Response to 'Eruptive keratoacanthomas associated with dupilumab therapy'.

Case of a patient developing multiple rashes of squamous cell carcinoma 6 weeks after the introduction of dupilumab due to atopic eczema.

Radiological evolution of progestogen-induced meningioma: A monocentric retrospective study.

Cyproterone acetate (CPA) is known to induce meningioma, and recently, nomegestrol acetate (NMA) and chlormadinone acetate (CMA) were also involved. Progestagen-induced meningioma management starts with progestogen discontinuation and is either interventional (surgery and/or radiotherapy) or conservative (clinical and MRI radiological follow-up). We performed a retrospective volumetric radiological outcomSe study of progestogen-induced meningiomas diagnosed in our hospital. We analysed progestogen-related meningiomas diagnosed until 30 June 2021, with at least one diagnostic and one follow-up MRI results. Meningioma volumes were centrally retrospectively measured using a T1-weighted 3D millimeter sequence with gadolinium injection on a postprocessing console. We analysed 98 meningiomas of 38 females and one transgender (male-to-female), of which 25 (64.1%) had taken CPA, seven (17.9%) NMA, three (7.7%) CMA, and four (10.2%) several progestogens. Eleven patients (24 meningiomas) underwent interventional management, seven patients had meningiomas followed by conservative or interventional management, and 21 patients (51 meningiomas) had only conservative management. Of these 21 patients, 17 had discontinued their progestogen less than 6 months before, of which 14 (82.3%) had decreased or stable meningioma(s) during a 24-month median follow-up (3 to 75) period. Overall, four of the 39 patients experienced meningioma progression (three during conservative treatment and one after surgery), including two patients who had continued NMA or CMA treatment several years after diagnosis. Our study confirms a generally favourable outcome of progestogen-related meningioma after conservative treatment, especially for CPA. It also underlines the need for progestogen discontinuation at meningioma diagnosis.

Incidence and preventability of hospital admissions for adverse drug reactions in France: A prospective observational study (IATROSTAT).

AIMS: In the last French study in 2007, the incidence of hospital admissions (HAs) related to adverse drug reactions (ADRs) was 3.6%. The objective was to assess the current ADR-HA incidence in France and to describe both its characteristics and preventability. METHODS: A prospective multicentre study was conducted among randomly selected French public hospital medical wards (April-July 2018). Patients admitted during a week period were included. ADR-HA cases were collected by the French Regional Pharmacovigilance Centres network. An independent committee validated potential cases and ADR preventability. RESULTS: ADR-HA incidence was 8.5% (95% confidence interval [CI]: 7.6-9.4%), increasing with age (3.3% [95%CI: 1.8-5.5%] ≤16 y vs. 10.6% [95%CI: 9.3-12.0%] ≥65 y). The most common ADRs were haemorrhagic events (8.8%), haematological disorders (6.5%), acute renal failure (6.3%), fluid and electrolyte disorders (6.0%), and falls (5.2%). New drugs were involved: targeted therapies (22.8% of antineoplastics), direct oral anticoagulants (29.6% of antithrombotics) and incretin-based drugs (20.0% of antidiabetics). ADRs were preventable in 16.1% of cases because the drugs involved had not been used in accordance with monographies, package leaflets or other therapeutic guidelines. The main situations of noncompliance addressed either dose or duration of use (27.9%), warning (23.2%), use precaution (18.6%) and inappropriate self-medication or misuse by patients (11.6%). CONCLUSION: In France, ADR-HA incidence dramatically increased over the last decade. A significant proportion was related to new pharmacological classes and considered as preventable. These findings should lead to in-depth thought on preventive actions on at-risk drug classes.

IL-17 Inhibitors and Inflammatory Bowel Diseases: A Postmarketing Study in Vigibase.

Several gastrointestinal symptoms and chronic inflammatory bowel diseases (IBDs) have been reported after therapy with IL-17 inhibitors. To date, however, no study has shown a clear association between these drugs and IBD onset. We searched on Vigibase, the worldwide pharmacovigilance database, to investigate reporting prevalence, characteristics, and prognosis of all gastroenterological adverse events in patients treated with IL-17 inhibitors. In total, 1,129 gastrointestinal Individual Case Safety Reports (ICSRs) were identified, including 850 IBD (42.5% Crohn's disease, 31.9% ulcerative colitis, and 25.6% undifferentiated IBD) and 279 colitis (mainly undifferentiated colitis (79.2%), and microscopic colitis (10.4%)). ICSRs were associated with secukinumab (SEC, 83.6%) or ixekizumab (IXE, 16.3%), whereas only one colitis occurred with brodalumab (0.1%). Most IBD and colitis cases were detected within 6 months from therapy start in both the SEC (68.8% and 73.5%) and IXE groups (100% and 66.7%). Patients' outcomes were reported in 428 ICSRs (37.9%). Complete or ongoing recovery from symptoms was detected in about two-thirds of patients experiencing IBD (59.5%) or colitis (64.2%), whereas in the other cases, there was no recovery (33.9% and 29.5%) or there were sequelae (5.4% and 4.2%). Fatal events occurred in four patients (1.2%) in the IBD group (3 after SEC and on1e with IXE) and two SEC-treated subjects in the colitis group (2.1%). Treatment with IL-17 inhibitors is associated with a relevant number of exacerbations and new onset of IBD and colitis. Careful evaluation of gastrointestinal symptoms and the monitoring of intestinal inflammatory biomarkers should be recommended before prescribing these drugs.

TNF-α inhibitors and psychiatric adverse drug reactions in the spectrum of bipolar (manic) or psychotic disorders: Analysis from the French pharmacovigilance database.

OBJECTIVE: This study aimed to describe reports of psychiatric adverse drug reaction (ADR) in the spectrum of bipolar (manic features) or psychotic disorders that occurred under tumor necrosis factor alpha (TNF-α) inhibitors therapy. METHODS: We searched the French pharmocovigilance database for reports of psychiatric ADR in the spectrum of bipolar (manic features) or psychotic disorders during treatment with TNF-α inhibitors. Psychiatric symptoms were divided in 2 categories: (i) confirmed diagnosis of manic episode or acute psychosis and (ii) psychiatric symptoms with psychotic or manic features but not meeting sufficient criteria for diagnosis of psychosis or manic disorder. RESULTS: Overall, 9942 reports of ADR were registered in the French pharmacovigilance database with TNF-α inhibitors, including 243 reports of psychiatric ADR. Among them, we identified 41 reports of psychotic or manic disorders as define above: 9 characterised manic episodes and 32 psychiatric disorders with psychotic or manic features. TNF-α inhibitors were the only medication suspected in 23 reports (56%). The delay between starting TNF-α inhibitors treatment and onset of symptoms varied from hours to years with a median time of 40 days. Psychiatric symptoms improved in 22/23 patients in whom the TNF-α inhibitor was withdrawn. CONCLUSION: Depressive disorders are well-known ADR of TNF-α inhibitors, but we report, here, 41 reports of psychiatric ADR diagnosed as manic or psychotic disorders or in the spectrum of bipolar or psychotic disorders with these treatments. Epidemiological studies are needed to confirm this signal.

Hepatitis B reactivation and immune check point inhibitors.

BACKGROUND: Liver toxicity during immune checkpoint inhibitor treatment is mostly due to immune mediated hepatitis. Viral hepatitis, as well as auto-immune or metabolic hepatitis, are considered as exclusion criteria for ICI induced immune hepatitis diagnosis. However, considering the high prevalence of viral hepatitis B infection and the increasing prescription of immune checkpoint inhibitors, their use in patients with HBV chronic viral infection may be common, even more if patients are treated for hepatocellular carcinoma. Few clinical studies directly deal with the risk of HBV reactivation during ICI therapy and real-life data is currently based on five reported cases of HBV reactivation, one with fatal outcome. In this review, we summarize the current available clinical information about HBV reactivation risk during ICI treatment, its hypothetic mechanism, and propose practical recommendations about verifying and monitoring HBV status throughout the treatment.

Paradoxical gastrointestinal effects of interleukin-17 blockers.

Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn's disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.

Paradoxical adverse drug reactions: descriptive analysis of French reports.

INTRODUCTION: Paradoxical adverse drug reactions (ADRs) are defined as being opposing reactions to the pharmacological effect of drugs in relation to its pharmacodynamic properties. Their diagnosis is difficult as they are relatively rare with atypical clinical presentation (with the possibility of being confused with drug ineffectiveness or the worsening of the underlying disease). This kind of ADR may be particularly subject to under-notification. The aim of the present study is to describe paradoxical ADRs using the French PharmacoVigilance DataBase (FPVDB). METHOD: We analysed all reports recorded in the FPVDB with drugs defined as "suspect" and which included the term "paradoxical reaction" (PR) (according to MedDRA classification) from 01/01/1984 to 12/31/2018. The drugs were classified according to the Chemical Therapeutic Anatomical Classification (ATC). RESULTS: We found 57 reports of PR, with half of them recorded between 2015 and 2018. The median age of patients was 46 years, mainly male (54%). The most frequently involved drugs were immunomodulating agents (n = 28, 49%) and psychotropics (n = 28, 49%). The leading paradoxical ADRs were psychiatric (anxiety, sleep and behavioural disorders) and skin-related. In 19 cases (33%), PR was related to benzodiazepines mainly occurring in patients in extreme ages (five cases in children and patients > 70, respectively, 53%). For psychotropic-induced PR (n = 28), known contributory factors (alcohol consumption, underlying psychiatric diseases) were found in 18 cases (64%). Paradoxical reactions with immunomodulating agents were mainly related to skin ADRs (n = 25). For psychotropics, paradoxical ADRs occurred rapidly after a mean delay of 1 day, predominantly following high doses. We also identified several "unexpected" paradoxical reactions, such as cognitive degradation with donepezil, or a return to impulsive smoking addiction with varenicline. CONCLUSION: This study highlights that pharmacovigilance databases like the French database make it possible to investigate the main characteristics of paradoxical reactions to drugs. This ADR was mainly found in the FPVDB with psychotropic drugs and immunomodulating agents. Moreover, pharmacovigilance databases enable the identification of some signs of "unexpected paradoxical reactions". In order to identify this type of ADR more effectively, work on awareness and harmonization is required to register these reports. The addition of the term "paradoxical reaction to the drug" to the list of other symptoms would facilitate their identification and analysis.

Immunoglobulin Preparations Can Mislead Clinical Decision-Making in Follow-Up of Differentiated Thyroid Cancer.

OBJECTIVE: Intravenous and subcutaneous immunoglobulins are commonly used for immune substitution or as immune modulators in a variety of inflammatory and autoimmune disorders. Exogenous thyroid-specific thyroglobulin (Tg) antibodies present in the donor plasma may interfere with the interpretation of measurements of Tg autoantibodies (Tg-Abs) in the recipient's plasma and potentially trigger an immune response in the recipient's immune cells. Levels of antibodies causing bioassay interferences or those leading to clinically relevant changes in patient outcomes are not known. Tg is used as a biomarker in the long-term surveillance of patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioactive iodine ablation. However, the presence of Tg-Abs in the circulation interferes with Tg measurements. Assessment of levels of Tg-Abs is thus recommended as a part of standard follow-up of DTC together with Tg testing. METHODS: To understand the potential mechanisms and pathophysiologic significance of possible interferences associated with administration immunoglobulin preparations and Tg measurement, we overview the current knowledge on interactions between Tg autoimmunity and immunoglobulin preparations and illustrate diagnostic challenges and perspectives for follow-up of patients with DTC treated with exogenous immunoglobulins. RESULTS: In patients with DTC treated with immunoglobulin preparations, monitoring of thyroid cancer using Tg and Tg-Abs is challenging due to possible analytical interferences through passive transfer of exogenous antibodies from immunoglobulin preparations. CONCLUSION: Analytical interferences must be suspected when a discrepancy exists between clinical examination and diagnostic tests. Collaboration between endocrinologists, biologists, and pharmacologists is fundamental to avoid misdiagnosis and unnecessary medical or radiologic procedures. ABBREVIATIONS: CT = computed tomography; DTC = differentiated thyroid cancer; FNAB = fine-needle aspiration biopsy; HAb = heterophile antibody; IMA = immunometric assay; IVIg = intravenous immunoglobulin; RAI = radioactive iodine; RIA = radioimmunoassay; SCIg = subcutaneous immunoglobulin; Tg = thyroglobulin; Tg-Ab = thyroglobulin autoantibody; Tg-MS = thyroglobulin mass spectrometry; TPO-Ab = thyroid peroxidase autoantibody; TSHR-Ab = thyrotropin receptor autoantibody.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

BACKGROUND: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal. METHODS: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups. RESULTS: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53). CONCLUSIONS: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.

Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

TNFα modulation has been reported to be either beneficial or detrimental in amyotrophic lateral sclerosis (ALS) and therefore appears as a key issue. We analysed the relationship between TNFα inhibitor (TNFi) exposure and ALS. We performed descriptive analysis of ALS reports in patients treated with TNFi, registered in the French Pharmacovigilance Database (FPvD) and disproportionality analyses by the 'case'/'non-case' method in FPvD and worldwide database (Vigibase® ). The 8 retrieved ALS cases from the FPvD were 5 with limb-onset and 3 with bulbar-onset forms, in patients aged 43-75 years old, mainly treated for inflammatory rheumatism. The time to onset of the first symptoms ranged from 12 to 108 months, and the cumulative TNFi exposure before the diagnosis ranged from 12 to 120 months. TNFi was discontinued and thereafter survival ranged between 12 and 20 months. Disproportionality analyses showed significant associations between TNFi exposure and ALS in the FPvD and Vigibase® (160 ALS cases), regardless comparators. A putative association between TNFi and ALS must be interpreted cautiously, but TNFi could act as a predisposing or risk factor. TNFi should therefore be avoided in patients with a known risk of ALS and discontinued in the case of neurological signs of ALS.

Thyroiditis and immune check point inhibitors: the post-marketing experience using the French National Pharmacovigilance database.

Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation.

Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation.

BACKGROUND: Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context. MATERIALS AND METHODS: A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day × 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality. RESULTS: Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality. DISCUSSION: This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.

Detection of drug safety signals from clinical trials data: Role of SUSARs.

One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.

[Cutaneous pigmentation related to intravenous iron extravasation: Analysis from the French pharmacovigilance database]. / Pigmentation cutanée liée à l'extravasation de fer injectable. Analyse de la base française de pharmacovigilance de 2000 à 2016.

INTRODUCTION: Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. METHODS: We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000-2016 period. RESULTS: Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. CONCLUSION: Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB). METHODS: Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment. RESULTS: One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease. CONCLUSIONS: Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).

Tumor necrosis factor inhibitors added to nonbiological immunosuppressants vs. nonbiological immunosuppressants alone: a different signal of cancer risk according to the condition. A disproportionality analysis in a nationwide pharmacovigilance database.

We aimed at detecting a signal of an increased risk of cancer in patients treated with TNF inhibitor (TNFi) and nonbiological immunosuppressant (NBIS), compared with NBIS alone for autoimmune diseases. Secondly, we aimed at comparing this risk between the different TNFis. We conducted a disproportionality analysis (case/noncase study) from the French National PharmacoVigilance Database. We selected all the reports of serious adverse drug reactions from 2000 to 2010 in patients treated with NBIS for labeled indications of TNFi. Cases were all the reports of cancer that occurred after a minimal 3-month exposure to NBIS. Noncases were all the other reports. We searched for exposure to TNFi and calculated reporting odds ratios (RORs), stratified by condition and type of cancer and adjusted by age, gender, history of cancer, type of NBIS and year of reporting. Of the 1918 reports included in the study population, 217 were cases (135 solid and 82 blood cancers). A safety signal was found in rheumatoid arthritis (RA) (ROR: 5.43, 95% CI[3.52-8.38]) particularly for nonmelanoma skin cancer (NMSC) (20.17[2.49-163.36]), and in psoriasis/psoriatic arthritis (3.45[1.09-10.92]). No signal was found in inflammatory bowel diseases (IBD) and ankylosing spondylitis, whatever the type of cancer. There was no difference between TNFis. This study puts the argument of an increased risk of cancer (particularly NMSC) in patients with rheumatoid arthritis exposed to TNFi and NBIS compared with NBIS alone, but not in IBD and ankylosing spondylitis patients. No signal was detected for melanoma potentially related to the lack of power. The signal seems similar whatever the TNFi.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009-2013 French PharmacoVigilance assessment.

BACKGROUND: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS: This study suggests different ADR patterns between romiplostim and eltrombopag.