Increased seroprevalence of human herpesvirus 8 in patients with hematological disorders

Human herpesvirus 8 (HHV8) has been consistently linked to Kaposi's sarcoma and many hematological diseases such as pleural effusion lymphoma, multicentric Castleman's disease, some lymphoproliferative diseases and posttransplantation bone marrow failure. However, whether patients with hematological disorders are at a higher risk of HHV8 infection has not been determined. In this study, indirect immunofluorescence was used to detect antibodies against lytic antigens of HHV8 in 265 patients with hematological disorders. Our data showed that 24.5% of patients (65/265) were seropositive for HHV8 IgG antibody, which was significantly higher than in our general population (p < 0.001). A significantly higher seropositive rate can be found in patients with lymphoma, leukemia, autoimmune cytopenias and myeloproliferative disorders, but not in patients with myeloma or aplastic anemia. No difference in the seropositive rate is associated with gender or age. We conclude that some patients with hematological disorders are at a higher risk of HHV8 infection.     

Hematologic malignancies in patients with cryoglobulinemia: association with autoimmune and chronic viral diseases

OBJECTIVE: To determine the prevalence and clinical characteristics of hematologic malignancies occurring in a large series of patients diagnosed with cryoglobulinemia, and to study their association and overlap with autoimmune and/or chronic viral diseases. METHODS: We retrospectively analyzed the occurrence of hematologic malignancies in 607 patients diagnosed with cryoglobulinemia in a single institution. Clinical, histologic, and serologic characteristics of patients were recorded on a protocol form. Hematologic malignancies were diagnosed according to the Revised European-American Lymphoma/World Health Organization classification criteria. RESULTS: Of the total cohort of 607 patients with cryoglobulinemia, we retrospectively identified 27 patients (5%) in whom a hematologic malignancy was diagnosed, including 24 (89%) lymphoproliferative and 3 (11%) myeloid malignancies. Fifteen (56%) were men and 12 (44%) women, with a median age at diagnosis of hematologic malignancy of 67 years (range, 44 to 88 years). The identified hematologic malignancies were non-Hodgkin lymphoma (n = 18), Hodgkin lymphoma (n = 2), chronic lymphocytic leukemia (n = 2), and 1 case each of multiple myeloma, Waldenstr?m macroglobulinemia, Castleman disease, chronic myeloid leukemia and myelodysplastic syndrome. Of the 18 patients with non-Hodgkin lymphoma, there was a predilection for specific histologic types (diffuse large B-cell lymphoma in 8 cases and small lymphocytic lymphoma in 4) and a higher frequency of a primary extranodal origin in 6 (33%) cases. Conditions associated with hematologic malignancies were hepatitis C virus (HCV) infection in 14 patients (52%) and systemic autoimmune diseases in 13 (48%), with both HCV and systemic autoimmune disease in 6 cases (22%). CONCLUSIONS: Hematologic neoplasia associated with cryoglobulinemia is defined by a clear predominance of lymphoproliferative disorders (mainly non-Hodgkin lymphoma), with substantial extranodal involvement and an elevated presence of immunologic markers. HCV infection is the main etiologic factor associated with hematologic malignancies in patients with cryoglobulinemia, followed by specific systemic autoimmune diseases such as Sj?gren syndrome and systemic lupus erythematosus, highlighting the close relationship between lymphoproliferation, autoimmunity, and viruses.     

Red pulp in splenomegaly syndrome: morphometric light and electron microscopy studies

From a series of consecutively studied spleens, perfusion-fixed and investigated according to a standardized procedure allowing morphometric investigations at the light and electron microscopic levels, 33 spleens causing splenomegaly syndrome (12 lymphoproliferative diseases, 10 hairy cell leukaemia, 11 myeloproliferative diseases) were compared with data in controls and autoimmune haemolytic anaemia and hereditary spherocytosis from previous studies. In splenomegaly syndrome, especially in hairy cell leukaemia and myeloproliferative diseases, less so in lymphoproliferative diseases, there is a disproportionate increase in the volume of pulp cords in the red pulp. Values for erythrocyte volume density are of the same order as splenic erythrocyte concentration determined by scintigraphic kinetic methods. Cases with complicating immunohaemolysis show a rather high proportion of erythrocyte profiles with nearly spheric shape as in autoimmune haemolytic anaemia and hereditary spherocytosis.     

Malignant lymphoma-associated autoimmune diseases--a descriptive epidemiological study

Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance. We reviewed 940 patient charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 421 non-Hodgkin's lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an autoimmune disease (26 females, six males, mean age 48.3 years). The most common diagnosis was Sj?gren's syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addison's disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkin's lymphoma patients (308 males, 211 females), an associated autoimmune disease occurred in 45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and vasculitis (1). We also analyzed histology, choice of treatment, and sequence of appearance of the disease types. We found a difference between NHL and Hodgkin's lymphoma patients, since in NHL autoimmunity - mostly from Sj?gren's syndrome - preceded the lymphoma diagnosis (70%), but in Hodgkin's the autoimmunity developed mainly after the treatment of malignancy. The relatively high prevalence of autoimmune diseases in malignant lymphomas has several explanations. Clinicians have to consider autoimmunity when treating lymphoproliferative disorders.     

Hepatitis C virus infection and lymphoproliferative diseases: prospective study on 1,576 patients in France

CONTEXT: Discordant data have been reported about the prevalence of hepatitis C virus (HCV) infection in patients with lymphoproliferative diseases and the putative role of HCV in lymphomagenesis. OBJECTIVE: To assess the prevalence of HCV infection in patients admitted to a hematology department in Paris, France. DESIGN: Prospective, controlled study. SETTING: University medical center. PATIENTS: 813 patients admitted to the Hematology department (164 B-cell non-Hodgkin's lymphoma, 34 Hodgkin's diseases, 107 chronic lymphocytic leukemia, 54 multiple myeloma, 12 Waldenstr?m's macroglobulinemia, 17 acute lymphoblastic leukemia, 6 hairy cell leukemia, 189 myeloproliferative diseases, 6 solid organ tumors, and 224 nonmalignant diseases) and 694 patients admitted to the Internal Medicine department (control group). MEASUREMENTS: All patients were tested for antibodies to HCV by a third-generation enzyme-linked immunosorbent assay. RESULTS: HCV antibodies were detected in 20 of 813 (2.46%) patients in Hematology including 11 of 394 (2.79%) patients with lymphoproliferative diseases, 3 of 164 (1.83%) B-cell non-Hodgkin's lymphoma, 2 of 107 (1.87%) chronic lymphocytic leukemia, 1 of 54 (1.85%) multiple myeloma, 1 of 189 (0.5%) myeloproliferative diseases, and 8 of 224 (3.57%) nonmalignant hematologic diseases. HCV antibodies were detected in 3 of 694 (0.43%) patients in the control group. HCV contamination preceded B-cell non-Hodgkin's lymphoma only in 2 of 3 HCV-positive patients. CONCLUSION: The prevalence of HCV infection was low (1.83%) in patients with B-cell non-Hodgkin lymphoma. HCV seems not to play a major role in the pathogenesis of B-cell lymphoma in France. Cofactors should be stressed to explain geographical discrepancies.     

High prevalence of autoimmune phenomena in hepatitis C virus antibody positive patients with lymphoproliferative and connective tissue disorders

The aim of this study was to investigate whether hepatitis C virus (HCV) may perturb the immune system towards autoreactivity. We studied the relationship between the prevalence of anti-HCV and the presence of laboratory and/or clinical autoimmune features in 300 patients: lymphoid malignancies (167) and autoimmune disorders (connective tissue diseases 100; idiopathic thrombocytopenic purpura (ITP) 33). As a control, hepatitis B surface antigen (HBV) and anti-hepatitis B core antigen (anti-HBc) were related to the same parameters.   Anti-HCV and anti-HBV were detected in 68/300 (22.6%) and 70/300 (24.6%) patients, respectively. HCV prevalence was 18% in lymphoproliferative disorders (anti-HBc 28.1%) and 26% in connective tissue disease (anti-HBc 16.3%). Among ITP cases, 12/33 (36.4%) were anti-HCV⁺ and 10/33 (30.3%) anti-HBc⁺. In 24/30 (80%) anti-HCV⁺ patients with lymphoproliferative disorders at least one serologic or clinical autoimmune abnormality was detected. To the contrary, only 10/45 (22.2%) anti-HBc⁺ patients with lymphoproliferative disorders had at least one serologic or clinical abnormality ( P  < 0.0001). A statistically significant correlation was observed between HCV prevalence and the number of autoimmune alterations in both lymphoproliferative and connective tissue disorders, which was not found for anti-HBc.   These data suggest that HCV may skew the immune system toward the production of autoantibodies and also support the possibility that some cases of ITP may be linked to both HCV and HBV infection.     

Malignant lymphomas and autoimmunity—a single center experience from Hungary

Autoimmune diseases and malignant lymphomas have numerous similarities in their etiology and pathogenesis. Patients with autoimmune disorders have increased risk to develop non-Hodgkin's lymphomas, yet little is known about the occurrence of autoimmune features within lymphoma patients. Our aim was to examine the prevalence of autoimmune diseases among patients with non-Hodgkin's (NHL) and Hodgkin's lymphoma (HL). We reviewed 352 patients' charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 231 NHL patients, 30 (12.9%) had autoimmune disorders, while there were 11 patients who suffered from more than one disease entity. It was Sj?gren's syndrome that occurred in the largest number (eight cases), other frequent entities were undifferentiated connective tissue disease (seven), thyroiditis (six), rheumatoid arthritis (four), and systemic vasculitis (four). The female/male ratio was significantly different between patients with or without autoimmune diseases, while no other clinical features differed significantly between the two groups. Ten patients (33.3%) were initially diagnosed with lymphoma, 13 (43.3%) of them had already been diagnosed with autoimmune disease at the time of lymphoma occurrence. Six patients (20%) with previously diagnosed immunological disorder developed new autoimmune condition after the treatment of lymphoma. Lymphoma and autoimmune disease occurred simultaneously in one patient. Among the 121 HL patients, 14 (11.5%) had associated autoimmune disease. Ten patients developed thyroiditis after the lymphoma treatment, two had immune thrombocytopenia, and one had autoimmune hemolytic anemia. One female patient was diagnosed with systemic sclerosis 10 years before the onset of HL. Our results highlight that an increased risk for the development of autoimmune diseases should be considered in patients both with NHL and HL.     

Lymphoproliferative and intestinal malignancies in 214 patients with biopsy-defined celiac disease

Prior studies have suggested that the incidence of some neoplastic disorders, particularly malignant lymphoma, is increased in celiac disease. In the present study, lymphoproliferative and intestinal cancers in 214 consecutive biopsy-defined celiac disease patients, including 148 females (69.2%) and 66 males (30.8%), seen by a single clinician over more than 20 years were tabulated. Of the 214 patients, 151 were diagnosed with celiac disease before age 60 and 63 at or after age 60. In total, 18 malignant lymphomas and 3 small intestinal adenocarcinomas were detected. While the overall incidence of malignant lymphoma was 8.4%, similar to other European centers, the incidence in elderly celiacs in this study was 22.2%. Celiac disease was detected before or even after the diagnoses of lymphoma or small intestinal adenocarcinoma were established. In some, epithelial lymphocytosis was evident in gastric, colonic, or biliary ductal epithelium. In addition, other immune-mediated disorders, dermatitis herpetiformis, and autoimmune thyroid disease were common, suggesting a distinct clinical and pathologic phenotype in celiac disease that may predispose to malignant complications. Finally, except for a single hypopharyngeal carcinoma in a celiac disease patient with a malignant lymphoma, other malignant disorders of esophagus, stomach, and colon were not detected.     

Studies of Splenic Function in the Myeloproliferative Disorders and Generalized Malignant Lymphomas

The relative importance of splenic red-cell pooling, sequestration and cell destruction in the causation of anaemia has been studied in 29 patients—16 with generalized lymphoproliferative disease, 12 with myeloproliferative disease and one with idiopathic autoimmune haemolytic anaemia.
A scanning method with [¹¹C]carbon monoxide was used for direct in vivo measurement of splenic red-cell volume, and the spleen was delineated by-a scan after injection of ⁸¹Rb-labelled red cells, damaged with non-radioactive 1-mercuri-2-hydroxypropane (MHP). The clearance time of the damaged cells from the circulation was used as an index of splenic function. The fraction of red cells in the spleen varied from 2.9% to 32% and the splenic red-cell volume ranged from 38 to 1000 ml. In patients with lymphoproliferative disorders their spleens contained a smaller proportion of red cells, relative to splenic size, than patients with myeloproliferative disease. Clearance of cells damaged with 1-mercuri-2-hydroxypropane (MHP) was 30–60 min in normal subjects. Slow clearances were found in some patients with lymphosarcoma; fastest clearances occurred in patients with obvious haemolytic anaemia. No clear relationship was noted between the rate of clearance and splenic size or splenic red-cell volume.     

Anti-neutrophil cytoplasmic antibodies (ANCA) in myelodysplasia and other haematological disorders

Background: Anti-neutrophil cytoplasmic antibodies (ANCA) are typically associated with small vessel vasculitides. They are also found in situations where other autoantibodies are common, sometimes after infections and possibly in individuals who have received multiple blood transfusions. Aims: The aim of this study was to determine the incidence of ANCA in a variety of haematological disorders, where these predisposing factors may be at work. Methods: Sera from patients with myelodysplasia (n= 26), acute myeloid leukaemia (AML) (n= 3), and myeloproliferative (n= 25) or lymphoproliferative syndromes (n= 16) were screened for ANCA using a crude neutrophil cytoplasmic extract ELISA and indirect immunofluorescent examination of normal peripheral blood neutrophils. Positive results were confirmed by ELISAs for anti-proteinase 3, anti-myeloperoxidase or anti-elastase antibodies. Results: ANCA were demonstrated in two patients with myelodysplasia, both with chronic myelomonocytic leukaemia and greater than 5% blasts in the bone marrow. Both of these individuals were infected at the time that ANCA were demonstrated and other autoantibodies were present. One of these individuals had never had evidence of any vasculitis; the other probably developed myelodysplasia after treatment with cyclophosphamide for Wegener's granulomatosis. ANCA were demonstrated in one individual with AML secondary to myelodysplasia. ANCA were also found in a patient with lymphoma in whom autoantibodies against red cells and platelets were already noted. ANCA were demonstrated in one further individual with lymphomatoid granulomatosis, a condition that resembles Wegener's granulomatosis clinically and histologically, but which is treated as a lymphoma. No ANCA were present in any of the patients with myeloproliferative syndromes. Discussion: ANCA probably occur secondary to immune dysregulation in myelodysplasia and the lymphoproliferative conditions and they are not necessarily associated with the presence of a vasculitis.     

Prevalence of hepatitis B and C viruses in patients with lymphoproliferative disorders

The etiology of most lymphoproliferative disorders remains unclear, though several hypotheses have been proposed. One of the conjectured mechanisms is infection of a tumor clone by an oncologic virus. Recently, evidence has arisen implicating both hepatitis B and, even more so, hepatitis C viruses in the pathogenesis of lymphoproliferative disease. Based on this information, we surveyed the prevalence of hepatitis B and C virus in patients with lymphoproliferative disease. A total of 334 newly-diagnosed lymphoproliferative disease patients (200 males, 134 females) and 1,014 (133 females, 881 males) healthy controls were randomly recruited from the university blood bank. Serologic evaluation for hepatitis B and C viruses was conducted and confirmed using PCR analyses. Those with hepatitis B and/or C, controls, and subgroups of patients with lymphoproliferative disease were compared using Pearson Chi-square analysis. Among patients with lymphoid tumors, the seropositivity of HbsAg and/or anti-HCV was 8.7% (29/334), and among the controls 6.1% (49/802), however this difference did not achieve statistical significance (P = 0.23, OR: 1.36, 95% CI: 0.82–2.26). We found no significant gender- or age-related differences for either hepatitis B or C seropositivity. There were no significant differences between the seropositivity rates of hepatitis B, C, or both in either NHL or Hodgkin’s lymphoma. However, in the diffuse large cell lymphoma and follicular lymphoma subgroups, the HbsAg seropositivity rate was significantly higher than that in the controls (P = 0.017, P = 0.048, respectively), as was the seropositivity rate for hepatitis C in those with diffuse B cell lymphoma versus controls (P = 0.008). We did not identify any significant difference in the combined prevalence of hepatitis B or C seropositivity between patients with lymphoproliferative disorders and controls. However, significant differences were revealed among certain patient subgroups versus the controls. These two viruses could play a role in the development of certain specific lymphoproliferative disorders. Nevertheless, larger epidemiological studies are necessary and should focus, particulary on specific patient subgroups.     

A Longitudinal Comparison of Antibodies to Epstein-Barr Virus and Clinical Parameters in Chronic Lymphocytic Leukemia and Chronic Myelocytic Leukemia

Elevated titers to the Epstein-Barr virushave previously been reported in a number of lymphoproliferative diseases, including Burkitt’s lymphoma, infectiousmononucleosis, and Hodgkin’s disease.This study also demonstrates a significantly higher titer against EBV in agroup of patients with chronic lymphoproliferative disease (CLL) than in agroup of patients with chronic myeloproliferative disease (CML) or normal individuals. No significant antibody changeswere detected in the 20 CML patientsor 23 of the 24 CLL patients who werefollowed for a period of time up to 5 yr.It appears that the elevated EBV titersseen in patients with CLL reflect anevent or process occurring prior to theonset of disease or in the very earlystages rather than a nonspecific riseparalleling the increase in total-bodylymphocytes.

Submitted on March 22, 1971 Revised on May 18, 1971 Accepted on May 19, 1971     

Non HCV-related mixed cryoglobulinemia

A striking association (>90%) between mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) infection has been established by means of clinico-epidemiological and laboratory studies. However, little information is available as regards the etiopathogenesis and the actual percentage of HCV-negative MC. This latter seems to be more frequent in the same geographical areas where the overall prevalence of MC is low. In 195 Italian patients with serum mixed cryoglobulins consecutively analyzed at the laboratory of our hospital, during one year, the prevalence of HCV-negative MC was 15.9%. Moreover, we evaluated the clinico-serological characteristics of our whole series of 65 HCV-negative MC patients: “essential” MC was present in only 25%, while the majority of cases showed different connective tissue diseases or neoplastic disorders. Interestingly, patients with Sjögren's syndrome or lymphoma had higher levels of cryocrit with cryoglobulinemic syndrome comparable to that found in HCV-positive MC patients.MC is a multifactorial disorder; considering possible etiological factors and clinical associations the disease may present different subsets: the prevalent group of HCV-positive MC; HCV-positive MC associated with different autoimmune lymphoproliferative disorders; two MC subsets without any apparent causative agent: those with well-known autoimmune lymphoproliferative disorders and the rare cases of “essential” MC; and finally MC associated with other infectious agents.     

Cold agglutinins, clinical presentation and significance; retrospective analysis of 58 patients

PURPOSE: To describe clinical, biological characteristics and associated diseases of cold agglutinins in adults. METHODS: Retrospective study in a single department of internal medicine from 1997 to 2002. The inclusion criteria were a positive direct Coombs test and a positive research for cold-reactive autoantibodies. We recorded for each patient: clinical presentation at onset and during follow-up, biological parameters of haemolysis, biological characteristics of the cold agglutinin and associated diseases. RESULTS: Fifty-eight patients (34 females, 24 males), with medium age of 58.8 were included in the study. Clinical presentation was highly variable between acute life-threatening haemolysis and absence of symptoms. Results of direct antiglobulin test were C3 (74%), IgG + C3 (22.4%), IgG (3.4%). Titer, thermal amplitude, strength and specificity of Coombs test were correlated, in all cases except 6, with cold agglutinin haemolytic activity. In 77.6% of cases cold agglutinin was secondary; related to: autoimmune disorders (n = 19), lymphoproliferative disorders (n = 11) and infections (n = 10). CONCLUSION: Clinical presentation of cold agglutinin is highly variable and not always related to the biological characteristics of the bound antibody (titer, thermal amplitude, specificity). In our single center study, diseases associated with cold agglutinin were various with the highest frequency of auto-immune disorders. Our study underlined also the high frequency of lymphoproliferative disorders and justifies a close follow-up of these patients. Finally, we reported a high frequency of hepatitis C virus infection among the infectious aetiologies.     

Helicobacter pylori and autoimmune neutropenia

Recent studies have suggested a high prevalence of Helicobacter pylori infection in patients with immune thrombocytopenia. Eradication therapy for H. pylori led to an increase in platelet count in a significant number of patients. No evidence of lymphoproliferative disorder has been reported in any of the patients in these studies. We describe a patient who presented initially with autoimmune neutropenia but was subsequently found to have a mucosa-associated lymphoid tissue (MALT) lymphoma. An impressive recovery of the neutrophil count was noted on H. pylori eradication therapy. To our knowledge this is the first reported case of autoimmune neutropenia associated with H. pylori-induced MALT lymphoma. The relationship between lymphoproliferative disorders and autoimmunity is discussed.     

Thrombotic manifestations of the antiphospholipid syndrome in patients with malignancies

The presence of antiphospholipid antibodies has been reported in a large variety of patients with malignancies. Many case reports and reviews have appeared indicating that the presence of the antiphospholipid antibodies is related to thrombotic associations with the antiphospholipid syndrome (APS) in a proportion of these patients. We investigated the frequency of the thrombotic manifestations in 58 patients demonstrating antiphospholipid antibodies and with a history of neoplasia, including haematologic and lymphoproliferative malignancies. Antiphospholipid antibodies were detected by clotting assay [lupus anticoagulant (LAC)] or by enzyme-linked immunosorbent assay [anticardiolipin antibodies (aCL)] according to the Sapporo criteria. Patients, 39/58, suffered from solid tumours and 19/58 patients from malignant haematologic or lymphoproliferative diseases. One patient was suffering simultaneously from two solid tumours and a malignant lymphoma. Among the patients with solid tumours, 18/39 (46%) patients had thromboembolic complications of the antiphospholipid syndrome. Among the patients with haematologic and lymphoproliferative malignancies, only 6/19 (32%) suffered from thromboembolic complications. There was, however, no relation between the titres of aCL antibodies and the clinical manifestations. The presence, but not the titres, of antiphospholipid antibodies may identify a subset of cancer patients with a high risk of developing thrombotic complications. The frequency of thrombosis, however, is lower in aPL-positive patients with lymphoproliferative and haematological malignancies.     

Autoantibodies to platelet glycoproteins in patients with disease-related immune thrombocytopenia

Although increased platelet destruction and elevated platelet-associated IgG have been shown in patients with lymphomas and various autoimmune diseases, such as systemic lupus erythematosus (SLE), there have been few studies evaluating autoantibodies against platelet-specific antigens. We evaluated 24 patients retrospectively with disease-related thrombocytopenia (12 with lymphoproliferative diseases and 12 with various autoimmune disorders) using a recently reported antigen-specific assay. Autoantibodies against platelet GPIIb/IIIa or GPIb/IX were noted in 15 of the 24 patients (10 of 12 with autoimmune disease and five of 12 with lymphoproliferative disorders). Platelet-associated autoantibodies were present in 60% and plasma autoantibodies in 33%. Anti-GPIIb/IIIa autoantibodies were much more common than those against GPIb/IX. In one patient each with thrombocytopenia and either SLE or myasthenia gravis, absorption of plasma with platelets completely removed the anti-GPIIb/IIIa autoantibodies, but did not affect the level of anti-cochlear autoantibody involved with immune-mediated hearing loss in the SLE patient or the anti-acetylcholine receptor autoantibody in the myasthenic patient. These findings show that, in some cases of disease-related immune thrombocytopenia, autoantibodies against GPIIb/IIIa or GPIb/IX can be detected similar to those seen in chronic ITP. As shown in two patients with multiple autoimmune manifestations, the various autoantibodies have diverse specificities and do not crossreact.     

New Evidence of Significant Association between EBV Presence and Lymphoproliferative Disorders Susceptibility in Patients with Rheumatoid Arthritis: A Systematic Review with Meta-Analysis

Development of lymphoproliferative disorders (LPDs) is one of the well-known life-threatening complications in rheumatoid arthritis (RA) patients. However, there is a lack of definitive conclusions regarding the role of Epstein-Barr virus (EBV) activity in RA initiation and progression, especially in promoting LPDs. A systematic review and meta-analysis of studies that reported an EBV positive result in RA-LPD patients and controls were conducted. Studies published before 27 July 2021 were identified through PubMed, Web of Science, and SCOPUS. A total of 79 articles were included in the systematic review. The prevalence of EBV positive result among RA-LPD patients was 54% (OR = 1.54, 95% CI = 1.45–1.64). There was a statistically significant association between EBV presence and LPD susceptibility in RA patients in comparison with all controls (OR = 1.88, 95% CI = 1.29–2.73) and in comparison with LPD patients only (OR = 1.92, 95% CI = 1.15–3.19). This association was not shown in comparison with patients with autoimmune diseases other than RA who developed LPD (OR = 0.79, 95% CI = 0.30–2.09). This meta-analysis confirmed a high prevalence of EBV in the RA-LPD population. Furthermore, it provides evidence for the association between EBV presence and LPD susceptibility in RA patients, but not in those with other autoimmune diseases who developed LPD.     

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.     

Cryoglobulinemic vasculitis

PURPOSE OF REVIEW: Cryoglobulinemic vasculitis is an immune-complex-mediated systemic vasculitis involving small-medium-sized vessels. A causative role of hepatitis C virus in over 80% patients has been definitively established, with heterogeneous geographical distribution. This review focuses on recent etiopathogenetic, clinico-diagnostic, and therapeutical studies. RECENT FINDINGS: Hepatitis C virus cannot be integrated into the host genome; it may exert a chronic stimulus to the immune system. The interaction between hepatitis C virus envelope protein E2 with B-cell CD 81 receptor may increase the frequency of VDJ rearrangement in antigen-reactive B lymphocytes. One consequence is the activation of various protooncogenes, including anti-apoptotic Bcl-2. The extended B-cell survival is responsible for autoantibody and immune-complex production, including mixed cryoglobulins; some malignancies, mainly B-cell lymphomas, may complicate cryoglobulinemic vasculitis. Environmental or viral/host genetic cofactors should be relevant in the pathogenesis of hepatitis C virus-related diseases. Cryoglobulinemic vasculitis may overlap with other diseases (systemic vasculitides, Sj?gren's syndrome, autoimmune hepatitis, lymphoma), which should be carefully considered for a correct diagnosis and treatment. Cumulative survival of cryoglobulinemic vasculitis is significantly lower compared with the general population. Therapeutic strategies for cryoglobulinemic vasculitis include etiologic (antiviral), pathogenetic (cyclophosfamide, rituximab), or symptomatic (steroids, plasmapheresis) treatments, which should be tailored to the individual patient according to the severity/activity of clinical symptoms. SUMMARY: Cryoglobulinemic vasculitis represents a crossroads among autoimmune and lymphoproliferative disorders; as hepatitis C virus infection is the major causative factor, cryoglobulinemic vasculitis is an important model for etiopathogenetic studies of virus-related diseases.