Clinical characteristics and treatment outcome of type I cryoglobulinemia in Chinese patients: a single-center study of 45 patients.

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Expert opinion on managing chronic HCV in patients with mixed cryoglobulinaemia vasculitis.

Mixed cryoglobulinaemia vasculitis (CryoVas) is a small-vessel systemic vasculitis caused by deposition of mixed cryoglobulins and is characterized by a wide range of clinical symptoms. HCV is the primary cause of CryoVas, which is associated with significant morbidity and mortality. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. First-line treatment for CryoVas is anti-HCV therapy because viral clearance is associated with clinical improvement. The introduction of highly effective, interferon-free, direct-acting antiviral regimens provides additional treatment options for these patients. Here, we review recent studies investigating the effect of antiviral therapy on HCV-associated CryoVas and provide expert opinion for health-care professionals managing these patients.

Long-Term Outcomes of Patients With HCV-Associated Cryoglobulinemic Vasculitis After Virologic Cure.

Patients with hepatitis C virus-associated cryoglobulinemic vasculitis (HCV-CV) have high rates of clinical remission after treatment with direct-acting antivirals (DAAs), but circulating cryoglobulins persist, and vascular disorders reappear in some patients shortly after DAA treatment ends. We performed a prospective study to assess the long-term clinical and immune system effects of HCV eradication with DAAs in 46 patients with HCV-CV and 42 asymptomatic patients with circulating cryoglobulins. A median of 24 months after DAA treatment (range, 17-41 months), 66% of patients with HCV-CV and 70% of asymptomatic patients with circulating cryoglobulins had an immunologic response, with comparable reductions in cryocrit from 2.6% to 0% (P < .05). However, 20% of patients still had positive test results for cryoglobulins after DAA therapy. Among patients with HCV-CV, 42 (91%) had a clinical response, in that their Birmingham Vasculitis Activity Score (version 3) decreased from 7 to 0 (P < .01). Nevertheless, within 2 years after a sustained viral response to DAA therapy, 5 patients with HCV-CV (11%, 4 with cirrhosis) had relapses of vasculitis that included severe organ damage and death.

HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC).

OBJECTIVES: To investigate the clinical and laboratory patterns of HCV-unrelated cryoglobulinaemic vasculitis (CV), and the factors influencing its outcome. METHODS: Prospective study of all anti-HCV and HCV-RNA negative patients with CV who have been observed since January 2004 in 17 centres participating in the Italian Group for the Study of Cryoglobulinaemias (GISC). RESULTS: 175 enrolled were followed up for 677 person-years. The associated conditions were primary Sjögren's syndrome (21.1%), SLE (10.9%), other autoimmune disorders (10.9%), lymphoproliferative diseases (6.8%), solid tumours (2.3%) and HBsAg positivity (8.6%), whereas 69 patients (39.4%) had essential CV. There were significant differences in age (p<0.001), gender (p=0.002), the presence of purpura (p=0.005), arthralgia (p=0.009), liver abnormalities (p<0.001), sicca syndrome (p<0.001), lymphadenopathy (p=0.003), splenomegaly (p=0.002), and rheumatoid factor titres (p<0.001) among these groups. Type II mixed cryoglobulins were present in 96 cases (54.9%) and were independently associated with purpura and fatigue (odds ratio [OR]4.3; 95% confidence interval [CI] 1.8-10.2; p=0.001; and OR2.8; 95%CI 1.3-6.3; p=0.012). Thirty-one patients died during follow-up, a mortality rate of 46/1000 person-years. Older age (for each additional year, adjusted hazard ratio [aHR] 1.13; 95%CI 1.06-1.20; p<0.001), male gender (aHR 3.45; 95%CI 1.27-9.40; p=0.015), type II MCG (aHR 3.31; 95%CI 0.09-1.38; p=0.047) and HBsAg positivity (aHR 7.84; 95%CI 1.20-36.04; p=0.008) were independently associated with greater mortality. CONCLUSIONS: HCV-unrelated CV is a multifaceted and often disabling disorder. The associated conditions influence its clinical severity, giving rise to significantly different clinical and laboratory profiles and outcomes.

Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia.

We describe a series of 102 patients diagnosed from January 1, 1990 to December 31, 2015 with Type 1 monoclonal cryoglobulinemia (MoC). Symptoms were seen in 89 (87%) patients, including: cutaneous symptoms in 64 (63%) patients, with purpura (n = 43, 42%) and ulcers/gangrene (n = 35, 34%) being most common; neurological findings in 33 (32%) patients, most frequently sensory neuropathy (n = 24, 24%); vasomotor symptoms, mainly Raynaud's phenomenon in 25 (25%); arthralgias in 24 (24%); and renal manifestations, primarily glomerulonephritis in 14 (14%) patients. An underlying lymphoproliferative disorder was identified in 94 (92%) subjects; MGUS-39, myeloma-20, lymphoplasmacytic lymphoma-21 and others-14. Treatment was initiated in 73 (72%) patients, primarily for cryoglobulinemia-related symptoms in 57. Treatment regimens consisted of: steroids ± alkylating agents in 29 (40%), novel myeloma therapies in 16 (22%), rituximab with alkylating agents in 12 (16%) and rituximab ± steroids in 11 (15%) patients; 22 patients received plasmapheresis. Six patients underwent autologous stem cell transplant. Cryocrit at treatment initiation, change in cryocrit and time to nadir cryocrit were predictive of symptom improvement. Treatment directed toward the underlying clonal disorder resulted in improvement (n = 47) or stabilization (n = 16) of symptoms in the majority of patients and disappearance of cryoglobulin in over one-half.

Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients.

OBJECTIVE: To evaluate the fulfilment of classification criteria for cryoglobulinaemic vasculitis (CV) at diagnosis in a large cohort of patients with primary SS and their correlation with poor outcomes. METHODS: We included 515 consecutive patients tested for serum cryoglobulins who fulfilled the 2002 classification criteria for primary SS. CV classification criteria and serum cryoglobulins at diagnosis were assessed as predictors of death and lymphoma using Cox proportional-hazards regression analysis adjusted for age and gender. RESULTS: Positive serum cryoglobulins were detected in 65 (12%) patients, of whom 21 (32%) fulfilled CV classification criteria. Compared with patients positive for cryoglobulins who did not fulfil CV criteria, patients with CV had a higher frequency of type II cryoglobulinaemia (86% vs 43%, P = 0.04), a higher mean cryocrit level (6.58% vs 1.25%, P < 0.001) and a higher cumulated mean EULAR-SS disease activity index score (35.3 vs 16.2, P < 0.001). After a mean follow-up of 110 months, 45 (9%) patients developed B-cell lymphoma and 33 (6%) died. Compared with patients without cryoglobulins, patients with cryoglobulins who fulfilled [hazard ratio (HR) = 7.47, 95% CI: 3.38, 16.53] and did not fulfil (HR = 2.56, 95% CI: 1.03, 6.35) CV criteria both showed a higher risk of B-cell lymphoma in the univariate analysis, but not in the multivariate models. Compared with patients without cryoglobulins, patients with CV had a higher risk of death in both the univariate (HR = 11.68, 95% CI: 4.44, 30.74) and multivariate (HR = 4.36, 95% CI: 1.32, 14.47) models. CONCLUSION: Patients with primary SS who fulfilled criteria for cryoglobulinaemic vasculitis at diagnosis are at higher risk of death.

Cryoglobulinemia Vasculitis.

Cryoglobulinemic vasculitis (CryoVas) is a small-vessel vasculitis involving mainly the skin, the joints, the peripheral nervous system, and the kidneys. Type I CryoVas is single monoclonal immunoglobulins related to an underlying B-cell lymphoproliferative disorder. Type II and III cryoglobulins, often referred to as mixed cryoglobulinemia, consist of polyclonal immunoglobulin (Ig)G with or without monoclonal IgM with rheumatoid factor activity. Hepatitis C virus (HCV) infection represents the main cause of mixed CryoVas. The 10-year survival rates are 63%, 65%, and 87% in HCV-positive mixed CryoVas, HCV-negative mixed CryoVas, and type I CryoVas patients, respectively. In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis, and central nervous system, kidney, and heart involvement. Treatment with antivirals is associated with a good prognosis, whereas use of immunosuppressants (including corticosteroids) is associated with a poor outcome. In HCV-negative patients, pulmonary and gastrointestinal involvement, renal insufficiency, and age > 65 years are independently associated with death. Increased risk of lymphoma also should be underlined. Treatment of type I CryoVas is that of the hemopathy; specific treatment also includes plasma exchange, corticosteroids, rituximab, and ilomedine. In HCV-CryoVas with mild-to-moderate disease, an optimal antiviral treatment should be given. For HCV-CryoVas with severe vasculitis (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease, intestinal ischemia…) control of disease with rituximab, with or without plasmapheresis, is required before initiation of antiviral therapy. Other immunosuppressants should be given only in case of refractory forms of CryoVas, frequently associated with underlying B-cell lymphoma.

Long-term outcome of monoclonal (type 1) cryoglobulinemia.

The aim of this study is to investigate long-term outcome of symptomatic type 1 cryoglobulinemia (CG) and its determinants. Retrospective cohort study was conducted in two French University Hospitals. Patients with type 1 CG were identified using laboratory databases. Inclusion criterion was the presence of persistent symptoms of CG. Among 227 screened patients, 36 were included. Skin or vasomotor symptoms were the most frequent features (75%). Nephropathy and neuropathy occurred in 30% and 47% of cases, respectively. The underlying B cell disease (BCD) was a nonmalignant monoclonal gammopathy (NMMG) in 13 (36%) and a hematologic malignancy (HM) in 23 (64%; Waldenstrom macroglobulinemia (WM) in 12, low-grade non-Hodgkin lymphoma (NHL) in 6, multiple myeloma (MM) in 4, and chronic lymphocytic leukemia in 1 patient. Severe manifestations affected half the patients and were more frequent with IgG (82 vs. 30% (P = 0.006)). At last follow-up, 64% of patients had suffered no hematologic manifestation. Potent chemotherapeutic regimens were mainly used in HM. For patients with NMMG, WM, or NHL, fludarabine or rituximab-based regimens appeared to yield better responses. Five-year survival rate was 82%. In multivariate analysis, mortality was significantly higher in older patients (HR: 1.17 per year [95% CI: 1.06-1.28], P = 0.001) and those with nephropathy (HR: 8.9 [95% CI: 1.9-43], P = 0.006). Kidney disease, infections, Richter's transformation, and second malignancies were important sources of morbi-mortality. Despite its limitations, this series provide novel information regarding type 1 CG. Further studies are needed to improve its management. To date, therapeutic strategy should be tailored according to patient's characteristics (age, comorbidities, underlying BCD), and therapeutic target.

Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey.

BACKGROUND: Data on the prognosis of non-infectious mixed cryoglobulinaemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. METHODS: The French multicentre and retrospective CryoVas survey included 242 patients with non-infectious mixed CryoVas. Causes of death and prognostic factors of survival were assessed and a prognostic score was determined to predict survival at 5 years. RESULTS: After a median follow-up of 35 months, 42 patients (17%) died. Causes of death were mainly serious infections (50%) and vasculitis flare (19%). One-, 2-, 5- and 10-year overall survival rates were 91%, 89%, 79% and 65%, respectively. A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised. Pulmonary and gastrointestinal involvement, glomerular filtration rate <60 ml/min and age >65 years were independently associated with death. At 5 years the death rates were 2.6%, 13.1%, 29.6% and 38.5% for a CVS of 0, 1, 2 and ≥3, respectively. At 1 year the death rates were 0%, 3.2%, 18.5% and 30.8% for a CVS of 0, 1, 2 and ≥3, respectively. The CVS was strongly correlated with the Five Factor Score (FFS) 2009, another prognostic score validated in primary necrotising vasculitis (r=0.82; p<0.0001). The area under the curve for the CVS was 0.74 compared with 0.67 for the FFS, indicating a better performance of the CVS (p=0.052). CONCLUSIONS: In patients with non-infectious mixed CryoVas, the main prognostic factors are age >65 years, pulmonary and gastrointestinal involvement and renal failure. A score including these variables is significantly associated with the prognosis.

Hemorragia alveolar como causa de muerte en paciente con crioglobulinemia mixta asociada a VHC / Alveolar hemorrhage as a cause of death in a patient with mixed cryoglobulinemia associated with HCV

Presentamos el caso de una mujer de 80 años con hepatopatía crónica secundaria a infección por virus de la hepatitis C (VHC) y linfoma primario marginal esplénico. Ingresó por episodios de descompensación cardiaca siendo éxitus por insuficiencia respiratoria. Se le diagnosticó crioglobulinemia mixta tipo II asociada a infección por VHC debido a la presencia de crioglobulinas en sangre. El estudio necrópsico reveló hallazgos cutáneos y renales compatibles con esta entidad y determinó la presencia de infiltración de diferentes órganos por linfoma. La causa de muerte fue una hemorragia alveolar pulmonar bilateral masiva. La crioglobulinemia mixta asociada a virus de la hepatitis C (CMVHC) es una entidad reconocida que puede presentar complicaciones, entre las que destacan la afectación renal y la pulmonar. La hemorragia pulmonar es una de las complicaciones más graves, con un alto índice de mortalidad(AU)

An 80 year old woman, who had cronic liver disease secondary to a hepatitis C virus (HCV) infection and primary splenic marginal zone lymphoma, was admitted to hospital with heart failure. The presence of cryoblobulins in the blood led us to diagnose type II mixed cryoglobulinemia associated with HCV (HVCMC). The autopsy revealed cutaneous and renal findings related to HVCMC and lymphoma infiltration was observed in different organs. The cause of death was massive bilateral alveolar haemorrhage. HVCMC is a recognized entity which may have different complications, especially in the lung and kidney; pulmonary hemorrhage is one of the most serious, with a high mortality rate(AU)

Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus.

OBJECTIVES: Mixed cryoglobulinaemia (MC) is a chronic small-vessel vasculitis. Shortly after the discovery of hepatitis C virus (HCV) in 1989, an association between HCV infection and MC was being increasingly reported, suggesting the potential pathogenetic implication of HCV in most of the cases that had been previously diagnosed as essential MC. A number of studies have pointed out prognostic factors linked to mortality in this disorder. None of them, however, have clarified the impact of HCV discovery on the natural history of the disease. The aim of the present study was to evaluate mortality in MC after the discovery of HCV infection. METHODS: We retrospectively collected clinical and serological data in 70 unselected HCV-positive patients being followed up at our unit from 1990. Clinical and prognostic factors linked to poor outcome were evaluated. RESULTS: Chronic hepatitis, renal involvement, and intestinal vasculitis were the most frequent causes of death. CONCLUSION: Compared to other series, the outcome in our MC seemed to be better. Factors linked to a poor outcome were renal involvement, widespread vasculitis, male sex, and cryocrit.

Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy.

OBJECTIVE: Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder with significant morbidity and mortality. Renal involvement was associated with an increased mortality, and was the most common cause of death; these data were obtained before effective antiviral treatment was available. We studied causes of death and predictive factors in patients with HCV-associated MC vasculitis treated with antivirals. METHODS: Case histories of 85 patients with HCV-associated MC vasculitis treated in a single center between 1990 and 2006 were retrospectively reviewed. Prognostic factors affecting mortality were studied by comparing 23 patients who died with 62 survivors, using the Cox model regression analysis. RESULTS: The most common cause of death was infection, accounting for 34.7%, followed by endstage liver disease in 30.4% (including 4 patients with hepatocellular carcinoma), and cardiovascular disease in 17.4% of patients. Endstage renal disease accounted for only 8.7% of deaths, as did central nervous system vasculitis and nonhepatic malignancy. Increased mortality was strongly associated with immunosuppressive treatment [hazard ratio (HR) 6.51, 95% CI 2.75-15.37], cutaneous ulcers (HR 5.37, 95% CI 1.79-16.14), and renal insufficiency (HR 3.25, 95% CI 1.37-7.72). A 2 log10 decrease in HCV viral load at month 3 after starting antiviral treatment was associated with decreased mortality (HR 0.39, 95% CI 0.16-0.95). CONCLUSION: While renal involvement is still associated with poorer prognosis, infectious processes are now the most common cause of death in HCV cryoglobulinemia vasculitis. Immunosuppressive treatment is associated with an increased risk of death, independently from disease severity. Response to antiviral treatment is associated with significantly reduced mortality risk.

Mixed cryoglobulinemia and mortality: a review of the literature.

Mixed cryoglobulinemia is a highly heterogeneous clinical syndrome in terms of clinical presentation, extent and severity of organ involvement, immunological abnormalities and clinical course. Modern management began with the discovery of the close association between this syndrome and hepatitis C virus (HCV) infection. In this review we examined previously published studies on mortality in different series of patients with mixed cryoglobulinemia (MC). Patients with mixed cryo-globulinemia have higher mortality rates, predicted by age, renal involvement, intestinal vasculitis, widespread vasculitis and type of cryoglobulins.

Causes of death in symptomatic cryoglobulinemia: 30 years of observation in a Department of Internal Medicine.

UNLABELLED: Cryoglobulinemic Syn&come (CS) is a multi-systemic disease, and its fatal evolution can involve different organs. AIMS: To describe the most frequent causes of death in CS, by researching different evolutions between older cases and those of the last 15 years. PATIENTS: The data of 238 patients affected by symptomatic cryoglobulinemia followed by our Medicine Department in the last 30 years are recorded in a database. 54 are presently living and being followed, 70 (36F, 34M) have died. The type II/type III ratio is 5/4. We distinguish between two groups, the oldest, without any data on HCV, and the most recent who were tested for HCV. The follow-up ranges from 0.5 to 16 years. RESULTS: Liver diseases (25 cases, 9 with hepatic carcinomas), lymphomas and myeloproliferative diseases (12), and cardiovascular events (8) are the most reported causes of death. Sepsis, neurological syndromes, nephropathy, other malignancies and diffuse vasculitis are also reported. The median age at death was 67.2 years (58.4 in the oldest group, 71.9 in the other). Hepatic carcinomas are reported only after 1991. CONCLUSION: Cirrhosis complications are more frequent in patients affected by HCV. The increase in instrumental diagnostic ability and the improved survival of patients with cirrhosis account for the increase in patients with hepatic carcinomas. Improved treatment has resulted in a reduction of deaths from renal failure.

Response to rituximab in patients with type II cryoglobulinemia.

Type II cryoglobulinemia (CG) is a heterogeneous, generally indolent disorder caused by a monoclonal antibody with activity against polyclonal antibodies and is commonly associated with hepatitis C, lymphoproliferative disorders (LPDs), or autoimmune diseases. It can lead to substantial morbidity, including renal failure, cutaneous ulcers, or neuropathy. Medical records were reviewed for 8 patients with previously treated symptomatic CG who were part of a prospectively held dysproteinemia database. Patients subsequently received 14 total courses of rituximab treatment (standard infusion, 375 mg/m2 for 4 or 8 doses) between February 1999 and March 2005. One patient had essential CG, and 1 had Gaucher disease with hypersplenism. Six patients had an LPD, and 4 of them had concomitant disorders (2 with hepatitis C and 2 with Sjogren syndrome). Treatment indications included purpura, LPD, cutaneous ulcers, and renal failure. Clinical improvement was evaluated by improved cryocrit, total complement, C4, and rheumatoid factor. Six patients had some clinical improvement. Cutaneous manifestations were the most responsive; renal disease and lymphoma were more refractory. Laboratory values showed improvement after 7 of 12 available treatment courses. No adverse reactions were noted. Overall, rituximab appears to be a safe and effective therapy.

Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia.

BACKGROUND: Data on essential mixed cryoglobulinemia (MC) are scarce, and most date back to studies before 1989 (ie, before the discovery of hepatitis C virus [HCV] infection). Our objective was to describe the spectrum of MC in the era of HCV infection. METHODS: Retrospective study from a single university hospital's database of 1434 patients who tested positive for MC between January 1989 and December 2003. RESULTS: One hundred thirty-three patients (9%) with persistent MC without HCV were included in the study. Sixty-five of 133 patients who fulfilled the criteria for MC vasculitis were compared with 118 patients with HCV-related MC vasculitis. The patients without HCV had increased frequencies of renal involvement and B-cell non-Hodgkin lymphoma (NHL), lower gammaglobulin levels, and higher death rates. Twenty-three of the patients had B-cell NHL (primarily of the lymphoplasmocytic and marginal zone types), and 8 patients had Sjögren syndrome. In multivariate analysis, a cryoglobulin level higher than 0.6 g/L (odds ratio [OR], 1.44) and the presence of MC vasculitis (OR, 4.3) and hypogammaglobulinemia (OR, 6.7) were independently associated with B-cell NHL. After a mean follow-up of 49.4 months, 18 (14%) of 133 patients had died, primarily of sepsis. In multivariate analysis, age at diagnosis older than 60 years (OR, 1.06) and renal involvement (OR, 5.20) were independently associated with death. CONCLUSION: Patients with non-HCV-related MC vasculitis have a poor outcome and have a 4-fold increased risk of developing B-cell NHL.

Natural history and therapy of 66 patients with mixed cryoglobulinemia.

Cryoglobulinemia, a relatively uncommon disorder, is classified into types I, II, and III, with type II consisting of a monoclonal immunoglobulin possessing activity toward a polyclonal component. Many disease associations and therapies have been described but clinical trials are few, and the natural history, causes, therapy, and pathways of cryoglobulinemia require further investigation. Here, we describe the symptoms, comorbidities, treatments, and response of 66 patients with type II cryoglobulinemia by examining the records of all patients evaluated at Mayo Clinic, Rochester, Minnesota, between 3/2/1994 and 11/27/2000, using our prospective dysproteinemia database. Symptoms varied greatly among patients and during the disease course. Most common were purpura (55% of patients), renal disease (26%), edema (24%), neuropathy (18%), and arthralgia (21%). Renal disease required the most aggressive intervention. Laboratory findings did not correlate with disease manifestations or severity. Only age was a significant predictor of mortality. Ten patients had cryoglobulinemia without an identified comorbidity. Thirty-three patients had viral hepatitis alone, 6 had a lymphoproliferative disorder alone, and 5 had a rheumatologic disease alone. Ten patients had a combination of disorders, such that hepatitis C was identified in a total of 40 patients, lymphoproliferative disorders in 16, and rheumatologic disease in 8. Twenty-two different treatments were administered. Corticosteroids were the most common treatment, followed by interferon with or without ribavirin. Type II cryoglobulinemia is a nonfatal disease most frequently associated with hepatitis C. Treatment is generally directed at the underlying condition. Not all patients require treatment, and many can be followed and treated symptomatically.

Mixed cryoglobulinemia is associated with increased risk for death, or neoplasia in HIV-1 infection.

BACKGROUND: Cryoglobulinemia has been reported in several chronic infectious and autoimmune diseases, and in patients with HIV-1 infection. Cryoglobulinemia associated with hepatitis C virus infection is considered a risk factor for the development of neoplasia, especially B-cell non-Hodgkin lymphoma. This study was undertaken to investigate whether the presence of circulating cryoglobulins is associated with survival or development of neoplastic disease in HIV-1 infection. DESIGN: We evaluated 87 unselected consecutive HIV-1 infected patients for the presence of cryoglobulinemia and they were prospectively followed up for a median of 34 months, with clinic visits at 4-month intervals. None of the patients had neoplasia at study entry. Time-to-event analysis for death, neoplasm and B-cell lymphoproliferative disorder were performed with Cox proportional hazards models. RESULTS: Mixed cryoglobulinemia (types II and III) was detected in 24 (28%) of the 87 patients. During the follow up, 12 patients died and 8 developed neoplastic disease. Multivariate analysis showed that circulating cryoglobulins were an independent predictor of death [relative risk (RR), 4.97; 95% confidence intervals (CI), 1.26-19.63] and development of neoplasia (RR, 5.18; 95% CI, 1.23-21.83). In addition, cryoglobulinemia reached borderline significance as a predictor of lymphoproliferative disorder of B-cell origin (P = 0.08; RR, 4.53; 95% CI, 0.83-24.75). CONCLUSIONS: Our results suggest that cryoglobulinemia is associated with an increased risk for death, neoplasia or development of lymphoproliferative disorder of B-cell origin, in HIV-1 infected patients.

[Cryoglobulinemia in Sjögren's syndrome]. / Krioglobulinemiia pri bolezni Shegrena.

As many as 130 patients with Sjögren's disease (SD) were examined for blood cryoglobulins during 1977-1982. Cryoglobulinemia was discovered in 25 (19.2%) patients with SD. The clinical manifestations such as severe xerostomia, appreciable increase of the parotid salivary glands, hepatosplenomegaly, purpura, polyneuropathy, lesions of the lungs and kidneys were mostly detectable in SD patients with cryoglobulinemia. Ten cryoprecipitates of SD patients with cryoglobulinemia showed the monoclonal immunoglobulins IgMk-9 and IgA-1. All the patients had high titers of antinuclear antibodies and 90% manifested antinuclear Ro/La antibodies. Over the 5-year period. SD patients with cryoglobulinemia manifested the growth of hepatosplenomegaly, ulcerous-necrotic vasculitis, polyneuropathy, polyneuritis, cerebral vasculitis, lesions of the lungs and kidneys. The development of the grave systemic manifestations of the disease was attended by a decrease of immunological activity and the rise of inflammatory activity. The 5-year survival of SD patients with cryoglobulinemia was 64% against 98% in SD patients without cryoglobulinemia (p less than 0.001).