Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences ...in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.
Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France ...has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 109/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 109/L (interquartile range, 75-167 × 109/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 109/L (interquartile range, 35-44 × 109/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
To describe features of reactive haemophagocytic syndrome (RHS) in HIV-1-infected adult patients. To compare characteristics of patients with malignancy-associated RHS and infection-associated RHS.
...Retrospective study in three departments of Infectious Diseases/Internal Medicine at three French tertiary centres.
Medical charts of HIV-1-infected adult patients and RHS seen between January 2006 and December 2007 were reviewed. Demographic, clinical and laboratory data obtained at the time of RHS episode were compared between patients with malignancy-associated RHS and infection-associated RHS using non-parametric tests. The overall survival was assessed using the Kaplan-Meier method.
Fifty-eight HIV-1-infected patients were diagnosed with RHS certain RHS n = 43, possible RHS n = 15, median (range) age 42 (23-85) years, men 76%. At time of RHS, the median duration of HIV infection was 4 (0-22) years and 57% received HAART. The median CD4 lymphocyte count was 91 (2-387)/microl and 35% of patients had a plasma HIV-1 RNA less than 50 copies/ml. Underlying haemopathy/malignancy (Hodgkin lymphoma n = 10) or infection (tuberculosis n = 9, cytomegalovirus infection n = 5) were evidenced for 31 and 23 patients, respectively. Patients with haemopathy/malignancy-associated RHS presented more frequently with splenomegaly (97 vs. 70%, P < 0.01), lower aspartate aminotransferase (36 vs. 84 UI/l, P < 0.01) and lactate dehydrogenase (530 vs. 911 UI/l, P < 0.01) levels and CD8 cell count (234 vs. 588/microl, P < 0.01). Eighteen (31%) patients died. The overall survival was not statistically different between the two groups (P = 0.68).
In the HAART era, RHS is frequently associated with underlying haemopathy/malignancy, especially Hodgkin lymphoma. The prognosis remains poor but seems, however, better than in the pre-HAART era.
Direct bacterial recognition by innate receptors is crucial for bacterial clearance. Here, we show that the IgA receptor CD89 is a major innate receptor that directly binds bacteria independently of ...its cognate ligands IgA and c-reactive protein (CRP). This binding is only partially inhibited by serum IgA and induces bacterial phagocytosis by CD11c+ dendritic cells and monocytes and/or macrophages, suggesting a physiological role in innate host defense. Blood phagocytes from common variable immunodeficiency patients bind, internalize, and kill bacteria in a CD89-dependent manner, confirming the IgA independence of this mechanism. In vivo, CD89 transgenic mice are protected in two different models of sepsis: a model of pneumonia and the cecal ligation and puncture (CLP) polymicrobial model of infection. These data identify CD89 as a first-line innate receptor for bacterial clearance before adaptive responses can be mounted. Fc receptors may emerge as a class of innate receptors for various bacteria with pleiotropic roles.
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•CD89 directly binds Streptococcus pneumoniae and Escherichia coli•CD89 acts as an innate receptor before adaptive responses take place•CD89 protects from sepsis by inducing innate immune responses against infections
de Tymowski et al. demonstrate that CD89 serves as an innate receptor during the early phase of infection. During the late phase, the receptor acts in both innate and adaptive immune responses through double interaction with IgA- or CRP-opsonized and non-opsonized bacteria.
BACKGROUND: The objective was to assess the efficacy and safety of splenectomy and cyclophosphamide as salvage therapies in severe thrombotic thrombocytopenic purpura (TTP).
STUDY DESIGN AND METHODS: ...During a 10‐year period, patients who did not improve with plasma exchanges, steroids, vincristine, and/or rituximab were considered for splenectomy or cyclophosphamide. Patients with a documented severe (<10% of normal value) acquired ADAMTS13 deficiency are reported here.
RESULTS: Eighteen patients with a severe acquired ADAMTS13 deficiency required a salvage therapy. Thirteen patients had a splenectomy 19 (interquartile range IQR, 10‐51) days after TTP diagnosis. One patient died the day after splenectomy. The remaining patients improved platelets (PLTs) until Day 6, along with a rapid and major lactate dehydrogenase improvement. Six patients, however, subsequently experienced a transient worsening. Durable PLT count recovery in survivors was observed within 13 (IQR, 11.5‐25.5) days. Postoperative complications included thromboembolic events (two cases) and infections (five cases). Five patients received pulses of cyclophosphamide 12 (IQR, 12‐15) days after TTP diagnosis. All patients recovered PLTs 10 (IQR, 9‐24) days after the first pulse and two experienced a transient worsening. Three patients experienced infections. Three relapses occurred 5 months, 2.5 years, and 4.5 years after splenectomy and one relapse occurred 3.5 years after cyclophosphamide. After a 2.5 (IQR, 0.75‐6.2)‐year follow‐up, the overall survival was 94%.
CONCLUSION: Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies.
Multiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains ...an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.
The effects of nelfinavir (1-10 μM) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.
Nelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.
These results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.
Heavy‐chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy‐chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, ...showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1‐HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ‐HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.
Introduction
The prognosis of thrombotic thrombocytopenic purpura (TTP) has considerably improved since the introduction of plasma exchange (PEX) therapy. However, unresponsive thrombotic ...thrombocytopenic purpura (Un-TTP) still carries high morbidity and mortality rates, indicating a need for early specific treatments.
Patients and Methods
In a retrospective study including consecutive adults with TTP admitted between January 1997 and January 2011 in a teaching hospital intensive care unit (ICU), our objective here is to identify early clinical and laboratory features predicting Un-TTP. Patients who responded to plasma exchange and steroids (
N
= 49) were compared with patients with unresponsive TTP defined as requirement for other treatments, protracted course, or death (
N
= 37, 43 %).
Results
Hospital mortality was 24.3 % in the Un-TTP group. Variables associated with Un-TTP on univariate logistic regression were older age, cardiac involvement, neurological involvement, higher anti-a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) immunoglobulin G (IgG) titer, lower platelet counts starting on day 2, higher Sequential Organ Failure Assessment (SOFA) scores starting on day 3, need for higher plasma volumes to obtain remission, and greater use of adjuvant treatments and life-sustaining interventions. Multivariate logistic regression identified four factors independently associated with Un-TTP: age over 60 years odds ratio (OR) 7.90; 95 % confidence interval (95 % CI) 1.06–78.34, cardiac (OR 5.17; 95 % CI 1.63–16.39) or neurological (OR 8.04; 95 % CI 1.27–51.03) manifestations at diagnosis, and day 2 platelet count less than 15 G/l (OR 3.88; 95 % CI 1.30–11.62).
Conclusion
Therapeutic intensification starting on day 3 or even earlier in patients with the independent risk factors for unresponsive TTP identified in our study deserves evaluation in a multicenter prospective study.
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