Nonviral cryoglobulinemic vasculitis: an updated review for clinical practice

Abstract

The clinical spectrum of cryoglobulinemic-associated diseases is broad and heterogeneous, with manifestations ranging from mild symptoms (e.g., isolated palpable purpura) to organ- and life-threatening involvement (e.g., membranoproliferative glomerulonephritis). Cryoglobulins are classified into three types. Type I cryoglobulinemia consists of one monoclonal immunoglobulin (Ig) and is practically always associated with B-cell lymphoproliferative disorders. In contrast, type II/III (mixed) cryoglobulinemia is composed of mono- or polyclonal IgM with rheumatoid factor activity bound to polyclonal IgG. Since the introduction of more efficient therapies for chronic hepatitis C virus (HCV), other diseases such as systemic autoimmune disorders and lymphoproliferative neoplasms have been established as the main causes of mixed cryoglobulinemic vasculitis. The pathogenesis of cryoglobulinemic vasculitis is a complex multifactorial process that involves B-cell aberrant lymphoproliferation and autoantibody production. Therefore, treatment of these patients may involve not only measures aimed to mitigate the severity of clinical manifestation but also those that address the associated underlying disease responsible for Ig production. The treatment of patients with type I cryoglobulinemia is primarily focused on controlling B lymphocyte clones responsible for cryoglobulin production, mostly with chemotherapy drugs. Treatment of mixed cryoglobulinemia syndrome is based on rituximab plus glucocorticoids, which induces remission in the vast majority of cases. In the rare patients that do not respond to rituximab administration, potential rescue approaches include alkylating agents, biologic therapies, conventional immunosuppression, and plasma exchange, although with partial efficacy. This narrative review explores the etiology, pathophysiology, clinical manifestations, treatment, and prognosis of nonviral cryoglobulinemic disease. A special focus is placed on the treatment of type I cryoglobulinemia and rituximab-resistant non-HCV cryoglobulinemic vasculitis.