Vasculitis crioglobulinémica por hiperviscosidad y formación de criogel como debut de mieloma múltiple. Caso clínico / Cryoglobulinemic vasculitis due to hyperviscosity and cryogel formation as the onset of multiple myeloma. Report of one case

Multiple Myeloma (MM) is characterized by a clonal expansion of plasma cells in the bone marrow. These cells typically produce a monoclonal immunoglobulin, and its symptoms arise either from plasma cell infiltration in several organs, or secondary to the presence of a monoclonal protein peak. Symptoms can be summarized by the acronym CRAB (hypercalcemia, renal failure, anemia and bone lesions). Sometimes, in the setting of a protein secreting monoclonal gammopathy, formation of cryoglobulins develops. Cryoglobulins are plasma proteins that precipitate at low temperatures, forming a cold - induced precipitate at small vessels, causing a wide range of clinical manifestations. We report a female consulting for ulcers lasting 2 months in the left foot associated with purpuric lesions in both lower limbs. Protein electrophoresis showed a monoclonal peak in the gamma region. Bone marrow aspirate showed 27% of plasma cells with kappa chain restriction by cytometry. The presence of cryoglobulins was confirmed. The patient was treated with dexamethasone and bortezomib, with a progressive healing of lower limb lesions and disappearance of cryoglobulins. She was discharged in good conditions.

Crioglobulinemia: una entidad heterogénea / Cryoglobulinemia: a heterogeneous entity

La crioglobulinemia se define como la presencia de inmunoglobulinas en el suero que se precipitan reversiblemente a bajas temperaturas. Se la clasifica en tipos I, II y III, según las características de las inmunoglobulinas. La primera suele asociarse a enfermedades linfoprolife-rativas y las de tipos II y III, denominadas crioglobulinemias mixtas, a infección por el virus de la hepatitis C, seguida de las enfermedades autoinmunes. Las manifestaciones clínicas se relacionan con obstrucción intravascular en el caso de la crioglobulinemia de tipo I, mientras que las de tipos II y III se manifiestan con vasculitis por depósito de inmunocomplejos. El compromiso cutáneo es el hallazgo principal, seguido del articular, el neurológico y el renal. Se presentan 3 casos de crioglobulinemia que, por los datos de laboratorio y las enfermedades asociadas, difieren de la descripción clásica publicada en los textos.

Cryoglobulinemia is defined as the presence of immunoglobulins in serum that reversibly precipitate at low temperatures. It is classified into types I, II and III on the basis of immunoglobulin characteristics. Type I is associated with lymphoproliferative disorders, type II and III known as mixed cryoglobulinemia, are associated with hepatitis C virus infection and autoimmune diseases. Clinical manifestations are related with occlusion of small and medium blood vessels common in type I cryoglobulinemia while immune-mediated vasculitis is frequent in mixed cryoglobulinemia. Cutaneous damage is the main manifestation, followed by joint, peripheral nerves and renal involvement. We present three cases of cryoglobulinemia that differ from the literature due to their laboratory findings and associated diseases.

Vasculitis crioglobulinémica con compromiso renal y síndrome de Sjögren / Cryoglobulinemic vasculitis with renal involment and Sjögren's syndrome

La vasculitis crioglobulinémica es una vasculitis de vasos pequeños que se da en presencia de crioglobulinas séricas. Las crioglobulinemias mixtas son las más frecuentes y se asocian a infecciones crónicas, típicamente al virus de la hepatitis C, así como a enfermedades linfoproliferativas y autoinmunes, más a menudo al síndrome de Sjögren. Las manifestaciones clínicas incluyen púrpura de los miembros inferiores, neuropatía periférica, artralgias y glomerulonefritis. La presencia de vasculitis crioglobulinémica en el contexto de un síndrome de Sjögren es marcadora de peor pronóstico. Presentamos el caso de una paciente con vasculitis crioglobulinémica con compromiso cutáneo y renal, que condujo al diagnóstico de un síndrome de Sjögren primario. (AU)

Cryoglobulinemic vasculitis is a small-sized vasculitis that occurs in the context of serum cryoglobulins. Mixed cryoglobulinemias are the most frequent and are associated with chronic infections, typically hepatitis C and autoimmune diseases, most commonly Sjögren's syndrome. Clinical manifestations include purpura of lower limbs, peripheral neuropathy, arthralgias and glomerulonephritis. The presence of cryoglobulinemic vasculitis in the context of Sjögren's syndrome is a marker of poor prognosis. We present the case of a patient with cryoglobulinemic vasculitis associated to cutaneous and renal involvement that led us to the diagnosis of primary Sjögren's syndrome. (AU)

Correlação entre a síndrome antifosfolipídica e a crioglobulinemia: série de quatro casos e revisão da literatura / The correlation between antiphospholipid syndrome and cryoglobulinemia: case series of 4 patients and review of the literature

Resumo Introdução: A crioglobulinemia é uma vasculite de pequenos vasos mediada por imunocomplexos que normalmente envolvem a pele, os rins e os nervos periféricos. A síndrome antifosfolipídica (SAF) é um transtorno da hipercoagulabilidade autoimune que provoca trombose dos vasos sanguíneos. Pode se manifestar como um distúrbio microtrombótico que afeta múltiplos órgãos, denominado SAF catastrófica. Objetivo: Esta série de casos objetiva descrever os desafios de diagnóstico e tratamento que surgem quando esses dois graves transtornos estão presentes simultaneamente no mesmo paciente. Métodos: Foram descritos quatro pacientes internados em nosso hospital em decorrência de danos graves a múltiplos órgãos mediados pela vasculite crioglobulinêmica com SAF concomitante. Resultados: As manifestações clínicas incluíram úlceras de perna, livedo reticular, insuficiência renal e neuropatia periférica. As etiologias sugeridas para a combinação de síndromes foram a hepatite C, o lúpus eritematoso sistêmico e a doença mieloproliferativa retal associada a linfoma de zona marginal tipo células B. Todos os pacientes foram tratados com anticoagulantes, altas doses de corticosteroides, rituximabe, gamaglobulinas intravenosas e troca de plasma. Conclusão: A rara associação entre a SAF grave ou catastrófica e a crioglobulinemia deve ser considerada por médicos que atendem pacientes com isquemia ou necrose de múltiplos órgãos.

Abstract Background: Cryoglobulinemia is an immune-complex-mediated small vessel vasculitis that classically involves the skin, kidneys and peripheral nerves. Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder which causes blood vessel thrombosis. It can present as a multi-organ microthrombotic disorder which is called catastrophic APS. Objective: In this case series we aim to describe the diagnostic and management challenges that arise when these two severe disorders simultaneously present in the same patient. Methods: We describe four patients who were admitted to our hospital due to multi-organ life threatening damage mediated by cryoglobulinemic vasculitis with concurrent APS. Results: Clinical manifestations included leg ulcers, livedo reticularis, renal failure, and peripheral neuropathy. Suggested etiologies for the combined syndromes were hepatitis C, systemic lupus erythematosus and myeloproliferative disease rectal maltoma. All of our patients were treated with anticoagulation, high-dose corticosteroids, rituximab, intravenous gammaglobulins and plasma exchange. Conclusion The rare association of severe or catastrophic APS with cryoglobulinemia in patients should be considered by physicians who treat patients with multi-organ ischemia or necrosis.

Cutaneous lesions and finger clubbing uncovering hypocomplementemic urticarial vasculitis and hepatitis C with mixed cryoglobulinemia / Lesoes cutaneas e baqueteamento digital reveladores de vasculite urticariforme hipocomplementemica e hepatite C com crioglobulinemia mista

Urticarial vasculitis is a rare clinicopathologic entity characterized by urticarial lesions that persist for more than 24 hours and histologic features of leukocytoclastic vasculitis. Patients can be divided into normocomplementemic or hypocomplementemic. The authors report the case of a healthy 49-year-old woman with a 1-year history of highly pruritic generalized cutaneous lesions and finger clubbing. Laboratory tests together with histopathologic examination allowed the diagnosis of hypocomplementemic urticarial vasculitis, chronic hepatitis C and type II mixed cryoglobulinemia. The patient started symptomatic treatment and was referred to a gastroenterologist for management of the hepatitis C, with progressive improvement of the skin condition. The development of hypocomplementemic urticarial vasculitis in the context of chronic hepatitis C is exceedingly rare and possible pathogenic mechanisms are discussed.

A vasculite urticariforme é uma entidade clinico-patológica rara caracterizada por lesões urticariformes com duração superior a 24 horas e uma vasculite leucocitoclásica na histologia. É dividida em normo e hipocomplementêmica. Os autores relatam o caso de uma mulher saudável de 49 anos, com lesões cutâneas intensamente pruriginosas e baqueteamento digital com 1 ano de evolução. O estudo efectuado permitiu efectuar os diagnósticos de vasculite urticariforme hipocomplementêmica, hepatite C crônica e crioglobulinêmia mista tipo II. A doente iniciou tratamento sintomático e foi referenciada para a Gastroenterologia para orientação da hepatite, com melhoria progressiva das lesões cutâneas. O desenvolvimento de vasculite urticariforme hipocomplementêmica no contexto de hepatite C crónica é raro e os possíveis mecanismos patogênicos são discutidos.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8 percent and cryoglobulinemia was demonstrated in 36.9 percent patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

Chronic Hepatitis C Virus [HCV]-associated Cryoglobulinemia and its possible impact on the skin in Egyptian Patients

Chronic hepatitis C virus [HCV] infection may have extremely variable clinical consequences and is more than just a liver disease; it has been associated with numerous extra-hepatic manifestations [EHM]. According to various international studies Mixed Cryoglobulinemia [MC] was found to be the most common EHM, however its local prevalence in Egyptian HCV patients was not clearly studied. The aim of our study was to investigate the frequency of cryoglobulinaemia in sera of chronic HCV patients and their association with clinical symptoms especially, vasculitis. One hundred patients with chronic HCV infection attending the outpatient clinic of the National Hepatology and Tropical Medicine Research Institute were interviewed. Patients with decompensated liver disease, on interferon therapy, having end-stage renal disease or coexisting viral infection like hepatitis B surface antigen positive patients were all excluded from the research. All patients were subjected to general and dermatological examination for liver affection signs; Cryoglobulinemia related clinical manifestations and/or associated dermatoses. Cryoglobulins, CBC, LFT. AFP, ALP, KFT, ANA and RF were assessed. Overall 15% of 100 patients were positive for presence of cryoglobulins in their sera. We found a relatively high incidence of clinical symptoms commonly accompanying cryoglobulinemic cases in the form of Purpura, Arthralgia, Generalized weakness, Peripheral Neuropathy and Reynaud's phenomenon with prevalence of 26.67%, 46.67%, 53.33%, 40% and 6.67% respectively. Our data also demonstrated that 46.67% [7] of our 15 cryopositive patients had concomitant skin manifestations in the form of Pruritus 40% [6] and Vasculitis 26.67% [4] [P=0.004] which was significant in comparison with prevalence of vasculitis in all patients 4.7% [4 patients]. Generalized weakness and fatigue, which is the most prevalent symptoms related to Chronic Hepatitis C [CHC] patients whether positive or negative for Cryoglobulinemia, were present in 52% of all patients. Other associated dermatological diseases in all patients were Lichen Planus, Psoraiasis, Urticaria, Necrolytic Acral Erythema [NAE] and Vitiligo with prevalence of [1%], [1%], [5%], [1%] and [2%] respectively. The most common dermatological disease was pruritus 36% [36] of all patients and 40% [6] in cryopositive patients. Regarding liver condition there was no significant correlation between presence of cryoglobulins and biochemical parameters. However, we found a significant correlation between presence of Cryoglobulinemia and presence of ANA in sera of HCV patients with incidence of 40% in comparison to 4.7% in cryonegative patients respectively while there is no significant correlation as regard RF [40% in cryopositive and 55.3% in cryonegative patients]. Among all patients 10% [10] were ANA positive and 53% [53] were RF positive. We also found that 26.67% [4] of our cryopositive patients were associated with vasculitic skin lesions. For each patient a skin biopsy was taken from the lesional area and tissue [Insitu] PCR was done to detect the presence of HCV RNA within it. Biopsy results revealed that 3 biopsies were positive and 1 biopsy was negative for HCV RNA by tissue PCR. The prevalence of cryoglobulinaemia in Egypt may be lower than other areas. In HCV patient complaining from generalized weakness, arthralgia, purpuric skin lesions, peripheral neuropathy, Reynaud's phenomenon or renal troubles, serum cryoglobulins presence should be searched for

Cryoglobulinemia presenting as acute polyneuropathy.

A 48 years male presented with acute axonal neuropathy and palpable purpura over bilateral lower limb, RA factor, and cryoglobulins were present in the serum. Nerve biopsy revealed myelinated fibre loss, axonal degeneration and necrotizing vasculitis of epineural vessels.

Moya Moya disease : an unusual clinical presentation.

Moya Moya disease is a rare cause of stroke in adults, and is a rarity secondary to hepatitis C virus infection (HCV) and cryoglobulinemia (CG). We report such a rare association in a young patient who presented with intracerebral hemorrhage.

Frequency and role of hepatitis-C virus and type II cryoglobulinemia in membranoproliferative glomerulonephritis.

BACKGROUND: Many studies have claimed a major role of chronic hepatitis-C virus (HCV) infection in immune-mediated diseases such as membranoproliferative glomerulonephritis (MPGN). Chronic HCV infection is also known to produce essential mixed cryoglobulinemia (EMC), which in turn may manifest as vasculitis and cryoglobulinemic MPGN. OBJECTIVE: The aim of the study therefore, was to determine frequency of association and pathogenetic role of HCV infection as well as that of EMC in MPGN patients. METHODS: Fifty-three adult patients of MPGN were studied for HCV, HBsAg, EMC, C3, anti-nuclear antibody (ANA), rheumatoid factor serologically. Histopathology, immunofluorescence (IF) were conducted in all patients and electron microscopy (EM) in those who were found HCV positive. Simultaneously 37 follow-up patients of HCV associated chronic hepatitis were investigated for EMC, renal functions and urinalysis done for evidence of glomerulonephritis (GN). RESULTS: Thirteen percent MPGN patients were HCV positive, however, no viral particle could be seen in electron microscopy in glomeruli of these patients. There was no serologic evidence of HCV induced immune complex GN. None of the MPGN patients showed cryoglobulinaemia. Similarly none from HCV associated chronic hepatitis group had EMC nor showed evidences of glumerulonephritis. CONCLUSION: Thirteen percent of adult MPGN patients in north India were seropositive for HCV, indicating significant association. However, clear evidence in favour of its pathogenetic role was lacking in our study. Secondly, this study reveals that MPGN is non-cryoglobulinemic and HCV is not a major cause in our population compared to what is reported from other countries. These observations need confirmation by a larger study.

Type 2 cryoglobulinemia treated with plasmapheresis associated with IgA nephropathy.

Cryoglobulinemia is caused by antibodies which precipitate in blood on exposure to cold, and redissolve on warming. The authors present a child with essential, Type 2 cryoglobulinaemia, successfully treated with plasmapheresis, who developed glomerulonephritis due to IgA nephropathy. Conservative treatment resulted in spontaneous improvement with no deterioration in renal function.

Manifestaçöes estra-hepáticas do virus da hepatite C - Parte 1 e 2 / Extrahepatic manifestations of hepatitis C vurus

Após a identificação do vírus da hepatite C (HCV), em 1989, diversos estudos vêm demonstrando a "relação" deste agente viral com desordens imunológicas e manifestações, tidas como extra-hepáticas, tornando-se a mais relevante a crioglobulinemia mista. O presente trabalho visa rever estas manifestações do HCV, analisando os dados publicados, citando exemplos pertinentes e resultados de atividades desenvolvidas no ambulatório de Hepatites da Disciplina de Gastroenterologia da Escola Paulista de Medicina (EPM) - UNIFESP. Serão discutidas amplamente as manifestações bem conhecidas e melhor definidas, tais como a indução de auto-anticorpos (antinúcleo e antimúsculo liso), a crioglubulinemia mista (tipos II e III), o linfoma não-Hodgkin (células B), a glomerulonefrite (membranoproliferativa), a porfiria cutânea tarda e o líquen plano. As manifestações menos freqüentes ou mais polêmicas, tidas ainda com supostas, entre as quais se incluem o diabetes mellitus (tipo 2), a tireoidite (Hashimoto), a sialoadenite a fibrose pulmonar, entre outras, também serão abordadas. Em virtude da grande quantidade de artigos levantados, como conseqüência provavelmente da controvérsia de seus resultados, esta revisão, para fins de publicação, será dividida em duas partes.

Relación entre algunos agentes microbianos y ciertas dermatosis, incluidas algunas colagenopatías / The relation between some microbial agents and some dermatoses, including collagen diseases

Basándonos en una amplia revisión bibliográfica, consideramos que la mayoría, sino todas las enfermedades del tejido conectivo tienen agentes etiológicos disparadores de fenómenos inmunes. La identificación de éstos permitirá ajustar las medidas terapéuticas y profilácticas e impedir, cuando sea posible, el contagio y/o las consecuencias alejadas de estas infecciones

Crioglobulinemia mista policlonal associada a hepatite crônica persistente / Polyclonal mixed cryoglobulinemia associated with persistent chronic hepatitis

Relata-se caso de paciente portadora de hepatite crônica persistente, que após cinco meses do quadro da hepatite desenvolveu crioglobulinemia mista policlonal, na forma de síndrome de Meltzer. Concluiu-se que muitos casos de "crioglobulinemia mista essencial", na verdade, säo secundárias a doenças hepáticas preexistentes