Biologic Agents in Systemic Vasculitis
Biologic Agents in Systemic Vasculitis
The treatment of systemic necrotizing vasculitis has made great strides in both efficacy and outcomes. Standard therapies, however, are associated with numerous side effects, and not all patients will respond to conventional immunosuppression. These realities have prompted the search for safer and more efficacious treatments, most notably among biologic agents. For example, the role of TNF-α in the pathophysiology of several vasculitides has led to the investigation of targeted inhibitors of this cytokine, albeit with mixed results. There have been some disappointing results in the area of giant cell arteritis and Wegener's granulomatosis (granulomatosis with polygiitis), but anti-TNF therapy has shown promise in the treatment of Takayasu's arteritis, although additional trials to demonstrate its efficacy are required. Anti-B-cell therapy seems to be the most promising advance in the management of these diseases. Complete and partial responses have been seen in both primary and secondary mixed cryoglobulinemic vasculitis. Recent trials have demonstrated that rituximab is effective for the treatment of Wegener's granulomatosis and microscopic polyangiitis. These trials have, however, raised concerns regarding the long-term safety of these agents. The future holds promise for additional targeted therapies with improved patient response and fewer side effects.
The systemic necrotizing vasculitides are a broad family of conditions characterized by injury or destruction of the blood vessel walls by inflammatory cells (Table 1). Untreated, these diseases can be devastating, with high rates of morbidity and mortality. Over the past few decades, the use of high-dose glucocorticoids and cytotoxic agents has dramatically improved the prognosis of these patients, leading to remission in many patients who, in the past, would have succumbed to their illnesses. However, current standard therapies, are far from ideal. Some patients with systemic vasculitis will not respond to conventional immunosuppression; a far greater number will relapse, or develop morbidity as a direct result of the drugs used to treat the disease. This was illustrated in a cohort of 158 granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) patients treated with a combination of cyclophosphamide and prednisone. In this cohort, 91% of subjects demonstrated a marked improvement in their disease and 75% had complete remission. It was observed, however, that 86% experienced significant morbidity, 50% relapsed within 5 years and 13% died as a result of either their disease or adverse events associated with therapy.
For this reason, despite the great strides that have been made in the treatment of the systemic vasculitides, there is clearly a need for therapies with better efficacy and fewer adverse effects. The advent of biologic therapy has resulted from advances in our understanding of the pathogenesis of autoimmune diseases, allowing increasingly specific, targeted therapies to be developed for clinical use. In broad strokes, these therapies may be classified as falling into one of two distinct approaches: anticytokine strategies, and drugs that target specific subsets of immune cells. The ultimate goal of these therapies is to target pathways that contribute to disease initiation and propagation, while avoiding the disruption of pathways that are necessary for the health of the patient. Although there has been widespread enthusiasm for the use of biologic agents to treat systemic vasculitis, the literature supporting this approach has only recently become robust. This article will focus on the use of the two most popular classes of biologic agents.
Abstract and Introduction
Abstract
The treatment of systemic necrotizing vasculitis has made great strides in both efficacy and outcomes. Standard therapies, however, are associated with numerous side effects, and not all patients will respond to conventional immunosuppression. These realities have prompted the search for safer and more efficacious treatments, most notably among biologic agents. For example, the role of TNF-α in the pathophysiology of several vasculitides has led to the investigation of targeted inhibitors of this cytokine, albeit with mixed results. There have been some disappointing results in the area of giant cell arteritis and Wegener's granulomatosis (granulomatosis with polygiitis), but anti-TNF therapy has shown promise in the treatment of Takayasu's arteritis, although additional trials to demonstrate its efficacy are required. Anti-B-cell therapy seems to be the most promising advance in the management of these diseases. Complete and partial responses have been seen in both primary and secondary mixed cryoglobulinemic vasculitis. Recent trials have demonstrated that rituximab is effective for the treatment of Wegener's granulomatosis and microscopic polyangiitis. These trials have, however, raised concerns regarding the long-term safety of these agents. The future holds promise for additional targeted therapies with improved patient response and fewer side effects.
Introduction
The systemic necrotizing vasculitides are a broad family of conditions characterized by injury or destruction of the blood vessel walls by inflammatory cells (Table 1). Untreated, these diseases can be devastating, with high rates of morbidity and mortality. Over the past few decades, the use of high-dose glucocorticoids and cytotoxic agents has dramatically improved the prognosis of these patients, leading to remission in many patients who, in the past, would have succumbed to their illnesses. However, current standard therapies, are far from ideal. Some patients with systemic vasculitis will not respond to conventional immunosuppression; a far greater number will relapse, or develop morbidity as a direct result of the drugs used to treat the disease. This was illustrated in a cohort of 158 granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) patients treated with a combination of cyclophosphamide and prednisone. In this cohort, 91% of subjects demonstrated a marked improvement in their disease and 75% had complete remission. It was observed, however, that 86% experienced significant morbidity, 50% relapsed within 5 years and 13% died as a result of either their disease or adverse events associated with therapy.
For this reason, despite the great strides that have been made in the treatment of the systemic vasculitides, there is clearly a need for therapies with better efficacy and fewer adverse effects. The advent of biologic therapy has resulted from advances in our understanding of the pathogenesis of autoimmune diseases, allowing increasingly specific, targeted therapies to be developed for clinical use. In broad strokes, these therapies may be classified as falling into one of two distinct approaches: anticytokine strategies, and drugs that target specific subsets of immune cells. The ultimate goal of these therapies is to target pathways that contribute to disease initiation and propagation, while avoiding the disruption of pathways that are necessary for the health of the patient. Although there has been widespread enthusiasm for the use of biologic agents to treat systemic vasculitis, the literature supporting this approach has only recently become robust. This article will focus on the use of the two most popular classes of biologic agents.
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