The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements

Abstract

Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as “essential” (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.

Ocular Manifestations of Cryoglobulinemia: a Reappraisal

“…The demographic, clinical, and immunological characteristics of the 57 patients included in this study are summarized in Table 1. Consistent with the findings in larger patient series [15,16,21] and with our own experience [14], almost two-thirds of the patients were female and in nearly 75% of the cohort the CGs were of type II. With the exception of 2 patients with type I cryoglobulinemia and hyperviscosity syndrome (HVS), who were diagnosed with Waldenström macroglobulinemia (WM) and B-cell non-Hodgkin lymphoma (B-NHL) respectively, all patients were RF-positive.…”

“…In the past, CPH, MTX, MMF, and cyclosporine were repeatedly and empirically employed, usually in conjunction with GCs, to mitigate the most severe manifestations of vasculitis [14,51,52]. These drugs have now been almost invariably replaced by Bcell-depleting biological agents, whose prototype is the chimeric monoclonal antibody RTX [53,54].…”

“…This retrospective, observational study was carried out at the University of Bari on a cohort of 57 patients diagnosed with CV between 2005 and 2020 at a single tertiary referral center of Internal Medicine with multi-year experience in the diagnosis and treatment of CV [14,20]. All patients underwent a comprehensive ocular assessment, whether or not they complained of visual disturbances.…”

“…It is also important to emphasize that in > 90% of patients with chronic HCV infection the widespread therapeutic use of direct-acting antiviral agents (DAAs) has resulted in both a sustained virologic response (SVR) [12] and a gradually decreasing prevalence of HCV-related MC. The obvious consequence is that autoimmune diseases, particularly pSS and SLE, are progressively replacing HCV infection as the major causative condition underlying the onset of MC and CV [13,14].…”

“…The clinical manifestations of HCV-related CV include a wide spectrum of signs and symptoms, ranging in severity from PWAS to leg ulcers, Raynaud's phenomenon, type I membranoproliferative glomerulonephritis, sensory or sensory-motor polyneuropathy, and low-grade indolent non-Hodgkin lymphoma (NHL) [14][15][16][17][18]. In a study of 246 patients with MC, the overall 10-year survival rate was 74% (95% confidence interval: 67-79%), with a statistically significant difference between patients with type III (84%) and type II (71%) MC [19].…”