Purpose: Approximately 6% of patients with rheumatoid arthritis (RA) in the USA have refractory disease that is resistant to standardof-care therapies. A recent phase IV clinical trial affirmed the safety and efficacy of repository corticotropin injection (RCI; ActharÒ Gel) for refractory RA. This post hoc analysis of the clinical trial data assessed whether changes in clinical measures correlated with patientreported outcome (PRO) improvements. Methods: Data were assessed from the trial's open-label period when patients received RCI (80 U) twice weekly for 12 weeks. Clinical assessments included hemoglobin A1c, C-reactive protein, erythrocyte sedimentation rate (ESR), total joint count (TJC), swollen joint count (SJC), Disease Activity Score with 28 joint
Purpose: Repository corticotropin injection (RCI; Acthar ® Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogs and other pituitary peptides that exerts antiinflammatory and immunomodulatory properties via melanocortin receptors. RCI is approved as a short-term adjunctive therapy for rheumatoid arthritis (RA) and is typically used in patients with refractory RA. The objective of this study was to describe real-world outcomes of RA patients treated with RCI by retrospective analysis of an electronic medical records (EMR) database. Patients and Methods: EMR data were obtained from the United Rheumatology-Normal Integrated Community Evidence (UR-NICE TM ) data repository for patients who used RCI for the treatment of RA. Demographics, comorbidities, disease history, medications, and laboratory evaluations 365 days prior to and 365 days after initiation of RCI were examined. Results: The patient cohort was predominantly White females with a mean age of 60 years and high RA activity prior to RCI therapy. Clinical measures of disease severity indicated that patients had high RA activity before starting RCI therapy. Clinical Disease Activity Index (CDAI) scores were significantly reduced 365 days post-initiation of RCI. Swollen and tender joint counts and patient-reported outcomes, including Routine Assessment of Patient Index Data 3 (RAPID3), Physician Global Assessment, and patient assessment of pain severity were also significantly lower. The number of patients taking conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), biologic (b) DMARDs, nonsteroidal anti-inflammatory drugs (NSAIDS), and opioids decreased, as did the number of drugs tried within each class for csDMARDs, bDMARDs, NSAIDs, and glucocorticoids. Conclusions: These findings suggest that RCI significantly improves clinical outcomes of RA and decreases the need for concomitant medications for up to 1 year following initiation of therapy. The study provides valuable insights into the use of RCI and management of these difficult-to-treat RA patients during routine clinical practice.
The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis. Phosphoproteomics was applied and identified MC1R pathways confirmed using biochemical analysis. We found that glomerular MC1R expression was increased in nephrotic syndrome, both in humans and in a rat model. A MC1R agonist protected podocytes from protamine sulfate induced stress fiber loss with the top ranked phoshoproteomic MC1R activated pathway beeing actin cytoskeleton signaling. Actin stabilization through the MC1R consisted of ERK1/2 dependent phosphorylation and inactivation of EGFR signaling with stabilization of synaptopodin and stressfibers in podocytes. These results further explain how patients with nephrotic syndrome show responsiveness to MC1R receptor activation by decreasing EGFR signaling and as a consequence restore filtration barrier function by stabilizing the podocyte actin cytoskeleton.
Repository corticotropin injection (RCI) is indicated as adjunctive, short-term therapy in selected patients with RA. To characterize RCI users and identify predictors of RCI initiation in RA, we compared preindex characteristics, treatment patterns, comorbidities, healthcare resource utilization (HCRU), and costs for patients who had initiated RCI treatment (RCI cohort) versus patients with no RCI claims and ≥ 1 targeted synthetic or biologic disease-modifying antirheumatic drugs (ts/bDMARD) claim (non-RCI ts/bDMARD cohort). We analyzed pharmacy and medical claims data from a large commercial and Medicare supplemental administrative database. Inclusion criteria were age ≥ 18 years, ≥ 1 inpatient or ≥ 2 outpatient claims with RA diagnosis (January 1, 2007–December 31, 2018), and 12-month continuous medical and pharmacy coverage preindex. Results from baseline cohort comparisons informed multiple logistic regression analysis. Compared with the non-RCI ts/bDMARD cohort ( n = 162,065), the RCI cohort ( n = 350) had a greater proportion of patients with higher Charlson comorbidity index (CCI) scores; higher mean claims-based index of RA severity and CCI scores; greater frequency of almost all comorbidities; higher use of nontraditional DMARDs, glucocorticoids, and opioids; higher all-cause HCRU; and higher medical and total costs. By multivariable analysis, the most significant predictors of RCI initiation were intermittent glucocorticoid use at any dose (odds ratio [OR] 1.67), extended-use glucocorticoids at medium (OR 2.03) and high doses (OR 2.99), nontraditional DMARD use (OR 2.09), anemia (OR 1.39), and renal disease (OR 2.45). Before RCI initiation, patients had more severe RA, higher comorbidity burden, greater use of glucocorticoids and opioids, and higher HCRU compared with non-RCI initiators. The most significant predictors for starting RCI in patients with RA were intermittent use of glucocorticoids at any dose, extended-use high-dose glucocorticoids, use of nontraditional DMARDs, and comorbid anemia and renal disease. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-020-00272-x.
Background Focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar® Gel), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation. Methods Two studies in a preclinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model assessed the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (N = 27), and a 12-week chronic RCI dose range study (N = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by assessing urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers. Results Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38% reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18, 47, and 44%, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model. Conclusions These results provide evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors’ knowledge, this is the first evidence that a drug for the treatment of FSGS supports podocyte recovery after repeated injury.
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