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Drug Safety Oct 2021This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal...
INTRODUCTION
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.
OBJECTIVE
We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.
METHODS
Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated.
RESULTS
The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients.
CONCLUSIONS
Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.
Topics: Animals; Biological Products; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Genetic Therapy; Humans; Mice; Muscular Atrophy, Spinal; Prednisolone
PubMed: 34383289
DOI: 10.1007/s40264-021-01107-6 -
The Cochrane Database of Systematic... Jan 2023Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) that mainly affects children. Symptoms include fever, chapped lips, strawberry... (Review)
Review
BACKGROUND
Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) that mainly affects children. Symptoms include fever, chapped lips, strawberry tongue, red eyes (bulbar conjunctival injection), rash, redness, swollen hands and feet or skin peeling; and enlarged cervical lymph nodes. High fevers and systemic inflammation characterise the acute phase. Inflammation of the coronary arteries causes the most serious complication of the disease, coronary artery abnormalities (CAAs). The primary treatment is intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA/aspirin), with doses and regimens differing between institutions. It is important to know which regimens are the safest and most effective in preventing complications.
OBJECTIVES
To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 26 April 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) investigating the use of IVIG for the treatment of KD. We included studies involving treatment for initial or refractory KD, or both.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were incidence of CAAs and incidence of any adverse effects after treatment. Our secondary outcomes were acute coronary syndromes, duration of fever, need for additional treatment, length of hospital stay, and mortality. We used GRADE to assess the certainty of the evidence for each outcome.
MAIN RESULTS
We identified 31 RCTs involving a total of 4609 participants with KD. Studies compared IVIG with ASA, another dose or regimen of IVIG, prednisolone, or infliximab. The majority of studies reported on primary treatment, so those results are reported below. A limited number of studies investigated secondary or tertiary treatment in IVIG-resistant patients. Doses and regimens of IVIG infusion varied between studies, and all studies had some concerns related to risk of bias. Primary treatment with IVIG compared to ASA for people with KD Compared to ASA treatment, IVIG probably reduces the incidence of CAAs in people with KD up to 30 days (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41 to 0.87; 11 studies, 1437 participants; moderate-certainty evidence). The individual studies reported a range of adverse effects, but there was little to no difference in numbers of adverse effects between treatment groups (OR 0.57, 95% CI 0.17 to 1.89; 10 studies, 1376 participants; very low-certainty evidence). There was limited evidence for the incidence of acute coronary syndromes, so we are uncertain of any effects. Duration of fever days from treatment onset was probably shorter in the IVIG group (mean difference (MD) -4.00 days, 95% CI -5.06 to -2.93; 3 studies, 307 participants; moderate-certainty evidence). There was little or no difference between groups in need for additional treatment (OR 0.27, 95% CI 0.05 to 1.57; 3 studies, 272 participants; low-certainty evidence). No study reported length of hospital stay, and no deaths were reported in either group. Primary treatment with IVIG compared to different infusion regimens of IVIG for people with KD Higher-dose regimens of IVIG probably reduce the incidence of CAAs compared to medium- or lower-dose regimens of IVIG up to 30 days (OR 0.60, 95% CI 0.40 to 0.89; 8 studies, 1824 participants; moderate-certainty evidence). There was little to no difference in the number of adverse effects between groups (OR 1.11, 95% CI 0.52 to 2.37; 6 studies, 1659 participants; low-certainty evidence). No study reported on acute coronary syndromes. Higher-dose IVIG may reduce the duration of fever compared to medium- or lower-dose regimens (MD -0.71 days, 95% CI -1.36 to -0.06; 4 studies, 992 participants; low-certainty evidence). Higher-dose regimens may reduce the need for additional treatment (OR 0.29, 95% CI 0.10 to 0.88; 4 studies, 1125 participants; low-certainty evidence). We did not detect a clear difference in length of hospital stay between infusion regimens (MD -0.24, 95% CI -0.78 to 0.30; 3 studies, 752 participants; low-certainty evidence). One study reported mortality, and there was little to no difference detected between regimens (moderate-certainty evidence). Primary treatment with IVIG compared to prednisolone for people with KD The evidence comparing IVIG with prednisolone on incidence of CAA is very uncertain (OR 0.60, 95% CI 0.24 to 1.48; 2 studies, 140 participants; very low-certainty evidence), and there was little to no difference between groups in adverse effects (OR 4.18, 95% CI 0.19 to 89.48; 1 study; 90 participants; low-certainty evidence). We are very uncertain of the impact on duration of fever, as two studies reported this outcome differently and showed conflicting results. One study reported on acute coronary syndromes and mortality, finding little or no difference between groups (low-certainty evidence). No study reported the need for additional treatment or length of hospital stay.
AUTHORS' CONCLUSIONS
The included RCTs investigated a variety of comparisons, and the small number of events observed during the study periods limited detection of effects. The certainty of the evidence ranged from moderate to very low due to concerns related to risk of bias, imprecision, and inconsistency. The available evidence indicated that high-dose IVIG regimens are probably associated with a reduced risk of CAA formation compared to ASA or medium- or low-dose IVIG regimens. There were no clinically significant differences in incidence of adverse effects, which suggests there is little concern about the safety of IVIG. Compared to ASA, high-dose IVIG probably reduced the duration of fever, but there was little or no difference detected in the need for additional treatment. Compared to medium- or low-dose IVIG, there may be reduced duration of fever and reduced need for additional treatment. We were unable to draw any conclusions regarding acute coronary syndromes, mortality, or length of hospital stay, or for the comparison IVIG versus prednisolone. Our findings are in keeping with current guideline recommendations and evidence from long-term epidemiology studies.
Topics: Child; Humans; Mucocutaneous Lymph Node Syndrome; Immunoglobulins, Intravenous; Acute Coronary Syndrome; Prednisolone; Aspirin; Inflammation; Fever
PubMed: 36695415
DOI: 10.1002/14651858.CD014884.pub2 -
Ugeskrift For Laeger Nov 2023Juvenile dermatomyositis (JDM) is a rare condition, which causes inflammation in children's skin and musculoskeletal systems. Symptoms include characteristic skin rashes...
Juvenile dermatomyositis (JDM) is a rare condition, which causes inflammation in children's skin and musculoskeletal systems. Symptoms include characteristic skin rashes on the face and extremities, muscle pain and weakness. This is a case report of a ten-year-old boy initially suspected of having lupus erythematosus. He was later diagnosed with JDM by dermatologists. Treatment with methotrexate and prednisolone proved to be effective.
Topics: Male; Child; Humans; Dermatomyositis; Methotrexate; Skin; Inflammation; Prednisolone
PubMed: 37987452
DOI: No ID Found -
Ugeskrift For Laeger May 2023This case report presents two patients who were diagnosed with non-systemic vasculitic neuropathy (NSVN). The phenotypes were atypical: 1) slowly progressive neuropathy...
This case report presents two patients who were diagnosed with non-systemic vasculitic neuropathy (NSVN). The phenotypes were atypical: 1) slowly progressive neuropathy and 2) plexopathy in contrast to the classic NSVN phenotype: painful, asymmetric with subacute progression. Both patients had remarkable responses to the immunosuppressants prednisolone and rituximab, and the cases highlight the importance to consider NSVN as a differential diagnosis of patients with neuropathy of unknown aetiology, as treatment can be initiated to avoid irreversible nerve damage.
Topics: Humans; Vasculitis; Time-to-Treatment; Peripheral Nervous System Diseases; Pain; Prednisolone
PubMed: 37170743
DOI: No ID Found -
Gut Jan 2022In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid... (Randomized Controlled Trial)
Randomized Controlled Trial
First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.
OBJECTIVE
In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.
DESIGN
In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis.
RESULTS
100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004).
CONCLUSIONS
FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Registry (NCT02517684).
Topics: Adolescent; Anti-Inflammatory Agents; Azathioprine; Child; Child, Preschool; Crohn Disease; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Prednisolone; Remission Induction; Severity of Illness Index
PubMed: 33384335
DOI: 10.1136/gutjnl-2020-322339 -
Journal of Hepatology Apr 2024Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH.
METHODS
In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability.
RESULTS
Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018).
CONCLUSIONS
In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF.
IMPACT AND IMPLICATIONS
This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis.
TRIAL REGISTRATION NUMBER
#NCT02900443.
Topics: Humans; Female; Male; Azathioprine; Mycophenolic Acid; Hepatitis, Autoimmune; Prospective Studies; Treatment Outcome; Immunosuppressive Agents; Prednisolone; Remission Induction
PubMed: 38101756
DOI: 10.1016/j.jhep.2023.11.032 -
Ugeskrift For Laeger Dec 2023In this case report, a 55-year-old man presented with back pain, urinary retention, sensory disturbances, erectile dysfunction, leg paresis and orthostatism. Spinal MRI...
In this case report, a 55-year-old man presented with back pain, urinary retention, sensory disturbances, erectile dysfunction, leg paresis and orthostatism. Spinal MRI showed longitudinal extensive myelitis. Lymph node biopsy was compatible with sarcoidosis and a diagnosis of probable neurosarcoidosis (NS) was made. The patient benefited from prednisolone but relapsed during withdrawal. Infliximab resulted in almost complete remission. In conclusion, relapse is often seen when phasing out prednisolone, whereas infliximab appears to have a lasting effect and should be considered in the early stages of severe NS.
Topics: Male; Humans; Middle Aged; Infliximab; Central Nervous System Diseases; Sarcoidosis; Myelitis; Prednisolone; Magnetic Resonance Imaging
PubMed: 38078475
DOI: No ID Found -
Biomolecules Nov 2022Reports of eosinophilic pneumonia (EP) as a side effect of dupilumab administration are limited in previous studies. Herein, we report two cases in which EP developed...
Reports of eosinophilic pneumonia (EP) as a side effect of dupilumab administration are limited in previous studies. Herein, we report two cases in which EP developed subsequent to the administration of dupilumab for eosinophilic chronic rhinosinusitis (ECRS). Case 1: A 55-year-old woman presented with ECRS, eosinophilic otitis media, and bronchial asthma, and was treated with dupilumab for ECRS. Five weeks later, fever and dyspnea developed, and infiltration shadows were observed in her lungs. The peripheral blood eosinophil count (PBEC) was 3848/μL (26%), bronchoalveolar lavage fluid showed eosinophilic infiltration, and EP was subsequently diagnosed. Her condition improved following prednisolone treatment. Case 2: A 59-year-old man presented with fatigue and dyspnea after receiving dupilumab for ECRS. He had infiltrative shadows throughout his left lung field, and his PBEC was 4850/μL (26.5%). Prednisolone was initiated, and his condition improved. EP developed in both patients during the period of elevated PBEC after dupilumab administration, and dupilumab was suspected to be the causative agent in their EP. Hence, EP should be considered as a differential diagnosis when fever and dyspnea appear following dupilumab administration.
Topics: Humans; Male; Female; Middle Aged; Pulmonary Eosinophilia; Lung; Prednisolone; Dyspnea; Chronic Disease
PubMed: 36551171
DOI: 10.3390/biom12121743 -
BMJ Case Reports May 2020
Topics: Adult; Female; Glucocorticoids; Humans; Mouth Diseases; Pemphigus; Prednisolone
PubMed: 32404374
DOI: 10.1136/bcr-2020-235410 -
CMAJ : Canadian Medical Association... Aug 2019
Topics: Back; Glucocorticoids; Granuloma; Hand Dermatoses; Humans; Male; Middle Aged; Prednisolone; Skin Diseases; Thorax
PubMed: 31405837
DOI: 10.1503/cmaj.190120