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Comorbidities in RA: Focus on Difficult-to-Treat Disease

There have undoubtedly been major advances in the treatment of rheumatoid arthritis (RA) over the years. We live in an era of true innovation and treatment revolution, which has changed the lives of many people diagnosed with the disease. As clinicians, we are also learning and adapting fast to shifting treatment paradigms and the way we think and care about our patients living with RA. We have come a long way, learning to appreciate the importance of providing a more patient-centred care that is closer to what patients really need. A type of care that places the focus not just on RA as the ‘index’ rheumatic disease, but also on any other disease that may co-exist and other biological as well as non-biological, social factors, that may complicate patient management and outcomes. In this regard, the presence of co-existing conditions, what we refer to as ‘comorbidities’, takes particular relevance. 

Patients with RA have on average two additional other clinical conditions and research shows that these accumulate over time and with longer disease duration. The presence of comorbidities naturally complicates treatment choice, patient adherence to medication and patient outcomes, increasing also the risk of making RA ‘difficult-to-treat’ (D2T). In fact, comorbidities are increasingly mentioned in the context of D2T disease, both in terms of the challenges they pose in the evaluation of disease activity, but also in terms of the potential impact on treatment choice and outcomes. Over or underestimation of disease activity can be an issue in the presence of comorbidities, challenging the accuracy of disease activity evaluation. 

Let’s take the example of obesity; a common and potentially reversible comorbidity seen in RA, in related directly to the disease itself and its consequences such as the impact on physical function, as well as its treatment (e.g. use of glucocorticoids).  The presence of higher body mass index (BMI) can introduce bias to the clinical interpretation of disease activity. Specifically, clinical assessment of joint swelling can be very subjective in overweight or obese individuals, challenging the correct identification (or not) of clinically active disease. This can lead to an underestimation or even overestimation of disease activity, demonstrated nicely in studies that compare ultrasound versus clinician assessment of joints. 

Aside from the challenge though that high BMI can bring to the assessment of disease activity, one should not forget the direct effects of adiposity on inflammation too. Obesity has been shown to perpetuate pro-inflammatory states, reflected also in higher systemic inflammatory markers. Decreased efficacy with drugs such as Tumour Necrosis Factor inhibitors (TNFi) has also been shown with higher BMI, partly attributed to decreased absorption of drugs with increased adiposity. Several studies now support the association between obesity and worse disease activity, function and overall quality of life. Obesity therefore demands attention in the routine management of patients with RA. Complicating matters further, is the link between obesity and chronic pain syndromes such as fibromyalgia, which cannot be ignored. The co-existence of both types of comorbidities can add considerable complexity to the management of patients with RA and lead to D2T disease. 

Other common, albeit potentially less reversible, comorbidities, have also been associated with a higher risk of D2T disease through limitation of RA-treatment options, polypharmacy and reduced treatment-adherence, not to mention the overall contribution to ill-health states. Cardiovascular disease including accelerated atherosclerosis has been associated with inflammation and we have learnt over the years that there are common mechanistic links between the inflammatory processes implicated in RA and CVD, challenging previous notions that cardiovascular disease in RA was a distinct clinical entity. Lung-related comorbidities such as obstructive e.g. chronic obstructive pulmonary disease (COPD) or restrictive e.g. interstitial lung disease (ILD), are other common comorbidities in RA that demand early identification and management. Related lifestyle choices such as smoking, have been linked with worse outcomes in RA, such as higher disease activity and radiographic damage. Smoking cessation should therefore be discussed and encouraged, to improve clinical outcomes in RA, but also to reduce the risk of comorbidities such as cardiovascular and pulmonary diseases. Furthermore, clinicians should have high vigilance for the presence of infections and malignancies, whether these relate to RA itself or its treatment, keeping in mind that these comorbidities can perpetuate inflammatory states, challenge treatment choice and result in adverse patient outcomes. 

Last, but certainly not least, aside from physical comorbidity, the significant burden of mental health disease to the patients themselves but also to those around them, should not be forgotten. Both depression and anxiety are frequent comorbidities in people with RA and are also closely linked with widespread pain, fatigue, obesity, poor treatment adherence and generally worse patient outcomes. Addressing mental health is thus necessary to improve patient care and outcomes, including quality of life.  

Taking it all together, the screening and management of comorbidities early in RA should be central to patient management. Taking a more patient-centred approach to care is necessary for the provision of more optimal and comprehensive care, that could prevent the development of D2T disease and ensure the best possible outcomes for our patients.


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Dr Elena Nikiphorou (MBBS/BSc, MD (Res), PhD, FRCP, PGCME, FHEA) is a Consultant Rheumatologist at Kings’ College Hospital and Adjunct Senior Lecturer at Kings College London (KCL). She has a clinical and academic interest in inflammatory arthritis with a focus on Rheumatoid Arthritis and Spondyloarthritis, multi-morbidity and long-term outcomes of disease. She has been involved in the development of several international recommendations, including on the management of Difficult-to-treat RA, axial Spondyloarthritis and self-management strategies in inflammatory arthritis. Follow her @ElenaNikiUK.