Objective
The relapse rate of patients with giant cell arteritis (GCA) treated with glucocorticoids (GCs) alone varied widely in observational series and randomized controlled trials (RCTs). The ...purpose of this systematic review was to evaluate the prevalence of relapse and predisposing factors in patients receiving GCs alone.
Methods
We searched Medline up to December 2017. The prevalence of relapse was pooled using a random‐effects model.
Results
A total of 34 studies (2,505 patients), comprising 8 RCTs, were included. The overall prevalence of relapse was 47.2% (95% confidence interval 40.0, 54.3) with a high heterogeneity (I2 = 93%). Prevalence of relapse was significantly higher for patients included in an RCT compared to those included in an observational study (P < 0.0001), but was not significantly different according to design (P = 0.06). The relapse rate was associated with year of publication (34 studies, rate increase of 8.3% for 1 decade; P < 0.0001) and with shorter GC regimens (17 studies, rate decrease of 1.7% for 1 additional month; P < 0.001), the duration of scheduled GC therapy being shorter in RCTs (12.8 months) compared to observational studies (28.8 months). The effective duration of GC therapy (P = 0.23), initial GC dose (P = 0.49), duration of follow‐up (P = 0.14), sex (P = 0.29), and age (P = 0.43) were not associated with the prevalence of relapse.
Conclusion
GCA relapses occur in half of patients and without improvement across decades in patients receiving GC alone, and the relapse rate is more related to short duration of GC administration than to the initial dose at induction. These results advocate for trial design with at least 12 months of GC therapy.
Background
Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. ...However, a new kind of adverse event called immune‐related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate.
Objective
The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma.
Methods
MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis.
Results
A total of 14 RCT including 7646 patients (median age: 59.3 years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti‐PD1 (or PDL1) and anti‐CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R2 3%, p = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R2 6%, p = 0.33).
Conclusion
Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma.
Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial ...hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH.
We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model.
Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% 332 of 1940 patients vs monotherapy 28% 517 of 1862 patients, risk ratio RR 0·65 95% CI 0·58-0·72, p<0·00001). We noted no heterogeneity between the studies (I(2)=18%, phomogeneity=0·25). A publication bias was suggested by the results of an Egger test (t=-2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 95% CI 0·58-0·73, p<0·00001).
In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed.
None.
ABSTRACT
Early survival is highly variable and strongly influences observed population growth rates in most vertebrate populations. One of the major potential drivers of survival variation among ...juveniles is body mass. Heavy juveniles are better fed and have greater body reserves, and are thus assumed to survive better than light individuals. In spite of this, some studies have failed to detect an influence of body mass on offspring survival, questioning whether offspring body mass does indeed consistently influence juvenile survival, or whether this occurs in particular species/environments. Furthermore, the causes for variation in offspring mass are poorly understood, although maternal mass has often been reported to play a crucial role. To understand why offspring differ in body mass, and how this influences juvenile survival, we performed phylogenetically corrected meta‐analyses of both the relationship between offspring body mass and offspring survival in birds and mammals and the relationship between maternal mass and offspring mass in mammals. We found strong support for an overall positive effect of offspring body mass on survival, with a more pronounced influence in mammals than in birds. An increase of one standard deviation of body mass increased the odds of offspring survival by 71% in mammals and by 44% in birds. A cost of being too fat in birds in terms of flight performance might explain why body mass is a less reliable predictor of offspring survival in birds. We then looked for moderators explaining the among‐study differences reported in the intensity of this relationship. Surprisingly, sex did not influence the intensity of the offspring mass–survival relationship and phylogeny only accounted for a small proportion of observed variation in the intensity of that relationship. Among the potential factors that might affect the relationship between mass and survival in juveniles, only environmental conditions was influential in mammals. Offspring survival was most strongly influenced by body mass in captive populations and wild populations in the absence of predation. We also found support for the expected positive effect of maternal mass on offspring mass in mammals (rpearson = 0.387). As body mass is a strong predictor of early survival, we expected heavier mothers to allocate more to their offspring, leading them to be heavier and so to have a higher survival. However, none of the potential factors we tested for variation in the maternal mass–offspring mass relationship had a detectable influence. Further studies should focus on linking these two relationships to determine whether a strong effect of offspring size on early survival is associated with a high correlation coefficient between maternal mass and offspring mass.
Summary
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).
Abstract
Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune ...diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the
SOCS1
gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence,
SOCS1
haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.
Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval ...of thrombopoietin receptor agonists (TPO‐RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO‐RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO‐RAs and/or rituximab before the splenectomy. The median follow‐up after splenectomy was 39.2 months 16.5–63.0. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow‐up, for an overall sustained response of 65.4%, similar to that observed in the pre‐TPO‐RA era. Among patients who received at least one TPO‐RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO‐RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO‐RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO‐RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re‐challenged with TPO‐RAs.
During the first wave of COVID-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials ...showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide.
We estimated the worldwide in-hospital mortality attributable to HCQ use by combining the mortality rate, HCQ exposure, number of hospitalised patients, and the increased relative risk of death with HCQ. The mortality rate in hospitalised patients for each country was calculated using pooled prevalence estimated by a meta-analysis of published cohorts. The HCQ exposure was estimated using median and extreme estimates from the same systematic review. The number of hospitalised patients during the first wave was extracted from dedicated databases. The systematic review included 44 cohort studies (Belgium: k = 1, France: k = 2, Italy: k = 12, Spain: k = 6, Turkey: k = 3, USA: k = 20). HCQ prescription rates varied greatly from one country to another (range 16–84%). Overall, using median estimates of HCQ use in each country, we estimated that 16,990 HCQ-related in-hospital deaths (range 6267–19256) occurred in the countries with available data. The median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 95 (range 92–128), 199 (range not estimable), 1822 (range 1170–2063), 1895 (range 1475–2094) and 12739 (3244− 15570), respectively.
Although our estimates are limited by their imprecision, these findings illustrate the hazard of drug repurposing with low-level evidence.
Display omitted
•Hydroxychloroquine was prescribed in hospitalised patients with Covid-19 despite of the low-level evidence.•Subsequently, HCQ use was associated with an 11% increase in the mortality rate in a meta-analysis of randomized trials.•The number of hydroxychloroquine related deaths in hospitalised patients is estimated at 16,990 in six countries.•These findings illustrate the hazard of drug repurposing with low-level evidence for the management of future pandemics.
Idiopathic inflammatory myopathies and the lung Lega, Jean-Christophe; Reynaud, Quitterie; Belot, Alexandre ...
European respiratory review,
06/2015, Letnik:
24, Številka:
136
Journal Article
Recenzirano
Odprti dostop
Idiopathic inflammatory myositis (IIM) is a group of rare connective tissue diseases (CTDs) characterised by muscular and extramuscular signs, in which lung involvement is a challenging issue. ...Interstitial lung disease (ILD) is the hallmark of pulmonary involvement in IIM, and causes morbidity and mortality, resulting in an estimated excess mortality of 50% in some series. Except for inclusion body myositis, these extrapulmonary disorders are associated with the general and visceral involvement frequently found in other CTDs including fever, Raynaud's phenomenon, arthralgia, nonspecific cutaneous modifications and ILD, for which the prevalence is estimated to be up to 65%. Substantial heterogeneity exists within the spectrum of IIMs, and each condition is associated with various frequencies and subtypes of pulmonary involvement. This heterogeneity is partly related to the presence of various autoantibodies encompassing anti-synthetase, anti-MDA5 and anti-PM/Scl. ILD is present in all subsets of IIM including juvenile myositis, but is more frequent in dermatomyositis and overlap myositis. IIM can also be associated with other presentations of respiratory involvement, namely pulmonary arterial hypertension, pleural disease, infections, drug-induced toxicity, malignancy and respiratory muscle weakness. Here, we critically review the current knowledge about adult and juvenile myositis-associated lung disease with a detailed description of therapeutics for chronic and rapidly progressive ILD.
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