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Journal of Comparative Effectiveness... Apr 2023To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Data from daily steroid users (placebo-treated) were...
To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.
Topics: Child; Humans; Adrenal Cortex Hormones; Disease Progression; Functional Status; Muscular Dystrophy, Duchenne; Prednisone
PubMed: 36749302
DOI: 10.57264/cer-2022-0190 -
International Journal of Chronic... 2022The burden of chronic obstructive pulmonary disease (COPD) disproportionately affects patients in low to middle-income countries. Although the Theophylline and Steroids... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
The burden of chronic obstructive pulmonary disease (COPD) disproportionately affects patients in low to middle-income countries. Although the Theophylline and Steroids in COPD Study (TASCS) showed no clinical benefit from administering low-dose theophylline and prednisone in COPD patients compared to placebo, it was hypothesized that those with elevated blood eosinophil counts would receive clinical benefit from the intervention.
METHODS
This was a post-hoc analysis of the TASCS dataset - a double-blinded, placebo-controlled trial conducted in patients with moderate-severe COPD in China. Participants were allocated 1:1:1 to low-dose oral theophylline (100mg bd) and prednisone (5mg qd; PrT), theophylline (100mg bd) and prednisone-matched placebo (TP), or double-matched placebo (DP) groups and followed-up for 48 weeks. A baseline count of ≥300 eosinophils/µL blood was categorized as elevated/eosinophilic, and the primary outcome was the annualized moderate-severe exacerbation rate.
RESULTS
Of 1487 participants eligible for analysis, 325 (22%) were eosinophilic. These participants were predominantly male (82%), had a mean (SD) age of 64 (±8) years and a predicted forced expiratory volume in 1s (FEV) of 43% (±16). The annualized moderate-severe exacerbation rate was significantly higher in the PrT group compared to the pooled results of the TP and DP groups (incidence rate ratio = 1.6; ([95% CI 1.06-1.76]) p = 0.016). Changes in spirometry values and reported disease impact scores (St. George's Respiratory Questionnaire and COPD Assessment Test) at week 48 were not significantly different between groups.
CONCLUSION
Combination low-dose theophylline and prednisone was associated with a significant increase in the annual moderate-severe exacerbation rate in participants with a blood eosinophil count ≥300 cells/µL compared to placebo.
Topics: Aged; Bronchodilator Agents; Double-Blind Method; Eosinophils; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Prednisone; Pulmonary Disease, Chronic Obstructive; Theophylline
PubMed: 35153479
DOI: 10.2147/COPD.S339889 -
Journal of Medical Case Reports Sep 2023Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical...
BACKGROUND
Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical manifestations of myasthenia gravis are isolated to the eye muscles, only causing weak eye movements, it is referred to as ocular myasthenia gravis, which can mimic a 1 and ½ syndrome.
CASE PRESENTATION
An African-American female in her fifties with past medical history of hypertension presented to our outpatient clinic with complaints of blurred vision for two weeks. Her symptoms were associated with facial discomfort and a generalized headache. On physical examination upon her initial presentation, there was demonstratable swelling of the left upper eyelid with drooping. Her extraocular movements revealed defects with the abduction and adduction of the right eye, and the left eye would not adduct, although the outward movement was normal. The left eye failed to lift/elevate completely when looking upwards, a pseudo 1 and ½ syndrome. A positive Cogan lid twitch was also noticed. Imaging of the brain and orbit ruled out central causes. Diagnosis of ocular myasthenia gravis was made in accordance with positive anti-acetylcholine receptor antibodies. With 120 mg pyridostigmine oral dose, the patient experienced improvement subjectively and objectively, and the patient was discharged on oral pyridostigmine and prednisone. Six months later, with prednisone having been tapered off, the patient developed a myasthenic crisis and was treated with plasmapheresis and intravenous immunoglobulins. After recovering from the myasthenic crisis, efgartigimod infusions were instituted, which helped our patient restore normal life.
CONCLUSION
Our patient who presented with "blurred vision" was discovered to have binocular diplopia due to significant dysconjugate eye movements. After diligently ruling out central etiologies, we concluded that her presentation was due to a peripheral etiology. Her serologies and her presentation helped confirm a diagnosis of ocular myasthenia gravis. Also, as in most cases, our patient also progressed to develop generalized myasthenia gravis while on pyridostigmine. Efgartigimod infusions instituted after our patient recovered from a myasthenic crisis have helped her restore a normal life.
Topics: Female; Humans; Diplopia; Pyridostigmine Bromide; Prednisone; Vision Disorders; Myasthenia Gravis; Muscle Weakness
PubMed: 37679826
DOI: 10.1186/s13256-023-04089-4 -
Journal of Medical Economics 2023The ongoing Phase III randomized POLARIX study (GO39942; NCT03274492) demonstrated significantly improved progression-free survival (PFS) with polatuzumab vedotin plus...
OBJECTIVE
The ongoing Phase III randomized POLARIX study (GO39942; NCT03274492) demonstrated significantly improved progression-free survival (PFS) with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We compared statistical methodologies to extrapolate long-term PFS data from POLARIX.
MATERIALS AND METHODS
This analysis explored four different approaches to extrapolate the POLARIX data: standard parametric survival, mixture-cure, landmark, and spline models. The resulting extrapolation curves were validated comparison with the corresponding Kaplan-Meier (KM) curves from POLARIX and the POLARIX-like population of the Phase III GOYA study (NCT01287741; R-CHOP arm).
RESULTS
The R-CHOP PFS KM curve from the GOYA validation set was well aligned with the POLARIX KM curve. As we anticipated that PFS in POLARIX would evolve similarly to that of GOYA, the data from GOYA were used to externally validate the extrapolated modelling results. While all four statistical methods were able to fit the data to the POLARIX KM curve, the mixture-cure model was the most accurate in predicting long-term PFS in the GOYA external validation set. In the mixture-cure model, generalized gamma distribution estimated 64% (95% confidence intervals [CI]: 56-71%) of patients to have long-term remission in the R-CHOP arm of POLARIX and GOYA, and 75% (95% CI: 70-79%) in the Pola-R-CHP arm of POLARIX. A limitation of this study was the comparison of the statistical models only in the PFS KM curves, since it was not possible to determine which statistical method was more appropriate to extrapolate the overall survival KM curves.
CONCLUSIONS
Within this analysis, the mixture-cure model provided the best prediction of long-term outcomes from the primary PFS analysis of the POLARIX study.
Topics: Humans; Rituximab; Prednisone; Antineoplastic Combined Chemotherapy Protocols; Lymphoma, Large B-Cell, Diffuse; Cyclophosphamide; Doxorubicin; Vincristine
PubMed: 37702406
DOI: 10.1080/13696998.2023.2259107 -
Rheumatology (Oxford, England) Aug 2022Evidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline...
OBJECTIVES
Evidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM.
METHODS
Muscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package.
RESULTS
Female sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate-severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months.
CONCLUSION
Early IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.
Topics: Autoantibodies; Autoimmune Diseases; Bayes Theorem; Female; Humans; Immunoglobulins, Intravenous; Methylprednisolone; Muscle, Skeletal; Muscular Diseases; Myositis; Prednisone; Retrospective Studies
PubMed: 35022671
DOI: 10.1093/rheumatology/keac014 -
Kidney & Blood Pressure Research 2022Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing... (Review)
Review
BACKGROUND
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO-AAV. CCX168, i.e., avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the proinflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability.
SUMMARY
Avacopan was found to be safe in healthy volunteers given a wide range of doses in a phase 1 clinical trial. The phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the standard-of-care therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The phase 3 ADVOCATE study compared the ability of an avacopan-associated regimen to induce and sustain remission in AAV patients versus a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given avacopan and in 54.9% receiving prednisone. The avacopan-associated regimen was noninferior at week 26 and superior at week 52 in sustaining remission as compared to the GC-based scheme.
KEY MESSAGES
The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of avacopan in a routine clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Complement Activation; Humans; Mice; Prednisone; Receptor, Anaphylatoxin C5a
PubMed: 35665698
DOI: 10.1159/000525357 -
Journal of Neuromuscular Diseases 2022Glucocorticoid steroids are standard of care in Duchenne Muscular Dystrophy (DMD) to slow disease course. Use of glucocorticoids in other muscular dystrophies, including... (Clinical Trial)
Clinical Trial
BACKGROUND
Glucocorticoid steroids are standard of care in Duchenne Muscular Dystrophy (DMD) to slow disease course. Use of glucocorticoids in other muscular dystrophies, including Becker (BMD) and Limb Girdle (LGMD), has been less explored. Recently, preclinical studies conducted in DMD and LGMD mouse models showed once-weekly prednisone was associated with improved muscle performance without activation of muscle atrophy genes.
OBJECTIVE
To determine safety and tolerability of once-weekly prednisone in patients with LGMD and BMD.
METHODS
We conducted an open label, exploratory single center study of of once-weekly prednisone at 0.75-1 mg/Kg in LGMD (n = 19) and BMD (n = 1) (mean age 35, range 18-60). The LGMD participants represented multiple different LGMD subtypes, and the study included ambulatory and non-ambulatory participants. Participants were assessed at baseline and 24 weeks for vital signs, blood biomarkers, and for patient-reported side effects. As secondary endpoints, functional muscle testing and body composition were measured.
RESULTS
Over the 24-week study, there were no significant changes in blood pressure, HgbA1C, or lipid profiles. We observed a reduction in serum creatine kinase over the study interval. Whole body DEXA scanning suggested a possible increase in lean mass and a reduction in adiposity. Functional measures suggested trends in improved muscle performance.
CONCLUSIONS
In this single center, open label pilot study, once-weekly prednisone was safe and well tolerated. Additional investigation of once-weekly prednisone in a larger cohort and for a longer period of time is warranted.
Topics: Drug Administration Schedule; Humans; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Pilot Projects; Prednisone
PubMed: 35124660
DOI: 10.3233/JND-210741 -
Annals of the Rheumatic Diseases May 2023Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term...
OBJECTIVES
Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common. We strived for an improved therapy for fibrosis remission while reducing side effects.
METHODS
We surveyed gene-disease-drug databases and discovered that mammalian target of rapamycin (mTOR) was a key signalling protein in RPF and the mTOR inhibitor compound sirolimus affected many RPF pathways. We designed a therapy combining a gradual reduction of prednisone with a long-term, stable dosage of sirolimus. We then implemented a single-arm clinical trial and assessed the effects in eight RPF patients at 0, 12 and 48 weeks of treatment by measuring fibrous tissue mass by CT, markers of inflammation and kidney functions by lab tests, immune cell profiles by flow cytometry and plasma inflammatory proteins by Olink proteomics.
RESULTS
With the combined therapy, fibrous tissue shrunk about by half, markers of acute inflammation reduced by 70% and most patients with abnormal kidney functions had them restored to normal range. Molecularly, fibrosis-related T cell subsets, including T2, T17 and circulating T cells, were reduced and tumour necrosis factor and related cytokines restored to healthy levels. No severe long-term side effects were observed.
CONCLUSIONS
Our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states, while achieving good tolerance. We concluded that this new therapy had the potential to replace the steroid monotherapy for treating RPF.
Topics: Humans; Retroperitoneal Fibrosis; Prednisone; Sirolimus; Fibrosis; Inflammation; TOR Serine-Threonine Kinases
PubMed: 36720581
DOI: 10.1136/ard-2022-223736 -
European Neurology 2021The aim of the study was to estimate the exacerbation incidence rate (IR) in acetylcholine receptor antibody (AChR)-positive generalized myasthenia gravis (MG) and its...
OBJECTIVE
The aim of the study was to estimate the exacerbation incidence rate (IR) in acetylcholine receptor antibody (AChR)-positive generalized myasthenia gravis (MG) and its predictors.
METHODS
The primary outcome in this retrospective study was to estimate moderate-to-severe (M-S) exacerbations IR in the early course of generalized MG. The secondary outcome was to explore the predictors of MG exacerbations.
RESULTS
Between 1999 and 2015, we identified 78 AChR-positive generalized MG patients and 37 M-S exacerbations over the first 6 years following the onset of generalized MG symptoms. The M-S exacerbation IR was 12.2 per 100 person years (95% confidence interval [CI] 8.8-16.8). Any exacerbation (including mild) IR was 24.4 per 100 person years (95% CI 19.4-30.7). After controlling for confounding factors, MG exacerbation IR predictors included gender, disease severity at onset, and prednisone dose reduction with risk ratio of 0.34 (male gender), 2.67, and 20.8, respectively (all p values <0.05). M-S exacerbation occurred in 25 cases (32.1%), while any exacerbation (mild or M-S) was detected in 45 cases (57.7%).
CONCLUSION
More than half of newly diagnosed AChR + MG cases experience an exacerbation in the first 6 years. Gender, disease severity at onset and prednisone dose reduction are predictors that could inform clinical practice and future research.
Topics: Autoantibodies; Humans; Male; Myasthenia Gravis; Prednisone; Receptors, Cholinergic; Retrospective Studies
PubMed: 33321491
DOI: 10.1159/000512077 -
Neurological Sciences : Official... Apr 2023To explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients. (Observational Study)
Observational Study
PURPOSE
To explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients.
METHODS
A retrospective, observational cohort study was performed for 435 OMG patients with onset age older than 14 years old. Multivariate Cox regression was used to identify the independent factors affecting generalized conversions that then were incorporated into the construction of the nomogram.
RESULTS
Two hundred thirty-seven patients (54.5%) had transformed into GMG after a median of 1.1 years (range 0.1--9.1 years). The 6-, 12-, and 24-month generalized conversion rates were 31.7%, 49.8%, and 65.4%, respectively. Multivariable analysis showed that the early-onset age, male sex, concomitant autoimmune diseases (AID), positive results of anti-acetylcholine receptor antibodies, repetitive nerve stimulation abnormalities, the presence of thymoma, and prednisone treatment were significantly associated with the generalized conversions (hazard ratio [HR] = 0.598, 0.686, 1.554, 1.541, 2.020, 2.510, and 0.556, respectively). A nomogram was established to predict the possibility of generalization-free survival (GFS) in adult-onset OMG patients, and the model demonstrated good predictive performance with a C-index of 0.736 (95% confidence interval 0.703 ~ 0.769). Moreover, subgroup analyses were performed based on the presence or absence of prednisone therapy, and the results indicated that prednisone therapy has better prevention of generalized conversions in male, non-thymoma patients, and patients without other AID.
CONCLUSION
A new predictive nomograph and web-based survival calculator we developed show favorable applicability and accuracy in predicting long-term GFS in adult-onset OMG patients.
Topics: Humans; Adult; Male; Adolescent; Prednisone; Retrospective Studies; Nomograms; Disease Progression; Myasthenia Gravis
PubMed: 36469201
DOI: 10.1007/s10072-022-06519-5