Understanding the Cryoglobulinemias.

PURPOSE OF THE REVIEW: Cryoglobulins are immunoglobulins with the ability to precipitate at temperatures <37 °C. They are related to hematological disorders, infections [especially hepatitis C virus (HCV)], and autoimmune diseases. In this article, the state of the art on Cryoglobulinemic Vasculitis (CV), in a helpful and schematic way, with a special focus on HCV related Mixed Cryoglobulinemia treatment are reviewed. RECENT FINDINGS: Direct - acting antivirals (DAA) against HCV have emerged as an important key in HCV treatment to related Cryoglobulinemic Vasculitis, and should be kept in mind as the initial treatment in non-severe manifestations. On the other hand, a recent consensus panel has published their recommendations for treatment in severe and life threatening manifestations of Mixed Cryoglobulinemias. HCV-Cryoglobulinemic vasculitis is the most frequent form of CV. There are new treatment options in HCV-CV with DAA, with an important number of patients achieving complete response and sustained virologic response (SVR). In cases of severe forms of CV, treatment with Rituximab and PLEX are options. The lack of data on maintenance therapy could impulse future studies in this setting.

Successful renal transplantation to a recipient with type II cryoglobulinemia: a case report.

BACKGROUND: Recurrence of glomerulonephritis is an important risk factor for renal graft dysfunction. Cryoglobulinemia is known as a relatively rare cause of renal failure, and doctors are usually hesitant to perform transplantation on a recipient with cryoglobulinemia because of the risk for graft loss. We present a case of renal transplantation on a patient with organ manifestations of type II cryoglobulinemia. CASE PRESENTATION: At the age of 44 years, the patient developed acute kidney injury and purpura on the lower extremities with type II cryoglobulinemia after interferon therapy for hepatitis C virus. Cryoglobulinemic glomerulonephritis was suspected; however, despite immunosuppressive therapy combined with plasmapheresis, she eventually needed hemodialysis treatment. She was referred to us at the age of 49 years for renal transplantation. Cryocrit was 14% and the organ manifestations persisted, including the lower extremity purpura and neurologic symptoms. After monitoring and confirming sufficient suppression of cryoglobulin concentration by immunosuppressive treatment with prednisolone, cyclophosphamide, and rituximab combined with plasmapheresis, the operation was performed. After transplantation, the cryoglobulin concentration was continuously monitored, and plasmapheresis and rituximab infusion were performed as appropriate. Her graft function has remained stable for 2 years and 6 months. CONCLUSION: Our case suggested that a patient with cryoglobulinemia and persistent organ manifestations can receive a renal graft if the cryoglobulin concentration is sufficiently controlled by pretransplant treatment.

Successful Antifungal Combination Therapy and Surgical Approach for Aspergillus fumigatus Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports.

In immunocompromised patients, Aspergillus infections are important causes of morbidity and mortality. We describe a patient with cryoglobulinemic vasculitis who developed disseminated invasive aspergillosis with thyrotoxicosis caused by Aspergillus fumigatus. The diagnosis was based upon radiological, microbiological and pathological findings. The patient was treated successfully with voriconazole and caspofungin treatment followed by total thyroidectomy. We provide an overview of published reports on Aspergillus thyroiditis with an emphasis on therapeutic approaches.

[Cryoglobulinemic vasculitis]. / Kryoglobulinämische Vaskulitiden.

Cryoglobulinemic vasculitis is a disease of the small arteries and affects the skin, joints, peripheral nerves, kidneys and other organs. Even small amounts of cryoglobulins can lead to severe impairment for the patient but the detection of such low amounts of cryoglobulins can be difficult. The causes of cryoglobulinemic vasculitis include monoclonal hematological diseases, autoimmune diseases and chronic infections. Therapy involves treatment of the underlying disease and glucocorticoids, rituximab and plasmapheresis depending on the severity of the vasculitis. Recognition of typical clinical symptoms is essential in order to initiate appropriate laboratory diagnostic procedures. Sometimes many investigations are necessary. In the absence of clinical trials treatment recommendations can often only be derived from registry data.

[Successful treatment with rituximab for type III cryoglobulinemia].

A 71-year-old man with rheumatoid arthritis was referred to our hospital with complaints of face and leg edema and was admitted for management of acute renal failure. Type III cryoglobulinemia was diagnosed based on histopathological findings of a kidney biopsy which revealed cryoglobulinemic nephropathy. Immunofixation showed no serum M-proteins. Steroid pulse and apheresis were initiated but the proteinuria did not improve. Rituximab was administered four times weekly as a second-line treatment, eliminating the proteinuria, after which the steroid dose was gradually tapered until discontinuation. No recurrence of proteinuria was observed more than 1 year after termination of rituximab therapy. This suggests that rituximab exerts a long-term effect. Although this patient developed candidiasis during rituximab therapy, the therapy could be continued as the antifungal agents prevented exacerbation of the infection. Rituximab can be used for the treatment of steroid-refractory cryoglobulinemia. However, clinicians should remain aware of possible infections associated with immunosuppression.

Cryoglobulinemic vasculitis in systemic sclerosis successfully treated with mycophenolate mofetil.

Cryoglobulinemic vasculitis is extremely rare in patients with systemic sclerosis (SSc). So far, only two cases of cryoglobulinemic vasculitis in SSc were described in the literature. This report is about a patient with SSc and secondary Sjogren's syndrome, who developed typical clinical features of small-vessel vasculitis, including arthritis, purpura, microhaematuria, gangrene of fingers, and toes and myocardial ischemia, in the presence of mixed cryoglobulinemia, ANA, rheumatoid factor, and anti-SSA/Ro antibodies. Symptoms and signs of vasculitis worsened despite initial treatment with corticosteroids and cyclophosphamide, but improved significantly when mycophenolate mofetil was used instead cyclophosphamide.

Antiviral therapy for HCV-associated cryoglobulinemic glomerulonephritis: case report and review of the literature.

We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis--preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I(2) = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I(2) = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population.

Treatment of mixed cryoglobulinemia: a rheumatology perspective.

The treatment of the cryoglobulinemic syndrome or vasculitis (CV) must be targeted to the individual patient, and requires clinical expertise and knowledge of the disease biology. In general, the treatment is suggested by the clinical picture, but biologic issues should also be considered. Both immunosuppressive and antiviral approaches deserve equal attention based on the wide clinical spectrum and on disease biology, where the viral trigger and the downstream autoimmune response may play a different role in different disease stages. The severity of the disease, previous history and therapies administered, comorbidities and other individual factors should be analysed in the single case. Acute and life-threatening conditions usually require high dose steroids, plasmapheresis and/or cyclophosphamide. Rituximab often represents the best option for severe CV. Antiviral therapy is a cornerstone for the management of CV in hepatitis-related cases, and has the strongest biologic rationale, in general, in this disease and should be always considered in stabilised patients. A multispecialistic approach is needed to better define treatment strategies in different subsets of patients.

Vasculitis in a patient with mixed cryoglobulinemia treated with rituximab biosimilar CT-P10: a case report.

Rituximab represents a milestone in the treatment of mixed cryoglobulinemic vasculitis. Despite usually well-tolerated, rituximab may induce different types of adverse drug reactions, including exacerbation of vasculitis. Rituximab biosimilar have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of rituximab biosimilar in the treatment of mixed cryoglobulinemic vasculitis. We describe a severe skin vasculitis reactivation in a patient affected by rheumatoid arthritis and mixed cryoglobulinemic vasculitis treated with rituximab biosimilar. After 7 days from the first infusion, a severe purpuric rash at lower limbs appeared, that resolved in about 2 weeks with high dose-corticosteroid. Rituximab-induced vasculitis has also been described since 2001, but its pathophysiology is still controversial due to the anecdotical descriptions in literature and the variability of the time between the rituximab infusion and the onset of skin lesions. Up to date, this is the first report describing a vasculitic flare in a patient affected by mixed cryoglobulinemic vasculitis treated with rituximab biosimilar.

Rare cause of bilateral foot gangrene: coexisting essential cryofibrogenaemia and cryoglobulinaemic vasculitis.

Cryofibrinogenaemia is a rare haematological disorder characterised by cold temperature-induced precipitation of plasma proteins causing small-vessel occlusive vascular disorder with a hallmark of skin ulceration. It remains an underdiagnosed entity because of a lack of diagnostic criteria. Cryoglobulinaemia vasculitis is a small-vessel vasculitis involving the skin, the joints, the peripheral nerve system and the kidneys. Its association with cryofibrinogenaemia causes more severe phenotype with poor prognosis. We describe the case of a 59-year-old woman presenting with cold-induced extensive bilateral foot gangrene due to coexisting cryofibrinogenaemia and cryoglobulinaemic vasculitis that required bilateral amputation and rituximab perfusions as maintenance therapy.

[Renal involvement during type 1 cryoglobulinemia]. / Atteinte rénale au cours des cryoglobulinémies de type 1.

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.

Hypertrophic cardiomyopathy secondary to hepatitis C virus-related vasculitis.

: Almost invariably associated with chronic HCV infection, cryoglobulinemic vasculitis is a small-vessel vasculitis commonly affecting the skin, kidneys, and peripheral nervous system. Cardiac involvement, possibly due to cardiac microcirculation involvement, is an utterly rare and severe complication. We describe a case of hypertrophic cardiomyopathy secondary to cryoglobulinemic vasculitis. Evaluation with transthoracic cardiac ultrasound and cardiac MRI evidenced severe left ventricular hypertrophy and diffuse hypokinesia, a marked decrease in left ventricular ejection fraction, and a subtle late enhancement of inferior and lateral left ventricular walls. Upon clinical stabilization, the patient received treatment with anti-CD20 monoclonal antibody rituximab. Clinical and radiological follow-up with cardiac ultrasound and cardiac MRI documented a dramatic and sustained clinical improvement, with marked reduction of left ventricular hypertrophy, resolution of late enhancement, recovery of left ventricular contractility and function.

Hepatitis C virus-related cryoglobulinemia and glomerulonephritis: pathogenesis and therapeutic strategies.

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. MC is a non-neoplastic B cell lymphoproliferative process induced by HCV in an antigen-driven mechanism. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. Glomerulonephritis is predominantly associated with MC, and almost always takes the form of membranoproliferative glomerulonephritis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. The treatment of these virus-related diseases must be individualized on the basis of the severity of clinical symptoms. Antiviral therapy with interferon alpha and ribavirin (the currently recommended treatment of HCV infection) may be successful in patients with mild-to-moderate disease, but sustained responses are uncommon. In case of severe and rapidly progressive disease, although it is capable of suppressing viremia and cryoglobulinemia, antiviral therapy is not fully effective in controlling the inflammatory and self-perpetuating reaction consequent to the deposition of cryoglobulins in the glomeruli and vessel walls. In such cases, a short course of steroids and cytotoxic drugs (with or without plasmapheresis) may be needed to improve the vascular manifestations and decrease the production of cryoglobulins. Once the acute disease flare has been controlled, antiviral therapy may be administered to eradicate HCV, the causative agent of the cryoglobulinemic syndrome. In patients in whom antiviral therapy is ineffective, contraindicated or not tolerated, rituximab, a monoclonal anti-CD20 antibody, may be an alternative to standard immunosuppression.

Successful treatment of HCV-associated cryoglobulinemia with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin: A case report.

Cryoglobulinemia is an important extrahepatic manifestation of chronic hepatitis C virus infection. Current treatments are suboptimal, resulting in relapse or refractoriness in 30-40% of patients. Hereby, we describe the case of a 40-year old man with severe hepatitis C virus-associated cryoglobulinemia, effectively treated with an interferon-free combination regimen. The patient was treated for 12 weeks with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin. Rapid clinical and immunological response, i.e., the resolution of symptoms and disappearance of serum cryoglobulins, ensued as early as 4 weeks after initiating direct acting antiviral therapy. Our reported case directs the attention to the possible consequences and importance of new, effective, interferon-free antiviral treatments in devastating lymphoproliferative and immunological manifestations of chronic hepatitis C virus infection.

A Young Lady with Hypertension - Rare Presentation of a Common Disease.

Hypertension is a common finding in patients with renal impairment but it is frequently difficult to establish if one feature is the cause or the effect of the other. Even rarer is the identification of an underlying cause for hypertension or renal failure in such patients. We present a case of hypertension in a young lady as part of nephritic syndrome due to HCV associated essential mixed cryoglobulinemia. She presented with difficult to control hypertension and deranged renal functions. On detailed evaluation, she was found to have nephritic syndrome as part of essential mixed cryoglobulinemia. She tested positive for HCV RNA and underwent treatment with combination of standard interferon and ribavirin. All her symptoms were relieved with this treatment, HTN subsided and renal function tests returned to normal values. Her HCV RNA was negative at the end of treatment as well as 6 months later; confirming a sustained virological response.

HBV and HCV infection, polyarteritis nodosa and mixed cryoglobulinaemia: a case report.

HCV infection has been associated with a broad spectrum of extrahepatic manifestations. In some of these, such as mixed cryoglobulinaemia (MC), the association is firmly established, whereas in others, such as polyarteritis nodosa (PAN), it is anecdotal; in fact, in this disorder the importance of the association is controversial, since it seems to be related to the frequent coinfection of HBV and HCV. The pathogenesis of MC and PAN is far from clear, but recent developments have added a plethora of information on the mechanisms underlying these disorders. Although both could be induced by a viral infection, the pathophysiological processes underlying the two diseases are different. We describe the occurrence in the same patient of HBV-related PAN and HCV-related MC.

Inflammatory myopathy as the initial presentation of cryoglobulinaemic vasculitis.

Cryoglobulinaemic vasculitis is characterised by immunoglobulin deposition at low temperatures. The most common manifestations are cutaneous involvement, arthralgias, Raynaud's phenomenon, peripheral neuropathy and renal disease. Myopathy is unusual and only a few cases have been reported. Here, we present a 31-year-old woman who developed progressive muscle weakness involving upper and lower extremities, dysphagia, paraesthesias and palpable purpura. Diagnostic studies revealed elevated creatine kinase, diffuse myopathic and sensorimotor axonal neuropathy on electromyography and nerve conduction studies, and inflammatory myopathy on muscle biospsy. Cryoglobulin levels were elevated on two occasions. She responded favourably to cyclophosphamide and high-dose corticosteroids. Cyclophosphamide was continued for 1 year followed by methotrexate. Prednisone was gradually tapered and discontinued 1 year later. She remained in clinical remission after 4 years of follow-up. This case suggests that cryoglobulinaemia should be considered in the differential diagnosis of a patient presenting with inflammatory myopathy.