First Results From a Propensity Matching Trial of Mycophenolate Mofetil vs. Azathioprine in Treatment-Naive AIH Patients

Background/AimsAs previous real-world studies and meta-analyses have shown that mycophenolate mofetil (MMF) might have better efficacy than azathioprine (AZA) in autoimmune hepatitis (AIH), we conducted a propensity matching study to assess the efficacy and safety of MMF vs. AZA.MethodsAll 126 consecutive treatment-naive adult AIH patients, diagnosed and followed in our department since 2016, were included. Patients received prednisolone 0.5–1 mg/kg/day plus either AZA 1–2 mg/kg/day or 1.5–2 g/day MMF. The tapering of prednisolone was identical between groups.ResultsAfter propensity matching score and adjustment for known factors affecting response to treatment and outcome, 64 patients were included in the study (MMF = 32 and AZA = 32). Rates of non-response, complete biochemical response (CBR) at 6 and 12 months, and prednisolone withdrawal (6 months, 12 months, and end of follow-up) were identical between groups. However, MMF treatment was significantly associated with CBR at the end of follow-up [odds ratio (OR) 11.259; 95% CI: 1.3–97.4, p = 0.028]. AZA patients were more prone to stop treatment due to AZA intolerance/insufficient response (p = 0.0001). At the end of follow-up, the overall efficacy of each schedule was also significantly higher in the MMF group compared to the AZA group (p = 0.0001).ConclusionWe showed for the first time in a propensity matching study that MMF can be used as first-line therapy in AIH as attested by the significantly higher CBR at end of follow-up compared to AZA. Whether this better efficacy is also associated with higher histological remission rates and sustained CBR off immunosuppression needs further evaluation.

Activity of genes of matrix metalloproteinases and their inhibitors in the Ligamentum flavum of patients with stenosing processes in spinal canal and dural sac

New data have been obtained for assessing the expression of genes of metalloproteinases and their tissue inhibitors (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2) in the Ligamentum flavum in patients with lumbar stenosis of spinal canal and dural sac. The features of the metabolism of the extracellular matrix (ECM) were revealed, the data obtained were compared with those for previously studied candidate genes. The search for relationships with the features of the ECM metabolic characteristics was carried out.The aim. To study the expression of genes of metalloproteinases and their tissue inhibitors in intraoperative biopsies of the Ligamentum flavum of patients with lumbar stenosis of the spinal canal and dural sac.Materials and methods. A group of 33 people (17 women, 16 men) with lumbar stenosis of the spinal canal and dural sac was studied; the average age is 45.73 ± 1.95 years. RNA was isolated from intraoperative biopsies of the Ligamentum flavum, reverse transcription was performed, and PCR using specific primers was performed.Results. In Ligamentum flavum of patients with stenosing processes of the spinal canal and dural sac, an increased activity of MMP-1 and insufficient response of TIMP-1 and TIMP-2 were found; the expression of MMP-1 increased synchronously with Dio2, and both genes decreased their activity with increasing age of the patient. In patients with Ligamentum flavum ossification, the MMR-8 gene was more actively expressed, and the synthesis of the mRNA of the MMR-9 gene decreased compared to the subgroup without ossification.

Antithrombotic effect of different acetylsalicylic acid drug formulations: is there a difference?

To date, a sufficient volume of clinical studies has been accumulated that have demonstrated a reduced antiplatelet effect of enteric-coated (EC) lowdose acetylsalicylic acid (ASA). Delayed and incomplete absorption from the intestinal alkaline medium, which significantly reduces the bioavailability of drug, is considered the main reason for laboratory aspirin resistance (pseudoresistance) to EC ASA. This phenomenon is of particular importance for patients with acute coronary syndrome, when a quick effect is required, as well as for patients with diabetes and obesity due to additional causes of increased platelet activity, on the one hand, and reduced bioavailability of ASA, on the other. Given the issue of efficacy, the dubious gastroprotective effect and the more pronounced damaging effect on the mucous membrane of small intestine, the use of EC ASA should be avoided, especially in patients with a multifactorial risk of insufficient response to therapy. A good alternative is buffered ASA, which quickly dissolves and is partially absorbed directly in the stomach, having antiplatelet activity comparable to simple ASA and a similar aspirin resistance, is associated with a lower risk of aspirin-induced enteropathy in comparison with ES ASA. In addition, according to a number of small studies and retrospective analyzes, buffered ASA is less likely to cause damage to gastric mucosa compared to EC ASA.

Rationale and Design of a Phase 3b Multicenter, Randomized, Double-Blind Placebo-Controlled, Parallel-Group Trial with an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Avatrombopag for the Treatment of Pediatric Patients with Immune Thrombocytopenia

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts (PCs) caused by a combination of both impaired platelet production and increased peripheral platelet destruction. ITP in children often resolves on its own, but it may become chronic and symptomatic in a proportion of children affected. After failure of first-line therapies (e.g. corticosteroids or immunoglobulin), treatment options for children include immunosuppressants, such as rituximab, and thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA) is an orally administered small molecule TPO-RA. It binds the human c-Mpl at a different site than endogenous TPO, stimulating signal transduction mimicking the biological effects of endogenous TPO in a non-competitive manner. In a phase 3 trial (NCT01438840) in adults with ITP, the primary efficacy endpoint of cumulative number of weeks with PC ≥50×10 9/L during 6 months of treatment in the absence of rescue therapy, was statistically significant favoring AVA over placebo. The most common treatment-emergent adverse events (AEs) in the phase 2 and 3 trials in adults (n=128) were headache, fatigue, and contusion. AVA has no significant hepatotoxicity, is administered with food, and has no restrictions on meal composition. AVA is approved by FDA and EMA for treatment of primary chronic ITP in adult patients with an insufficient response to a previous treatment. For pediatric patients with ITP, there is an unmet need for new treatment options, given the difficult administration requirements and variable, transient response, frequent relapse, and associated toxicities of available treatments. Study Design and Methods: Described here is the rationale and design of a phase 3b multicenter, randomized, double-blind placebo-controlled, parallel-group trial with an open-label extension phase (NCT04516967), evaluating the efficacy and safety of AVA for the treatment of pediatric patients with ITP for ≥6 months with an insufficient response to a previous treatment. Main inclusion criteria (Core phase) include: Age ≥1 and <18 years; informed consent; primary ITP for ≥6 months duration and an insufficient response to previous treatment; an average of 2 PCs <30×10 9/L, with no single count >35×10 9/L. Main exclusion criteria: secondary ITP; inherited thrombocytopenia; history of arterial or venous thrombosis, myelodysplastic syndrome; or congenital heart abnormalities or arrhythmias. Subjects will be randomized to blinded therapy of AVA or placebo (3:1 ratio) for 12 weeks, stratified by age cohort and baseline PC (Figure). AVA or placebo will be administered as an oral tablet (20 mg, age cohort 1 and 2) or as an age-appropriate pediatric formulation (10 mg, age cohort 3). Subjects who complete the Core Phase and are eligible may continue to the open label extension phase (2 years). The primary endpoint is durable platelet response, defined by the proportion of subjects achieving ≥6 out of 8 weekly PCs ≥50×10 9/L during the last 8 weeks of the 12 week treatment period in the Core Phase, in the absence of rescue medication. Secondary endpoints include proportion of subjects with ≥2 consecutive PCs ≥50×10 9/L during the Core Phase (12 weeks) in the absence of rescue medication; percentage of weeks with PC ≥50×10 9/L, and between ≥50×10 9/L and ≤150×10 9/L, during Core Phase (12 weeks) in the absence of rescue therapy; proportion of subjects with PC ≥50×10 9/L at day 8, proportion of subjects who require rescue medications during Core Phase; incidence and severity of bleeding symptoms; safety and PK/PD parameters. Statistics: The primary endpoint will be tested using the Cochran-Mantel-Haenszel 2-sided test at α=0.05, adjusting for age cohort and baseline PC (≤15×10 9/L vs >15×10 9/L), or the Fisher's exact test, when data is sparse. In addition, the numbers and percentages of responders in each treatment group, the associated 95% confidence intervals (CI), and the 95% CI for the difference between AVA and placebo will be estimated. Study Status: This global study is currently enrolling patients and aims to include at least 72 patients in total, at approximately 62 sites. Figure 1 Figure 1. Disclosures Grace: Principia: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Novartis: Research Funding. Xue: Dova Pharmaceuticals, a Sobi company: Current Employment. Jamieson: Sobi, Inc.: Current Employment. OffLabel Disclosure: Avatrombopag is an orally administered thrombopoietin receptor agonist (TPO-RA) that mimics the biologic effects of TPO in stimulating the development and maturation of megakaryocytes, resulting in increased platelet count. It is approved by the European Medicines Agency (EMA) and the US Food & Drug Administration (FDA) for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure, and for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Efficacy and Safety of Eltrombopag Combined with Cyclosporine As First-Line Therapy in Adults with Severe Acquired Aplastic Anemia: Results of the Interventional Phase 2 Single-Arm Soar Study

Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months; responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL; platelet count ≥20,000/μL; automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart; transfusion restrictions were also applied. For the primary endpoint to be considered 'clinically meaningful' at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%; 95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%; n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%; n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%; non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts; 45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3]; COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]); no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. Figure 1 Figure 1. Disclosures Vallejo: Novartis: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Finelli: Takeda: Consultancy; Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding; Alexion Brasil: Consultancy; Instituto Butantan: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals Inc: Consultancy, Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Consultancy; Roche: Consultancy; Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study

Background A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Methods Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. Results In triptan insufficient responders, lasmiditan was superior to placebo ( p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. Conclusions Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174)

Infantile Hemangiomas: An Update on Pathogenesis and Treatment

Infantile hemangiomas are the most common benign vascular tumors in infancy. This review includes an update on the current knowledge on pathogenesis, a discussion on indications for treatment, and a review of the mechanisms underlying the different treatment methods. Although most infantile hemangiomas require only active observation because of their natural course, which results in involution, about 10% present with complications that require immediate treatment. The basic treatment includes systemic and topical options. In cases of insufficient response or rebound growth, other forms of treatment should be considered. In some cases, combined therapy might be initiated.

Autoimmmune hepatitis

Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.