Safety of using anti-TNF-α blockers in cardiac failure associated with systemic inflammatory disease and the risk of Kounis syndrome

Abstract

Tumor necrosis factor (TNF-α) is a multifunctional cytokine that plays an important role in inflammation and immunity, as well as in the control of cell proliferation, differentiation and apoptosis. In the paper published in Int J Cardiol [1] and dealing with the safety of using anti-TNF-α blockers for systemic inflammatory disease the authors wisely wondered if it is safe to use TNF-α blockers for systemic inflammatory disease especially for rheumatoid arthritis with concomitant cardiac failure. Current guidelines, suggest that anti TNF-a therapy for rheumatoid arthritis associated with mild cardiac failure should be given with extreme caution, while higher doses should be avoided in all patients with a NYHA III and IV class [2]. It has been speculated that anti TNF-a therapy could induce cardiac toxicity [1]. In clinical practice there are five TNF-α blockers used for the treatment of inflammatory diseases: one fusion proteinmimicking the TNF receptor 2, the etanercept and four anti TNF-α chimeric monoclonal antibodies namely infliximab, adalimumab, golimumab and certolizumab. Other chimeric antibodies such as cetuximab and panitumumab targeting epidermal growth factor receptor are effective in treatment of metastatic colorectal cancer. Several clinical studies have shown the participation of proinflammatory cytokines in the pathogenesis of cardiac diseases [3]. The levels of circulating proinflammatory cytokines TNF-α and IL-1 and -6 are elevated in patients with myocarditis associated with or no heart failure [4, 5]. One, therefore, could expect that anti-TNF-α therapy would be beneficial for treating such conditions. However, in the antiTNF Therapy Against Congestive Heart Failure (ATTACH) trial [6] 10 mg/kg of infliximab deteriorated cardiac function while 5 mg/kg had no different effect than placebo. Infliximab is a genetically produced chimeric monoclonal antibody against TNF-a, which is widely used for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and systemic vasculitis. It consists of 25% murine sequences in the variable region of antibody and some patients have developed antichimeric antibodies against infliximab [7]. Indeed, such antichimeric antibodies have been found in 14.5– 17.1% of patients with Crohn's disease. In a recent study [7], including patients with rheumatoid arthritis, systemic vasculitis and spondylarthropathies, 11 out of 71 patients, receiving infliximab, developed hypersensitivity reactions such as urticaria, chest tightness, vomiting and oxygen desaturation. These patients had IgE, IgM and IgG antibodies against infliximab detectable in their serum. The antibodies were detected in the sera collected before the 2nd and the 3rd infliximab infusion, and their appearance was strictly related to the timing of the reaction. Furthermore, in rheumatoid arthritis, important effector cells such as mast cells, macrophages and few eosinophils have been found in inflamed rheumatoid synovial tissue and sites of cartilage. Such findings are at variance with those in allergic inflammation, in which the presence of inflammatory cells has been reported to be regulated by specific chemokines and adhesion molecules. Therefore an association with Kounis syndrome [8] cannot be excluded. The medical literature is replete with a variety of early or delayed hypersensitivity reactions that are associated with anti TNF-a therapy; some of which could be dangerous. Such reactions associated with the use of infliximab include [9]: anaphylaxis, atopic dermatitis, acne, allergic contact dermatitis, allergic pulmonary aspergillosis, alopecia areata, atopic dermatitis, cutaneous vasculitis, eruption, erythema nodosum, eczematoid eruption, eczematoid dermatitis, eczematiclike purpura of Doukas–Kapetanakis, granuloma annulare, lichen planus, necrotizing fasciitis, niacin-like reaction, nummular eczema, psoriasiform eruption, pustular eruption, redman syndrome (striking, “glowing” red discoloration of the skin), serum sickness, urticarial rash and urticarial vasculitis. Type I variant of Kounis syndrome has been also described [10]. Therefore, one should be always bring in mind that monoclonal chimeric antibodies used for treatment of inflammatory diseases can lead to the production of antichimeric antibodies, induce hypersensitivity reaction and worsen overt or incipient cardiac failure. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.