Although the hallmark symptoms of rheumatoid arthritis (RA) present substantial challenges, a wide range of comorbidities also affects this patient population. The prevalence of disorders such as cardiovascular disease (CVD), diabetes, and venous thromboembolism (VTE) are higher among RA patients compared with the general population, further increasing their disease burden and mortality risk while reducing physical function and quality of life.1,2

These comorbidities have largely been attributed to the chronic systemic inflammation characteristic of RA. “RA‐related inflammation has been linked to a range of conditions, from depression to cardiovascular and pulmonary diseases,” wrote Mark Tatangelo, PhD, a rheumatology researcher at the University of Toronto, and colleagues in a matched longitudinal study published in November 2020 in ACR Open Rheumatology.3 “A comorbid condition acquired by a patient with RA could be a result of RA or occur irrespective of RA diagnosis.”

Which Came First?

Their study aimed to elucidate this issue in a sample of 136,678 patients with RA and 2 groups of control participants without RA – one matched for age and sex only, and the other matched for age, sex, and a similar medical history. Compared with matched control participants, the RA patients demonstrated an increased number of comorbid disorders up to 5 years before RA diagnosis (4.6 vs 4.9 disorders per patient-year).


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Further increases occurred within the year of diagnosis (8.7 disorders), followed by a decline in the 5 years after diagnosis (6.9 disorders). The top comorbidities in patients with RA compared with control participants were musculoskeletal, hematologic, and neurologic disorders.3

Results of a 2019 study coauthored by Vanessa L. Kronzer, MD, an internal medicine resident at Mayo Clinic in Rochester, Minnesota, suggested that “inflammatory bowel disease, type 1 diabetes, and VTE might predispose to RA development, whereas CVD, VTE, and obstructive sleep apnea can result from RA,” according to the paper.2 “These findings have important implications for RA pathogenesis, early detection, and recommended screening.”

Interaction With RA Drugs

CVD, infections, and malignancies such as lymphoma and nonmelanoma skin cancers (NMSC) are important comorbidities requiring careful consideration due to their impact on mortality risk and potential interaction with RA medications. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to an increased CVD risk in RA patients, for example, while nonbiologic disease-modifying antirheumatic drugs (DMARDs) may improve CVD risk.1

In addition, findings from several studies indicate that tumor necrosis factor (TNF) inhibitors may reduce the risk of cardiovascular events in RA patients, likely due to their impact on systemic inflammation, which is a modifiable risk factor for CVD development. This effect appears to increase with longer durations of use.1

Glucocorticoids are strongly associated with an elevated risk for serious infection, and some studies have found an increased risk for infection with biologic DMARDs and TNF inhibitors. Methotrexate and TNF inhibitors have been associated with an increased risk for NMSC.1

These findings highlight the complexity of factors that must be continually weighed in the management of RA. To gain additional insights regarding this topic, we recently interviewed Dr Kronzer and Dr Tatangelo.

What are some of the most common comorbidities in RA, and how do these affect disease outcomes and quality of life?

Dr Kronzer: The most common comorbidities that developed after RA in our study included heart disease, sleep apnea, and blood clots.2 This was even after controlling for confounders like age and body mass index. Each of these diseases can have debilitating consequences for quality of life. Thus, we need to know about these associations and screen for them when indicated.

Dr Tatangelo: We found that the most common comorbidities of RA by quantity are musculoskeletal, cardiovascular, neurologic, gastrointestinal and hepatic, and respiratory comorbidities, respectively.3

When we compared patients with RA with matched control participants without RA, we found a difference of 134% more hematologic issues, a 148.9% increase in musculoskeletal issues, a 120% increase in neurologic issues, and a 106% increase in toxic effects and adverse events. These are percent differences relative to nondiseased control participants, not absolute differences, but they do show large differences in comorbidity profiles.

Quality of life is reduced in all patients with each additional comorbidity. RA patients are more susceptible to comorbid conditions and potentially have greater reductions in quality of life per additional comorbid condition compared with non-RA control participants. We certainly need more research to quantify quality of life changes compared with matched control participants with the addition of each comorbid condition.

It must be a tricky balance to effectively manage RA symptoms along with these comorbidities. What are some of the main challenges in this regard?

Dr Kronzer: Yes, balancing management of RA with its comorbidities is very difficult. One main barrier is lack of knowledge about the comorbidities that can be associated with RA, which is what we attempted to address with this study. After that, the main challenge – at least for me – is time.

Dr Tatangelo: Rheumatologists have a challenging task because they treat the primary manifestations of the disease – joint damage – but also, as our knowledge evolves, we realize that rheumatologists also treat systemic inflammation, which makes all comorbidities important to the treating rheumatologist.

For these reasons, rheumatologists face challenges with comorbid conditions conflicting with medications, and choices between reductions in systemic inflammation and other comorbid conditions patients may have. Therefore, rheumatologists need specific knowledge of musculoskeletal diseases but also a breadth of knowledge in the other clinical areas that may be affected by RA comorbidity manifestations.

How do you recommend that clinicians approach these issues in practice?

Dr Kronzer: Remember to think about heart disease, sleep apnea, and VTE in your patients with RA. Identifying these comorbidities and then asking for help with management from our primary care colleagues is very important.

Dr Tatangelo: Interdisciplinary care with cardiologists, respirologists, and neurologists, is very important for clinicians treating RA patients. Also, taking careful comorbidity profiles and considering the totality of the comorbidity profile when selecting treatments is a challenging yet rewarding aspect of care.

What are some notable emerging developments and remaining needs in this area?

Dr Kronzer: Ongoing studies, including those by our group, are expanding the search for other comorbidities and even studying multimorbidity as a whole to better understand the relationship between RA and comorbidities. A remaining need is to determine whether screening for RA-related comorbidities leads to improved outcomes.

Dr Tatangelo: Going forward, the rheumatology community needs to consider adding additional comorbidity-related measurements to the standard clinical and functional measurements of Clinical Disease Activity Index or CDAI, Disease Activity Score-28 calculator or DAS28, and Health Assessment Questionnaire or HAQ. We know that the DAS28 contains a laboratory measure of systemic inflammation (erythrocyte sedimentation rate/C-reactive protein or ESR/CRP), but currently this is the only indirect measurement of systemic inflammation, and by extension, comorbidity.

Because comorbidity plays an increasing role in the totality of the RA diagnosis, over time we may start to consider the comorbidities as a primary manifestation of the RA itself. Therefore, our clinical measurement tools must evolve to better capture these conditions.

Secondly, we must start to use more general measurement tools when quantifying the effectiveness and efficacy of medications for treating RA.

Rheumatology is a field in which innovation in treatment choices is possible with computer-assisted models for medication selection. In the future, we can quantify the benefit of medication choices based on reductions in comorbidities and joint damage instead of joint damage alone.

References

  1. Taylor PC, Atzeni F, Balsa A, Gossec L, Müller-Ladner U, Pope J. The key comorbidities in patients with rheumatoid arthritis: a narrative review. J Clin Med. 2021;10(3):509. doi:10.3390/jcm10030509
  1. Kronzer VL, Crowson CS, Sparks JA, Myasoedova E, Davis JM 3rd. Comorbidities as risk factors for rheumatoid arthritis and their accrual after diagnosis. Mayo Clin Proc. 2019;94(12):2488-2498. doi:10.1016/j.mayocp.2019.08.010
  1. Tatangelo MR, Tomlinson G, Keystone E, Paterson JM, Bansback N, Bombardier C. Comorbidities before and after the diagnosis of rheumatoid arthritis: a matched longitudinal study. ACR Open Rheumatol. 2020;2(11):648-656. doi:10.1002/acr2.11182