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.

Keywords: Cryoglobulin; Cryoglobulinemic vasculitis; Glucocorticoids; HCV; Non-Hodgkin lymphoma; Rituximab; Therapeutic apheresis.

Fig. 1

The spectrum of clinical manifestations observed in the personal cohort of 440 patients with HCV-related cryoglobulinemic vasculitis (updated from the data reported in 2019 [5])

Fig. 2

Cryoglobulinemia can be detected in a wide range of clinical conditions, gathered in 5 diagnostic groups. The number of patients and the corresponding percentage of each group refers to our cohort of 440 patients, collected in a time frame of 31 years. CV cryoglobulinemic vasculitis

Fig. 3

Suggested treatment algorithm in patients with HCV-positive CV according to the severity of the clinical features. In the large majority of the studies, this treatment resulted in sustained virologic response in over 90% of the patients and disappearance of CV manifestations in percentages ranging from 30 to 87% (see Table 1)

Fig. 4

Suggestion of a genomically driven therapeutic approach in patients with Waldenström macroglobulinemia and HCV-negative type I CV (Adapted from [84])