sort of data would be required to support the use of TZDs as preventative therapy for RA?

Zhao et al.: To support the use of TZDs as preventive therapy for RA, comprehensive data from [randomized controlled trials] or large-scale observational studies [are] essential. These studies should ideally include long-term follow-up data, diverse patient populations, comparative effectiveness and so on.

TR: How would you go about studying this in parts of the world where TZDs aren’t as commonly used for the treatment of diabetes as they are in China (e.g., the U.S.)?

Zhao et al.: We hope to establish collaborations with international research networks, academic institutions and healthcare organizations to access diverse patient populations across different regions. Collaborative efforts facilitate data sharing, harmonization of methodologies, and recruitment of larger sample sizes, enhancing the statistical power and generalizability of study findings.

TR: Are there any other major takeaways that you want to stress to readers?

Zhao et al.: The potential repurposing of TZDs, which are commonly used for diabetes management, as preventive agents for RA underscores the importance of exploring drug repositioning and the multifaceted effects of existing medications.

Conclusion

In summary, Zhao et al. revealed a fascinating association between TZD use and a decreased incidence of RA. Larger studies are needed to confirm causality before the routine use of TZDs for RA prevention can be routinely recommended, but the prospect is certainly exciting.

Samantha C. Shapiro, MD, is the executive editor of Harrison’s Principles of Internal Medicine. As a clinician educator, she practices telerheumatology and writes for both medical and lay audiences.

References

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