Search

The CARMEN-France registry is a prospective, multicenter registry in France including adult patients with a new diagnosis of immune thrombocytopenia or of autoimmune immune hemolytic anemia (2402 patients included in December 31, 2023). The recording of clinical, biological and treatment data allows detailed epidemiological and pharmacoepidemiological real-world studies. This review summarizes the CARMEN-France registry protocol, gives examples of studies conducted in the registry, and indicates future directions such as inclusion of patient reported outcomes, linkage with the French national health insurance database and linkage with other registries in Europe., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%-4.8% in total; 7.6%; 95% CI: 4.9%-10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months)., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Corticosteroids remain the first-line treatment of immune thrombocytopenia (ITP), but increase the risk of osteoporosis and fractures. Bisphosphonates are used for the treatment of osteoporosis, but their usage among patients with ITP has not been systemically described. We investigated the risk of fractures and the use of bisphosphonates in adult patients with primary (pITP) and secondary ITP (sITP) compared with matched comparators in a nationwide registry-based cohort study. We identified 4030 patients with pITP (median age 60 years [IQR, 40-74]), 550 with sITP (median age 59 years [IQR, 43-74]) and 182 939 age-sex-matched general population comparators. All individuals were followed for incident fractures. Bisphosphonate use was estimated for calendar-years and in temporal relation to the ITP diagnosis. Adjusted cause-specific hazard ratio (csHR) for any fracture was 1.37 (95% confidence interval [CI] 1.23; 1.54) for pITP and 1.54 (1.17; 2.03) for sITP. The first-year csHR was 1.82 (1.39; 2.40) for pITP and 2.78 (1.58; 4.91) for sITP. Bisphosphonate use over calendar-years and in the early years following ITP diagnosis was higher among patients with ITP diagnosis compared with the general population. In conclusion, the risk of fractures and the use of bisphosphonates are higher in patients with ITP compared with the general population., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy)., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Defining immune thrombocytopenia (ITP) in two age groups-children and adults-overlooks the specific clinical features and needs of adolescents and young adults (AYAS). We previously reported a high risk of chronic disease at 12 months (50%); however, data on the course of chronic ITP, the risk of refractoriness and treatment strategies in AYAS are limited. Data from patients aged 12-25 years with chronic primary ITP at 12 months were extracted from three large registries between 2004 and 2021. Clinical and laboratory data were evaluated until 48 months of follow-up (FU). Refractory ITP was defined as the administration of ≥3 different lines of therapy. A total of 427 AYAS (64% female) with chronic ITP were included. Overall, 7% and 14% were classified as 'refractory' at 12 and 48 months of FU respectively. The proportion of males was greater in the refractory group than in the non-refractory group (43% vs. 35%). AYAS with refractory disease displayed lower median platelet counts, more bleeding and a higher need for treatment at initial diagnosis and FU than non-refractory patients. This study reveals that refractory ITP is uncommon in AYAS; however, AYAS with refractory ITP display a high disease burden at all time points, including at initial diagnosis., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with an initial platelet counts of <100×109/L. Patients with secondary ITP or non-immune thrombocytopenia (n=57) and pregnant women (n=10) were excluded. Of the 656 cases of AYAS with primary ITP registered from 2004 up to 2021, 12-month follow-up data were available for 72%. The initial median platelet count was 12×109/L. In 109 patients (17%), the diagnosis was incidental, without documented bleeding. Apart from gynecological bleeding, the clinical and therapeutical characteristics of females and males were similar. Platelet-enhancing drugs were reported in 66%, 45%, and 30% of patients at diagnosis, 1-6 months, and 6-12 months after diagnosis, respectively. Corticosteroids were the preferred treatment at all time points. At 12 months, 50% of all patients developed chronic ITP. In the subgroup of patients with initial severe thrombocytopenia (<20×109/L), those receiving frontline treatment had a higher remission rate at 1 year than those who followed an initial watch-and-wait strategy (53% and 32%; P<0.05). Our analysis indicates that the remission rate at 1 year may be associated with the initial treatment strategy. This hypothesis must be confirmed in prospective studies.

There are discrepancies across guidelines about whether the dosage of antinuclear antibodies (ANAs) is of use at the diagnosis of primary immune thrombocytopenia (ITP). This review describes the current knowledge about ANA prevalence in patients with primary ITP, and their potential usefulness as biomarkers for ITP evolution, response to treatments and increased risk of subsequent development of systemic lupus and thrombosis., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Combining drugs could be an effective option for treating multirefractory ITP, that is, patients not responding to rituximab, thrombopoietin receptor agonists (TPO-RA) and splenectomy. We conducted a retrospective, multicenter, observational study including multirefractory ITP patients who received a combination of a TPO-RA and an immunosuppressive drug. We included 39 patients (67% women, median age 59 years [range 21-96]), with a median ITP duration of 57 months [3-393] and a median platelet count at initiation of 10 × 10 9 /L [1-35]. The combination regimen was given for a median duration of 12 months [1-103] and included eltrombopag (51%) or romiplostim (49%), associated with mycophenolate mofetil (54%), azathioprine (36%), cyclophosphamide (5%), cyclosporin (3%) or everolimus (3%). Overall, 30 patients (77%) achieved at least a response (platelet count ≥30 × 10 9 /L and at least doubling baseline during at least 3 months), including 24 complete responses (platelet count >100 × 10 9 /L during at least 3 months) with a median time to response of 30 days [7-270] and a median duration of response of 15 months [4-63]. Severe adverse event related to ITP treatment was observed in 31%. In conclusion, this study confirms that some patients with multirefractory ITP can achieve long lasting response with this combination., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974., (© 2023 by The American Society of Hematology.)

Impaired platelet production is a mechanism of immune thrombocytopenia (ITP). Morphological abnormalities of megakaryocytes (MKs) are sometimes observed in this disease. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for thrombopoietin-receptor agonists (TPO-RAs). This was the aim of this study. The source of population was the French CARMEN registry with prospective follow-up of adult patients with incident ITP. We included patients with primary ITP, treated by TPO-RA and with a bone marrow smear before initiating TPO-RA. MK abnormalities were categorized by the presence of dysplasia and by the stage of maturation. Among 451 patients screened, 38 were included in the analysis. There was no difference in the median percentage of dysplastic MKs between responders to TPO-RA (4.0%, 95% confidence interval - CI: 2.3-6.4) and non-responders (4.5%, 95% CI: 0.7-7.1). There was a slightly higher proportion of granular MKs (4.5%, 95% CI: 3-6) and basophilic MKs (30.1%, 95% CI: 21.9-39.1) in non-responders compared to responders (granular: 2.0%, 95% CI: 0-4.1; basophilic: 21.3%, 95% CI: 11.4-40.7). In conclusion, MK abnormalities were not associated with response achievement in ITP patients treated with TPO-RA in this series of 38 patients.

Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to describe ITP in this subgroup. The data source was the prospective CARMEN-France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65-79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first-line treatment, need of second-line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex [odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31-17·32] and platelet count of <20 × 10 9 /l (OR 10·05, 95% CI 4·83-67·39). Exposure to anticoagulants was strongly associated with severe bleeding (OR 7·61, 95% CI 1·77-32·83)., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.

New insights into immune thrombocytopenia (ITP) epidemiology in adult patients highlight three main outcomes of morbidity and mortality: bleeding, infection and thrombosis. This review depicts current evidence about incidence and risk factors of bleeding, infection and thrombosis as well as predictors of chronicity, and shows how this assessment impacts the choice of ITP second-line treatment at the individual-level basis., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Previous studies have found that patients with Immune thrombocytopenia (ITP) have an increased risk of arterial thrombosis (AT) and venous thromboembolism (VTE). However, risk factors for thrombosis in adults with primary ITP remain unassessed in large cohorts. Aim To assess the occurrence and impact of risk factors for AT and VTE in patients with primary ITP in France and Sweden., Methods: Both countries have national health databases, including hospital diagnoses and drug dispensing data. Adults with incident primary ITP identified using algorithms between the years 2009-2015 in France, and 2009-2016 in Sweden were included. Cumulative incidence rates (IR) of AT and VTE were calculated by risk factors and multivariable Cox models were used to estimate associations., Results: The study included 7225 patients from France and 2490 from Sweden. The IR of AT were 15.0 (95% CI: 13.4-16.7) and 14.7 (95% CI: 12.4-17.5) per 1000 person-years, respectively. The incidences of VTE were 6.9 (95% CI: 5.9-8.1) and 6.5 (95% CI: 5.1-8.4), respectively. Increasing age, male sex and a previous AT were associated with AT in both countries and so were exposure to antiplatelet drugs in France and a history of VTE and chronic kidney disease in Sweden. Increasing age and a history of VTE were associated with VTE in both countries, in France also cancer., Conclusion: The IR of AT and VTE were similar in France. Age and male sex remained the most important risk factors for AT, age for VTE., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 × 10 9 L -1 and < 10 × 10 9 L -1 . Exposure to anticoagulants was a major risk factor of severe bleeding., Summary: Background The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopénies Auto-immunes Registre Midi-PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 10 9 L -1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 10 9 L -1 versus ≥ 20 × 10 9 L -1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 × 10 9 L -1 and 19 × 10 9 L -1 versus ≥ 20 × 10 9 L -1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 × 10 9 L -1 and < 10 × 10 9 L -1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding., (© 2018 International Society on Thrombosis and Haemostasis.)

Objective: To assess the benefits and harms to initiate corticosteroids with intravenous methylprednisolone at a conventional dose (1 mg/kg/d) to treat adults with immune thrombocytopenia (ITP)., Methods: Population stemmed from the prospective multicenter CARMEN registry and included newly diagnosed hospitalized ITP adults with platelet counts<30 × 10 9 /L. We compared the patients treated with conventional-dose methylprednisolone (CDMP) before continuing with oral prednisone to patients treated with just conventional-dose oral prednisone (CDOP). The primary outcome was the time until response. Secondary outcomes were time until complete response, response rate, complete response rate, duration of hospital stay, and occurrence of adverse drug reactions. Analyzes were adjusted for propensity score and for exposure to intravenous immunoglobulin., Results: Among the included 87 patients, the median time to response was 3 days in the CDMP group vs 4 in the CDOP group (adjusted hazard ratio [aHR]: 1.35; 95%CI: 0.76-2.41). The CDMP group had an earlier complete response (aHR: 2.29; 95%CI: 1.20-4.36). There was no difference between the groups regarding other secondary outcomes., Conclusions: Initiating methylprednisolone at a conventional dose provided no significant benefit compared to giving oral prednisone only to adults with ITP., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To evaluate the accuracy of an algorithm identifying newly diagnosed immune thrombocytopenia (ITP) patients in the French national health insurance database (SNIIRAM)., Methods: The source of data was the SNIIRAM of Midi-Pyrenees region (southwest of France, three million inhabitants). Data of patients with at least one ITP code (D69.3 code of the International Classification of Disease, version 10) were extracted between January 1, 2012, and December 31, 2014. We used an algorithm that identifies newly diagnosed primary ITPs. Medical charts of incident ITPs were reviewed. Positive predictive values (PPVs) of identification of true, incident, and primary ITP cases were estimated., Results: Of the 168 patients selected, 161 were true ITP cases yielding a PPV of 95.8% (95% confidence interval-95% CI: 92.8-98.8). Among them, 128 were truly incident according to symptom onset date and 134 according to the diagnosis date yielding PPVs of 79.5% (95% CI: 73.2-85.7) and 83.2% (95% CI: 77.4-89.0), respectively. Median time between estimated diagnosis date by the algorithm and true diagnosis date was 0 days (interquartile range: 0 to 15)., Conclusions: This study showed a very good PPV of this algorithm identifying incident primary ITP patients in the SNIIRAM., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

During the last decade, the development of large clinical and population-based cohorts led to new findings in the epidemiology and the pharmacoepidemiology of immune thrombocytopenia (ITP). The incidence is estimated to 3-4 for 10 5  inhabitants/year, with a slight female predominance and peaks in children and patients after 60 years. The incidence rate is 9 for 10 5  inhabitants/year in males after 75 years. Variations across ethnic groups are discussed. In France, there is a North-South gradient and a peak of incidence during winter suggesting the role of viruses in ITP pathophysiology. Myelodysplastic syndromes are an emergent cause of secondary ITP. The incidence of intracranial bleeding is about 1% by year and the risk increases with aging. Exposure to splenectomy decreases while rituximab and thrombopoietin receptor agonists (TPO-RA) are the most used second-line drugs for persistent ITP. Mortality is slightly increased in primary ITP as compared with the general population. ITP patients have an increased risk of infection, thrombosis and hemorrhage. Aging, lung diseases, splenectomy, corticosteroids and rituximab are risk factors for infection while influenza and pneumococcal vaccines are associated with a 50% decrease of infection risk. Aging, cardiovascular risk factors, lupus anticoagulant and splenectomy are risk factors for thrombosis. The risk of thrombosis associated with corticosteroids and TPO-RAs must be further investigated., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

The clinical epidemiology of immune thrombocytopenia (ITP) is not well known in adults. This study was aimed at assessing the clinical epidemiology of incident ITP adults, the factors associated with chronicity and exposure to treatments. This study was conducted in the CARMEN registry, a multicentric prospective cohort aimed at including all newly diagnosed ITP adults in the French Midi-Pyrénées region, South of France (3 million inhabitants) from June 2013. Descriptive analyses and multivariate logistic regression models were conducted. Out of 121 newly diagnosed ITP until December 2014, 113 patients were followed in the region and gave informed consent. Median age was 65 years. Half of the patients were female, 20.3% had a secondary ITP, 50.4% had a Charlson's score ≥1, median platelet count was 17 × 10 9 /L; 50.9% had bleeding symptoms, including 2 severe gastrointestinal tract and 1 intracranial bleedings; 21.4% had another autoimmune disease and 20.3% experienced an infection within the six weeks before ITP onset. Persistency and chronicity rates were 68.2% and 58.7%, respectively. Antinuclear antibodies were associated with chronicity (OR: 2.89, 95% CI: 1.08-7.74). Sixty-eight (60.2%) patients were treated during the week following the diagnosis. Factors associated with the use of intravenous corticosteroids were secondary ITP and high bleeding score. Those associated with the use of intravenous immunoglobulin (IVIg) were a high bleeding score and low platelet count. In conclusion, severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections were frequent. Antinuclear antibodies seem predictors of chronicity. Intravenous corticosteroids and IVIg were frequently used., (© 2017 Wiley Periodicals, Inc.)

Essentials The risk factors for infection in immune thrombocytopenia are not well known. We conducted a national pharmacoepidemiological study. Pulmonary disease, corticosteroids and rituximab were the main risk factors for infections. Pneumococcal and influenza vaccines were protective against infections., Summary: Introduction Risk factors for infection and protective effect of vaccines in immune thrombocytopenia (ITP) patients in the era of rituximab therapy are unknown. Objectives To assess the risk factors for serious and non-serious infections (respectively, SIs and NSIs) in non-splenectomized adults treated for persistent or chronic primary ITP, including the effect of pneumococcal and influenza vaccines. Patients/Methods The population was the 2009-2012 FAITH cohort (n = 1805), which is the cohort of all incident (newly diagnosed) primary ITP adults treated > 3 months in France built into the national health insurance database (SNIIRAM). SIs were hospitalizations with any infection as the primary diagnosis code. NSIs were identified using out-of-hospital antibiotic dispensing. Cox models were performed. Results Incidence rates were 6.3/100 patient-years (95% confidence interval [CI], 5.4-7.4) for SIs (lower respiratory tract in 42.8% of the cases) and 100.5/100 patient-years (95% CI, 95.0-106.3) for NSIs. In multivariate analyses, increasing age and chronic pulmonary disease were associated with both SI and NSI occurrence. The hazard ratios (HRs) for corticosteroids and rituximab were, respectively, 3.83 (95% CI, 2.76-5.31) and 2.60 (95% CI, 1.67-4.03) for SIs and 2.46 (95% CI, 2.19-2.76) and 1.49 (95% CI, 1.28-1.74) for NSIs. Pneumococcal vaccine showed a protective effect for both SIs and NSIs (0.38 [95% CI, 0.20-0.73] and 0.52 [95% CI, 0.43-0.65], respectively), as did influenza vaccine (0.42 [95% CI, 0.27-0.64] and 0.49 [95% CI, 0.41-0.59], respectively). Conclusions Chronic pulmonary disease, corticosteroids and rituximab are the main risk factors for infections, whereas pneumococcal and influenza vaccines are protective against SIs and NSIs., (© 2017 International Society on Thrombosis and Haemostasis.)

Introduction: Thrombopoietin-receptor agonists (TPO-RA) are marketed for immune thrombocytopenia (ITP). They have been associated to thrombosis occurrence in randomized controlled trials. However, the characteristics of these thromboses in the real-life practice as well as their management are poorly known. The objectives of this study were to determine the risk factors, circumstances and management of thrombosis occurring during exposure to TPO-RA in ITP., Methods: We carried out a multicentre retrospective study in France. Moreover, all cases reported to the French pharmacovigilance system were also analyzed., Results: Overall, 41 thrombosis (13 arterial) in 36 ITP patients (14 males and 22 females, mean age: 59 years) were recorded between January 2009 and October 2015. Twenty patients were treated with romiplostim, 15 with eltrombopag and 1 was treated by both medications. Thirty-three (92%) of the patients had another risk factor for thrombosis. Ten (28%) had an history of thrombosis and 13 (36%) received immunoglobulin in the month preceding the thrombotic event. Three had antiphospholipid antibodies; congenital low-risk thrombophilia was found in 4 cases; 18 patients (50%) were splenectomized. Median platelet count at the time of thrombosis was 172G/l (1-1049G/l). In 22 patients (56%), a good prognosis was associated with the thrombosis and was not linked with TPO-RA withdrawal. Bleeding events occurred in 14% of the patients treated with antiplatelet or anticoagulant drug, including 5% serious events (1 death of intracranial haemorrhage, 1 death of haemorrhagic shock)., Conclusions: The thrombotic risk may be carefully assessed before starting TPO-RA in ITP patients. The impact of antiphospholipid antibodies and of congenital thrombophilia remains to be defined. Thrombosis evolution seems independent of TPO-RA management. Bleeding manifestations seem rare. Poor prognosis was mainly due to ischemic sequelae., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Refractory immune thrombocytopenia (ITP) was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the risk of significant bleeding events. In this multicenter study, we included 37 patients with multirefractory ITP, defined as no response to splenectomy, rituximab, romiplostim, and eltrombopag. As compared with a historical cohort of 183 ITP patients, matched on the calendar year of ITP diagnosis with a 5:1 ratio, patients with multirefractory ITP were more likely to have secondary ITP (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.31-17.86; P = .018) and monoclonal gammopathy of undetermined significance (OR, 5.94; 95% CI, 1.08-32.48; P = .04). The median duration of ITP before being recognized as multirefractory was 78 months (range, 6-450). The patients showed failure of a median of 10.5 prior treatment lines for ITP (range, 6-15). At the end of follow-up (median, 84 months; range, 12-455), only 1/14 patients achieved response with immunosuppressant therapy alone. By contrast, 7/10 patients achieved response with a combination of immunosuppressant therapy and thrombopoietin-receptor agonists that lasted for a median of 15 months (range, 6-32). Throughout the course of ITP, 5/37 patients died, 3 with ITP (bleeding, n = 2; sepsis n = 1); 15 (40%) had at least 1 bacterial infection and 9 (24%) at least 1 episode of thrombosis. In conclusion, multirefractory ITP was associated with high morbidity and mortality. Combining an immunosuppressant therapy with thrombopoietin-receptor agonists may be a good strategy for management for these patients with severe disease., (© 2016 by The American Society of Hematology.)

Antiphospholipid antibodies (aPL) are common in ITP, but their role for the occurrence of ITP-related thrombosis is controversial. We performed a systematic review and a meta-analysis to investigate the risk of thrombosis associated with lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2GP-I antibodies in primary ITP. The literature search was run on Medline, Cochrane and ISI Web of Science from January 1st 1980 to December 31st 2014. Unpublished studies were searched in meeting abstracts. The main analysis assessed the risk of all thromboses (arterial or venous) associated with the presence of LA, aCL or anti-β2GP-I antibodies. Random-effect models were used to calculate odds ratios (OR) and their 95% confidence intervals (CI). Searches in electronic databases retrieved 776 citations. Twelve additional studies from unpublished literature were added. Eventually, 10 cohort studies totalizing 1574 patients were included in the analysis. The pooled OR for the risk of all thromboses associated with LA was 6.11, 95% CI [3.40-10.99]; it was 2.14, 95% CI [1.11-4.12] with aCL. The ORs were similar when stratifying on the type of thrombosis (arterial vs. venous). Only two studies assessed the risk of thrombosis associated with anti-β2GP-I antibody positivity; consequently, no pooled OR was computed for these antibodies. This meta-analysis highly suggests that LA positivity, and to a less extent aCL antibodies, are associated with an enhanced risk of thrombosis in primary ITP patients. Further prospective studies are needed to identify the factors associated with the risk of thrombosis among LA patients before assessing prevention strategies., (Copyright © 2015. Published by Elsevier B.V.)

Corticosteroid (CS)-related infection risk in immune thrombocytopenia (ITP) is unknown. The aim of this study was to assess the adjusted CS risk function of severe infection in persistent or chronic primary ITP adults. We designed a nested case-control study in the FAITH cohort. This cohort is built through the French national health insurance database named SNIIRAM and includes all treated incident persistent or chronic primary ITP adults in France (ENCePP n°4574). Patients who entered the FAITH cohort between 2009 and 2012 were eligible (n = 1805). Cases were patients with infection as primary diagnosis code during hospitalization. Index date was the date of first hospitalization for infection. A 2:1 matching was performed on age and entry date in the cohort. Various CS exposure time-windows were defined: current user, exposure during the 1/3/6 months preceding index date and from the entry date. CS doses were converted in prednisone equivalent (PEQ). The cumulative CS doses were averaged in each time-window to obtain daily PEQ dosages. Each CS exposure definition was assessed using multivariate conditional regression models. During the study period, 161 cases (9 opportunistic) occurred. The model with the best goodness of fit was CS exposure during the month before the index date (OR: 2.48, 95% CI: 1.61-3.83). The dose-effect relation showed that the risk existed from averaged daily doses ≥5 mg PEQ (vs. <5 mg: 2.09, 95% CI: 1.17-3.71). The risk of infection was mainly supported by current or recent exposure to CS, even with low doses.

International guidelines on immune thrombocytopenia (ITP) management recommend vaccination against Streptococcus pneumoniae (S.p.), Haemophilus influenza b (Hib) and Neisseiria meningitidis (N.m.) before splenectomy. French guidelines also recommend these vaccinations before rituximab. The aim of this study was to assess the application of these recommendations. The French Adult ITP: a French pHarmacoepidemiological study (FAITH, n°ENCEPP 4574) is aimed at following in the French national health insurance system database (SNIIRAM) the cohort of all incident and persistent or chronic primary ITP adults treated in France. We assessed vaccine exposure in the 1,106 patients who entered the FAITH cohort between 2009 and 2011. Vaccination was said "recommended" if performed at least 2 weeks before rituximab or splenectomy accordingly with French guidelines. Among the 423 non-splenectomized patients exposed to rituximab, vaccination rates against S.p., Hib and N.m. were respectively 32.4%, 18.9%, and 3.8%. It was recommended in 12.8%, 6.6%, and 1.2% of the patients, respectively. Among the 178 splenectomized patients, vaccination rates were 70.2%, 47.0%, and 11.9%, respectively (recommended: 60.1%, 35.7%, and 9.5%). Among the splenectomized patients previously exposed to rituximab (n = 67), 53.3% of the vaccinations occurred during the semester following a rituximab infusion that is during the maximal B-cell depletion period. In multivariate analyses, a disease duration exceeding 3 months was the sole factor associated to recommended vaccination in rituximab-treated patients as well as in splenectomized patients. This study stresses the need of better and earlier vaccination of ITP patients., (© 2014 Wiley Periodicals, Inc.)

The objective of this study was to describe the exposure to non-corticosteroid treatments in adult primary immune thrombocytopenia (ITP) patients before the chronic phase at a nationwide level. Study population is derived from the 2009-2011 cohort of the French Adult Immune Thrombocytopenia: a French pHarmacoepidemiological study (FAITH, no. ENCEPP 4574). The FAITH cohort includes all incident and persistent or chronic adult primary ITP patients treated in France. It was built through the nationwide French health insurance database, called SNIIRAM. For the present study, we included FAITH patients who were followed by at least 12 months and who had at least one exposure to a non-corticosteroid treatment before the ITP chronic phase. Exposure to non-corticosteroid treatments was searched through in- and out-hospital dispensing. Predictors of the choice among first-line non-corticosteroid treatments (rituximab, splenectomy or other drugs) were studied using a multinomial regression. The study population included 443 patients. Non-corticosteroid treatments used in more than 10% of the patients at any time before the chronic phase were: rituximab (57.8%), splenectomy (22.1%), TPO-RAs (16.8%), repeated intravenous immunoglobulin (IVIg) courses (15.0%), danazol (14.4%) and dapsone (10.8%). Rituximab was the most used first-line non-corticosteroid treatment (45.4%). TPO-RAs and dapsone were more frequently used after 65 years of age (respectively, 24.8% versus 12.8%, p=0.01 and 17.6% versus 7.2%, p=0.0008), unlike splenectomy (16.4% versus 25.2%, p=0.03). Age over 65 years was the sole independent predictor of first-line non-corticosteroid treatment choice. In conclusion, rituximab was the leading non-corticosteroid treatment used before the chronic phase. TPO-RAs were mainly used in accordance with their labeling. IVIgs were consistently used as a chronic non-corticosteroid treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The epidemiology of immune thrombocytopenia (ITP) is not well known. The purpose of this study was to assess ITP incidence at a nationwide level (France) with recent data (mid-2009 to mid-2011; 129 248 543 person-years). The data source is the French health insurance database. We selected cases with diagnosis codes for in-hospital stays and long-term disease attributions, thus restricting our search to ITPs necessitating health care. We studied incidence by age, gender, calendar month, regions, and proportion of secondary ITPs, of ITPs becoming persistent or chronic, and of severe bleeding at disease onset. We identified 3771 incident ITP patients. Incidence was 2.9/100,000 person-years, with peaks among children and in those >60 years of age. ITP was more frequent among males in these subgroups. The incidence was lower in overseas Caribbean French departments, suggesting a lower incidence among Afro-American people. There was a north-south gradient in mainland France and seasonal variations (peak in winter and nadir in summer). Persistence or chronicity occurred in 36% of children compared with 67% of adults. Among adults, 18% of ITPs were secondary. Malignancy was the main cause (10.9%). Myelodysplastic syndromes were not rare (2.3%). Severe gastrointestinal or central nervous system bleeding at ITP onset was rare (<1%)., (© 2014 by The American Society of Hematology.)

Immune thrombocytopenia (ITP) is a rare condition. Its epidemiology is not well-known. First-line treatment is based on corticosteroids. ITP leads to persistency (lasting more than 3 months) in 70% of adult cases. Then, several second-line treatments (SLTs) are available, mainly splenectomy, rituximab (off-label) and thrombopoietin-receptor agonists. Their efficacy and safety have not been compared, particularly in the long-term. FAITH (French Adult primary Immune Thrombocytopenia: a pHarmacoepidemiological study) is dedicated to the building and follow-up of the cohort of all adults with primary ITP in France persistently treated (>3 months) through the database of French Health Insurance system (système national d'information interrégimes d'Assurance maladie, SNIIRAM), in order to assess the benefit-to-risk balance of SLTs in real-life practice. CARMEN (Cytopénies Auto-immunes : Registre Midi-PyrénéEN) is a clinical registry of all incident adult ITP patients in the Midi-Pyrénées region. It is aimed at describing ITP clinical features, assessing SLT benefit-to-risk balance and adherence to guidelines for ITP management. FAITH is registered n°ENCEPP/SDPP/4574., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Splenectomy and rituximab are both recommended as second-line treatment in immune thrombocytopenia (ITP), but they have never been directly compared. We compared their efficacy and serious adverse outcomes in a retrospective cohort of 105 adult primary ITP patients exposed to one or other of these treatments. Primary outcome was composite: death from hemorrhage or from infection and hospitalization for bleeding or for infection. Secondary outcomes were overall mortality, hospitalization for bleeding, hospitalization for infection, as well as response and complete response (international definitions). Analyses were adjusted on a propensity score. Patients treated with rituximab (n = 43) were older and had more comorbidities than the splenectomized patients (n = 62). Mean follow-up was, respectively, 3 and 8.4 years. After adjustment on the propensity score, there was no difference between the two groups regarding the primary and other clinical outcomes. In the multivariate analysis, only a history of mucosal bleeding (HR 3.2 95% CI [1.2-8.5]) and a Charlson score ≥1 (HR 4.2 95% CI [1.8-9.6]) were associated with the primary outcome. These two factors were also associated with hospitalization for bleeding. As expected, response, complete response and maintenance rates were higher in the splenectomy group. Splenectomy compared with rituximab was independently associated with a response at 12 months (OR 4.4, 95% CI [1.7-11.8]). Then, adjusted analyses in this real-life cohort confirmed the better results of splenectomy compared with rituximab., (Copyright © 2013 Wiley Periodicals, Inc.)