Evaluating safety and compatibility of anti-tumor necrosis factor therapy in patients with connective tissue disorders

Abstract

Inhibition of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) has been utilized as a treatment strategy for a variety of immune-mediated inflammatory disorders (IMID), including rheumatoid arthritis, Crohn's disease and psoriasis. A wide array of biologic therapies targeting the TNFα molecule, including etanercept, infliximab, certolizumab, golimumab and adalimumab, are routinely used in the care of patients with these conditions. In addition to their therapeutic potential, anti-TNFα agents commonly induce the formation of autoantibodies such as anti-nuclear antibodies and anti-double stranded DNA antibodies; however, the vast majority of these are of IgM isotype and of unclear clinical significance, uncommonly leading to drug-induced autoimmune disease. For these reasons, TNFα inhibition has been a controversial strategy in the treatment of primary connective tissue disorders (CTDs). However, as new therapeutics continue to be developed for the management of CTDs, the potential utility for anti-TNFα agents has become of great interest, demonstrated in several recent case series and small open-label trials. We review the safety and compatibility of anti-TNFα therapy in the management of systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE), two well-studied example CTDs, as well as summarize the risks of autoantibody generation, infection, malignancy, and iatrogenic lupus flares as side effects of blocking TNFα in patients with these conditions.

Cytokines in Systemic Lupus Erythematosus—Focus on TNF-α and IL-17

“…Patients with SLE have higher serum TNF-α levels, which correlate with disease activity and many systemic manifestations, such as SLE-related cardiovascular disease and lupus nephritis [16]. Further findings indicate that TNF-α expression in SLE may have a "dose-like effect": aggravation of the condition being correlated with elevated cytokine concentration [20]. However, an anti-TNF-α treatment in SLE is questionable due to the development of antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA) antibodies, and anticardiolipin antibodies [1].…”

“…TNF-α is produced by various immune cells, primarily macrophages, lymphocytes, cutaneous mast cells, eosinophils, and natural killer cells [20,23]. Bacterial lipopolysaccharide (LPS), endotoxin, viral antigens, immune complexes, IL-1, and TNF-α itself can all trigger the release of TNF-α; additionally, some pathophysiological circumstances (inflammation, trauma, heart failure) can stimulate its production [16,24,25].…”

“…TNF-α also acts as an immunomodulatory molecule, stimulating cells of the innat immune system. It can induce fever on the hypothalamus-pituitary axis in conjunctio with IL-1 and IL-6 [20]. When TNFR-associated factor 2 (TRAF2) binds to TNFR2, both the conventional and non-canonical NF-κB signaling pathways are activated [16].…”

Drug-induced lupus erythematosus

“…This seems to be a class effect but is particularly evident for infliximab 45 and etarnecept 53 . These drugs induce: -apoptosis enhancing formation of autoantibodies against nuclear antigens 8 ; -negative regulation on C-reactive protein and TNFα with consequent decrease in the expression of the adhesion molecule CD44 and reduced clearance of apoptotic material 8 ; -and increase in type I interferon levels, which influences plasma cell differentiation 51 -"cytokine shift" with suppression of T-helper 1 and increase of T-helper 2 cells, with B-cell activation and autoantibody formation 45,54 .…”

“…In milder cases, patients can tolerate substitution to another anti-TNFα 25,54 , and some might tolerate treatment continuation, eventually adding immunosuppressive drugs 45 .…”