Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

DNA repair XRCC1 Arg399Gln polymorphism is associated with the risk of development of end-stage renal disease

Patients with end-stage renal disease (ESRD) display enhanced genomic damage. DNA repair gene polymorphisms may affect DNA repair capacity and modulate susceptibility to ESRD. In this study, we aimed to determine the frequency of polymorphisms in two DNA repair enzyme genes, Xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1), in patients with ESRD and to evaluate their association with ESRD development. By using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), we genotyped four single nucleotide polymorphisms (SNPs) in XPD codons 312 and 751 and XRCC1 codons 194 and 399 in 136 dialysis patients (71 patients undergoing hemodialysis and 65 subjected to peritoneal dialysis) and 147 healthy controls. Patients having XRCC1 399 Arg/Gln (OR:1.98; 95% CI: 1.21-3.25, P = 0.007) or XRCC1-399 Gln/Gln (OR: 3.95; 95% CI: 1.45-10.76, P = 0.005) genotype had a significantly higher risk of ESRD than those with XRCC1 399 Arg/Arg genotype. We also found a significantly higher frequency of the XRCC1 399Gln allele in patients with ESRD than in controls, with OR = 2.03 (95% CI = 1.08-3.81, P = 0.03). We further investigated the potential combined effect of these DNA repair variants on the risk of ESRD development. It was found that combination of the Arg/Gln or Gln/Gln genotypes of XRCC1 Arg399Gln polymorphism with the two possible genotypes of XPD-Asp312Asn or with the Lys/Gln or Gln/Gln genotypes of XPD Lys751Gln was significantly associated with the development of ESRD. This is the first report showing an association between DNA repair gene polymorphisms and ESRD development, and suggests that XRCC1 Arg399Gln polymorphism may confer increased risk for the development of the disease. Further larger studies should be conducted to confirm these results

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019

Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study

Introduction/Aims Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti‐acetylcholine receptor antibody‐positive (AChR+) gMG previously treated with rituximab. Methods This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open‐label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous‐rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no‐previous‐rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous‐rituximab and no‐previous‐rituximab groups (least‐squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least‐squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post‐intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously

Correction to: Eculizumab improves fatigue in refractory generalized myasthenia gravis (Quality of Life Research, (2019), 28, 8, (2247-2254), 10.1007/s11136-019-02148-2)

The article “Eculizumab improves fatigue in refractory generalized myasthenia gravis”, written by “Henning Andersen, Renato Mantegazza, Jing Jing Wang, Fanny O’Brien, Kaushik Patra, James F. Howard Jr. and The REGAIN Study Group” was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 23 March 2019 without open access