Efficacy of Therapeutic Apheresis for Cryoglobulinemic Vasculitis Patients with Renal Involvement: A Systematic Review.

INTRODUCTION: Therapeutic apheresis (TA) is commonly used for cryoglobulinemic vasculitis (CV) patients, but its efficacy remains uncertain. This systematic review aimed to assess the efficacy of different TA modalities, such as plasma exchange (PE), plasmapheresis (PP), and cryofiltration (CF), in treating CV patients with renal involvement. METHODS: Literature search of MEDLINE, EMBASE, and Cochrane Databases was conducted up to December 2022. Studies that reported the outcomes of TA in adult CV patients with renal involvement were assessed. The protocol for this systematic review has been registered with PROSPERO (No. CRD42023417727). The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score. RESULTS: 154 patients who encountered 170 episodes of serious events necessitating TA were evaluated across 76 studies. Among them, 51% were males, with a mean age ranging from 49 to 58 years. The CV types included 15 type I, 97 type II, and 13 type III, while the remaining patients exhibited mixed (n = 17) or undetermined CV types (n = 12). Among the treatment modalities, PE, PP, and CF were performed in 85 (56%), 52 (34%), and 17 patients (11%), respectively, with no identical protocol for TA treatment. The overall response rate for TA was 78%, with response rates of 84%, 77%, and 75% observed in type I, II, and III patients respectively. Most patients received steroids, immunosuppressants, and treatment targeting the underlying causative disease. The overall long-term renal outcome rate was 77%, with type I, II, and III patients experiencing response rates of 89%, 76%, and 90%, respectively. The renal outcomes in patients receiving PE, PP, and CF were comparable, with rates of 78%, 76%, and 81%, respectively. CONCLUSIONS: This study presents compelling evidence that combination of TA with other treatments, especially immunosuppressive therapy, is a successful strategy for effectively managing severe renal involvement in CV patients. Among the TA modalities studied, including PE, PP, and CF, all demonstrated efficacy, with PE being the most frequently employed approach.

Refractory type I cryoglobulinaemia requiring serial amputations.

We present a rare case of a man in his 40s who presented with bilateral lower extremity necrosis. After an extensive workup, he was diagnosed with type I cryoglobulinaemia (TIC) based on severe vaso-occlusive symptoms, presence of serum cryoglobins and tissue biopsy showing small-vessel vasculitis. Treatment was multimodal and targeted both his underlying lymphoproliferative disorder (monoclonal gammopathy of undetermined significance) and inflammatory state. Steroids, plasmapheresis and immunotherapy were administered with temporary remission of symptoms. After discharge, patient continued to repeatedly present with progressive bilateral lower extremity necrosis and new upper extremity digital necrosis necessitating further pharmacological treatment and surgical intervention-bilateral above the knee amputation and multiple digital hand amputations. This case illustrates a severe example of TIC where diagnosis was difficult due to atypical presentation, and disease was refractory to multimodal therapies necessitating surgical intervention to achieve temporary remission.

Cryofibrinogen-Characteristics and Association with Cryoglobulin: A Retrospective Study Out of a Series of 1,712 Samples over 7 Years.

OBJECTIVE: Cryofibrinogens (CFs) and cryoglobulins (CGs) are cryoproteins responsible for obstructive vasculopathy and vasculitis. The aim of this study was to compare the characteristics of CF and CG, and to define the conditions of their association. METHODS AND RESULTS: This retrospective study was conducted at the Lyon University Hospitals, and included patients with at least one sample tested for CF and/or CG between September 2013 and April 2021. Serum and plasma samples were analyzed in very strict conditions of temperature. After cold precipitation, CF and CG were characterized and quantified in the cryoprecipitates. CRP and plasma fibrinogen levels were also investigated. Over this 7-year period, 1,712 samples for CF detection and 25,650 samples for CG detection were sent to the laboratory. Simultaneous testing of CF and CG was performed in 1,453/1,712 samples (85%). CF was less often positive than CG (8.3 vs. 13.5%, p < 0.0001). In positive CF samples, CG was associated in 28.9% of cases. In CF, fibrinogen was associated with fibronectin in 98/142 (69%) samples, especially in highly concentrated CF. CF concentration was independent of C-reactive protein and plasma fibrinogen concentrations. CONCLUSION: The simultaneous detection of CF and CG is essential for the diagnosis of vasculitis or thromboembolic events and their treatment.

Acrocyanosis and Progressive Skin Necrosis as Manifestation of Waldenstrom Macroglobulinemia Associated With Type I Cryoglobulinemia: A Case Report.

Waldenstrom macroglobulinemia (WM), a rare malignant disorder, occurs as a result of abnormal proliferation of lymphocytes that produce immunoglobulin M. In rare cases, WM complicates by type I cryoglobulinemia. Type I cryoglobulinemia usually presents with cutaneous manifestations such as Raynaud's phenomenon, purpura, necrosis, and gangrene. Various medical conditions, including thrombotic events, rheumatologic disorders, and malignancies, may present with skin discoloration and necrosis. Patients suffering from malignant diseases who initially present with skin manifestations usually are misdiagnosed by physicians. Here, we describe a 72-year-old man presenting with a 6-month acrocyanosis and progressive skin necrosis who was misdiagnosed by physicians. Finally, he was diagnosed to have WM associated with type I cryoglobulinemia. Though uncommon, hematologic malignancies can present with cutaneous manifestations. In some cases, patients may manifest with skin disorders alone. Early and prompt treatment of these diseases may save the patient life, relieve patient symptoms, and increase life quality.

Cryoglobulinemia and double-filtration plasmapheresis: Personal experience and literature review.

BACKGROUND: Cryoglobulinemia is defined as the presence of an abnormal immunoglobulin that may be responsible for vasculitis of small-caliber vessels. Apheresis can be used in order to temporarily eliminate circulating cryoglobulins. The aim of this study was to assess the effectiveness of apheresis (double-filtration plasmapheresis-DFPP-) in symptomatic and/or severe cryoglobulinemias. METHODS: Four male patients presenting cryoglobulinemic vasculitis and who received DFPP sessions were included. RESULTS: Their mean age was 57 ± 15 years. One patient had hepatitis-C virus (HCV)-related cryoglobulinemia and the other three patients were carriers of an IgM Kappa monoclonal gammopathy. Mean duration of follow-up was 15 ± 2 months. DFPP allowed healing of ulcerative skin lesions in the first patient and remission of nephrotic syndrome in the other patients after a median of 6(5-10) sessions. CONCLUSION: DFPP can be used safely in cryoglobulinemic-vasculitis and can be considered early to achieve a faster and sustained clinical-biological response.

Crioglobulinemia / Cryoglobulinemia

Las crioglobulinas son inmunoglobulinas que precipitan in vitro a temperaturas inferiores a 37°C, cuya precipitación reversible tras la exposición a bajas temperaturas permite su detección en el laboratorio. Esta característica tan especial tiene también implicaciones patógenas, aunque los mecanismos moleculares involucrados no están totalmente dilucidados. La enfermedad asociada a las crioglobulinas es heterogénea, ya que no todos los pacientes la presentan, incluye diversas presentaciones sindrómicas (la vasculitis es la más frecuente, el síndrome de hiperviscosidad es excepcional), y puede asociarse a cuadros clínicos agudos de una elevada mortalidad. Hasta la aparición de los tratamientos específicos antivirales, la principal etiología ha sido la infección crónica por el virus hepatitis C (VHC), y en la actualidad se asocia principalmente a enfermedades autoinmunes sistémicas, neoplasias malignas y casos sin etiología identificada (crioglobulinemia esencial). El tratamiento debe ser modulado según la etiopatogenia predominante (vasculitis o hiperviscosidad), la gravedad de la afectación de órganos internos y, especialmente, la enfermedad subyacente asociada (viral, autoinmune o hematológica). Debido al complejo escenario etiológico, clínico y patológico de la crioglobulinemia, resulta esencial el reconocimiento temprano de las presentaciones clínicas más frecuentes, una evaluación clínica integral de los diferentes órganos que pueden verse afectados, y el trabajo multidisciplinar liderado desde una unidad especializada en enfermedades autoinmunes sistémicas. (AU)

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37 ̊C. Cryoglobulin-associated disease is heterogeneous, as not all patients present with it, includes various syndromic presentations (vasculitis is the most common, hyperviscosity syndrome is more exceptional), and can be associated with acute clinical pictures with high mortality. Until the appearance of specific antiviral treatments, the main aetiology has been chronic HCV infection, and currently it is mainly associated with systemic autoimmune diseases, malignant neoplasms and cases with no identified aetiology (essential cryoglobulinemia). Treatment should be modulated according to the predominant etiopathogenesis (vasculitis or hyperviscosity), the severity of internal organ involvement and, especially, the associated underlying disease. Due to the complex aetiological, clinical and pathological scenario of cryoglobulinaemia, early recognition of the most common clinical presentations, a comprehensive clinical assessment of the different organs that may be affected, and multidisciplinary work led by a unit specialised in systemic autoimmune diseases is essential. (AU)

[Cryoglobulinemic vasculitis]. / Kryoglobulinämische Vaskulitis.

Cryoglobulinemic vasculitis (CV) is a rare immune complex disease of small vessels (capillaries, venules or arterioles) with detection of cryoglobulins (CG). These are serum proteins that precipitate at temperatures below the normal body temperature. The laboratory diagnostics are logistically challenging because the temperature of the blood sample must be maintained continuously at 37 °C until arrival in the laboratory to prevent early precipitation of the proteins with adsorption to corpuscular blood components. Cryoglobulins can be divided into three classes (types I-III), with each class associated with specific underlying diseases and symptom complexes. Cryoglobulinemia can be caused by hematological, virological or autoimmune diseases and mixed forms also occur. The most common cause to date is a hepatitis C infection. Treatment of the underlying disease is obligatory, with antiviral treatment of hepatitis C offering the rare possibility of causal treatment. Depending on the severity of cryoglobulinemia, immunosuppressive therapy is indicated to prevent permanent damage caused by the inflammation.

[Cryoglobulinemia]. / Crioglobulinemia.

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37 ̊C. Cryoglobulin-associated disease is heterogeneous, as not all patients present with it, includes various syndromic presentations (vasculitis is the most common, hyperviscosity syndrome is more exceptional), and can be associated with acute clinical pictures with high mortality. Until the appearance of specific antiviral treatments, the main aetiology has been chronic HCV infection, and currently it is mainly associated with systemic autoimmune diseases, malignant neoplasms and cases with no identified aetiology (essential cryoglobulinemia). Treatment should be modulated according to the predominant etiopathogenesis (vasculitis or hyperviscosity), the severity of internal organ involvement and, especially, the associated underlying disease. Due to the complex aetiological, clinical and pathological scenario of cryoglobulinaemia, early recognition of the most common clinical presentations, a comprehensive clinical assessment of the different organs that may be affected, and multidisciplinary work led by a unit specialised in systemic autoimmune diseases is essential.

[Cryoglobulinemic vasculitis]. / Vascularites cryoglobulinémiques.

Cryoglobulins are immunoglobulins that precipitate in vitro when serum is incubated at temperatures lower than 37°C. Cryoglobulins are classified under three subgroups according to their components. Cryoglobulinemic vasculitis corresponds to manifestations associated with vascular occlusion by cryoglobulins or inflammatory manifestations induced by the deposition of cryoglobulins containing immune complex. Main manifestations are skin lesions, including vascular purpura, necrosis, kidney involvement, and peripheral nerve involvement. Initial work-up aims at identifying the underlying disease, which may be a B-lineage hematological malignancy, a connective tissue disorder, or a chronic viral infection like hepatitis C. Treatment and prognosis are closely dependent of the underlying disease.

Vascularites Cryoglobulinémiques. La cryoglobuline est une protéine du sérum qui précipite in vitro à une température inférieure à 37°C. Les cryoglobulinémies sont classées en trois sous-groupes selon leur composition. La vascularite cryoglobulinémique correspond à l'ensemble des manifestations induites par l'occlusion vasculaire par la cryoglobuline ou les manifestations inflammatoires liées aux dépôts de complexes immuns contenant la cryoglobuline. Les manifestations principales sont des atteintes cutanées dont purpura vasculaire et nécrose, une atteinte rénale et une atteinte neurologique périphérique. Le bilan étiologique doit rechercher une hémopathie maligne B, une connectivite, une infection virale chronique (notamment par l'hépatite C). Le traitement et le pronostic dépendent de la pathologie sous-jacente.

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins.

Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.

Hepatitis B Virus-Related Cryoglobulinemic Vasculitis: Review of the Literature and Long-Term Follow-Up Analysis of 18 Patients Treated with Nucleos(t)ide Analogues from the Italian Study Group of Cryoglobulinemia (GISC).

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90-100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.

Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy.

Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is <37 °C, precipitate in a reversible manner in the serum, and redissolve after rewarming. The presence of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) identifies the mixed cryoglobulinemia (MC). The identification of the Hepatitis C virus (HCV) infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. The kidney represents the most common organ presentation, and the presence of glomerulonephritis is a key element when considering prognosis. We discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.

Hypothermic circulatory arrest for aortic dissection with cryoglobulinemia.

Cryoglobulinemia is a cold-reactive autoimmune disease. A 64-year-old man with active cryoglobulinemia presented Stanford type A acute aortic dissection. He had been treated with immunosuppressive drugs and plasma exchange (PE) at our hospital; subsequently, qualitative analysis of cryoglobulin (CG) was negative. He underwent emergency ascending aorta replacement using cardiopulmonary bypass (CPB) under deep hypothermia circulatory arrest with selective cerebral perfusion. The total CPB time, aortic cross-clamp time, and selective cerebral perfusion time were 255, 153, 56 minutes, respectively, and the minimal nasopharyngeal temperature was 17.3°C. Our patient had no significant perioperative complications. Hence, if PE is performed appropriately and CG is negative, patients with cryoglobulinemia who exhibit severe preoperative symptoms can safely undergo surgery with deep hypothermia.

Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?

BACKGROUND: Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection. CASE PRESENTATION: We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years' follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren's syndrome in three cases. CONCLUSION: Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.

Peripheral neuropathy in mixed cryoglobulinaemia: clinical assessment and therapeutic approach.

Peripheral neuropathy (PN) has been detected in up to 69% of patients with mixed cryoglobulinaemic syndrome (MCS). PN should be considered in any patient with sensory and/or motor signs and symptoms in the limbs. Electrodiagnostic tests are mandatory for the diagnosis of PN. Several different sets of diagnostic criteria have been created to assess it. All patients suspected of having neuropathy should undergo a nerve conduction study. A complete neurological evaluation at baseline and periodically should be done possibly by the same neurologists. The authors recommend rigorous scientific evidences that may help to obtain superior tools for accurate diagnosis and management of these conditions. Clinicians, armed with experience and recommendations, can find in this review data-driven guidelines to apply treatments of MCS and closely related disorders.

Retiform purpura: Workup and therapeutic considerations in select conditions.

In this article we focus on updates in select etiologies of retiform purpura. These causes of retiform purpura, in addition to bacterial or fungal sepsis, disseminated intravascular coagulation, purpura fulminans, and catastrophic antiphospholipid syndrome, are important diagnoses with potential for morbidity and mortality. Important aspects in the pathophysiology, patient demographics and risk factors, updates in the diagnostic workup, histopathology, and treatment of these specific conditions are discussed.

Plasmaféresis, experiencia del Hospital Regional de Talca en pacientes con indicaciones nefrológicas / Plasmapheresis, experience of the Regional Hospital of Talca, in patients with nephrological indications

INTRODUCTION: Plasmapheresis is an extracorporeal procedure that allows the plasma to be separated from the figurative elements of the blood, removing specific elements involved in pathological processes. OBJECTIVE: To show the experience of the Regional Hospital of Talca (HRT) in the use of Plasmapheresis from 2017 to March 2019. METHODS: Corresponds to a retrospective study of all patients undergoing plasmapheresis from January 2017 to March 2019 (27 months). The clinical profile of this group of patients is analyzed, emphasizing in the nephrological etiologies and showing the clinical evolution of the diseases submitted to this procedure and aspects such as number of sessions, complications and associated therapies. RESULTS: In this period 14 patients have required plasmapheresis in our center, 9 cases for renal causes (64.2%) and 5 for non-renal causes (35.7%). A deceased was recorded during the acute stage of the disease (7.14%), in the context of a negative antineutrophil cytoplasmic antibody (ANCA) in patient with pulmonary-renal syndrome. 78% of those who needed plasmapheresis for renal etiologies are on hemodialysis at the end of the work. The clinical improvement experienced in the majority of the cases studied allows us to attribute a beneficial effect of plasmapheresis.

Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome.

OBJECTIVE: Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion. METHODS: The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews. RESULTS: Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals.