ABSTRACT
BackgroundSystemic sclerosis (SSc) is a severe, progressive multisystem rheumatic disease with high mortality, but without approved disease-modifying treatment to stop or reverse course of disease. Intravenous immunoglobulin G (IgG) may have a positive impact on SSc based upon available literature reports. However, to date, there have been no clinical trials evaluating subcutaneous IgG (SCIG) in SSc. In particular, the impact of pathologically altered skin in SSc on local safety and pharmacokinetics (PK) of SCIG has not been explored yet.ObjectivesThe primary and secondary objectives of this trial (NCT04137224) included safety, including local infusion safety, and bioavailability of subcutaneous IgG (IgPro20) in adults with diffuse cutaneous SSc (dcSSc).MethodsThis was a randomized, open-label, crossover study. Adult subjects with dcSSc diagnosis within 5 years from first non-Raynaud's phenomenon and modified Rodnan Skin Score of 15-45 at screening were randomized 1:1 to sequence A (IgPro20, 20% normal human subcutaneous immunoglobulin followed by IgPro10, 10% normal human intravenous immunoglobulin) or sequence B (IgPro10 followed by IgPro20). Each subject was to complete two treatment periods (16 weeks each), with up to 40 weeks (including screening) study duration for an individual subject. Doses received were 0.5g/kg/week split over two sessions for IgPro20, and 2g/kg/4 weeks split over 2-5 days for IgPro10. The primary endpoint was safety of IgPro20, described as treatment-emergent adverse events (TEAEs) and changes in clinical observations.Results27 subjects were randomized, with 13 subjects to sequence A and 14 subjects to sequence B. In total, 25 subjects completed the study. Of 27 treated subjects, 107 TEAEs occurred in 22 subjects (81.5%) over the 36-week study period, the majority of which were mild or moderate. The most common TEAEs (>10% of subjects) by preferred term (PT) were headache (12 events occurring in 6 subjects [22.2%]), COVID-19 (3 events occurring in 3 subjects [11.1%]), diarrhoea (3 events occurring in 3 subjects [11.1%]), and vomiting (3 events occurring in 3 subjects [11.1%]).A total of 10 serious AEs (SAEs) were reported in 6 subjects (Viral infection, Chronic gastritis, Vomiting, Dehydration, Upper gastrointestinal haemorrhage, Chest pain, Myocardial infarction, Myocardial ischemia, Breast cancer, Interstitial lung disease). Among these, one subject experienced 2 SAEs (myocardial ischemia & myocardial infarction) and was discontinued from study treatment. None of the SAEs were considered related to study treatment by the investigator, and no deaths were reported.For IgPro20, 14 infusion site reactions (ISRs) occurred in 5 subjects (19.2%), all were mild or moderate in severity. The most common ISRs were infusion site pain and infusion site swelling (3 events in 2 subjects each, 7.7%). In total, 686 IgPro20 infusions were performed, resulting in an overall ISR rate per infusion of 0.02, ie 2 ISRs per 100 infusions. No ISRs were reported for IgPro10.No clinically relevant trends in vital signs, body weight, clinical laboratory tests, electrocardiograms, or pulmonary function tests were observed.PK profiles and bioavailability in dcSSc subjects were similar to those observed in other approved indications such as Primary Immunodeficiency. Population relative bioavailability of IgPro20, based on dose-normalized, baseline-corrected AUC0-tau was 0.761 (90% CI: 0.7033, 0.8232), ie 76.1% compared to IgPro10 (intravenous IgG).ConclusionThe overall safety profiles of IgPro20 and IgPro10 in subjects with dcSSc were consistent with that in approved indications such as CIDP, including a relatively low ISR rate for IgPro20. PK profiles and bioavailability were also similar to other indications. This study indicates that subcutaneous administration of IgPro20 has acceptable safety, bioavailability and PK profiles in patients with dcSSc. AcknowledgementsEditorial assistance was provided by Meridian HealthComms Ltd., funded by CSL Behring.Disclosure of InterestsChristopher P Denton Speakers bureau: Ja ssen, Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Otylia Kowal-Bielecka Speakers bureau: Abbvie, Janssen-Cilag, Boehringer Ingelheim, Medac, MSD, Novartis, Pfizer, Sandoz, Consultant of: Boehringer Ingelheim and Novartis, Grant/research support from: Received congress support from Abbvie, Boehringer Ingelheim, and Medac, Susanna Proudman Speakers bureau: Boehringer Ingelheim, Grant/research support from: Janssen, Marzena Olesińska Consultant of: AstraZeneca, Margitta Worm Consultant of: Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Leo Pharma GmbH, Boehringer Ingelheim Pharma GmbH &Co.KG, ALK-Abelló Arzneimittel GmbH, Kymab Limited, Amgen GmbH, Abbvie Deutschland GmbH & Co. KG, Pfizer Pharma GmbH, Mylan Germany GmbH (A Viatris Company), AstraZeneca GmbH, Lilly Deutschland GmbH and GlaxoSmithKline GmbH & Co. KG., Nicoletta Del Papa Speakers bureau: Janssen Cilag, Boehringer Ingelheim., Marco Matucci-Cerinic Speakers bureau: Biogen, Sandoz, Boehringer Ingelheim, Consultant of: CSL Behring, Boehringer Ingelheim, Grant/research support from: MSD, Chemomab, Jana Radewonuk Shareholder of: CSL Behring, Employee of: CSL Behring, Jeanine Jochems Shareholder of: CSL Behring, Employee of: CSL Behring, Amgad Shebl Shareholder of: CSL Behring, Employee of: CSL Behring, Anna Krupa Shareholder of: CSL Behring, Employee of: CSL Behring, Jutta Hofmann Shareholder of: CSL Behring, Employee of: CSL Behring, Maria Gasior Shareholder of: CSL Behring, Employee of: CSL Behring.
ABSTRACT
Gastro-oesophageal reflux disease (GERD) is associated with substantial morbidity in patients with systemic sclerosis. Although the introduction of proton pump inhibitors (PPIs) into clinical care represents a major achievement in the management of gastro-oesophageal problems in systemic sclerosis, PPIs are seldom fully effective in patients with systemic sclerosis, and the use of maximum PPI doses is a very frequent clinical practice. However, there is little evidence to support the empirical use of PPIs in systemic sclerosis. This scarcity of evidence is especially relevant with regards to the safety concerns of long-term exposure, which have been raised in the general population. The purpose of this Viewpoint is to highlight the substantial beneficial impact of PPIs on GERD in patients with systemic sclerosis, while considering the potential adverse effects in this patient population. Furthermore, we highlight the unmet needs of people with systemic sclerosis and GERD and propose an agenda for future research to optimise the safe and effective use of PPIs in systemic sclerosis. Copyright © 2022 Elsevier Ltd
ABSTRACT
The COVID-19 pandemic represents one of the biggest challenges of the 21st century. In addition to the general effect on society and health-care systems, patients with systemic sclerosis and their physicians face specific challenges related to the chronic nature of their disease, the involvement of multiple organs, and the use of immunosuppressive treatments. Data from registries and single centre cohorts indicate that the risk of contracting SARS-CoV-2 does not seem to increase substantially in people with systemic sclerosis;conversely, severe COVID-19 outcomes are seen more frequently in these patients than in the general population. Vaccination against SARS-CoV-2 is therefore highly recommended for patients with systemic sclerosis;however, no specific recommendations are available regarding the different vaccine platforms. Both patients and physicians should be aware that the effectiveness of vaccines might be reduced in patients taking immunosuppressive therapy, because antibody responses might be blunted, specifically in patients treated with rituximab and mycophenolate mofetil.
ABSTRACT
Background: A highly controversial question is whether or not corticosteroids should be prescribed for patients with early diffuse cutaneous systemic sclerosis (dcSSc). Although the painful and disabling features of early dcSSc (including tight itchy skin, contractures, fatigue) have an infammatory basis and are likely to respond to corticosteroids, corticosteroids are a risk factor for potentially life-threatening scleroderma renal crisis. Objectives: Our aim was to examine safety and efficacy of moderate dose prednisolone in patients with early dcSSc. Specific objectives were to evaluate whether moderate dose prednisolone reduced pain and disability, and improved skin score, and whether prednisolone was safe with particular reference to renal function Methods: PRedSS set out as a Phase II, multicentre, double-blind randomised controlled trial, converted to open-label because of the Covid-19 pandemic. Patients were randomised to receive either moderate dose prednisolone (approximately 0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. The co-primary endpoints were the Health Assessment Questionnaire Disability Index (HAQ-DI) and modifed Rodnan skin core (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures refecting pain, itch, anxiety and depression, fatigue and helplessness. 72 participants randomised 1:1 were planned and anticipated to yield 60 evaluable, giving over 80% power for each co-primary outcome in ANCOVA analyses [assumptions;HAQ-DI (a = 0.025, ô =-0.6, o = 0.9, p = 0.6), mRSS (a = 0.025, ô =-5.5, a = 8.2, p = 0.6)]. Mixed Models for Repeated Measures (week 6, month 3, month 6) were ftted with covariates trial arm, baseline score, anti-Scl-70 and their interactions with time point. An unstructured covariance matrix was assumed with the primary focus being the trial arm effect at 3 months. Results: The study terminated early due to the Covid-19 pandemic and consequently did not meet the recruitment target of 72 patients. Thirty-five patients (Table 1) were randomised (17 to prednisolone and 18 to placebo/control, 25 during the double-blind phase), of whom 34 completed the 3 month assessment. The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was-0.10 (97.5% CI-0.29 to 0.10), p=0.25, and in mRSS-3.90 (97.5% CI-8.83 to 1.03), p=0.070, both favouring prednisolone but not signifcantly. Patients in the prednisolone group experienced less pain, helplessness and anxiety than control patients at 3 months: mean difference in pain scores-0.49, 95%CI (-0.93 to-0.06), p=0.027, in Hospital Anxiety and Depression (HADS) anxiety scores-2.05, 95%CI (-3.73 to-0.37), p=0.018, and in helplessness scores-1.54, 95%CI (-3.01 to-0.07), p=0.040. There were no renal crises. Conclusion: PRedSS exemplifed the challenges of running a clinical trial of an investigational medicinal product potentially associated with increased infection risk during the Covid-19 pandemic. Because PRedSS was terminated prior to target recruitment, it was underpowered, and any conclusions have to be extremely cautious. Although PRedSS suggested some beneft from moderate dose predni-solone, the small sample indicates the need for a further randomised trial.
ABSTRACT
Background/AimsEvaluation of skin is central to both clinical practice and trials insystemic sclerosis (SSc). This is generally done with the modifiedRodnan Skin Score (mRSS). Remote consultations are now widelyimplemented in response to the COVID-19 pandemic, which hasinevitably limited evaluation of skin. To monitor skin during thispandemic and to further explore ways to assess skin, we developedthe PASTUL (Patient self-Assessment of Skin Thickness in UpperLimb) questionnaire. The aim of this study was to evaluate feasibilityand validity of the PASTUL in SSc.MethodsThe PASTUL questionnaire specifies a simple grading of skin asnormal, mild, moderate, or severely thickened at eight sites of upperlimb corresponding to mRSS. Assessed grades were converted to aninteger scale [0, 1,2,3]. Detailed instructions for patients wereprovided. Scleroderma Skin PRO (SSPRO) and Scleroderma HealthAssessment Disability Index (SHAQ-DI) were also completed. ThemRSS was done in a selection of patients. Construct validity wasevaluated by examining the correlation between PASTUL, mRSS, SSPRO and SHAQ-DI using Pearson's correlation coefficient. Contentvalidity was evaluated by scoring relevance, clarity and practicaldifficulty. Test-retest reliability was estimated using intraclass correlation coefficient (ICC).ResultsIn total, 107 patients were invited of which 83 (77.6%) completed thequestionnaires. The mRSS was undertaken in 61 patients. ThePASTUL was completed by patients (83.1%) or by a partner/friend(16.9%). Mean PASTUL score was 11 (SD 6), mean HAQ-DI 1.47 (SD0.76) and mean SSPRO 49.8 (SD 26.6). PASTUL and SSPRO physicallimitations correlated strongly (0.62, p < 0.001). Correlations betweenPASTUL and total SSPRO and mRSS upper limbs were moderate toweak (0.59, 0.50 and 0.32 respectively). Correlation between PASTULand mRSS was stronger in lcSSc compared to dcSSc patients (0.61 vs0.29) and when assessed by a partner/friend compared to patientsthemselves (0.98 vs 0.45). The PASTUL demonstrated excellent testretest reliability (ICC of 0.92) and good content validity. ConclusionModerate and significant correlations of PASTUL scores with totalSSPRO, physical limitation scores and mRSS support the usefulnessof PASTUL as an outcome measure and indicates it's potential for usein virtual clinical settings.