Kooperativer Bibliotheksverbund

In: Rheumatology, Oxford University Press (OUP), Vol. 62, No. SI ( 2023-02-06), p. SI54-SI63

Abstract: The early trajectory of skin fibrosis provides insights into the disease course of systemic sclerosis (SSc) including mortality; however, little is known about late skin fibrosis. The aims of our study were to ascertain the prevalence and characteristics of late skin fibrosis in SSc. Methods We developed and tested three conceptual scenarios of late ( & gt;5 years after first non-RP feature) skin fibrosis including new worsening of skin disease, and failure to improve after worsening within 5-year window. We defined skin worsening as change in modified Rodnan skin score (mRSS) ≥5 units or ≥25%. Using strict inclusion criteria including complete mRSS, we identified 1,043 (out of 19 115) patients within the EUSTAR database for our analysis. We further restricted analysis within 887 (out of 1043) patients who had lcSSc or dcSSc at baseline. Results One-fifth of patients among the whole cohort (n = 208/1043, 19.9%) experienced mRSS worsening, including in patients with lcSSc or dcSSc at baseline (n = 193/887, 21.8%). This was largely due to new skin worsening after the 5-year window or failure to improve with worsening within the 5-year window. Patients with lower baseline mRSS and lcSSc were more likely to develop late skin fibrosis. Anti-Scl-70 was associated with progression from baseline lcSSc to dcSSc, and anticentromere was protective. Conclusions Late skin fibrosis is not uncommon in SSc. We have identified different patterns relevant to clinical practice and trial design. Late skin fibrosis is a neglected manifestation of SSc and warrants further investigation including to determine clinical outcomes and optimal therapeutic strategy.

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/keac363

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2023

detail.hit.zdb_id: 1474143-X

In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. Suppl 1 ( 2021-06), p. 385-386

Abstract: In SSc, ILD is a major cause of morbidity and mortality. High resolution computed tomography (HRCT) is the gold standard for the diagnosis. Predictors of ILD onset are eagerly awaited to improve SSc-ILD management. Pulmonary function test (PFTs) are routinely performed to measure lung function changes. Objectives: Our aim was to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) in predicting the development of SSc-ILD. Methods: The longitudinal data of DLCO, FVC and ILD on HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t 0 ), after 12 (±4) (t 1 ) and 24 (±4) (t 2 ) months. Patients with negative HRCT for any sign of ILD both at t 0 and t 1 were included. Patients who presented or developed pulmonary hypertension during the study period were excluded. At baseline, demographic data, disease duration from Raynaud’s onset, disease subsets, autoantibodies and other laboratory and instrumental data were recorded. Results: 474/17805 patients were eligible for the study (403 females, 71 males): 26.0% dcSSc, 58.3% lcSSc, 220 (48.0%) patients with positive anticentromere antibodies (ACA) and 117 (25.4%) with positive antitopoisomerase I antibodies (Topo-I abs). Among all enrolled patients, 46 (9.7%) developed HRCT signs of ILD at t 2 . Patients with Topo-I abs showed an association with ILD development at t 2 (16.7% vs 7.8%, p=0.0031), contrarily ACA positive patients were negatively associated with ILD appearance after 2 years of follow-up (4.4% vs 14.4%, p=0.0001). Positive t 2 HRCT patients had a significant lower value of DLCO and FVC at all three assessments when compared to patients with a negative HRCT at t 2 (Table 1) and both t 0 DLCO and FVC values negatively correlated with ILD development (Table 1). The mean t 0 to t 1 change (Δ) of DLCO in patients with negative t 2 HRTC and positive t 2 HRCT were -0.5 (±12.6) and -1.0 (±15.1), respectively. The mean t 0 to t 1 ΔFVC in patients with negative t 2 HRTC and positive t 2 HRCT were -0.2 (±10.6) and 0.1 (±11.5), respectively. None of them predicted the appearance of ILD at t 2 (ΔDLCO: OR (IC) 0.997 (0.97-1.02), p=0.8024; ΔFVC OR (IC) 1.002 (0.97-1.03), p=0.8664). The data showed an association between t 0 DLCO value 〈 80% and ILD appearance after 2 years of follow-up [OR(IC): 3.09(1.49-6.40), p=0.0023]. Such association was not observed for t 0 FVC value 〈 80% [OR(IC): 1.95(0.81-4.68), p=0.1329]. The predictive capability of t 0 DLCO 〈 80% was moderate but stronger than FVC 〈 80% [AU ROC: 0.62 (0.56-0.69), 0.53 (0.48-0.59) respectively, p=0.0205]. Conclusion: Our data suggest that an impaired baseline DLCO ( 〈 80%) may have a predictive value for the development of ILD on HRCT after 2 years of follow-up. Further rigorous prospective studies are warranted to understand the role of DLCO evaluation in the course of SSc. Table 1. DLCO and FVC values at t 0 , t 1 and t 2 values in patients with positive or negative HRCT for ILD at t 2 and their statistical differences. Patients without ILD at t2 (mean±SD) Patients with ILD at t2 (mean±SD) OR (95%CL) p-value DLCO at t 0 79.0 ± 16.6 69.9 ± 17.4 0.97 (0.95 - 0.99) 0.0006 DLCO at t 1 78.4 ± 16.8 68.9 ± 18.6 0.97 (0.95 - 0.98) 0.0005 DLCO at t 2 78.0 ± 17.0 65.1 ± 19.1 0.95 (0.93 - 0.97) 〈 0.0001 FVC at t 0 102.2 ± 17.3 94.6 ± 16.2 0.97 (0.96 - 0.99) 0.0052 FVC at t 1 101.9 ± 17.9 94.7 ± 16.5 0.98 (0.96 - 0.99) 0.0092 FVC at t 2 101.6 ± 17.6 94.5 ± 20.0 0.98 (0.96 - 1) 0.0126 Disclosure of Interests: Gemma Lepri: None declared, Cosimo Bruni Speakers bureau: CB reports personal fees from Actelion, personal fees from Eli Lilly, Grant/research support from: CB reports personal fees from Actelion, personal fees from Eli Lilly, grants from European Scleroderma Trial and Research (EUSTAR) group, grants from New Horizon Fellowship, grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull’Artrite (FIRA), outside the submitted work, Lorenzo Tofani: None declared, Alberto Moggi Pignone: None declared, Martina Orlandi: None declared, Tomasetti Sara Speakers bureau: Speaker’s fees for Roche and Boehringer Ingelheim, Mike Hughes: None declared, Francesco Del Galdo: None declared, Rosaria Irace: None declared, Oliver Distler Grant/research support from: OD (last three years) has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Valeria Riccieri: None declared, Yannick Allanore Speakers bureau: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Grant/research support from: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Ana Maria Gheorghiu: None declared, Elise Siegert: None declared, Jeska de Vries-Bouwstra: None declared, Eric Hachulla: None declared, Mohammed Tikly: None declared, Nemanja Damjanov: None declared, Francois Spertini: None declared, Luc Mouthon: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Consultant of: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Grant/research support from: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Armando Gabrielli: None declared, Serena Guiducci: None declared, Marco Matucci-Cerinic Speakers bureau: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Daniel Furst: None declared, Silvia Bellando Randone: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2021-eular.3027

Language: English

Publisher: BMJ

Publication Date: 2021

detail.hit.zdb_id: 1481557-6

In: JAMA Dermatology, American Medical Association (AMA), Vol. 159, No. 8 ( 2023-08-01), p. 837-

Abstract: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc. Objective To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database. Design, Setting, and Participants This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023. Main Outcomes and Measures Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers). Results Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P   & amp;lt; .001; and 68.3% in dcSSc; P   & amp;lt; .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P   & amp;lt; .001; and 87.6% in dcSSc; P   & amp;lt; .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P  = .03) but significantly higher in dcSSc (75.0%; P   & amp;lt; .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P   & amp;lt; .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti–Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P  = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P  = .06) and dcSSc (55.5%; P   & amp;lt; .001) after up to 15 years of follow-up. Conclusions and Relevance Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease ( & amp;gt;40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.

Type of Medium: Online Resource

ISSN: 2168-6068

URL: Article

DOI: 10.1001/jamadermatol.2023.1729

Language: English

Publisher: American Medical Association (AMA)

Publication Date: 2023

In: Rheumatology, Oxford University Press (OUP), Vol. 62, No. 6 ( 2023-06-01), p. 2178-2188

Abstract: The prevalence and characteristics of SSc-associated interstitial lung disease (SSc-ILD) vary between geographical regions worldwide. The objectives of this study were to explore the differences in terms of prevalence, phenotype, treatment and prognosis in patients with SSc-ILD from predetermined geographical regions in the EUSTAR database. Material and methods Patients were clustered into seven geographical regions. Clinical characteristics and survival of patients with SSc-ILD were compared among these pre-determined regions. Results For baseline analyses, 9260 SSc patients were included, with 6732 for survival analyses. The prevalence of SSc-ILD in the overall population was 50.2%, ranging from 44.0% in ‘Western Europe and Nordic countries’ to 67.5% in ‘Eastern European, Russia and Baltic countries’. In all regions, anti-topoisomerase antibodies were associated with SSc-ILD. Management also significantly differed; mycophenolate mofetil was prescribed at baseline in 31.6% of patients with SSc-ILD in ‘America (North and South)’ and 31.7% in ‘Middle East’ but only 4.3% in ‘Asia and Oceania’ (P  & lt;0.0001). Patients from ‘America (North and South)’ and ‘Middle East’ had the highest survival rate at the end of follow-up (85.8% and 85.2%, respectively). Conclusions Our study highlights key differences among regions in terms of clinical presentation and prognosis of SSc-ILD. This work also demonstrates that the management of SSc-ILD is highly variable among the different regions considered, suggesting that efforts are still needed for the standardization of medical practice in the treatment of this disease.

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/keac576

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2023

detail.hit.zdb_id: 1474143-X

In: Scandinavian Journal of Rheumatology, Informa UK Limited, Vol. 49, No. 3 ( 2020-05-03), p. 214-220

Type of Medium: Online Resource

ISSN: 0300-9742 , 1502-7732

URL: Article

DOI: 10.1080/03009742.2019.1657492

Language: English

Publisher: Informa UK Limited

Publication Date: 2020

detail.hit.zdb_id: 1497111-2

In: Rheumatology, Oxford University Press (OUP), Vol. 61, No. 3 ( 2022-03-02), p. 1141-1147

Abstract: Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or ‘never’ DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud’s duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51–24.87), active digital ischaemia: 6.30 (5.34–7.42) and death: 1.86 (1.48–2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/keab510

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2022

detail.hit.zdb_id: 1474143-X

In: Nature Reviews Rheumatology, Springer Science and Business Media LLC, Vol. 17, No. 6 ( 2021-06), p. 363-374

Type of Medium: Online Resource

ISSN: 1759-4790 , 1759-4804

URL: Article

DOI: 10.1038/s41584-021-00603-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2491533-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 1251.1-1252

Abstract: Rheumatoid arthritis (RA) has been described in virtually every ethnic population. Most RA patients harbor anti-modified protein antibodies (AMPAs), including anti-citrullinated protein (ACPA), anti-carbamylated protein (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (AAPA). However, it is unclear whether differences exist in the AMPA response between different ethnic groups. Such differences could provide new clues to genetic and environmental factors contributing to autoantibody development. Objectives: To investigate the prevalence of different AMPA in four ethnically diverse RA populations, and their association with smoking. Methods: Enzyme-linked immunosorbent assays were used to measure anti-CarP IgG, anti-MAA IgG (both in-house), and anti-acetylated vimentin IgG (Orgentec) in ACPA-positive sera of Dutch (NL, n=103), Japanese (JP, n=174), Canadian First Nations People (FN, n=100), and black South Africans (SA, n=67) fulfilling the 1987 ACR classification criteria for RA. Ethnicity-matched local healthy controls were used to calculate cohort-specific cut-offs. Logistic regression was used to identify whether ever-smoking was associated with AMPA seropositivity in each cohort, corrected for age, gender, and disease duration. Random-effects meta-analysis was used to pool the resulting odds ratios (OR). Results: For all three AMPAs, median levels were higher in FN and especially SA than NL and JP patients (Figure 1). The median autoantibody levels in arbitrary units (in % of patients positive) for NL, JP, FN and SA RA patients were: anti-CarP IgG: 1157 (47%), 994 (43%), 1642 (58%) and 2336 (76%) (p 〈 0.001); anti-MAA IgG: 131 (29%), 179 (22%), 251 (29%) and 257 (53%) (p 〈 0.001); AAPA: 133 (20%), 136 (17%), 153 (38%) and 316 (28%) (p 〈 0.001). Prevalence, meaning positivity, also differed significantly between cohorts for all AMPAs (p 〈 0.001).There were also marked differences in total IgG levels in mean (SD) g/L: 13 (4) for NL, 17 (6) for JP, 18 (6) for FN, and 25 (8) for SA (p 〈 0.001). When the autoantibody levels were normalized to total IgG, the differences in became less pronounced between cohorts (Figure 2). The median arbitrary units per g/L Total IgG for NL, JP, FN and SA RA patients were: anti-CarP IgG: 54, 25, 53, and 79; anti-MAA IgG: 6, 5, 8, and 9; and AAPA: 2, 2, 2, and 3, suggesting that autoantibody level differences may partly correspond to cohort-specific differences in total IgG, although the overall trend of higher levels in SA persisted. There was no association between smoking and anti-CarP or anti-MAA positivity, with pooled OR (95% CI) of 1.31 (0.79-2.18) and 0.85 (0.46-1.56), respectively. However, smoking was positively and consistently associated with AAPA positivity in each cohort: pooled OR (95% CI) of 2.01 (1.06-3.81). Conclusion: In these ACPA-positive ethnically diverse RA populations, levels and prevalence of various AMPAs differ, suggesting that ethnic background and environment may influence the development of the autoantibody response in RA. Despite these differences, our results imply smoking as a consistent risk factor for AAPA across different ethnic backgrounds. Disclosure of Interests: Emma C. de Moel: None declared, Veerle Derksen: None declared, Leendert A Trouw: None declared, Chikashi Terao: None declared, Mohammed Tikly: None declared, Hani El-Gabalawy: None declared, Holger Bang Grant/research support from: Employee of Orgentec Diagnostika, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Rene Toes: None declared, Diane van der Woude: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.3146

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 31, No. 24 ( 2022-12-16), p. 4286-4294

Abstract: The complex pathogenesis of rheumatoid arthritis (RA) is not fully understood, with few studies exploring the genomic contribution to RA in patients from Africa. We report a genome-wide association study (GWAS) of South-Eastern Bantu-Speaking South Africans (SEBSSAs) with seropositive RA (n = 531) and population controls (n = 2653). Association testing was performed using PLINK (logistic regression assuming an additive model) with sex, age, smoking and the first three principal components as covariates. The strong association with the Human Leukocyte Antigen (HLA) region, indexed by rs602457 (near HLA-DRB1), was replicated. An additional independent signal in the HLA region represented by the lead SNP rs2523593 (near the HLA-B gene; Conditional P-value = 6.4 × 10−10) was detected. Although none of the non-HLA signals reached genome-wide significance (P  & lt; 5 × 10−8), 17 genomic regions showed suggestive association (P  & lt; 5 × 10−6). The GWAS replicated two known non-HLA associations with MMEL1 (rs2843401) and ANKRD55 (rs7731626) at a threshold of P  & lt; 5 × 10−3 providing, for the first time, evidence for replication of non-HLA signals for RA in sub-Saharan African populations. Meta-analysis with summary statistics from an African-American cohort (CLEAR study) replicated three additional non-HLA signals (rs11571302, rs2558210 and rs2422345 around KRT18P39-NPM1P33, CTLA4-ICOS and AL645568.1, respectively). Analysis based on genomic regions (200 kb windows) further replicated previously reported non-HLA signals around PADI4, CD28 and LIMK1. Although allele frequencies were overall strongly correlated between the SEBSSA and the CLEAR cohort, we observed some differences in effect size estimates for associated loci. The study highlights the need for conducting larger association studies across diverse African populations to inform precision medicine-based approaches for RA in Africa.

Type of Medium: Online Resource

ISSN: 0964-6906 , 1460-2083

URL: Article

DOI: 10.1093/hmg/ddac178

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2022

detail.hit.zdb_id: 1474816-2

SSG: 12

In: Chest, Elsevier BV, Vol. 163, No. 3 ( 2023-03), p. 586-598

Type of Medium: Online Resource

ISSN: 0012-3692

URL: Article

DOI: 10.1016/j.chest.2022.09.044

Language: English

Publisher: Elsevier BV

Publication Date: 2023

detail.hit.zdb_id: 2007244-2