Mixed Cryoglobulinemia Syndrome Associated with Non-HCV B-Cell Lymphoproliferative Disorder Presenting with Gangrene and Peripheral Neuropathy.

Mixed cryoglobulinemia is a rare disorder characterized by gangrene, weakness, and arthralgias with variable organ involvement. It is often associated with hepatitis C, HIV, and immunological disorders. Diagnosis is based on clinical features and laboratory testing with serology detecting cryoglobulins. Our patient, a 64-year-old female, presented with weakness, fatigue, and discoloration of her fingers and toes. Physical examination showed upper- and lower-extremity skin changes with dry gangrene. Serology showed a non-hepatitis C status, positive cryoglobulin test with a positive rheumatoid factor, and monoclonal IgM-kappa, confirming the diagnosis of mixed cryoglobulinemia. She was treated with intravenous immunoglobulins, glucocorticoids, multiple cycles of rituximab, cyclophosphamide, and plasma exchange. Following a significant event of exacerbation and relapse requiring a below-knee amputation, this case report aims to raise awareness among clinicians to consider this as a rare cause of gangrene and peripheral neuropathy in an elderly adult.

Cryoglobulinemic vasculitis triggered by Staphylococcus aureus endocarditis with chronic hepatitis C virus co-infection: a case report and literature review.

Infective endocarditis is a rare but life-threatening condition, occasionally linked to diverse immunologic manifestations, including mixed cryoglobulinemia. This can lead to cryoglobulinemic vasculitis, which has the potential for widespread organ damage. Although some cases have highlighted the relationship between infective endocarditis and cryoglobulinemic vasculitis, no comprehensive epidemiological evaluation or optimal treatment strategies have been advanced for such a combination. We present a case of methicillin-sensitive Staphylococcus aureus infective endocarditis associated with cryoglobulinemic vasculitis and conduct a literature review to compare management and outcomes in similar cases. Our patient presented with classical Meltzer's triad and mild renal involvement. Cryoimmunofixation confirmed type III cryoglobulinemia, and serum cytokines showed elevated IL-6 levels. The differential diagnosis included infective endocarditis and chronic active hepatitis C virus infection. Rapid symptom resolution after antibiotic treatment identified infective endocarditis as the likely cause of cryoglobulinemic vasculitis. Our case and review of the literature highlight that early identification of the cause of cryoglobulinemic vasculitis is crucial for selecting appropriate treatment and preventing recurrence or morbidity.

Acquired Fanconi syndrome in mixed cryoglobulinemia patients: a single-center case series.

PURPOSE: Cryoglobulinemia is a pathological condition characterized by the presence of cryoglobulins in the blood, with cryoglobulinemic glomerulonephritis being the most frequent form of renal involvement. Fanconi syndrome presents as a generalized dysfunction of the proximal tubule, characterized by the presence of polyuria, phosphaturia, glycosuria, proteinuria, proximal renal tubular acidosis, and osteomalacia. We aimed to present five cases co-occurring with Fanconi syndrome and cryoglobulinemia. METHODS: We retrospectively summarized the cases of five patients with Fanconi syndrome and cryoglobulinemia at Peking Union Medical College Hospital from January 2012 to June 2022. The clinical features, diagnosis, treatment, and prognosis were systematically analyzed. RESULTS: All five patients exhibited typical features of Fanconi syndrome, and cryoglobulinemia was concurrently detected in all cases. These patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, and IgM constitutes the predominant monoclonal component in cryoglobulins. In addition to supplemental treatment, timely immunosuppressive therapy may potentially benefit the long-term renal prognosis of patients with this condition. CONCLUSION: Our findings highlight the rare co-occurrence of Fanconi syndrome and cryoglobulinemia in clinical practice. Despite the lack of causal evidence, the coexistence of Fanconi syndrome and tubulointerstitial injury is also noteworthy in patients with cryoglobulinemia, underscoring the importance of thorough evaluation and tailored management in patients presenting with overlapping renal manifestations. Key Points • Patients with mixed cryoglobulinemia can clinically present with tubulointerstitial injury, specifically manifesting as Fanconi syndrome. • In addition to typical symptoms of Fanconi syndrome, these patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, while IgM constitutes the monoclonal component in cryoglobulins. • Timely immunosuppressive therapy may improve long-term renal prognosis in these patients.

Extrahepatic manifestations of HCV where do we stand? / Manifestaciones extrahepáticas del VHC. ¿Dónde nos encontramos?

Hepatitis C virus (HCV) infection has been associated as up 40–70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.(AU)

La infección por el virus hepatitis C (VHC) se ha asociado a 40-70% de los pacientes con alguna manifestación extrahepática (MEH) y 36 síndromes diferentes, atribuibles a que el VHC es linfotrópico, particularmente linfotrópico B, y no simplemente hepatotrópico. El VHC podría desencadenar alteraciones inmunológicas al ejercer un estímulo crónico del sistema inmunológico con producción de inmunoglobulinas con actividad reumatoide y formación de complejos inmunes y crioglobulinas. Estas desempeñan un papel fundamental en la mayoría de las MEH como vasculitis, glomerulonefritis, artritis y neuropatías, mientras, menos frecuentemente, el efecto citopático viral directo podría conducir a MEH independientes de crioglobulinas. El principal tratamiento de las MEH ha sido el antiviral, desde la era del interferón hasta la de los fármacos de acción directa, sin diferencias entre las dos épocas, a pesar de la mejor respuesta virológica. Son necesarias evaluaciones más prolongadas de la respuesta virológica e investigación clínica con seguimientos más largos.(AU)

[Anterior orbital ischemia secondary to type 1 cryoglobulinemia: A case report and literature review]. / Ischémie du segment antérieur de l'œil secondaire à une cryoglobulinémie de type 1 : à propos d'un cas et revue de la littérature.

INTRODUCTION: Type 1 cryoglobulinemia is characterized by a large number of clinical signs. The lack of specificity of these signs can make diagnosis difficult. Ocular manifestations are rarely described across medical literature. Only 15 cases of ophthalmological involvement secondary to cryoglobulinaemia have been reported. COMMENT: We report the case of a 69-year-old patient with cutaneous type 1 cryoglobulinaemia. He presented with bilateral anterior segment ischemia without retinal involvement with unilateral neovascularisation. Treatment of the B lymphocyte clone with rituximab and bendamustine and plasma exchange were initiated with successfully. Two similar cases describing ischaemic damage to the iris during type 1 cryoglobulinemia have been reported in the literature. CONCLUSION: Irial ischaemia should be considered as a potential in type 1 cryoglobulinaemia.

Ocular manifestations of cryoglobulinemia: a reappraisal.

BACKGROUND/OBJECTIVES: To describe frequency and type of ocular manifestations in patients with cryoglobulinemic vasculitis (CV), as well as management approaches and outcomes. SUBJECTS/METHODS: This was a retrospective, observational, cohort study of patients who were diagnosed with CV at a single center and regularly underwent a comprehensive ocular assessment. RESULTS: Ophthalmologic manifestations were recorded in 16 patients (28%). The diagnoses included dry eye disease and primary Sjögren syndrome in 5 and 2 patients, respectively; peripheral ulcerative keratitis and anterior scleritis in 1 patient each; hyperviscosity syndrome and hypertensive retinopathy in 2 patients each; and Purtscher- like retinopathy in 3 patients. Twelve patients (75%) were anti-HCV/HCV RNA-positive, 11 of whom achieved a sustained virologic response (SVR) following treatment with interferon-α2b plus ribavirin or direct-acting antivirals. All patients were treated with ocular lubricants. Systemic therapeutic measures, including glucocorticoids, immunosuppressive and biologic agents, induced the disappearance or ≥50% reduction of cryoglobulins and major signs of vasculitis in 11 patients (68.7%). In the remaining 5 patients (31.3%), cryoglobulins and CV manifestations remained unchanged or decreased by <50%. The corresponding ophthalmologic assessment showed a variable degree of improvement in the ocular symptoms in all but 2 patients (87.5%). The best corrected visual acuity following treatment improved in 26 eyes, was unchanged in 3 eyes, and worsened in 3 eyes. CONCLUSIONS: Eye involvement is not a rare event in CV patients. A timely diagnosis and the correct employment of the available therapeutic measures may result in a favorable outcome of the ocular and extra-ocular manifestations.

Is there a connection between neurocognitive profile in treatment naïve non-cirrhotic HCV patients and level of systemic inflammation?

Hepatitis C virus (HCV) infection is a progressive, systemic disease which leads to the development of end-stage liver disease. In 70% of patients, HCV infection is followed by the development of extrahepatic manifestations (EHM). A common EHM is HCV associated neurocognitive disorder (HCV-AND), characterized by neuropsychological changes in attention, working memory, psychomotor speed, executive function, verbal learning, and recall. The aim of this study is to examine the correlation between the neurocognitive profile and routine, available laboratory parameters of inflammation, liver function tests, grade of liver fibrosis, and clinical and laboratory parameters of mixed cryoglobulinemia in treatment naïve non-cirrhotic HCV patients. This is a single-center exploratory study in which we examined 38 HCV + treatment naïve patients. The complete blood count and hematological parameters of systemic inflammation, liver function tests, biopsy confirmed grade of liver fibrosis, and clinical and laboratory parameters of mixed cryoglobulinemia caused by chronic HCV infection were observed. In the study, we used a battery of neuropsychological tests assessing multiple cognitive domains: executive functions, verbal fluency, delayed memory, working memory and learning, and one measure for visuo-constructive performance. Before the Bonferroni correction for multiple comparisons, the results show significant correlations between the scores in the neurocognitive variables and the single measures of inflammation, liver function parameters, and mixed cryoglobulinemia. It has not found a statistically significant correlation between systemic inflammation and neurocognitive variables. After the Bonferroni adjustment, no correlations remained significant. Certainly, the obtained results can be a recommendation for additional validation through future research.

Type II Cryoglobulinemic Membranoproliferative Glomerulonephritis Caused by Mucosa-associated Lymphoid Tissue Lymphoma.

A 67-year-old man complained of lower limb edema with a purpuric skin rash. Laboratory tests revealed proteinuria, elevated serum creatinine levels, and low serum albumin levels. The patient was also positive for cryoglobulin in serum, immunoglobulin (Ig) M gammopathy, hypocomplementemia, and rheumatoid factor. He was negative for anti-hepatitis C virus antibodies. A pathological analysis of the renal tissue revealed membranoproliferative glomerulonephritis, common histological features of cryoglobulinemic vasculitis (CV), and mucosa-associated lymphoid tissue lymphoma invasion. Although hematologic malignancy is a rare cause of type II CV, these clinical findings suggest that mucosa-associated lymphoid tissue lymphoma (MALT) lymphoma may have been the cause in the present case.

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.

Serological and Molecular Characterization of Hepatitis C Virus-Related Cryoglobulinemic Vasculitis in Patients without Cryoprecipitate.

Prolonged B cells stimulation due to the Hepatitis C virus (HCV) can result in autoimmunity, stigmatized by rising levels of cryoglobulins (CGs), the rheumatoid factor (RF), and free light chains (FLC) of immunoglobulins (Ig) associated with a range of symptoms, from their absence to severe cryoglobulinemic vasculitis and lymphoma. Here, we aimed to identify an immunological signature for the earliest stages of vasculitis when cryoprecipitate is still not detectable. We firstly analyzed the IgG subclasses, FLC, and RF in 120 HCV-RNA-positive patients divided into four groups according to the type of cryoprecipitate and symptoms: 30 asymptomatic without cryoprecipitate (No Cryo), 30 with vasculitis symptoms but without CGs that we supposed were circulating but still not detectable (Circulating), 30 type II and 30 type III mixed cryoglobulinemia (Cryo II and Cryo III, respectively). Our results revealed that patients with supposed circulating CGs displayed a pattern of serological parameters that closely resembled Cryo II and Cryo III, with a stronger similarity to Cryo II. Accordingly, we analyzed the groups of Circulating and Cryo II for their immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements, finding a similar mixed distribution of monoclonal, oligoclonal, and polyclonal responses compared to a control group of ten HCV-RNA-negative patients recovered from infection, who displayed a 100% polyclonal response. Our results strengthened the hypothesis that circulating CGs are the origin of symptoms in HCV-RNA-positive patients without cryoprecipitate and demonstrated that an analysis of clonal IGH and TCR rearrangements is the best option for the early diagnosis of extrahepatic complications.

Coexistence of cryoglobulinemia and ANCA-associated vasculitis in a chronic brucellosis patient -a case report and literature review.

BACKGROUND: The renal involvement of brucellosis is not common. Here we reported a rare case of chronic brucellosis accompanied by nephritic syndrome, acute kidney injury, the coexistence of cryoglobulinemia and antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) superimposed on iliac aortic stent implantation. The diagnosis and treatment of the case are instructive. CASE PRESENTATION: A 49-year-old man with hypertension and iliac aortic stent implantation was admitted for unexplained renal failure with signs of nephritic syndrome, congestive heart failure, moderate anemia and livedoid change in the left sole with pain. His past history included chronic brucellosis and he just underwent the recurrence and completed the 6 weeks of antibiotics treatment. He demonstrated positive cytoplasmic/proteinase 3 ANCA, mixed type cryoglobulinemia and decreased C3. The kidney biopsy revealed endocapillary proliferative glomerulonephritis with a small amount of crescent formation. Immunofluorescence staining revealed only C3-positive staining. In accordance with clinical and laboratory findings, post-infective acute glomerulonephritis superimposed with AAV was diagnosed. The patient was treated with corticosteroids and antibiotics and sustained alleviation of renal function and brucellosis was achieved during the course of a 3-month follow-up. CONCLUSIONS: Here we describe the diagnostic and treatment challenge in a patient with chronic brucellosis related glomerulonephritis accompanied by the coexistence of AAV and cryoglobulinemia. Renal biopsy confirmed the diagnosis of postinfectious acute glomerulonephritis overlapping with ANCA related crescentic glomerulonephritis, which was not ever reported in the literature. The patient showed a good response to steroid treatment which indicated the immunity-induced kidney injury. Meanwhile, it is essential to recognize and actively treat the coexisting brucellosis even when there are no clinical signs of the active stage of infection. This is the critical point for a salutary patient outcome for brucellosis associated renal complications.

Subretinal Deposits Associated With Type 1 Cryoglobulinemia.

This case report describes a female patient aged 30 years who presented with subretinal deposits and blurry vision in the setting of type 1 cryoglobulinemia.

[Diagnosis of cryoglobulinemic vasculitis based on B symptoms and peripheral neuropathy: a case report].

A man in his 50s presented with a 2-month history of paresthesia and hypoesthesia of the extremities and B symptoms including low-grade fever, weight loss, and night sweats. He also reported a 3-year history of skin discoloration in cold weather. Laboratory test results showed a high white blood cell count and elevated serum C-reactive protein and rheumatoid factor (RF) levels. Complement levels were low, and tests for cryoglobulin showed positive results. Computed tomography revealed generalized lymphadenopathy, and 18F-fluorodeoxyglucose-positron emission tomography showed increased uptake; therefore, we performed cervical lymph node and muscle biopsies. The patient was diagnosed with nodular marginal zone lymphoma and cryoglobulinemic vasculitis (CV) and received chemotherapy and steroid treatment with improvement in symptoms. CV is a rare immune complex small-vessel vasculitis. It is important to measure RF and complement levels and consider infections, collagen diseases, and hematological disorders in the differential diagnosis in patients with suspected vasculitis or CV.

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.