The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells.

The modification of proteins by ubiquitin has a major role in cells of the immune system and is counteracted by various deubiquitinating enzymes (DUBs) with poorly defined functions. Here we identified the ubiquitin-specific protease USP8 as a regulatory component of the T cell antigen receptor (TCR) signalosome that interacted with the adaptor Gads and the regulatory molecule 14-3-3ß. Caspase-dependent processing of USP8 occurred after stimulation of the TCR. T cell-specific deletion of USP8 in mice revealed that USP8 was essential for thymocyte maturation and upregulation of the gene encoding the cytokine receptor IL-7Rα mediated by the transcription factor Foxo1. Mice with T cell-specific USP8 deficiency developed colitis that was promoted by disturbed T cell homeostasis, a predominance of CD8(+) γδ T cells in the intestine and impaired regulatory T cell function. Collectively, our data reveal an unexpected role for USP8 as an immunomodulatory DUB in T cells.

Towards compatibility of EUnetHTA JCA methodology and German HTA: a systematic comparison and recommendations from an industry perspective.

OBJECTIVE: The transferability of the EU joint clinical assessment (JCA) reports for pharmaceuticals for the German benefit assessment was evaluated by systematically comparing EU JCA and German clinical assessments (CA) based on established assessment elements for HTA and assessing the potential impact of differences on Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) ability to derive the therapeutic added value. METHODS: Identification of all pharmaceuticals undergoing both, EU JCA and German CA between January 2016-June 2020. Qualitative review and data extraction from the assessments, assessment of methodological differences using a hierarchical model. Recommendations for harmonisation were developed and consented with pharmaceutical industry stakeholders. RESULTS: Differences with potentially major impact: (1) View on differing treatment algorithms and definition of corresponding subpopulations/respective comparators. (2) Clinical relevance of surrogate/intermediate endpoints. Inclusion of different/surrogate morbidity endpoints resulting in different relative effectiveness conclusions. (3) Tolerance of study interventions not used according to marketing authorisation. (4) Different operationalisation and/or weighting of individual safety endpoints leading to differing relative safety conclusions. Differences with potentially minor impact: (1) Disagreement in risk of bias assessment for overall survival and its robustness against study limitations. (2) Use of patient-reported outcome symptom scales as measurements for health-related quality of life instruments. CONCLUSION: While many synergies between EU JCA and German CA exist, we identified several aspects in HTA methodology that would benefit of harmonisation and ensure the transferability of future EU JCA to the German HTA process without duplicated evaluation requirements. For those, a set of recommendations was developed.

Treatment Patterns and Healthcare Resource Utilization Among Patients with Atopic Dermatitis: A Retrospective Cohort Study Using German Health Claims Data.

INTRODUCTION: Atopic dermatitis (AD) is a common inflammatory skin disease. Many patients are initiating a systemic therapy, if the disease is not adequately controlled with topical treatment only. Currently, there is little real-world evidence on the AD-related medical care situation in Germany. This study analyzed patient characteristics, treatment patterns, healthcare resource utilization and costs associated with systemically treated AD for the German healthcare system. METHODS: In this descriptive, retrospective cohort study, aggregated anonymized German health claims data from the InGef research database were used. Within a representative sample of four million insured individuals, patients with AD and systemic drug therapy initiation (SDTI) in the index year 2017 were identified and included into the study cohort. Systemic drug therapy included dupilumab, systemic corticosteroids (SCS) and systemic immunosuppressants (SIS). Patients were observed for one year starting from the date of SDTI in 2017. RESULTS: 9975 patients were included (57.8% female, mean age 39.6 years [SD 25.5]). In the one-year observation period, the most common systemic drug therapy was SCS (> 99.0%). Administrations of dupilumab (0.3%) or dispensations of SIS were rare (cyclosporine: 0.5%, azathioprine: 0.6%, methotrexate: 0.1%). Median treatment duration of SCS, cyclosporine and azathioprine was 27 days, 102 days, and 109 days, respectively. 2.8% of the patients received phototherapy; 41.6% used topical corticosteroids and/or topical calcineurin inhibitor. Average annual costs for medications amounted to € 1237 per patient. Outpatient services were used by 99.6% with associated mean annual costs of € 943; 25.4% had at least one hospitalization (mean annual costs: € 5836). 5.3% of adult patients received sickness benefits with associated mean annual costs of € 5026. CONCLUSIONS: Despite unfavorable risk-benefit profile, this study demonstrated a common treatment with SCS, whereas other systemic drug therapy options were rarely used. Furthermore, the results suggest a substantial economic burden for patients with AD and SDTI.

Cost-effectiveness of tofacitinib compared with infliximab, adalimumab, golimumab, vedolizumab and ustekinumab for the treatment of moderate to severe ulcerative colitis in Germany.

OBJECTIVES: Tofacitinib is an oral, small molecule Janus kinase (JAK) inhibitor for the treatment of ulcerative colitis (UC). This study assessed the cost-effectiveness of tofacitinib versus other available treatments for patients with moderate to severe UC following an inadequate response to conventional treatment and who are either naïve to or have failed previous biologics in Germany. METHODS: A Markov cohort model was developed to evaluate the differences in long-term costs and outcomes between tofacitinib and its comparators from the perspective of German statutory health insurance (SHI) for patients either naïve or exposed to biologics. Tofacitinib was compared to infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, golimumab, vedolizumab, ustekinumab, and conventional therapy. Health states modeled were remission, treatment response, active UC, and post-colectomy. Patients not responding to treatment could switch to a different treatment. Treatment efficacy for induction and maintenance phases were assessed by a systematic literature review (SLR) and network meta-analysis (NMA). The model included costs associated with drug administration, adverse events, and medical resource use. Extensive deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. RESULTS: Over a life-time horizon, patients treated with tofacitinib gained 0.035-0.083 quality-adjusted life-years (QALYs) and had direct cost savings to the SHI of €4,228-€17,184 compared to biologic treatments other than adalimumab biosimilar. When compared to adalimumab biosimilar, treatment with tofacitinib resulted in an incremental cost-effectiveness ratio (ICER) of €17,497 per QALY gained and can be considered a cost-effective alternative. Compared with conventional therapy, tofacitinib resulted in a lower ICER than all other biologics. The DSA showed that the model results were most influenced by differences in treatment efficacy. The PSA suggested confidence in the base-case results considering uncertainty around parameters. CONCLUSIONS: The results of this economic model suggest tofacitinib is a cost-effective treatment option for patients with moderate to severe UC in Germany.

Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo.

Posttranslational modification by ubiquitin controls multiple cellular functions and is counteracted by the activities of deubiquitinating enzymes. UBPy (USP8) is a growth-regulated ubiquitin isopeptidase that interacts with the HRS-STAM complex. Using Cre-loxP-mediated gene targeting in mice, we show that lack of UBPy results in embryonic lethality, whereas its conditional inactivation in adults causes fatal liver failure. The defect is accompanied by a strong reduction or absence of several growth factor receptor tyrosine kinases (RTKs), like epidermal growth factor receptor, hepatocyte growth factor receptor (c-met), and ERBB3. UBPy-deficient cells exhibit aberrantly enlarged early endosomes colocalizing with enhanced ubiquitination and have reduced levels of HRS and STAM2. Congruently immortalized cells gradually stop proliferation upon induced deletion of UBPy. These results unveil a central and nonredundant role of UBPy in growth regulation, endosomal sorting, and the control of RTKs in vivo.

Living with ulcerative colitis in Germany: a retrospective analysis of dose escalation, concomitant treatment use and healthcare costs.

Aims: To investigate treatment of moderate-to-severe ulcerative colitis (UC) using real-world German health insurance claims data.Materials and methods: A retrospective, longitudinal cohort study was conducted from a German statutory health insurance database for adult patients with UC indexed on biologic therapy initiation (2013-2015). Anonymized data were evaluated for 12 months prior to (baseline) through 24 months after (follow-up) indexing. Biologic dose escalations, steroid and immunosuppressant use, healthcare resource utilization (HCRU) and direct healthcare costs were evaluated, with significant differences assessed across and between index biologics. Descriptive statistics, chi-square or Fisher's exact tests, and analysis of variance were performed.Results: The analysis included 304 patients (adalimumab, n = 125; golimumab, n = 47; infliximab, n = 114; vedolizumab, n = 18). Demographic and clinical characteristics were similar across biologics. Dose escalations occurred in 58% of patients (73% of patients receiving adalimumab), with 41% receiving subsequent de-escalation. Steroids were used during follow-up by 74% of patients; 25% received steroids >14 weeks after indexing. Overall, 41% of patients received an immunosuppressant during follow-up. Steroid and immunosuppressant use were similar across biologics. Total direct healthcare costs were higher during follow-up than baseline and differed significantly across treatments (p < .05), with highest costs for golimumab. Biologic costs contributed to a major portion of follow-up costs. HCRU and costs for most resources were higher in the first 12-month follow-up period than baseline. All resource use except gastroenterology visits returned to, or below, baseline levels 13-24 months post-index date.Limitations: There was potential for inappropriate inclusion/exclusion due to miscoding. Patients may have received biologics >12 months prior to the index date. Biologic originators and biosimilars could not be differentiated.Conclusions: These data suggest that control with current biologics is suboptimal. Further treatment options that provide sustained steroid-free remission for this patient population without the need for dose escalations or concomitant therapies may be warranted.

Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice.

UBP43/USP18 was described as a specific protease that removes conjugated ubiquitin-like modifier ISG15 from target proteins. The severe phenotype of UBP43(-/-) mice characterized by premature death, brain cell injury, and deregulated STAT1 signaling was ascribed to an enhanced conjugation of ISG15. In contrast, no phenotypic changes were detected in ISG15(-/-) mice. To verify the role of ISG15 in the phenotype of UBP43(-/-) mice, we employed mice deficient for both ISG15 and UBP43. Here, we show that the phenotype of UBP43(-/-) mice was not rescued by the absence of ISG15, as evident from unchanged mortality, neurological symptoms, and occurrence of hydrocephalus. Also, the reported hypersensitivity of UBP43(-/-) mice to an interferon inducer, poly(I . C), was ISG15 independent. Furthermore, no evidence for a role of ISG15 in the modulation of STAT1 signaling or in the resistance against lymphocytic choriomeningitis virus and vesicular stomatitis virus was found. Presented results clearly demonstrate that the phenotypic alterations of UBP43(-/-) mice are not caused by the lack of ISG15 deconjugation and must be due to another, non-ISG15-mediated molecular mechanism.

Single-step scaffold-based cartilage repair in the knee: A systematic review.

Chondral lesions are difficult-to-treat entities that often affect young and active people. Moreover, cartilage has limited intrinsic healing potential. The purpose of this systematic literature review was to analyse whether the single-step scaffold-based cartilage repair in combination with microfracturing (MFx) is more effective and safe in comparison to MFx alone. From the three identified studies, it seems that the single-step scaffold-assisted cartilage repair in combination with MFx leads to similar short- to medium-term (up to five years follow-up) results, compared to MFx alone. All of the studies have shown improvements regarding joint functionality, pain and partly quality of life.

Factors influencing coverage decisions on medical devices: A retrospective analysis of 78 medical device appraisals for the Austrian hospital benefit catalogue 2008-2015.

BACKGROUND: Health technology assessments of medical devices (MD) present a well-recognized challenge to evaluators: the evidence on safety and clinical effectiveness is often of lower quality than for pharmaceuticals making a reliable assessment of the risk-benefit ratio difficult. Thus other factors might gain importance in decision making. OBJECTIVE: To analyse which factors impact MD reimbursement decisions within the Austrian appraisal programme on "extra medical services" (procedures reimbursed in addition to case flat rates) for inpatient care over the past eight years. METHODS: We collected variables on evidence base and device characteristics from all MD appraisals and assessed their impact on the reimbursement decision by means of odds ratios. Separate analyses were carried out for subgroups based on the risk class of the medical device subject of the assessment or the number of randomised controlled trials (RCTs) available for the assessment. RESULTS: Of 59 devices, 23 (39%) were accepted for reimbursement (18 with restrictions) and 36 (61%) were rejected. Variables addressing the quality of the evidence base were positive predictors for risk class II devices only, whereas no significant association could be determined in devices of risk class III. Inversely, high risk device characteristics were positive predictors in the subgroup not supported by RCTs only. CONCLUSION: Our data indicate that the combination of high risk characteristics and a low evidence base are factors favouring a positive reimbursement decision of MD, albeit with restrictions. Further research should analyse if these restrictions are appropriate to generate evidence development and to contain risks associated with early access to these MD.

Oncotyrol--Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research.

BACKGROUND: The Oncotyrol - Center for Personalized Cancer Medicine is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized healthcare strategies in cancer. The philosophy of Oncotyrol is to collaborate with relevant stakeholders and advance knowledge "from bench to bedside to population and back". Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). This article focuses on the role of health technology assessment (HTA) and outcomes research in personalized cancer medicine in the context of Oncotyrol. METHODS: Oncotyrol, which currently comprises approximately 20 individual projects, has four research areas: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 translates the results from Areas 1 to 3 to populations and society and reports them back to Area 3 to inform clinical studies and guidelines, and to Areas 1 and 2 to guide further research and development. RESULTS: In a series of international expert workshops, the Oncotyrol International Expert Task Force for Personalized Cancer Medicine developed the Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer and practical guidelines in this field. Further projects included applications in the fields of sequential treatment of patients with chronic myeloid leukemia (CML), benefit-harm and cost-effectiveness evaluation of prostate cancer screening, effectiveness and cost-effectiveness of multiple cervical cancer screening strategies, and benefits and cost-effectiveness of genomic test-based treatment strategies in breast cancer. CONCLUSION: An interdisciplinary setting as generated in Oncotyrol provides unique opportunities such as systematically coordinating lab and bench research, product development, clinical studies and decision science/HTA and transparent joint planning of research and development with a partnership of researchers, manufacturers and health policy decision makers. However, generating a joint research and legal framework with numerous partners from different sectors can be challenging, particularly in the starting period of such an endeavor. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it must be continued to turn vision into reality.