Importance of comorbidities in rheumatology – a historical perspective

Vishad Viswanath MD, DM
Medical Director and Consultant in Rheumatology, Institute for Rheumatology and Immunology Sciences (IRIS), Thiruvananthapuram, Kerala

Healthspan matters more than lifespan

The 21st century marked a paradigm shift in the management of autoimmune rheumatic diseases (AIRDs) with vast refinement in our understanding of optimal utilization of conventional DMARDs as well as the introduction of biologics. The outcome was better disease control, resulting in an improvement in survival of patients with rheumatic diseases. The improved survival unleashed a new epidemic of chronic comorbidities in auto-immune rheumatic diseases. The most significant among them were cardiovascular diseases (CVD), malignancies and infections.

Heart Strong, Rheumatic Resilient

The 1990s witnessed the recognition of the pivotal role of inflammation in atherosclerosis and cardiovascular diseases. Atherogenic diet as well as comorbidities such as Diabetes Mellites, Hypertension, and smoking lead to increased expression of ICAMs on the endothelial cell surface recruiting inflammatory cells into the vessel wall. Inflammation was demonstrated in all stages of atheromatous plaque from its inception to the formation of a fibrinous cap. Furthermore, CRP and later hs-CRP were recognized as markers of CVDs. As an extension of this hypothesis, an increased risk of CVDs was considered plausible in AIRDs and this emerged as a focus of fertile research for the next couple of decades.

Multiple epidemiological studies showed an increased mortality in RA and SLE due to CVD. The long-term burden of inflammation due to sub-optimally controlled disease activity was consistently demonstrated as one of the most important risk factors of CVDs in RA and SLE. Studies showed that the risk of CVD in patients with uncontrolled RA is tantamount to that in Diabetes Mellites. Later identical associations were established in Ankylosing Spondylitis, Psoriasis and Psoriatic Arthritis, Vasculitis, and Systemic sclerosis. Currently, practitioners of rheumatology are encouraged to proactively assess CVD risk in their patients opening up a new dimension to the treatment of AIRDs. Guidelines are still evolving and a major shift in targets in rheumatic diseases can be expected along this line.

Infections and Rheumatism: Hand in Hand

Autoimmunity and Immune deficiency are considered two sides of the same coin. Many monogenic immune deficiency disorders such as SCID, APECED, IPEX etc. have frequent autoimmune manifestations. The role of Complement pathway defects in SLE was the earliest recognized link between Immune deficiency and AIRD. Frequent infections are documented in patients with AIRDs such as SLE and RA. GWAS studies in RA and SLE show shared genetics with immune deficiency disorders. These genes are involved development of Lymphocytes, induction of tolerance, T cell receptor signaling, interferon pathway, and clearance of apoptotic debris. The use of immunosuppressants; both novel and conventional; is associated with their unique pattern of infections. Overall genetic factors, duration of disease and treatment, and dose of immunosuppression can be expected to influence the individual risk of infection. In recognition of the close association between autoimmunity and immune deficiency; screening for infections, appropriate vaccinations, and ongoing monitoring for infections are increasingly been recommended for patients with autoimmune rheumatic diseases.

Shared journeys of Cancer and Rheumatic diseases

Increased risk of malignancies and AIRDs have been well established in RA, Sjogren’s, Scleroderma, and Inflammatory Myositis since the 1980s. Earliest among them was the risk of NHL in uncontrolled RA and Sjogren’s; mirroring the role of dysregulated immune response in lymphomagenesis.  In Dermatomyositis, and Scleroderma, cancer immune response seems to trigger autoimmunity; with these diseases often going into remission with the treatment of malignancies. Remarkably a recent French study on patients with treated RA indicated an increased risk of all time cancers but low risk for NHL. This implies that factors beyond disease activity have a key role in oncogenesis in AIRDs.

Further reading

  1. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002 Mar 5;105(9):1135-43.
  2. Cafaro G, Perricone C, Gerli R, Bartoloni E. Cardiovascular risk in systemic autoimmune diseases. Lancet. 2023 Jan 7;401(10370):21-22.
  3. Huss V, Bower H, Wadström H, Frisell T, Askling J; ARTIS group. Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford). 2022 May 5;61(5):1810-1818.