Academic literature on the topic 'PGA460 model'

ABSTRACT Porphyromonas gingivalis is a gram-negative, anaerobic coccobacillus that has been implicated as a major etiological agent in the development of chronic periodontitis. In this paper, we report the characterization of a protein, IhtB (iron heme transport; formerly designated Pga30), that is an outer membrane hemin-binding protein potentially involved in iron assimilation by P. gingivalis. IhtB was localized to the cell surface of P. gingivalis by Western blot analysis of a Sarkosyl-insoluble outer membrane preparation and by immunocytochemical staining of whole cells using IhtB peptide-specific antisera. The protein, released from the cell surface, was shown to bind to hemin using hemin-agarose. The growth of heme-limited, but not heme-replete, P. gingivalis cells was inhibited by preincubation with IhtB peptide-specific antisera. TheihtB gene was located between an open reading frame encoding a putative TonB-linked outer membrane receptor and three open reading frames that have sequence similarity to ATP binding cassette transport system operons in other bacteria. Analysis of the deduced amino acid sequence of IhtB showed significant similarity to theSalmonella typhimurium protein CbiK, a cobalt chelatase that is structurally related to the ATP-independent family of ferrochelatases. Molecular modeling indicated that the IhtB amino acid sequence could be threaded onto the CbiK fold with the IhtB structural model containing the active-site residues critical for chelatase activity. These results suggest that IhtB is a peripheral outer membrane chelatase that may remove iron from heme prior to uptake byP. gingivalis.

Background:Upadacitinib (UPA) has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in randomized controlled trials,1-6 but there are limited data available on its real-world use and effectiveness in patients with RA.Objectives:To describe the characteristics and clinical outcomes at 3 months among real-world patients with RA initiating UPA.Methods:The data source for this study was the OM1 RA Registry, a subset of the OM1 Real-World Data Cloud (OM1, Inc, Boston, MA, US), a large, linked clinical and administrative dataset derived from medical and pharmacy claims, electronic medical record data, and death data. This analysis includes data collected in patients who initiated UPA during or after August 2019. Patients had ≥1 prescription for UPA (index date was first UPA prescription), were ≥18 years of age at index date, had ≥6 months of available data in the OM1 RA Registry prior to index date (ie, baseline period), ≥1 baseline disease activity measure, and ≥1 follow-up disease activity measure (3 or 6 months post-index). Disease activity was based on RAPID3 or CDAI. Multivariate analyses were conducted using a mixed-effects linear model adjusting for age, sex, and baseline scores. Outcomes were also assessed by therapy status (monotherapy or combination therapy) and targeted immunomodulator (TIM) use (naïve vs experienced).Results:Inclusion criteria were met by 1,102 patients, of whom 620 were on monotherapy and 482 were on combination therapy at index. Mean age was 57.7 years, 83% were female, 75% had prior treatment with a biologic, and 47% had prior treatment with a Janus kinase inhibitor. Of 651 patients with known disease activity category, 113 (17%) were in low disease activity (LDA)/remission. At baseline, overall mean±SD scores were 19.9±12.3 for CDAI, 4.5±2.4 for RAPID3, 5.7±2.8 for pain, 5.2±3.0 for fatigue, 3.1±2.7 for MDHAQ Physician Global Assessment (PGA), 5.2±2.8 for MDHAQ Patient Global Assessment (PtGA), and 3.1±2.3 for MDHAQ Functional Index. At 3 months post-UPA initiation, mean (95% CI) change in CDAI was –5.1 (–7.5 to –2.7) in the monotherapy group and –5.9 (–8.7 to –3.0) in the combination group. At 3 months, 29% (109/374) of patients were in LDA/remission and 32% (120/374) of patients showed improvement in disease activity. Of 94 patients with moderate disease at baseline, 34 (36%) were in LDA/remission at 3 months. Of 215 patients with high disease at baseline, 30 (14%) were in LDA/remission and 49 (23%) had moderate disease at 3 months. RAPID3 and other outcomes also improved at 3 months in the monotherapy and combination therapy groups (Figure 1). Improvements in disease activity were observed at 3 months and maintained at 6 months post-UPA initiation. Of 1,102 patients, 16% were TIM naïve and 84% TIM experienced. Both TIM-naïve and TIM-experienced patients achieved significant mean changes in CDAI (–5.7 [–10.8 to –0.6] and–5.0 [–7.0 to –3.0], respectively) and RAPID3 (–1.0 [–1.6 to –0.4] and –0.5 [–0.8 to –0.1]) at 3 months (Table 1). Improvements in clinical outcomes were maintained at 6 months in both TIM-naïve and TIM-experienced patients.Conclusion:Significant improvements in disease activity were consistently observed at 3 months and maintained at 6 months post-UPA initiation regardless of monotherapy, combination therapy, or prior TIM use.References:[1]Fleischmann R. Arthritis Rheumatol. 2019;71:1788–800.[2]Smolen JS. Lancet. 2019;393:2303–11.[3]Burmester GR. Lancet. 2018;382:2505–12.[4]Genovese MC. Lancet. 2018;391:2513–24.[5]van Vollenhoven R. Arthritis Rheumatol. 2020;72:1607–20.[6]Rubbert-Roth A. N Engl J Med. 2020;383:1511–21.Table 1.Change in clinical outcomes from baseline at 3 months: TIM-naïve and TIM-experienced groupsTIM naïve(N=179)TIM experienced(N=923)nMean changenMean changeCDAI36–5.7*160–5.0*RAPID367–1.0*189–0.5*Pain (VAS)76–1.5*237–0.9*Fatigue46–0.7149–0.5MDHAQ PGA65–0.7*251–0.7*MDHAQ PtGA97–0.6*383–0.3MDHAQ Functional Index72–0.7*215–0.2*Statistically significant change from baseline (P<0.05).Acknowledgements:Funding statement: Financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content.Acknowledgment:Medical writing services were provided by Joann Hettasch of Fishawack Facilitate Ltd, part of Fishawack Health, and funded by AbbVie.Disclosure of Interests:Martin Bergman Shareholder of: JNJ (parent of Janssen), Speakers bureau: AbbVie, Amgen, BMS, Genentech, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sandoz, Consultant of: AbbVie, Amgen, BMS, Genentech, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sandoz, Namita Tundia Shareholder of: AbbVie, Employee of: AbbVie, Allison Bryant: None declared, Ia Topuria: None declared, Tom Brecht: None declared, Kendall Dunlap Shareholder of: AbbVie, Employee of: AbbVie, Allan Gibofsky Shareholder of: AbbVie, Amgen, Horizon, J&J, Pfizer, Regeneron, Speakers bureau: AbbVie, Acquist, Amgen, Lilly, Merck, Pfizer, Sandoz, Samumed, Consultant of: AbbVie, Acquist, Amgen, Lilly, Merck, Pfizer, Sandoz, Samumed