G. Moulis

Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France.

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%).

Cancer Risk of Anti-TNF-α at Recommended Doses in Adult Rheumatoid Arthritis: A Meta-Analysis with Intention to Treat and per Protocol Analyses

Background The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown. Methodology/Principal Findings Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59–1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82–1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71–2.66] and 1.90 [0.98–3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97–2.64] and 1.22 [0.72–2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs. Conclusions/Significance This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.

Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: A french multicenter study

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5years (range: 1.6-35). Two patients developed Waldenströms macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.

Searching for a Polypharmacy Threshold Associated With Frailty

Second, psychosocial resources may serve as mediators of the relationship between frailty and adverse outcomes. Mediation analyses tell us why or how psychosocial resources affect clinical outcomes in frail older people, because mediator variables are usually in the causal pathway between predictors and outcomes.10 It is possible that frailty alters the psychosocial resources of individuals and makes them even more vulnerable to adverse outcomes. Mediation analyses test the extent to which a mediator accounts for the effects of the predictor (frailty) on the outcomes.10 A recent article investigating the mediation effects of several factors on frailty found that although social participation increased the likelihood of frailty worsening, the worsening of frailty was not able to be explained by social participation, or lack thereof.13 However, no studies have yet looked at psychosocial resources as mediators of the association of frailty with adverse outcomes. All in all, it is likely that psychosocial resources are both moderators and mediators of frailty. However, with so little research in existence, no conclusive results can be drawn. Moreover, the 2 studies known to date have used only relatively short follow-up periods ( 3 years). Given the long life-course progression of psychosocial resources14 and frailty,15 it is likely that both moderation and mediation effects will become more evident with longer-term follow-up. Subsequently, a need exists to investigate the long-term protective effect of psychosocial resources on frailty, particularly using mediation effect studies. Gaining a more comprehensive understanding of how an older person handles frailty, whether by the use of copingmechanisms, having a strong sense of self-control, or an involvement in social support networks, can be used to tailor patient-centered care and potentially reduce the burden associated with frailty.

Exposure to Atropinic Drugs and Frailty Status

BACKGROUND Atropinic drugs can increase the risk of falls, cognitive impairment, and mortality in older patients; however, whether exposure to atropinic drugs is associated with frailty status remains unknown. Our aim was to assess the association between frailty status and exposure to atropinic drugs in a geriatric day hospital population. METHODS We carried out a cross-sectional study that included all the patients consulting for the first time at the Geriatric Frailty Clinic for Assessment of Frailty and Prevention of Disability in Toulouse, France, from January 2013 to October 2013. Frailty was defined by 3 or more of Fried et als criteria. Atropinic drugs were those with clinical antimuscarinic effect from the Anticholinergic Drug Scale (excluding drugs weighted 1 point and not listed by Durán et al) and from Laroche et al list (to include drugs marketed in France not present in the Anticholinergic Drug Scale). To explore a dose-effect relationship, we calculated the atropinic burden using the Anticholinergic Drug Scale weights. We performed logistic regression models adjusted for age, gender, comorbidities, being community dwelling or not, cognitive status, educational level, and polypharmacy (≥6 drugs). RESULTS We included 437 patients (227 frail and 210 robust or prefrail). Exposure to at least one atropinic drug was associated with frailty (odds ratio 1.97, 95% confidence interval 1.10-3.53, P = .02). Due to a statistically significant interaction between age and atropinic burden, a dose-effect relationship for atropinic burden was explored in patients younger than 85 years, showing a significant association between atropinic burden score and frailty (P = .01). The Odds ratio for an atropinic burden greater than or equal to 3 versus 0 was 3.84, 95% confidence interval 1.43-10.34 (P < .01). CONCLUSIONS In a geriatric day hospital, population frailty is associated with a high atropinic burden.

Is the risk of tumour necrosis factor inhibitor-induced lupus or lupus-like syndrome the same with monoclonal antibodies and soluble receptor? A case/non-case study in a nationwide pharmacovigilance database

OBJECTIVE Each TNF-α inhibitor (TNFi) can induce lupus or lupus-like syndrome. Nevertheless, the risk may differ between drugs because of different apoptosis induction properties. The aim of this study was to assess the putative association of each TNFi with lupus or lupus-like-syndrome. METHODS All spontaneous reports of TNFi-related lupus recorded in the French pharmacovigilance database between January 2000 and December 2012 were described. We conducted disproportionality analyses (case/non-case method) to assess the link between TNFi and lupus, calculating reporting odds ratios (RORs). We used isoniazid as positive control and acetaminophen as negative control. We performed sensitivity analyses to test for event-related and drug-related competition biases. RESULTS Among 309 671 spontaneous reports, 5213 involved TNFi. Among these, 39 were lupus or lupus-like syndromes: 25 involved infliximab, 9 adalimumab and 5 etanercept. The male:female sex ratio was 0.1 and the mean age was 44.9 years. Among the 39 cases, 28% fulfilled at least four ACR criteria for SLE. Median time to lupus onset was 11 months. Cutaneous and rheumatological involvement were the most frequent. Antinuclear autoantibodies were present in all patients, with anti-DNA specificity in 77.8%. Improvement was observed after TNFi withdrawal. There was a significant association between TNFi and lupus (ROR = 7.72, 95% CI 5.50, 10.83). The ROR was similar for infliximab (10.97, 95% CI 7.27, 16.56) and adalimumab (9.03, 95% CI 4.64, 17.58) and was 4.02 (95% CI 1.66, 9.75) for etanercept. Sensitivity analyses led to similar results. CONCLUSION Although CIs overlap, there is a clear trend towards a decreased risk with etanercept compared with monoclonal TNFis.

Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity

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. Am. J. Hematol. 89:41–46, 2014.

Characteristics, outcome and response to therapy of multirefractory chronic immune thrombocytopenia

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.

Drug-induced immune thrombocytopenia: A descriptive survey in the French PharmacoVigilance database

The aim of this survey was to describe drug-induced immune thrombocytopenia (ITP) reported in the French PharmacoVigilance database (FPVD) and to discuss the drugs involved. The request to the FPVD used the seven most accurate diagnosis codes to identify ITP. The study was restricted to cases reported from 2007 to 2010 and at least “possible” according to the French causality assessment score. We then described the populations characteristics, the drugs involved, the clinical symptoms, and the course of ITP. For each drug, we estimated the causality assessment score developed by George for drug-induced ITP. We included 59 drug-induced ITP. Among them, 45.8% were post-vaccinal: they mainly occurred in children (median age: 16 years). Main vaccines were diphtheria–tetanus–poliomyelitis (DTP, 9 cases), influenza (n = 8) and measles, mumps, and rubella (MMR, n = 7). Regarding the 33 non-vaccinal cases: some drugs are well-known as triggering ITP (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), n = 5; abciximab, n = 4, acetaminophen, n = 2). Other drugs inducing ITP were involved, like serotonin reuptake inhibitors or bevacizumab. Mean age was 57.1 ± 21.7; 60.6% of the patients were male and 25% had autoimmune antecedents. Among the 55 suspected drugs, three were classified as “probable” and 28 as “possible” according to George scale. In both vaccinal and other cases, median delay was 14 days, median platelet value at nadir was < 10 000 µl−1 and hemorrhagic symptoms were rarely severe (only 2 gastrointestinal hemorrhages). Specific treatment was introduced in 45 (76.3%) patients. Five drug-induced cases led to chronicity. Among them, ezetimibe was suspected in two reports. In the FPVD, DTP, MMR, and influenza vaccines are the most often reported vaccines inducing ITP, perhaps because of their wide use. Our study confirmed that NSAIDs, abciximab, and acetaminophen frequently trigger ITP. It also allows to suspect other drugs like serotonin reuptake inhibitors or bevacizumab. Ezetimibe may induce chronic ITP. Drug-induced ITP is rarely severe. Finally, this study also shows that chronicity of ITP does not rule out the possibility of an iatrogenic cause.

Risk of thrombosis in patients with primary immune thrombocytopenia and antiphospholipid antibodies: A systematic review and meta-analysis.

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.