Management of pregnancy with diffuse cutaneous systemic sclerosis: a case report and literature review

Diffuse cutaneous systemic sclerosis may occur in women of childbearing age. Pregnancies in this population are associated with a markedly increased risk of adverse obstetric and maternal outcomes even before the onset of symptoms related to sclerosis. We report a case involving the management and outcome of pregnancy in a 30-year-old woman with diffuse cutaneous systemic sclerosis. The course of her pregnancy was good and was assisted by a group consultation including obstetricians and rheumatologists. Vaginal delivery was the patient’s preferred choice because she had irregular skin tightness in her lower abdominal skin. She underwent induction of labor and combined spinal-epidural analgesia, and successfully delivered. Importantly, these pregnancies need to be planned, where possible, to allow the opportunity to counsel women and their partners in advance and to decrease any risks. These pregnancies should be considered high risk, and they require close antenatal monitoring and good supervision from an expert multidisciplinary team experienced in high-risk pregnancies. The management of delivery for patients with cutaneous systemic sclerosis is challenging, and vaginal delivery with labor analgesia is an alternative option to cesarean section.

Systemic sclerosis – metamorphosis of a life

Systemic sclerosis is a complex autoimmune disorder marked by heterogeneous clinical manifestations and variable disease course. We present the case of a patient with diffuse cutaneous systemic sclerosis with anti-PM/Scl antibodies and associated calcinosis cutis. Currently, there is no uniformly effective therapy for calcinosis, but in the present case study combined therapy (calcium channel blocker, colchicine, bisphosphonate and minocycline) showed a good outcome with significant clinical improvement. Calcinosis in patients with systemic sclerosis is relatively common and it represents a challenge that requires appropriate management.

Information preferences about treatment options in diffuse cutaneous systemic sclerosis: A Delphi consensus study

Objectives: The aim of this study was to identify and prioritize aspects essential for decision making in patients with diffuse cutaneous systemic sclerosis (dcSSc) and to gain insight into information preferences of treatment options which could guide development of a leaflet for patients. Methods: A three-round Delphi study was conducted with a panel of patients with dcSSc. The questionnaire was based on a systematic literature search regarding benefits and harms of four main treatment options in dcSSc: methotrexate, mycophenolate mofetil, cyclophosphamide pulses and stem cell transplantation. Patients were asked to identify information that is essential for making a treatment decision. After the third round, a live, online discussion was held in order to reach consensus on these items and to discuss the content and design of the leaflet. Consensus was defined as ⩾75% agreement among panel members. Results: Of the 36 patients invited, 78% (n = 28) participated in one or more rounds, 67% (n = 24) completed the first, 69% (n = 25) the second and 75% (n = 27) the third round. In the last round, median age of participants was 51 years (interquartile range, 18) and median disease duration 4 years (interquartile range, 5); 52% were female. Patients had been treated with mycophenolate mofetil (67%), methotrexate (44%), cyclophosphamide (41%), autologous stem cell transplantation (26%), rituximab (4%) or were treatment-naïve (7%). Eight patients joined the live panel discussion. The panel reached consensus on seven benefits (prolonged progression-free survival, improved quality of life, improved daily functioning, improved pulmonary function, improved skin thickness, improved mobility and reduced fatigue) and four harms (treatment-related mortality, infections, cardiac damage, increased risk of cancer) as essential information for decision making. Also a design of a leaflet was made. Conclusion: This study identified information about treatment options in dcSSc that should be addressed with patients. Our results can be used to develop effective patient information.

Genome-wide DNA methylation pattern in systemic sclerosis microvascular endothelial cells: Identification of epigenetically affected key genes and pathways

Background: The etiology of systemic sclerosis is not clear, but there is evidence suggesting a critical role for epigenetic alterations in disease pathogenesis and clinical expression. We sought, in this study, to characterize the genome-wide DNA methylation signature in systemic sclerosis microvascular endothelial cells. Methods: We performed a genome-wide DNA methylation study in microvascular endothelial cells derived from seven diffuse cutaneous systemic sclerosis patients compared to seven age-, sex-, and ethnicity-matched healthy controls. We paired matched samples on Illumina HumanMethylation450 (three diffuse cutaneous systemic sclerosis microvascular endothelial cells and three controls), and reproduced the results in an independent set of matched patient and controls using Illumina Infinium MethylationEPIC (four diffuse cutaneous systemic sclerosis patients and four controls) to identify differentially methylated genes. Results: We identified 71,353 differentially methylated CpG sites in systemic sclerosis microvascular endothelial cells using Infinium MethylationEPIC microarray in the first group (0.081% of representative probes) and 33,170 CpG sites in the second group using HumanMethylation450 microarray (0.073% of representative probes) in diffuse cutaneous systemic sclerosis microvascular endothelial cells. Among the two groups of subjects, we identified differential methylation of 2455 CpG sites, representing 1301 genes. Most of the differentially methylated CpG sites were hypermethylated (1625 CpG), corresponding to 910 genes. Common hypermethylated genes in systemic sclerosis microvascular endothelial cells include NOS1, DNMT3A, DNMT3B, HDAC4, and ANGPT2. We also identified hypomethylation of IL17RA, CTNNA3, ICAM2, and SDK1 in systemic sclerosis microvascular endothelial cells. Furthermore, we demonstrate significant inverse correlation between DNA methylation status and gene expression in the majority of genes evaluated. Gene ontology analysis of hypermethylated genes demonstrated enrichment of genes involved in angiogenesis ( p = 0.0006). Pathway analysis of hypomethylated genes includes genes involved in vascular smooth muscle contraction ( p = 0.014) and adherens junctions ( p = 0.013). Conclusion: Our data suggest the presence of significant genome-wide DNA methylation aberrancies in systemic sclerosis microvascular endothelial cells, and identify novel affected genes and pathways in systemic sclerosis microvascular endothelial cells.

AB0436 OUTCOMES OF DOSE-REDUCTION OR DISCONTINUATION OF TOCILIZUMAB IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS

Background:Potential efficacy and favorable safety profiles of tocilizumab (TCZ) have been demonstrated in patients with diffuse cutaneous systemic sclerosis (dcSSc) [1, 2]. However, clinical outcomes after dose-reduction or discontinuation of TCZ due to an improvement of skin thickness remain unclear.Objectives:To investigate the clinical outcomes after dose-reduction or discontinuation of TCZ in patients with dcSSc in a real-world setting.Methods:This is a single-center, retrospective, observational study using a database of consecutive SSc patients who visited our center between April 2014 and October 2020. For this study, we selected eligible patients from the database based on the following criteria: patients who (i) fulfilled the ACR/EULAR classification criteria, (ii) were classified as having dcSSc, (iii) had been treated with TCZ for at least 6 months, and (iv) were follow-up >6 months after TCZ introduction. Clinical information including demographic and clinical characteristics at TCZ introduction; dosing, administration route, and adherence of TCZ; and serial clinical parameters (modified Rondan total skin thickness score [mRSS], and percent predicted forced vital capacity [%FVC]), safety profiles, and outcomes after TCZ introduction regardless of TCZ continuation were extracted from the database.Results:Of 404 patients enrolled in the database, 13 dcSSc patients were eligible for this study. Baseline characteristics included a mean age of 51 ± 9 years, 85% female, disease duration of 27 ± 24 months, and mRSS of 19.5 ± 10.6. Seven patients (54%) had HRCT-confirmed ILD at baseline, and 9 (69%) were positive for anti-topoisomerase I antibody. Two (14%) and 11 (85%) were on mycophenolate mofetil and low-dose prednisolone (7.2 ± 6.0 mg/day), respectively. Seven patients (54%) each had active skin disease and elevated inflammatory markers defined in the phase III clinical trial [2], while only 4 (31%) fulfilled the inclusion criteria. TCZ was initially administered intravenously (8 mg/kg every 4 weeks) in 8 patients and subcutaneously in 5 (162 mg every 2 weeks in 4 and every week in one). At one year, mRSS was improved from 20.9 ± 11.4 to 10.7 ± 8.9 in 11 patients (p = 0.007), and %FVC was stable in 7 patients with ILD (76.8 ± 15.0 to 78.6 ± 16.1). During the observation period of 60.4 ± 26.7 months, 4 patients were treated with a stable dose of TCZ, while TCZ dose was reduced and/or discontinued in 9. Four of them discontinued TCZ due to adverse events (n = 2; acute lung injury and phlegmon) or prominent improvement of skin thickening (n = 2). Of 9 patients with dose reduction/discontinuation of TCZ, 4 patients who discontinued TCZ (n = 3) or received dose reduction of TCZ (n = 1) experienced a recurrence of progressive skin thickening together with inflammatory complications, including edematous induration of the skin, progression of ILD, polyarthritis, and/or pericarditis with increased inflammatory markers. The interval between dose-reduction/discontinuation of TCZ and clinical worsening ranged from 2 to 11 months. These manifestations were promptly improved by dose-escalation or resumption of TCZ in all patients except one who experienced progressive ILD and died of respiratory failure 27 months later.Conclusion:In dcSSc patients who experienced improvement of skin thickness during treatment with TCZ, dose-reduction or discontinuation of TCZ may result in a recurrence of the disease. Randomized comparative studies are necessary to examine optimal timing for dose-reduction or discontinuation of TCZ in dcSSc patients after improvement of skin thickness.References:[1]Khanna, D., et al., Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis, 2018. 77(2):212-220.[2]Khanna, D., et al., Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med, 2020; 8(10): 963-974.Disclosure of Interests:Yohei Isomura: None declared, Yoshioki Yamasaki Speakers bureau: Boehringer-Ingelheim, Nippon Shinyaku, Bristol Myers, Yuichiro Shirai Speakers bureau: Janssen, Grant/research support from: Janssen, Masataka Kuwana Speakers bureau: Abbie, Astellas, Asahi Kasei Parma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Tanabe-Mitsubishi, Consultant of: Boehringer-Ingelheim, Chugai, Corbus, MBL, Mochida, Grant/research support from: Boehringer-Ingelheim, Chugai, Eisai, MBL, Ono Pharmaceuticals, Tanabe-Mitsubishi

AB0431 EXPLORING THE UTILITY OF THE AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) CRISS IN PATIENTS WITH DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS

Background:The ACR Composite Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) was developed to measure the probability of improvement in response to treatment in patients with early diffuse cutaneous SSc (dcSSc), accounting for new/worsening cardiopulmonary involvement and/or renal crisis, and changes in modified Rodnan skin score, forced vital capacity, health assessment questionnaire disability index, and patient’s and physician’s global impressions. In patients with SSc-ILD, treatment response may be reflected as slower progression, stabilisation or improvement.Objectives:Using data from patients with dcSSc and ILD in the placebo group of the SENSCIS trial, we analysed the probability of improvement using the ACR CRISS score at week 52. We also evaluated whether the CRISS numerator could provide information on the spectrum of responses in this patient population.Methods:The SENSCIS trial enrolled subjects with SSc-ILD with onset of first non-Raynaud symptom ≤7 years before screening, FVC ≥40% predicted, and fibrotic ILD ≥10% extent on an HRCT scan. Subjects on prednisone ≤10 mg/day (or equivalent) and/or stable therapy with mycophenolate or methotrexate were allowed to participate. Subjects were randomised to receive nintedanib or placebo. Subjects were not randomised by use of mycophenolate. In patients randomised to receive placebo who had dcSSc and/or mRSS >15 at baseline, we analysed the ACR CRISS and its numerator at week 52 in subgroups by use of mycophenolate at baseline. Analyses were exploratory and descriptive.Results:Of 117 analysed subjects in the placebo group who had dcSSc and/or mRSS >15 at baseline, 60 (51.3%) were taking mycophenolate at baseline. Compared with patients not taking mycophenolate at baseline, those taking mycophenolate had a lower mean age (48.4 [SD 11.8] vs 53.1 [13.4] years), lower mean FVC % predicted (68.8 [17.0] vs 73.0 [14.6]), and a greater proportion were female (76.7% vs 71.9%); median time since first onset of non-Raynaud symptom was similar (3.9 vs 4.5 years, respectively) as was mean (SD) mRSS (16.5 [7.7] vs 15.9 [8.0], respectively). One patient (taking mycophenolate at baseline) had limited cutaneous SSc. At week 52, median (Q1, Q3) ACR CRISS score was 0.036 (0.001, 0.601) in subjects taking mycophenolate and 0.002 (0.000, 0.112) in subjects not taking mycophenolate at baseline, and mean (SD) ACR CRISS score was 0.28 (0.37) in subjects taking mycophenolate and 0.16 (0.31) in subjects not taking mycophenolate at baseline (Figure 1). In these groups, respectively, 25.0% and 14.0% of subjects had CRISS score >0.6 (considered improved) at week 52. The CRISS numerator provided a broader distribution of response values, but was not informative in this patient population.Conclusion:In exploratory analyses, among subjects with dcSSc and ILD who received placebo in the SENSCIS trial, the proportion considered improved at week 52 based on ACR CRISS score was numerically greater in patients taking than not taking mycophenolate at baseline. There remains a need for composite scores that provide better interpretation of the magnitude of response in patients with SSc.Acknowledgements:The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by FleishmanHillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Francesco Del Galdo Speakers bureau: Actelion and AstraZeneca, Consultant of: Actelion, AstraZeneca, Boehringer Ingelheim, Capella BioScience, ChemomAb and Mitsubishi Tanabe Pharma, Grant/research support from: Capella BioScience, Kymab and Mitsubishi Tanabe Pharma, Oliver Distler Consultant of: AbbVie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Blade Therapeutics, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Glenmark Pharmaceuticals, Horizon (Curzion) Pharmaceuticals, Inventiva, IQVIA, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bioscience, Topadur Pharma and UCB, Grant/research support from: Kymera Therapeutics and Mitsubishi Tanabe Pharma, Christopher Denton Speakers bureau: Boehringer Ingelheim, Corbus, Janssen, and Mallinckrodt Pharmaceuticals, Consultant of: Acceleron Pharma, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mallinckrodt Pharmaceuticals, Roche, Sanofi and UCB, Grant/research support from: Arxx Therapeutics, GlaxoSmithKline and Servier, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals, Daniel Wachtlin Employee of: Currently an employee of Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Dinesh Khanna Shareholder of: Eicos Sciences, Inc. (less than 5%), Consultant of: Acceleron Pharma, Actelion, AbbVie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead Sciences, Galapagos NV, Genentech/Roche, GlaxoSmithKline, Horizon Therapeutics, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis and United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health and Pfizer, Employee of: Chief Medical Officer- CiviBioPharma/Eicos Sciences, Inc.