The Spectrum of Type I Cryoglobulinemia Vasculitis

Type I cryoglobulinemia vasculitis (CryoVas) is considered a life-threatening condition; however, data on the characteristics and outcome are scarce. To analyze the presentation, prognosis, and efficacy and safety of treatments of type I CryoVas, we conducted a French nationwide survey that included 64 patients with type I CryoVas between January 1995 and July 2010: 28 patients with monoclonal gammopathy of unknown significance (MGUS) and 36 with hematologic malignancy. Type I monoclonal CryoVas was characterized by severe cutaneous involvement (necrosis and ulcers) in almost half the patients and high serum cryoglobulin levels, contrasting with a lower frequency of glomerulonephritis than expected. The 1-, 3-, 5-, and 10-year survival rates were 97%, 94%, 94%, and 87%, respectively. Compared to MGUS, type I CryoVas related to hematologic malignancy tended to be associated with a poorer prognosis. Therapeutic regimens based on alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib showed similar efficacy on vasculitis manifestations, with clinical response rates from 80% to 86%. Data from the CryoVas survey show that the prognosis of type I CryoVas does not seem to be as poor as previously suggested. Besides alkylating agents, the use of regimens based on rituximab, thalidomide or lenalinomide, and bortezomib are interesting alternative options, although the exact role of each strategy remains to be defined. (Medicine 2013;92: 61Y68) Abbreviations: CR = complete response, CryoVas = cryoglobulinemia vasculitis, HCV = hepatitis C virus, MC = mixed cryoglobulinemia, MGUS = monoclonal gammopathy of unknown significance, PR = partial response. INTRODUCTION C ryoglobulinemia is defined as the presence of circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. After immunochemical typing, cryoglobulins are sorted according to the classification of Brouet et al: type I cryoglobulinemia comprises single monoclonal immunoglobulins, and types II and III are mixed cryoglobulinemias (MCs), with a monoclonal component in type II and only polyclonal immunoglobulins in type III. Cryoglobulinemia may cause systemic vasculitis (CryoVas), with manifestations ranging from MC syndrome (purpura, arthralgia, and asthenia) to more serious lesions with skin, neurologic, and renal involvement. Skin is the most frequently involved target organ, with palpable purpura, but chronic cutaneous ulcers may occur. Neurologic manifestations range from pure sensory axonopathy to mononeuritis multiplex, but the most frequently described form is distal sensory or sensorymotor polyneuropathy. Finally, the most frequent clinical and histologic picture of renal involvement is acute or chronic type I membranoproliferative glomerulonephritis with subendothelial deposits. Two major mechanisms are at play to varying degrees across the different types of cryoglobulinemia: cryoglobulin precipitation in the microcirculation, and immune complex-mediated inflammation of blood vessels. Vascular occlusion is more frequent in type I cryoglobulinemia, which is usually accompanied by high cryoglobulin concentrations, and can be associated with hyperviscosity syndrome and cold-induced acral necrosis. In contrast, immune complexYmediated vasculitis is more frequent in mixed cryoglobulinemia. The prevalence and incidence of CryoVas are unknown, in particular because of the heterogeneity in the cause, clinical presentation, and geographical distribution of the disease. However, the prevalence was initially reported as approximately 1:100,000 individuals. CryoVas appears more commonly in patients aged 45 to 65 years, with a maximum incidence in women (sex ratio women to men, 2Y3 to 1). Type I cryoglobulins are always linked to a B-cell lymphoproliferative disorder, that is, multiple myeloma, Waldenström macroglobulinemia, chronic lymphocytic leukemia, B-cell non-Hodgkin lymphoma, and hairy cell leukemia. In contrast, MCs (type II or III) are associated with systemic autoimmune diseases, lymphoproliferative disorders, and chronic infections, hepatitis C virus (HCV) infection representing 80% of the CryoVas cases. When MC is found in the absence of well-defined disease, the syndrome is designated ‘‘essential MC.’’ Since the discovery of HCV infection in 1989, it has become clear that HCV is associated with most cases of MC. Among patients with MC, 60%Y90% are infected with HCV. Type I cryoglobulinemia accounts for 10%Y15% of patients with cryoglobulinemia. Data on type I CryoVas are scarce in the literature, therefore the characteristics and outcome are poorly Medicine & Volume 92, Number 2, March 2013 www.md-journal.com 61 From the Department of Internal Medicine (BT, DS, P. Cacoub), Groupe Hospitalier Pitié-Salpetrière, Assistance Publique Hôpitaux de Paris, Universite Pierre et Marie Curie, Paris 6, Paris; Department of Nephrology (AK), Hôpital Européen Georges Pompidou, Paris; Department of Internal Medicine (J-EK), Hôpital Foch, Suresnes; Department of Internal Medicine (GG), CHU, ClermontFerrand; Department of Internal Medicine (IM), CHU, Rouen; Department of Internal Medicine, (LB) CHU, Marseille; Department of Nephrology (AL), CHU, Bordeaux; Department of Internal Medicine (ED), CHU, Tours; Department of Hematology (OH), Hôpital Necker-Enfants Malades, Paris; Department of Internal Medicine (LS-M), CHU, Brest; Department of Internal Medicine (P. Cathébras), CHU, Saint-Etienne; Department of Hematology (VL) and Department of Neurology (J-ML), Groupe Hospitalier Pitié-Salpetrière, Paris; Department of Dermatology (PM), CHRU, Lille; Department of Rheumatology (XM), Hôpital Bicêtre, Le Kremlin-Bicêtre; and Department of Dermatology (PS) and Department of Nephrology (EP), Hôpital Tenon, Paris, France. Dr. Kahn reports previous financial support for work outside this study from GlaxoSmithKline (GSK) (board membership and grant to his institution). The other authors have no funding or conflicts of interest to disclose. Reprints: Prof. Patrice Cacoub, Department of Internal Medicine, Hôpital Pitié-Salpétrière, 47-83 boulevard de l’Hôpital, 75013 Paris, France (e-mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e318288925c Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. known. To our knowledge the largest series of type I CryoVas, recently reported, included only 6 patients. Despite the lack of data and large case series of patients, type I CryoVas is considered a life-threatening disorder because of the severity of cutaneous and renal involvement and the underlying hemopathy. In the absence of prospective or randomized controlled trials, the management of type I CryoVas is based on empirical data. In patients with malignant hematologic disorders, the treatment of vasculitis is that of the hemopathy, while in those without overt B-cell lymphoma, the treatment of vasculitis may include plasma exchange, corticosteroids, alkylating agents, rituximab, or iloprost. A survey was initiated in France in 2010 to describe the presentation, prognosis, and efficacy and safety of treatments of patients with type I CryoVas. We report here data for 64 cases of type I CryoVas included in the survey.