Cryoglobulinemic Vasculitis Research Articles

Cutaneous symptoms of various vasculitides

The skin is one of the organs most frequently involved in vasculitides. Cutaneous vasculitis may present (1) part of a systemic vasculitis (e.g., IgA vasculitis), (2) a skin-restricted or skin-dominant variant of the corresponding systemic vasculitis without clinically apparent visceral involvement (e.g., cutaneous IgA vasculitis), or (3) a vasculitis occurring exclusively in the skin (e.g., erythema elevatun diutinum). The clinical symptoms of vasculitides are markedly determined by the size of the predominantly affected blood vessels. Systemic polyarteritis nodosa is regarded as a medium vessel vasculitis and is associated with multiple skin symptoms: (1) vasculitis of digital arteries with ensuing digital infarction, (2) livedo racemosa and subcutaneous nodules, and (3) in some patients even purpura and hemorrhagic macules due to additional small vessel vasculitis. In contrast, in its skin-restricted entity (i.e., cutaneous polyarteritis nodosa), the predominant symptoms are subcutaneous nodules surrounded by livedo racemosa, often on the lower legs. Among small-vessel vasculitides palpable purpura with predilection for the legs is a nearly pathognomonic feature of immune complex vasculitis. Variations in clinical symptoms indicate additional pathophysiological mechanisms or different vascultides: (1) ANCA-associated vasculitides often also entail nodules or sometimes livedo, (2) cryoglobulinemic vasculitis additionally may present with necrosis at cold exposed areas and involvement of vessels of various size, (3) small vessel vasculitis associated with systemic lupus erythematosus or rheumatoid arthritis shows predilection for additional sites (e.g., nailfolds) and also involvement of vessels beyond postcapillary venules, (4) recurrent macular vasculitis in hypergammaglobulinemia also occurs on dependent parts, but shows numerous small hemorrhagic macules instead of palpable purpura, (5) erythema elevatum diutinum begins with brightly red to violaceous plaques at extensor sites, followed by fibrotic nodules. Consequently, cutaneous symptoms provide pivotal clues for further diagnosis and ensuing management of vasculitides.

Inhibitors of T cell Activation in the Treatment of Sjögren’s Syndrome

Given the hypothesis of an initial exogenous agent attacking/infecting ocular and oral glands in Sjogren’s syndrome, we propose a primarily T cell-guided reaction with ensuing recruitment of B cells and finally resulting in auto-antibody production. From an immunological standpoint, the first clinical signs do represent established disease. Nevertheless, targeted therapy should start as early as possible, and they may target B as well as T cells. A primarily local therapy by CsA eye-drops is worthwhile applying in case of strictly ocular involvement only. Otherwise, a short cycle of leflunomide might prove efficient. If not, based on the most possibly underlying pathophysiology of T and B cell interaction and our own experience, a 6-month treatment with abatacept during the early phase of disease can reach the target cells and lead to clinical improvement. In the later stages, especially in case of cryoglobulinemic vasculitis or pulmonary involvement, a B cell depletional therapy may be highly effective. Based on the available data, it would be interesting to initiate a study targeting both cellular arms of the adaptive immune system, i.e., B cell depletion with, e.g., rituximab and T cell inhibition using abatacept. Trials with alefacept have shown T cell-targeted, positive effects on exocrine gland function in a primary SS (pSS)-associated non-obese diabetic (NOD) mouse model. Whether this molecular intervention is beneficial in human disease will have to be shown.

The role of rituximab in the therapy of secondary glomerulonephritis

Rituximab (RTX), a B-lymphocytes depleting monoclonal antibody, deeply changed the therapeutic landscape of secondary glomerulonephritis in the past decade.RTX has proved to be as effective as cyclophosphamide in inducing remission in ANCA-associated vasculitis and better than azathioprine as maintenance therapy in three different RCT. Treatment's duration and modality, however, remain debated.RTX has been widely used in resistant or relapsing proliferative lupus nephritis (LN), with positive results reported by retrospective studies; however, when employed as an “add-on” induction therapy in a RCT, it did not show a definite additive effect to standard therapy with mycophenolate mofetil and steroid in moderate forms of LN. In prospect, it remains a promising tool both as second-line therapy for resistant forms and as a “steroid-sparing” agent to strengthen induction and to allow reduced or minimal maintenance therapy.RTX is effective in the treatment of HCV-related cryoglobulinemic vasculitis, including ...

HCV Treatments and Their Integration Into Rheumatology.

Hepatitis C virus (HCV) has been associated with distinct rheumatic syndromes including arthritis, sialadenitis, and cryoglobulinemic vasculitis (CV). The therapy of these HCV-associated syndromes includes antiviral therapy with or without the addition of immunosuppressives while clinical response is mainly seen in patients who clear the virus after antiviral therapy. Despite significant therapeutic advances, existing antiviral therapies with interferon-a (IFNa)-based schemes achieve viral eradication only in approximately half the patients. Recently, oral antivirals that target specific HCV proteins referred as direct acting antivirals (DAAs) have been developed and approved. Short-term (12-24 weeks) combination schemes with or without IFN ("IFN-free" regimens) including these inhibitors clear the virus in more than 90 % of treated patients. Here, we review current therapeutic options in HCV-associated rheumatic syndromes and the potential role of the newly available antivirals in an integrated therapeutic approach.

Extrahepatic manifestations of chronic hepatitis C virus infection.

During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.

Assessment of free light chains in HCV-positive patients with mixed cryoglobulinaemia vasculitis undergoing rituximab treatment.

Mixed cryoglobulinaemia (MC) is an HCV-related lymphoproliferative disorder characterized by the presence of circulating immune complexes called cryoglobulins. Treatment with anti-CD20 monoclonal antibody rituximab is proved to be very useful, especially in patients ineligible to interferon-based antiviral therapy. Recently, free light chain (FLC) κ/λ ratio and FLC patterns were associated with MC. The aim of this study was to evaluate changes in FLC-κ, FCL-λ, FLC ratio following rituximab treatment in patients with HCV-related MC and to correlate FLC-κ, FCL-λ and FLC ratio values with therapy response. We retrospectively enrolled 46 patients with HCV infection (26 females, 20 males), including 10 patients without signs/symptoms of MC-related vasculitis, 36 with MC vasculitis. Clinical and biological data were recorded at baseline and 6months after RTX treatment. Nephelometric measurement of serum FLCs was taken. The mean serum FLC-κ level and FLC ratio were significantly higher in patients with MC, compared to HCV patients without MC and to blood donors. An abnormal FLC ratio at baseline correlated with the presence of cryoglobulins, C4 consumption, higher RF level and higher vasculitis rate. To evaluate the predictive value of FLCs, patients with MC were divided into two groups according to RTX therapy outcome (responders and no/partial responders). Abnormal baseline FLC ratio was significantly associated with no/partial response. RTX treatment in HCV-related MC induces a reduction in FLC-κ and RF levels. Moreover, pretreatment FLC ratio, which can be easily assessed by a routine test, may be useful to predict response to this expensive treatment for patients with HCV-related MC ineligible to IFN-based therapy.

Vasculitis related to viral and other microbial agents.

Vasculitis due to infection may occur as a consequence of the inflammation of vessel walls due to direct or contiguous infection, type II or immune complex-mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation triggered by bacterial toxin and/or superantigen production. As immunosuppressive therapy administered in the absence of antimicrobial therapy may increase morbidity and fail to effect the resolution of infection-associated vascular inflammation, it is important to consider infectious entities as potential inciting factors in vasculitis syndromes. The causality between infection and vasculitis has been established in hepatitis B-associated polyarteritis nodosa (HBV-PAN) and hepatitis C-associated (cryoglobulinemic) vasculitis (HCV-CV). The review summarizes the recent literature on the pathophysiological mechanisms and the approaches to the management of HBV-PAN and HCV-CV. Roles of other viral and microbial infections, which either manifest as vasculitic syndromes or are implicated in the pathogenesis of primary vasculitides, are also discussed.

Cryofibrinogenemia: A Marker of Severity of Cryoglobulinemic Vasculitis

BackgroundCryofibrinogenemia is frequently associated with cryoglobulinemia. The aim of this study was to determine the characteristics associated with the presence of cryofibrinogenemia in patients with cryoglobulinemic vasculitis. MethodsThis was a single-center retrospective study that included patients with cryoglobulinemic vasculitis who were tested for cryofibrinogen at a tertiary referral center between January 1, 2011 and December 31, 2012. Twenty-nine patients fulfilled the CryoVas (cryoglobulinemic vasculitis) Survey criteria for cryoglobulinemic vasculitis. Eighteen patients had a detectable cryofibrinogen (CF-positive) and 11 had no detectable cryofibrinogen (CF-negative). Median cryoglobulin levels were 89 ± 129 mg/L in the CF-positive group and 68 ± 82 mg/L in the CF-negative group (P = .32). Median cryofibrinogen level was 70 ± 174 mg/L. Clinical manifestations were similar in both groups. Cancers and hematological disorders were more frequent among CF-positive patients (39% vs 0%, P = .026). Levels of alpha-1 and alpha-2 globulinemia were higher in the CF-positive group. Cryofibrinogenemia ≥ 100 mg/L was associated with cryoglobulinemic vasculitis (odds ratio [OR] 2.86; 95% confidence interval [CI], 1.06-7.73) in cryoglobulinemic patients. Presence of cryofibrinogenemia was associated with use of corticosteroids, immunosuppressants, or plasmapheresis in cryoglobulinemic vasculitis patients (OR 22.7; 95% CI, 2.02-256.44). ConclusionsOur results strongly suggest that presence of cryofibrinogenemia is associated with a more severe phenotype among patients with cryoglobulinemic vasculitis.

Extrahepatic manifestations in chronic hepatitis C virus carriers.

Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.

Thymic stromal lymphopoietin in hepatitis C virus-related cryoglobulinemic vasculitis: gene expression level and protein distribution.

IntroductionHepatitis C virus (HCV) infection can be detected in virtually all patients with cryoglobulinemic vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV.MethodsSerum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures.ResultsSerum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20+ B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes.ConclusionOverall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.

Sjögren Syndrome and Cryoglobulinemic Glomerulonephritis

We report the case of a 53-year-old woman with Sjögren syndrome and cryoglobulinemia. The patient presented with nephrotic syndrome, hematuria, and reduced estimated glomerular filtration rate. The kidney biopsy revealed diffuse endocapillary proliferation and leukocyte exudation with focal intraluminal hyaline thrombi, prominent tubulointerstitial inflammation, and vasculitis. Diffuse granular mesangial and segmental to global capillary wall staining was observed on immunofluorescence with antisera to C3 and immunoglobulin M (IgM), with less intense staining indicative of IgG and κ and λ light chains. A biopsy diagnosis of Sjögren syndrome-related cryoglobulinemic membranoproliferative glomerulonephritis and vasculitis was rendered. Subsequent investigations revealed the presence of circulating type II cryoglobulins with cryocrit of 9%. Although rare, Sjögren syndrome is the most common cause of non-hepatitis C virus-related mixed cryoglobulinemia. We discuss the possible pathogenic mechanisms involved in the development of mixed cryoglobulinemia and its evolution to lymphoma, as best described in the setting of hepatitis C virus infection. Although the specific antigen involved is unknown, it is likely that the mixed cryoglobulinemia in Sjögren syndrome is triggered by the long-term B-cell stimulation, resulting in clonal proliferation of B cells. Additional chromosomal aberrations and cytokine milieu alterations, as seen in hepatitis C virus infection, may result in prolonged B-cell survival and progression to non-Hodgkin lymphoma.

THE RENAL LESION IN SYSTEMIC VASCULITIS

The aim and the objectives: to investigate the frequency and the character of renal lesion in systemic vasculitis, as well as aspects of the pathogenesis of nephropathy in this category of patients.&#x0D; Material and methods: investigate 525 patients, including 193 - with vasculitis Shenlayna-Henoch, 116- with microscopic polyangiitis, 93 - with cryoglobulinemic vasculitis, 39 - with polyarteritis nodosa, 29 - with aortoarteritis Takayasu, 28 - withWegener’s granulomatosis and 27 - with eosinophilic vasculitis Churg-Strauss.&#x0D; Results: the renal lesion is observed in 52-68% cases of vasculitis depends on the age and the sex of the patients, the duration of the disease, the degree of activity of the pathological process, alteration in the heart and lungs, integrated severity extrarenal signs of the disease, at that, the rate ofprogression of nephropathy associated with the character of the disorders of the immune system, the rheological properties of blood and endothelial vessels’function.&#x0D; Conclusions: kidney disease is one of the leading signs of systemic vasculitis and observed in most patients, it is determine the course of the disease.

Cold hard facts of cryoglobulinemia: updates on clinical features and treatment advances.

Cryoglobulins are immunoglobulins that precipitate at temperatures less than 37°C. They occur secondary to infectious, autoimmune, and malignant processes. In the Brouet classification, type I cryoglobulinemia is caused by hyperviscosity, whereas type II and III manifestations are caused by vasculitis in target organs (primarily skin, peripheral nerves, and kidney). New classification criteria were recently proposed that may help with study and treatment of cryoglobulinemic vasculitis (CryoVas). Hepatitis C virus is the most common cause of CryoVas and treatment with antivirals can be curative in mild cases, whereas rituximab is highly effective in treating active vasculitis in more severe cases.

Assessment of free light chains in HCV positive patients with mixed cryoglobulinemia vasculitis undergoing rituximab treatment

Introduction: Mixed Cryoglobulinemia (MC) is an HCV-related lymphoproliferative disorder, secondary to a systemic vasculitis of small vessels. Treatment with anti-CD20 monoclonal antibodies Rituximab (RTX) is proved to be very useful. Free light chain (FLC) κ/λ ratio and FLC patterns were associated with MC and/or B-non Hodgkin's lymphoma.

The correlation between antiphospholipid syndrome and cryoglobulinemia: case series of 4 patients and review of the literature

BackgroundCryoglobulinemia 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. ObjectiveIn 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. MethodsWe describe four patients who were admitted to our hospital due to multi-organ life threatening damage mediated by cryoglobulinemic vasculitis with concurrent APS. ResultsClinical 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. ConclusionThe 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.

Cryoglobulinemic vasculitis with renal involvement: A historic aspect of the problem

The paper presents the steps for studying cryoglobulinemia from essential to cryoglobulinemic vasculitis associated with hepatitis C virus. It shows advances in the study of the etiology of cryoglobulinemia, diagnosis, specific features of renal injury, and current approaches to treating HCV infection-related cryoglobulinemic vasculitis with renal involvement, by using 3 clinical cases (with a difference of a few decades during a follow-up).

Finger Necrosis Due to Cryoglobulinemic Vasculitis in Association with Membranous Nephropathy

Cryoglobulinemic vasculitis is a small vessel vasculitis that has been associated with chronic infections and autoimmune, lymphoproliferative, and neoplastic disorders. When no significant etiological factors are identified, it is called essential mixed cryoglobulinemia. A detailed and thorough laboratory investigation is required to exclude all possible causes of cryoglobulin formation. Although cryoglobulin testing is simple, careful temperature regulation is needed to avoid false-negative results. Consensus diagnosis should be developed and implemented for appropriate cryoglobulin detection and accurate clinical diagnosis for cryoglobulinemic vasculitis. Here we present an interesting, first-ever case report of a 54-year-old Hispanic-American woman with essential mixed cryoglobulinemia presenting with significant digital necrosis in association with membranous nephropathy.

Cognitive impairments in some cardiovascular and somatic diseases

The paper gives an update on the pathogenesis, clinical presentation, and pathomorphology of cognitive impairments (CIs) in different autoimmune, endocrine, and infectious diseases: systemic lupus erythematosus, Sjogren’s syndrome, Behchet’s disease, primary angiitis of the central nervous system, polyarteritis nodosa, cryoglobulinemic vasculitis, hypothyroidism, herpetic lesion, and neurosyphilis. It is noted that treatment for CIs should be individual in terms of virulence factors. In vascular CIs, therapy should be aimed primarily at modifying risk factors and eliminating or reducing chronic brain ischemia. The prevention of progressive CI encompasses antihypertensive and antithrombotic therapies and surgical correction of atherosclerotic great artery stenosis. Control of hyperlipidemia, hyperglycemia and treatment of other somatic diseases are also of great importance. Such patients are usually given cetylcholinesterase inhibitors, acetylcholine precursors, antiglutamatergic agents, and metabolic and vascular drugs. By taking into account brain ischemia/ hypoxia in the above diseases, it is shown to be advisable to use antioxidants, cerebral active agents in particular, which have a complex neurometabolic effect.

A strange rash with "gloves and socks" distribution.

A strange rash with "gloves and socks" distribution.

Cognitive impairments in common and rare somatic diseases

The paper gives an update on the pathogenesis, clinical presentation, and pathomorphology of cognitive impairments (CIs) in different autoimmune, endocrine, and infectious diseases, such as systemic lupus erythematosus, Sjögren's syndrome, BehНet's disease, primary angiitis of the central nervous system, polyarteritis nodosa, cryoglobulinemic vasculitis, hypothyroidism, herpetic lesion, and neurosyphilis. These patients are observed to have ischemic-hypoxic brain damage, the causes of which are free radical-induced cell injury, oxidative stress, excitation toxicity, cell necrosis and/or apoptosis, inflammation and immune disease, molecular sequestration, and cell death. There is enhanced imbalance in the pro-oxidant and antioxidant systems as cerebrovascular insufficiency progresses; as this takes place, the nerve cells are most susceptible to the induction of free radical reactions. In these cases, antioxidants that block the effects of free radicals and may potentially improve brain perfusion, by assisting the coupling of neurons and vessels, are first-choice drugs. To improve the cognitive status and to prevent the progression of CIs, it is important to build a cognitive reserve in a patient; this is largely favored by the preservation of a proactive approach to life and social bonds, as well as intellectual work.