Mixed cryoglobulinemia

Abstract

Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.

Figure 1

Cryocrit determination in a patient with mixed cryoglobulinemia (MC). Graduated glass tubes with serum sample from cryoglobulinemic patient at different time intervals: 0- soon after serum separation from the whole blood sample (at least 20 ml of whole blood); 7- after 7 days at +4°C; and cryocrit measurement after serum centrifugation, always at +4°C. (modified from [24], Ferri C et al, Sem Arthritis Rheum 2004, 33:355–74.).

Figure 2

Cutaneous manifestations of mixed cryoglobulinemia (MC). (a) recent onset orthostatic purpura; at this stage the histopathological evaluation shows (b) the classical necrotizing leukocytoclastic vasculitis characterized by diffuse fibrinoid necrosis and disintegrated neutrophil permeation of the vessel walls; (c) symmetrical hyperpigmentation of the skin on the legs after repeated episodes of purpura; both orthostatic purpura and these permanent ochraceous lesions represent the typical skin manifestations of MC; (d) severe vasculitic manifestation; (e) wide skin ulcer, often resistant to treatment.

Figure 3

Different referrals of patients with mixed cryoglobulinemia (MC). Given its clinical polymorphism, the MC syndrome may develop through different, often unpredictable symptoms. Consequently, MC patients may be referred to different specialties according to prevalent or apparently unique clinical manifestation, such as membranoproliferative glomerulonephritis (MPGN) or purpuric skin lesions. Patients with very mild manifestations, often arthralgias and/or serum rheumatoid factor (RF) positivity, are generally referred to rheumatologic clinic.

Figure 4

Relationship between cryoglobulin detection and overt mixed cryoglobulinemia (MC) syndrome. (1) Definite MC syndrome (or cryoglobulinemic vasculitis) is a combination of serological findings (mixed cryoglobulins with RF activity and frequent low C4) and typical clinico-pathological features (purpura, leukocytoclastic vasculitis, and frequent multiple organ involvement); see also Table 3. However, incomplete MC syndrome can be observed at any time during the natural history of the disease; (2) Isolated serological alterations may be detected in the early stages of the disease or during the clinical remission; on the contrary; (3) the absence of serum cryoglobulins in patients with overt MC syndrome may be a transient phenomenon due to the wide variability of the percentage of cryoprecipitable immune-complex during the natural history of the disease or, less frequently, to a switching from 'benign' B-cell lymphoproliferation to malignant lymphoma.

Figure 5

Schematic representation of different clinical and virological subsets of mixed cryoglobulinemia (MC) syndrome. 1) 'essential' MC (EMC); 2) and 3) 'essential' MC and HCV-associated MC syndrome in the setting of definite autoimmune-lymphoproliferative disorders (ALD), such as autoimmune hepatitis, Sjögren's syndrome or B-cell lymphomas; 4) the most frequent subset of HCV-associated MC syndrome; 5) MC associated with other infectious agents such as hepatitis B virus (HBV). (modified from [12,13]: Ferri C et al, B-cells and mixed cryoglobulinemia. Autoimm Rev 2007, 7: 114–20; Mascia MT et al, Non HCV-related mixed cryoglobulinemia. Dig Liver Dis 2007, 39: S61–4.).

Figure 6

Etiopathogenesis of mixed cryoglobulinemia (MC) syndrome. The figure summarizes the etiopathogenetic cascade of MC and other HCV-related disorders. This is probably a multifactorial and multistep process: the remote events include some infectious agents, mainly HCV, predisposing host factors, and possible unknown environmental/toxic triggers. Viral antigens (for example HCV core, envelop E2, NS3, NS4, NS5A proteins) may exert a chronic stimulus on the host immune- system through specific lymphocyte receptors, such as CD81 that may interact with the viral E2. Predisposing host factors may include particular HLA alleles, metabolic and hormonal conditions. The main consequence is a 'benign' B-cell proliferation with a variety of autoantibody production, among which rheumatoid factor (RF), and cryo- and non-cryoprecipitable immune-complexes (IC). These serological alterations may be correlated with different organ- and non-organ-specific autoimmune disorders, including the MC syndrome (or cryoglobulinemic vasculitis). Moreover, the activation of Bcl2 proto-oncogene, responsible for prolonged B-cell survival, may be a predisposing condition to other genetic aberrations, which may lead to frank B-cell lymphomas and other malignancies. The appearance of malignant neoplasias can be observed in a small but significant percentage of patients, usually as late complication. Both immunological and neoplastic disorders show a clinico-serological and pathological overlap. Often, autoimmune organ-specific manifestations may evolve to systemic conditions, and less frequently to malignancies. Conversely, it is not rare that patients with malignancies may develop one or more autoimmune manifestations. In this scenario, MC syndrome represents a crossing road between autoimmune and neoplastic disorders. (modified from [11,12]: Ferri C et al, HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig Liver Dis 2007, 39: S13–21; Ferri C et al, B-cells and mixed cryoglobulinemia. Autoimm Rev 2007, 7: 114–20.).

Figure 7

Differential diagnosis between mixed cryoglobulinemia and other autoimmune-lymphoproliferative disorders in the setting of HCV infection. Mixed cryoglobulinemia (MC) syndrome, primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) show a clinico-pathological overlap, including the possible association with HCV infection. The following parameters may be usefully employed for a correct differential classification/diagnosis: pSS shows typical histopathological pattern of salivary gland involvement and specific autoantibodies (anti-RoSSA/LaSSB), which are rarely found in MC patients; conversely, cutaneous leukocytoclastic vasculitis, visceral organ involvement (glomerulonephritis, hepatitis), low C4, and HCV infection, are typically found in MC. Moreover, erosive symmetrical polyarthritis and serum anti-cyclic citrullinated peptide antibodies (anti-CCP) characterize classical RA. Finally, B-cell non-Hodgkin's lymphoma (B-NHL) may complicate these diseases, more frequently MC and SS. The appearance of B-NHL can be timely suspected by careful clinico-serological monitoring and diagnosed by bone marrow/lymph node biopsies and total body CT scan. RF: rheumatoid factor. (modified from [25]. Ferri C and Mascia MT, Curr Opin Rheumatol 2006, 18: 54–63, with permission from Lippincott Williams & Wilkins).

Figure 8

Treatment of mixed cryoglobulinemia (MC) syndrome according to the etiopathogenesis of the disease (1). MC is the result of a multistep process including three main clinico-pathological levels: 1) chronic HCV infection, 2) B-lymphocyte proliferation, and 3) immune-complex-mediated vasculitis (cryoglobulinemic vasculitis). Following the cascade of events leading from HCV infection to overt vasculitic syndrome, we can treat the patients at different levels by means of etiologic, pathogenetic, and/or symptomatic therapies (see also Fig. 6, 9, and 10). RF: rheumatoid factor; CIC: circulating immune-complexes; LAC-diet: low-antigen-content diet. (modified from [25]: Ferri C and Mascia MT, Curr Opin Rheumatol 2006, 18: 54–63, with permission from Lippincott Williams & Wilkins).

Figure 9

Therapeutic strategy according to activity/severity of mixed cryoglobulinemia (MC) syndrome (2). Therapeutic strategy of mixed cryoglobulinemia (MC) syndrome (or cryoglobulinemic vasculitis) should be decided on the basis of the activity/severity of clinical symptoms and tailored for the single patient: in asymptomatic patients a careful monitoring is often sufficient; in those with moderate-severe manifestations, mainly in the presence of active chronic hepatitis, an attempt to eradicate the HCV infection should be carried out; particularly severe, rapidly progressive complications must be treated with more aggressive treatments, as in other systemic vasculitides. Sequential treatment schedules can be employed in individuals with particularly aggressive manifestations and/or partial response (clinical, pathological, or virological) to traditional treatments (see also Fig. 8 and 10). Purp.: purpura; weak.: weakness; arthr.: arthralgias; CPX: cyclophosphamide; CS: corticosteroids; LAC-diet, low-antigen-content diet; MPGN, membranoproliferative glomerulonephritis; peg-IFN: pegylated interferon-alpha; RIBA: ribavirin.

Figure 10

Flow chart of therapeutic strategies according to activity/severity of mixed cryoglobulinemia (MC) syndrome (3). HCV-positive MC patients with moderate-severe manifestations, mainly in the presence of active chronic hepatitis, antiviral treatment with pegylated interferon-alpha (peg-IFN) + ribavirin (RIBA) can be tried after exclusion of possible contraindications. In non-responders or in those with partial response (virological), a treatment with rituximab (RTX) can be proposed (a). Conversely, in HCV+ MC patients usefully treated with rituximab or other anti- inflammatory/immunosuppressive therapies, an attempt to eradicate HCV infection can be done (b). Finally, combined high dose corticosteroids (CS), plasma exchange (PE), and cyclophosphamide (CPX) are the first line treatment in life-threatening, rapidly progressive complications in both HCV+ and HCV- cryoglobulinemic vasculitis (see also Fig. 8 and 9). LAC-diet: low-antigen-content diet.