Infection as a trigger of acute, transient glomerular deposition of clonal immunoglobulins.

Glomerular deposition of monoclonal IgM, frequently in the form of intracapillary pseudothrombi, can be seen in Waldenström macroglobulinemia (WM) and type I cryoglobulinemia (CG). They are typically associated with plasma cell or B-lymphoid neoplasms, particularly lymphoplasmacytic lymphoma (LPL). While infection is a frequent trigger of mixed (type II and III) CG, its association with type I CG is uncommon. We report two cases in which striking lambda-chain-restricted IgM deposits and acute kidney injury (AKI) occurred in the setting of known or suspected systemic infections, with prompt resolution on treatment of the infection.

Hepatitis C virus-related autoimmunity before and after viral clearance: a single center, prospective, observational study.

BACKGROUND: Hepatitis C virus (HCV) chronic infection is frequently associated to autoimmune manifestations. The aim of this study was to prospectively evaluate the occurrence of clinical and/or laboratory features of autoimmunity in a cohort of 140 consecutive HCV chronically infected patients treated with direct-acting antiviral agents (DAAs) and followed-up for 96 weeks. METHODS: All patients were screened for cryoglobulins, rheumatoid factor (RF), C3, C4, antinuclear antibody (ANA), anti-smooth muscle (ASMA), anti-liver kidney microsome type 1 (anti-LKM1), anti-mitochondrial antibodies (AMA), anti-neutrophil cytoplasmic antibodies (ANCA), and anti-liver cytosol type 1/soluble liver antigen (anti-LC1/SLA) autoantibodies before therapy and 12, 48 and 96 weeks after treatment. They were then grouped according to the expression of laboratory findings and related autoimmune diseases. RESULTS: At baseline, autoimmune manifestations were found in 70 patients: 83% of them were cryoglobulinemic, whereas ANA, AMA, perinuclear ANCA (pANCA) and LKM/LC1 autoantibodies were found in the remaining 17%. An autoimmune disease was diagnosed in 9 cases, two of them featuring an autoimmune liver disease (AILD). At the end of follow-up, despite viral clearance and regression of vasculitis, cryoglobulins persisted in 12 patients (21%), and autoantibodies disappeared or decreased in most of cases but, with the exception of the 2 patients diagnosed as AILD, associated autoimmune diseases remained stable. In one patient with relapsing cryoglobulinemia and ANA positivity, type-1 autoimmune hepatitis was defined. Conversely, autoantibodies first appeared after viral clearance in 5 patients, of whom one was diagnosed with type-1 autoimmune hepatitis and one with pANCA+ primary sclerosing cholangitis. CONCLUSIONS: Following DAA-induced viral clearance, cryoglobulins may persist or reappear. Autoantibodies changed dynamically in step with the disappearance of a previously diagnosed or the occurrence of a new AILD. A longer follow-up will be necessary to establish the possible diagnosis of a newly onset AILD, the reactivation of cryoglobulinemic vasculitis and even its progression to non-Hodgkin lymphoma.

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.

Clinical characteristics, radiological features and outcomes in pulmonary involvement of cryoglobulinemia.

BACKGROUND: Cryoglobulinemia with pulmonary involvement is rare, and its characteristics, radiological findings, and outcomes are still poorly understood. METHODS: Ten patients with pulmonary involvement of 491 cryoglobulinemia patients at Peking Union Medical College Hospital were enrolled in this retrospective study. We analyzed the characteristics, radiological features and management of pulmonary involvement patients, and compared with those of non-pulmonary involvement with cryoglobulinemia. RESULTS: The 10 patients with pulmonary involvement (2 males; median age, 53 years) included three patients with type I cryoglobulinemia and seven patients with mixed cryoglobulinemia. All of 10 patients were IgM isotype cryoglobulinemia. All type I patients were secondary to B-cell non-Hodgkin lymphoma. Four mixed patients were essential, and the remaining patients were secondary to infections (n = 2) and systemic lupus erythematosus (n = 1), respectively. Six patients had additional affected organs, including skin (60%), kidney (50%), peripheral nerves (30%), joints (20%), and heart (20%). The pulmonary symptoms included dyspnea (50%), dry cough (30%), chest tightness (30%), and hemoptysis (10%). Chest computed tomography (CT) showed diffuse ground-glass opacity (80%), nodules (40%), pleural effusions (30%), and reticulation (20%). Two patients experienced life-threatening diffuse alveolar hemorrhage. Five patients received corticosteroid-based regimens, and four received rituximab-based regimens. All patients on rituximab-based regimens achieved clinical remission. The estimated two-year overall survival (OS) was 40%. Patients with pulmonary involvement had significantly worse OS and progression-free survival than non-pulmonary involvement patients of cryoglobulinemia (P < 0.0001). CONCLUSIONS: A diagnosis of pulmonary involvement should be highly suspected for patients with cryoglobulinemia and chest CT-indicated infiltrates without other explanations. Patients with pulmonary involvement had a poor prognosis. Rituximab-based treatment may improve the outcome.

A comparative study of different antiviral treatment protocols in HCV related cryoglobulinemic vasculitis.

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.

Case report: BTK inhibitors is effective in type II mixed cryoglobulinemia with wild-type MyD88.

This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.

Peripheral Neuropathy in Patients with Hepatitis C Infection-Reversibility after HCV Eradication: A Single Center Study.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

Liver Disease-Associated Glomerulopathies.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect a significant number of individuals globally and their extra-hepatic manifestations, including glomerular disease, are well established. Additionally, liver disease-associated IgA nephropathy is the leading cause of secondary IgA nephropathy with disease course varying from asymptomatic urinary abnormalities to progressive kidney injury. Herein we provide an updated review on the epidemiology, pathogenesis, clinical manifestations, and treatment of HBV- and HCV-related glomerulonephritis as well as IgA nephropathy in patients with liver disease. The most common HBV-related glomerulonephritis is membranous nephropathy, although membranoproliferative glomerulonephritis and podocytopathies have been described. The best described HCV-related glomerulonephritis is cryoglobulinemic glomerulonephritis occurring in about 30% of patients with mixed cryoglobulinemic vasculitis. The mainstay of treatment for HBV-GN and HCV-GN is antiviral therapy, with significant improvement in outcomes since the emergence of the direct-acting antivirals. However, cases with severe pathology and/or a more aggressive disease trajectory can be offered a course of immunosuppression, commonly anti-CD20 therapy, particularly in the case of cryoglobulinemic glomerulonephritis.

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.

[Comparative analysis of the development mechanisms of cryoglobulinemic vasculitis and Sjögren's syndrome]. / Sravnitel'nyi analiz mekhanizmov razvitiya krioglobulinemicheskogo vaskulita i sindroma Shegrena.

Cryoglobulinemic vasculitis is a disease characterized by damage of small vessels and in some cases can be a manifestation of mixed cryoglobulinemia. Mixed cryoglobulinemia is a condition in which immunoglobulins in the blood serum form precipitates at temperatures below 37 °C and dissolve again when it rises. Currently, hepatitis C (HCV) is considered the most common etiological factor of mixed cryoglobulinemia. In addition, mixed cryoglobulinemia may be associated with other infectious agents, as well as autoimmune and lymphoproliferative diseases. In the absence of such association, we can talk about essential mixed cryoglobulinemia. To understand how different nosologies in their clinical and morphological picture lead to the development of mixed cryoglobulinemia, it is necessary to carefully analyze the mechanisms of the development of some of them, namely, HCV-associated cryoglobulinemic vasculitis and Sjögren's syndrome. It is noteworthy that mixed cryoglobulinemia in relation to Sjögren's syndrome can be perceived both as its consequence and as a manifestation of the underlying disease. Such an ambiguous nature of mixed cryoglobulinemia makes it currently impossible to select clear diagnostic criteria. For this reason, it is necessary to carry out a comparison between different immunopathogenesis of mixed cryoglobulinemia in order to identify the features that form its classical manifestations.

Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies-A Case-Control Study.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

Long-term renal function alterations in hepatitis C patients with SVRs: Impacts of therapies and mixed cryoglobulinemia.

BACKGROUND / AIMS: Effects of anti-hepatitis C virus (HCV) therapeutic regimens and mixed cryoglobulinemia on long-term renal function of HCV-infected patients with viral clearance have not been determined. METHODS/MATERIALS: A prospective 10-year cohort study of 1212 HCV-infected patients (interferon-based therapy, n = 615; direct-acting antiviral (DAA) therapy, n = 434) was conducted. RESULTS: At baseline, age, body mass index (BMI), hemoglobin (Hb) and uric acid (UA) levels, and fibrosis-4 score were associated with estimated glomerular filtration rates (eGFRs) in HCV-infected patients. At 24 weeks posttherapy, age, BMI, and Hb and UA levels were associated with eGFRs in patients with a sustained virological response (SVR) (n = 930). Compared with those at baseline, the eGFRs were lower in SVR patients at 24 weeks posttherapy, regardless of the therapeutic regimen. The eGFRs reverted to baseline levels in interferon-treated SVR patients up to 10 years posttherapy but remained decreased in DAA-treated SVR patients up to 4 years posttherapy. Longitudinally, repeated measures analyses with generalized estimating equations showed that the interactions between DAA-based therapy and mixed cryoglobulinemia (OR: 3.291) and Hb levels (1.778) were positively, while DAA-based therapy (0.442), age (0.956), UA levels (0.698), homeostasis model assessment-insulin resistance index (0.961) and complement 4 levels (0.9395) were negatively associated with the eGFR. Among DAA-treated SVR patients, the baseline eGFR (OR: 1.014; 95%CI OR: 1.004-1.023) and high-sensitivity C-reactive protein (HR: 1.082; 95%CI HR: 1.018-1.15) were associated with eGFR reduction at 24 weeks and 4 years posttherapy, respectively. CONCLUSIONS: Hepatic fibrosis was an HCV-related factor for renal function. Longitudinally, DAA therapy was negatively, while the interaction between DAA therapy and mixed cryoglobulinemia was positively associated with renal function in SVR patients; deteriorated renal function was recovered in interferon-treated SVR patients. Particularly in DAA-treated SVR patients, baseline renal function and systemic inflammation were associated with short- and long-term reductions in renal function, respectively.

Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.

Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

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.