Rescue of Progeria in Trichothiodystrophy by Homozygous Lethal Xpd Alleles

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals

Indirect Treatment Comparison of the Efficacy and Safety of Sarilumab Monotherapy in Rheumatoid Arthritis Patients with Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs

Introduction: To evaluate the comparative efficacy and safety of subcutaneous sarilumab 200 mg monotherapy administered every 2 weeks (q2w) versus other monotherapies of biologic, targeted and conventional synthetic disease-modifying antirheumatic drugs (bDMARDs, tsDMARDs, csDMARDs) at recommended doses for treatment of rheumatoid arthritis in patients who are intolerant of or inadequate responders to csDMARDs (csDMARD-IR). Methods: A systematic literature review and network meta-analysis (NMA) were conducted on 24-week efficacy outcomes: Health Assessment Questionnaire Disability Index (HAQ-DI) score, American College of Rheumatology (ACR) 20/50/70 criteria, and European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28) < 2.6. In addition, serious infections and serious adverse events (SI/SAE) were examined at 24 weeks. Results: Nine trials were selected for the NMA. Sarilumab 200 mg showed superiority versus adalimumab monotherapy on all efficacy outcomes and versus tofacitinib monotherapy on ACR20. Compared with csDMARDs, sarilumab 200 mg showed superiority on ACR 20/50/70 criteria and DAS28 < 2.6 but had similar efficacy on HAQ-DI. Efficacy of sarilumab 200 mg was similar versus certolizumab, etanercept, tofacitinib and tocilizumab 8 mg/kg monotherapy across all efficacy outcomes. SI/SAE appeared similar for sarilumab 200 mg versus all comparators. Conclusion: In csDMARD-IR patients, sarilumab 200 mg monotherapy has superior efficacy and similar safety versus csDMARDs, superior efficacy and similar safety versus adalimumab, and similar efficacy and safety versus bDMARDs and tsDMARDs

Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor α inhibitors: Systematic literature review and network meta-analyses

Objective To compare efficacy and safety of subcutaneous sarilumab 200 mg and 150 mg every 2 weeks plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARDs) versus other targeted DMARDs+csDMARDs and placebo+csDMARDs, in inadequate responders to csDMARDs (csDMARD-IR) or tumour necrosis factor α inhibitors (TNFi-IR). Methods Systematic literature review and network meta-analyses (NMA) conducted on 24 week efficacy and safety outcomes: Health Assessment Questionnaire Disability Index, modified total sharp score (mTSS, including 52 weeks), American College of Rheumatology (ACR) 20/50/70, European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28)<2.6; serious infections/serious adverse events (including 52 weeks). Results 53 trials were selected for NMA. csDMARD-IR: Sarilumab 200 mg+csDMARDs and 150 mg+csDMARDs were superior versus placebo+csDMARDs on all outcomes. Against most targeted DMARDs, sarilumab 200 mg showed no statistically significant differences, except superiority to baricitinib 2 mg, tofacitinib and certolizumab on 24 week mTSS. Sarilumab 150 mg was similar to all targeted DMARDs. TNFi-IR: Sarilumab 200 mg was similar to abatacept, golimumab, tocilizumab 4 mg and 8 mg/kg intravenously and rituximab on ACR20/50/70, superior to baricitinib 2 mg on ACR50 and DAS28<2.6 and to abatacept, golimumab, tocilizumab 4 mg/kg intravenously and rituximab on DAS28<2.6. Sarilumab 150 mg was similar to targeted DMARDs but superior to baricitinib 2 mg and rituximab on DAS28<2.6 and inferior to tocilizumab 8 mg on ACR20 and DAS28<2.6. Serious adverse events, including serious infections, appeared similar for sarilumab versus comparators. Conclusions Results suggest that in csDMARD-IR and TNFi-IR (a smaller network), sarilumab+csDMARD had superior efficacy and similar safety versus placebo+csDMARDs and at least similar efficacy and safety versus other targeted DMARDs+csDMARDs

Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis

Objectives: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. Methods: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks’ double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. Results: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. Conclusion: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab

Dynamic Interaction of TTDA with TFIIH Is Stabilized by Nucleotide Excision Repair in Living Cells

Transcription/repair factor IIH (TFIIH) is essential for RNA polymerase II transcription and nucleotide excision repair (NER). This multi-subunit complex consists of ten polypeptides, including the recently identified small 8-kDa trichothiodystrophy group A (TTDA)/ hTFB5 protein. Patients belonging to the rare neurodevelopmental repair syndrome TTD-A carry inactivating mutations in the TTDA/hTFB5 gene. One of these mutations completely inactivates the protein, whereas other TFIIH genes only tolerate point mutations that do not compromise the essential role in transcription. Nevertheless, the severe NER-deficiency in TTD-A suggests that the TTDA protein is critical for repair. Using a fluorescently tagged and biologically active version of TTDA, we have investigated the involvement of TTDA in repair and transcription in living cells. Under non-challenging conditions, TTDA is present in two distinct kinetic pools: one bound to TFIIH, and a free fraction that shuttles between the cytoplasm and nucleus. After induction of NER-specific DNA lesions, the equilibrium between these two pools dramatically shifts towards a more stable association of TTDA to TFIIH. Modulating transcriptional activity in cells did not induce a similar shift in this equilibrium. Surprisingly, DNA conformations that only provoke an abortive-type of NER reaction do not result into a more stable incorporation of TTDA into TFIIH. These findings identify TTDA as the first TFIIH subunit with a primarily NER-dedicated role in vivo and indicate that its interaction with TFIIH reflects productive NER

Identification of a rule to predict response to sarilumab in patients with rheumatoid arthritis using machine learning and clinical trial data

Introduction In rheumatoid arthritis, time spent using ineffective medications may lead to irreversible disease progression. Despite availability of targeted treatments, only a minority of patients achieve sustained remission, and little evidence exists to direct the choice of biologic disease-modifying antirheumatic drugs in individual patients. Machine learning was used to identify a rule to predict the response to sarilumab and discriminate between responses to sarilumab versus adalimumab, with a focus on clinically feasible blood biomarkers. Methods The decision tree model GUIDE was trained using a data subset from the sarilumab trial with the most biomarker data, MOBILITY, to identify a rule to predict disease activity after sarilumab 200 mg. The training set comprised 18 categorical and 24 continuous baseline variables; some data were omitted from training and used for validation by the algorithm (cross-validation). The rule was tested using full datasets from four trials (MOBILITY, MONARCH, TARGET, and ASCERTAIN), focusing on the recommended sarilumab dose of 200 mg. Results In the training set, the presence of anti-cyclic citrullinated peptide antibodies, combined with C-reactive protein > 12.3 mg/l, was identified as the “rule” that predicts American College of Rheumatology 20% response (ACR20) to sarilumab. In testing, the rule reliably predicted response to sarilumab in MOBILITY, MONARCH, and ASCERTAIN for many efficacy parameters (e.g., ACR70 and the 28-joint disease activity score using CRP [DAS28-CRP] remission). The rule applied less to TARGET, which recruited individuals refractory to tumor necrosis factor inhibitors. The potential clinical benefit of the rule was highlighted in a clinical scenario based on MONARCH data, which found that increased ACR70 rates could be achieved by treating either rule-positive patients with sarilumab or rule-negative patients with adalimumab. Conclusions Well-established and clinically feasible blood biomarkers can guide individual treatment choice. Real-world validation of the rule identified in this post hoc analysis is merited

Dissociation of CAK from Core TFIIH Reveals a Functional Link between XP-G/CS and the TFIIH Disassembly State

Transcription factor II H (TFIIH) is comprised of core TFIIH and Cdk-activating kinase (CAK) complexes. Here, we investigated the molecular and cellular manifestation of the TFIIH compositional changes by XPG truncation mutations. We showed that both core TFIIH and CAK are rapidly recruited to damage sites in repair-proficient cells. Chromatin immunoprecipitation against TFIIH and CAK components revealed a physical engagement of CAK in nucleotide excision repair (NER). While XPD recruitment to DNA damage was normal, CAK was not recruited in severe XP-G and XP-G/CS cells, indicating that the associations of CAK and XPD to core TFIIH are differentially affected. A CAK inhibition approach showed that CAK activity is not required for assembling pre-incision machinery in vivo or for removing genomic photolesions. Instead, CAK is involved in Ser5-phosphorylation and UV-induced degradation of RNA polymerase II. The CAK inhibition impaired transcription from undamaged and UV-damaged reporter, and partially decreased transcription of p53-dependent genes. The overall results demonstrated that a) XP-G/CS mutations affect the disassembly state of TFIIH resulting in the dissociation of CAK, but not XPD from core TFIIH, and b) CAK activity is not essential for global genomic repair but involved in general transcription and damage-induced RNA polymerase II degradation