Stavroula Giannouli

Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia.

A systematic review and meta-analysis was carried out to compare the frequency of clinically significant outcomes between JAK2 V617F positive and wild type patients with essential thrombocythemia (ET). JAK2 V617F positivity in patients with ET was associated with a clear increase in the odds of thrombosis [OR=1.83 (95% CI, 1.32-2.53), p<0.0001], and much higher odds of transformation to polycythemia vera [OR=7.67 (95% CI, 2.04-28.87), p=0.0009]. The mean difference of the white blood cell count between JAK2 positive and negative patients was associated with an increased odds ratio for thrombosis (p=0.02). The JAK2 V617F mutation in patients with ET is associated with an increased risk of adverse cardiovascular outcomes via an increase in the leukocyte count.

Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment

Haematological abnormalities are common in systemic lupus erythematosus. Anaemia is found in about 50% of patients, with anaemia of chronic disease being the most common form. Impaired erythropoietin response and presence of antibodies against erythropoietin may contribute to the pathogenesis of this type of anaemia. Patients with autoimmune haemolytic anaemia usually belong to a distinct category, which is associated with anticardiolipin antibodies, thrombosis, thrombocytopenia, and renal disease, often in the context of secondary antiphospholipid syndrome. Autoantibodies, T lymphocytes, and deregulation of the cytokine network can affect bone marrow erythropoiesis, leading to anaemia.

Myelodysplasia-associated autoimmunity: clinical and pathophysiologic concepts.

Myelodysplastic syndrome (MDS), an acquired clonal disorder of haemopoietic progenitor cells, is characterized by haemopoietic insufficiency associated with cytopenias, leading to serious morbidity plus the additional risk of leukaemic transformation. In MDS an acquired insult to the haemopoietic stem cell leads to impaired differentiation and myelodysplasia. However, there is increasing evidence that the marrow failure of MDS is immune‐mediated. A model of MDS pathophysiology suggests that transformation of normal stem cells induces an autoimmune T‐cell response with the bone marrow as the target organ. This autoimmune attack results in chronic overproduction of pro‐apoptotic cytokines, especially tumour necrosis factor alpha (TNFα). In addition, several reports have revealed that approximately 10% of MDS patients have clinical autoimmune disorders. This review illustrates the cellular/molecular mechanisms and the implication of the tumour suppressor gene interferon regulatory factor‐1 (IRF‐1) in the pathophysiology of MDS‐associated autoimmune deregulation.

Long term remission of Sjögren’s syndrome associated aggressive B cell non-Hodgkin’s lymphomas following combined B cell depletion therapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)

Background: Primary Sjögren’s syndrome (SS) is associated with an increased frequency of non-Hodgkin’s lymphomas (NHLs), mainly of low histological grade. However, aggressive diffuse large B cell lymphomas (DLBCL) characterised by poor treatment outcome can also be encountered in SS. It has recently been shown that rituxan has significant therapeutic activity in this type of lymphoma. Objective: To evaluate the efficacy of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) in combination with rituxan in SS patients with DLBCL, and to determine the outcome in such patients. Methods: In an open, single case trial, six SS patients with DLBCL were assigned to receive eight cycles of CHOP every three weeks plus rituxan given on day 1 of each cycle. In a retrospective study, conducted by the European Concerted Action for SS, nine cases were diagnosed as DLBCL, all of whom had been treated with CHOP alone. These patients were used as historical controls. Results: The difference in the overall survival between the two treatment groups was significant. The group treated with rituxan plus CHOP had a 100% two year overall survival rate, while the historical controls had only a 37% survival rate. Extraglandular manifestations serving as predictors for lymphoma development such as palpable purpura and peripheral neuropathy disappeared. The remission of these signs was accompanied by a decrease in both circulating monoclonal cryoglobulins and rheumatoid factor activity and an increase in C4 levels. Clinically relevant toxicity was not detected. Conclusions: The addition of rituxan to standard CHOP chemotherapy results in improved treatment outcome in SS patients with aggressive DLBCL, without increasing toxicity.

Infliximab and methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of dosage regimens

BACKGROUND Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RRA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose. OBJECTIVES The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy. METHODS Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX. RESULTS From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kkg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mm/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration (> or = 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P =0.013 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy. CONCLUSIONS Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity.The benefits of high-dose treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy.

Suspects in the tale of lupus-associated thrombocytopenia

Immunologically mediated thrombocytopenia is a frequent clinical manifestation in patients with systemic lupus erythematosus (SLE). Autoantibodies targeting platelet membrane glucoproteins have a central role in peripheral platelet destruction. Autoantibodies against thrombopoietin are also present in about one‐third of patients, but their pathogenetic role is obscure. Thirty‐eight serum samples from SLE patients were tested for anti‐platelet antibodies, anti‐thrombopoietin antibodies and levels of circulating thrombopoietin. Bone marrow histology was also assessed. Thirty‐nine per cent of sera displayed anti‐thrombopoietin antibodies and 29% had circulating anti‐platelet antibodies. Anti‐thrombopoietin antibodies were associated with lower thrombopoietin concentrations, and lower mean platelet values in long‐term follow‐up. Anti‐platelet antibodies were present in about 40% of thrombocytopenic and non‐thrombocytopenic individuals but were absent in patients who had recovered from thrombocytopenia, supporting their pathogenetic role. Both autoantibodies were absent in control sera from patients with rheumatoid arthritis and primary Sjögren’s syndrome. Decreased bone marrow cellularity, normal or low number of hypolobulated, pyknotic megakaryocytes and stromal alterations were prominent findings in thrombocytopenic SLE patients, suggesting a defect in megakaryopoiesis. These findings were not evident in specimens from patients with idiopathic thrombocytopenic purpura who had increased megakaryocytes, normal cellularity and absence of stromal alterations. In conclusion, peripheral destruction due to platelet autoantibodies, anti‐thrombopoetin antibodies, lower effective circulating thrombopoetin and impaired compensatory response due to bone marrow damage interact in SLE and thrombocytopenia ensues.

Autoimmune manifestations in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a disorder characterized by decreased serum immunoglobulin concentrations and increased incidence of recurrent infections. Interestingly 20–25% of patients with CVID develop clinical features suggestive of an autoimmune disease. Although this association is well established, the immunodeficiency background of CVID patients manifesting autoimmune disorders is often overlooked. This study describes three CVID patients displaying a variety of autoimmune manifestations. The pathophysiologic mechanisms of autoimmunity in CVID are also reviewed.

Myelodysplasia and autoimmunity.

Purpose of reviewPrimary myelodysplastic syndromes (MDS) are heterogeneous clonal haemopoietic stem-cell disorders clinically presented with a varying degree of peripheral cytopenias and an increased probability of leukemic evolution. The natural history of MDS ranges from more indolent forms of disease spanning years to those rapidly progressing to overt leukemia. A distinct subset of MDS patients manifest overt autoimmune manifestations (AIMs), the pathogenesis and prognostic significance of which remain controversial. This review will briefly highlight aspects of immune-mediated myelosuppression and cytokine-induced cytopenias in MDS and further analyze MDS-associated AIMs clinically and pathogenetically. Recent findingsFacts provided by advanced studies suggest that an immune reaction against the evolving clone, operated by macrophages, T, natural killer and other effectors contribute to ineffective and dysplastic MDS hemopoiesis. Despite the fact that several immunologic abnormalities have been described in MDS, the precise pathophysiologic mechanism underlying AIMs remains unclear. SummaryThe encouraging biological insights into the autoimmune component of MDS pathophysiology can lead to the development of novel forms of treatment for controlling MDS process. MDS with AIMs constitute an ideal model in the investigation of disordered immune function in preleukemic states.

Effect of cA2 anti -tumor necrosis factor-α antibody therapy on hematopoiesis of patients with myelodysplastic syndromes

Purpose: Tumor necrosis factor α (TNF-α) plays a prominent role in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study was to explore the biological and immunoregulatory effect of the treatment with the anti–tumor necrosis factor-α monoclonal antibody cA2 on bone marrow (BM) progenitor/precursor and stromal cells and lymphocyte subsets, as well as the clinical response in MDS patients. Experimental Design: Ten low-intermediate risk MDS patients received i.v. cA2 (3 mg/kg) at weeks 0, 2, 6, and 12. The number, survival, and clonogenic potential of BM progenitor/precursor cells, the hematopoiesis-supporting capacity of BM stromal cells, and the lymphocyte activation status were investigated in the patients at baseline and following treatment using flow cytometry, clonogenic assays, and long-term BM cultures (LTBMC). Clinical response was evaluated according to standardized criteria. Results: cA2 administration reduced the proportion of apoptotic and Fas+ cells in the CD34+ cell compartment (P = 0.0215 and P = 0.0344, respectively) and increased the clonogenic potential of BM mononuclear and CD34+ cells (P = 0.0399 and P = 0.0304, respectively) compared with baseline. The antibody reduced tumor necrosis factor-α levels in LTBMC supernatants (P = 0.0043) and significantly improved the hematopoiesis-supporting capacity of LTBMC adherent cells. The proportion of activated peripheral blood and BM T-lymphocytes decreased significantly after treatment, suggesting an immunomodulatory effect of cA2. Two patients displayed minor hematologic responses whereas the remaining patients displayed stable disease with no disease progression. Conclusions: The encouraging biological insights from cA2 administration may be useful in conducting further clinical trials using cA2 for selected MDS patients, particularly those with evidence of immune-mediated inhibition of hematopoiesis.

The role of MTHFR gene in multiple myeloma

AbstractCase-control studies investigating associations between multiple myeloma (MM) and the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) have provided controversial results. In an attempt to interpret these results, a meta-analysis of all available studies was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using fixed effects (FE) and random effects (RE) models. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. The meta-analysis revealed non-significant heterogeneity between studies (Pq ≥ 0.65). The dominant model for the effect of 677T allele produced significant association overall [FE OR = 1.23 (1.04–1.47)] and in Caucasians [FE OR = 1.54 (1.14–2.08)], but not in East Asians [FE OR = 1.05 (0.82–1.34)]. Although the cumulative meta-analysis for the dominant model of 677T allele showed a downward trend of RE OR for the period 2000–2007, the association still remained significant. Analysis of the A1298C polymorphisms revealed lack of association both in Caucasians and in East Asians. There is an indication of potential bias: a differential magnitude of effect in large versus small studies emerged. In conclusion, the accumulated evidence indicated an association between MTHFR C677T polymorphism and MM in Caucasians under a dominant model.