Publications by authors named "Voon Ong"

82 Publications

Real-world experience of Tocilizumab in systemic sclerosis: potential benefit on lung function for anti-topoisomerase (ATA) positive patients.

Rheumatology (Oxford) 2021 Mar 18. Epub 2021 Mar 18.

Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UNITED KINGDOM.

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http://dx.doi.org/10.1093/rheumatology/keab273DOI Listing
March 2021

Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension.

Int J Biochem Cell Biol 2021 Mar 1;134:105961. Epub 2021 Mar 1.

Centre for Rheumatology and Connective Tissue Disease, Department of Inflammation, Division of Medicine, University College London, London, NW3 2PF, UK.

Connective tissue growth factor (CTGF, CCN2) is a matricellular protein which plays key roles in normal mammalian development and in tissue homeostasis and repair. In pathological conditions, dysregulated CCN2 has been associated with cancer, cardiovascular disease, and tissue fibrosis. In this study, genetic manipulation of the CCN2 gene was employed to investigate the role of CCN2 expression in vitro and in experimentally-induced models of pulmonary fibrosis and pulmonary arterial hypertension (PAH). Knocking down CCN2 using siRNA reduced expression of pro-fibrotic markers (fibronectin p < 0.01, collagen type I p < 0.05, α-SMA p < 0.0001, TIMP-1 p < 0.05 and IL-6 p < 0.05) in TGF-β-treated lung fibroblasts derived from systemic sclerosis patients. In vivo studies were performed in mice using a conditional gene deletion strategy targeting CCN2 in a fibroblast-specific and time-dependent manner in two models of lung disease. CCN2 deletion significantly reduced pulmonary interstitial scarring and fibrosis following bleomycin-instillation, as assessed by fibrotic scores (wildtype bleomycin 3.733 ± 0.2667 vs CCN2 knockout (KO) bleomycin 4.917 ± 0.3436, p < 0.05) and micro-CT. In the well-established chronic hypoxia/Sugen model of pulmonary hypertension, CCN2 gene deletion resulted in a significant decrease in pulmonary vessel remodelling, less right ventricular hypertrophy and a reduction in the haemodynamic measurements characteristic of PAH (RVSP and RV/LV + S were significantly reduced (p < 0.05) in CCN2 KO compared to WT mice in hypoxic/SU5416 conditions). These results support a prominent role for CCN2 in pulmonary fibrosis and in vessel remodelling associated with PAH. Therefore, therapeutics aimed at blocking CCN2 function are likely to benefit several forms of severe lung disease.
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http://dx.doi.org/10.1016/j.biocel.2021.105961DOI Listing
March 2021

Exploring molecular pathology of chronic kidney disease in systemic sclerosis by analysis of urinary and serum proteins.

Rheumatol Adv Pract 2021 7;5(1):rkaa083. Epub 2021 Jan 7.

UCL Centre for Rheumatology and Connective Tissue Diseases.

Objective: Renal involvement is common in systemic sclerosis (scleroderma; SSc) and includes chronic kidney disease (CKD). We have performed analysis of urinary proteins to gain insight into local molecular pathology of CKD in SSc and identify candidate markers for use in clinical trials.

Methods: To evaluate urinary proteins that might specifically reflect SSc-related CKD, patients were recruited with confirmed SSc and stratified for the presence or absence of CKD. Controls included patients with CKD and no SSc, in addition to healthy volunteers. Candidate markers were measured in serum and urine by multiplex immunoassay testing for IL6, IL18, TNF-α, monocyte chemoattractant protein 1 (MCP1), monocyte chemoattractant protein 3 (MCP3), VEGF and the soluble adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1).

Results: One hundred and two subjects were examined, including patients with SSc with no evidence of CKD ( = 40), SSc with CKD ( = 39), non-SSc CKD ( = 11) and healthy volunteers ( = 12). Urinary levels of IL6, MCP1, TNF-α, MCP3, IL18 and ICAM-1 were elevated in SSc patients compared with healthy controls. The most significant differences were for MCP1 and ICAM-1 (both  < 0.0001), and these analytes also showed the most significant differences between groups overall ( = 0.003 for MCP1 and  < 0.0001 for ICAM-1). These markers showed a trend (MCP1,  = 0.0868) or a significant difference (ICAM-1,  = 0.0134) between SSc-CKD and SSc with normal renal function.

Conclusion: Urinary levels of candidate molecular markers appear to reflect SSc-CKD more than serum markers. MCP1 and ICAM-1 are promising molecular markers for SSc-CKD and might be potential biomarkers of SSc renal involvement. This might be explored in future prospective analyses.
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http://dx.doi.org/10.1093/rap/rkaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878848PMC
January 2021

PASTUL questionnaire: a tool for self-assessment of scleroderma skin during the COVID-19 pandemic.

Ann Rheum Dis 2021 Jan 29. Epub 2021 Jan 29.

University College London, Centre for Rheumatology and Connective Tissue Diseases, Royal Free London NHS Foundation Trust, London, UK

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http://dx.doi.org/10.1136/annrheumdis-2020-219775DOI Listing
January 2021

Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression.

Respirology 2020 Dec 17. Epub 2020 Dec 17.

Interstitial Lung Disease Unit, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.

Background And Objective: The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.

Methods: Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.

Results: In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DL decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DL in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.

Conclusion: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.
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http://dx.doi.org/10.1111/resp.13988DOI Listing
December 2020

Efficacy of Rezafungin in Prophylactic Mouse Models of Invasive Candidiasis, Aspergillosis, and Pneumonia.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Cidara Therapeutics, Inc., San Diego, California, USA

Antifungal prophylaxis is recommended to prevent invasive fungal disease caused by spp., spp., and in patients at risk for opportunistic infections, such as allogeneic blood or marrow transplant recipients, patients with hematological disease undergoing chemotherapy, or patients on immunosuppressive therapies. Current approaches to antifungal prophylaxis require multiple agents to cover these key fungi. Rezafungin, a novel echinocandin designed for next-generation properties (e.g., greater stability and long-acting pharmacokinetics for once-weekly dosing), has demonstrated activity against and spp. and efficacy against spp. biofilms. Rezafungin was evaluated in studies of prophylactic efficacy using immunosuppressed mouse models of invasive candidiasis, aspergillosis, and pneumonia. Rezafungin reduction of CFU burden was generally greater with increasing drug concentrations (5, 10, or 20 mg/kg) and when rezafungin was administered closer to the time of fungal challenge (day -1, -3, or -5). Similarly, in the aspergillosis model, survival rates increased with drug concentrations and when rezafungin was administered closer to the time of fungal challenge. Against , rezafungin significantly reduced trophic nuclei and asci counts at all doses tested. Rezafungin prevented infection at the two higher doses compared to vehicle and had comparable activity to the active control trimethoprim-sulfamethoxazole at human equivalent doses for prevention. These findings support phase 3 development of rezafungin and the potential for single-agent prophylaxis against invasive fungal disease caused by spp., spp., and .
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http://dx.doi.org/10.1128/AAC.01992-20DOI Listing
February 2021

Systemic sclerosis in pregnancy.

Obstet Med 2020 Sep 30;13(3):105-111. Epub 2019 Oct 30.

Centre of Rheumatology and Connective Tissue Diseases, UCL Royal Free Medical School, London, UK.

Systemic sclerosis is a rare multisystem connective tissue disease. It predominantly affects women and poses a significant risk to mother and baby during pregnancy if not managed appropriately. The commonest manifestations are skin fibrosis and Raynaud's phenomenon. Subgroups of women have an increased risk of organ involvement, especially interstitial lung disease, pulmonary arterial hypertension and renal crises. Pregnancy increases the risk to the mother, especially those with established organ involvement, but also the development of new organ dysfunction; and risks to the fetus. Optimising these women prior to conception, along with careful management and surveillance during pregnancy, is vital for optimising pregnancy outcome. Women with scleroderma need to be managed in a specialised centre with coordinated care from the multi-disciplinary teams including physicians, obstetricians, anaesthetists, neonatologists and midwives. This review aims to describe the risks associated with systemic sclerosis and pregnancy, with management advice for physicians looking after pregnant women with this chronic condition.
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http://dx.doi.org/10.1177/1753495X19878042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543163PMC
September 2020

High proton pump inhibitor exposure increases risk of calcinosis in systemic sclerosis.

Rheumatology (Oxford) 2021 02;60(2):849-854

Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK.

Objective: To investigate the association between proton pump inhibitor (PPI) use and the presence and severity of calcinosis in SSc.

Methods: We analysed data from two SSc cohorts from a single centre. Cohort 1 included 199 patients reviewed over 10 years, for whom retrospective data on PPI use and calcinosis were available. Cohort 2 was recruited prospectively and included 215 consecutive patients, who underwent clinical assessment. Outcomes of interest were presence of current calcinosis (CC) or calcinosis at any time (CAT).

Results: The cohort 1 data analysis showed that among patients on standard dose PPI 20% had calcinosis, while in those on high doses of PPI calcinosis was present in 39% (P = 0.003). Analysis of the data from cohort 2 confirmed these findings, demonstrating that the odds of CAT increased significantly with longer PPI exposure [odds ratio (OR) 1.04, 95% CI: 1.02, 1.06; P < 0.001], longer disease duration (OR 1.08, 95% CI: 1.05, 1.12; P < 0.001) and greater age (OR 1.03, CI: 1.01, 1.05; P = 0.010). Multivariable logistic regression showed that higher exposure to PPI remained a significant predictor of calcinosis, with PPI exposure >10 years increasing the risk of CAT >6-fold, compared with no PPI (OR 6.37, 95% CI: 1.92, 21.17; P = 0.003) after adjusting for disease duration and antibodies.

Conclusion: We confirm a significant association between high PPI exposure with severity of calcinosis in SSc. Given the clinical impact of calcinosis and reflux in SSc, PPI exposure as a potentially modifiable risk factor for calcinosis requires further evaluation.
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http://dx.doi.org/10.1093/rheumatology/keaa332DOI Listing
February 2021

News and failures from recent treatment trials in systemic sclerosis.

Eur J Rheumatol 2020 Oct 20;7(Suppl 3):S242-S248. Epub 2020 Jul 20.

Division of Medicine, Centre for Rheumatology, University College London, London, UK.

There have been many recent trials in systemic sclerosis (SSc) that have explored treatment for skin or lung. Some have been encouraging, but there has also been disappointment reflecting potential limitations of treatment effect of study design. These trials are discussed and reviewed. Studies conducted in SSc are described and discussed with a focus on endpoint selection and trial design as well as potential mechanism of action and treatment effect. Studies have included very encouraging trials of interleukin 6 blockade, immunosuppression, and broad-spectrum tyrosine kinase inhibition. Other trials including recent studies of peroxisome proliferator-activated receptor agonists and specific intracellular signaling inhibitors such as imatinib or anti-transforming growth factor beta blocking strategies have been more disappointing. Trial design is improving, and overall, there are now almost positive trials using agents with great promise, and studies are also providing important biological insight into SSc. It is hoped that ongoing studies will further progress the field and move it toward better treatments for SSc that still represent a major unmet medical need.
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http://dx.doi.org/10.5152/eurjrheum.2020.19187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647678PMC
October 2020

Analysis of Anti-RNA Polymerase III Antibody-positive Systemic Sclerosis and Altered GPATCH2L and CTNND2 Expression in Scleroderma Renal Crisis.

J Rheumatol 2020 11 15;47(11):1668-1677. Epub 2020 Mar 15.

S.G. Guerra, PhD, H. Chinque, BSc, V. Acquaah, BSc, M. Ponticos, V.H. Ong, PhD, FRCP, K. Khan, BSc, S.I. Nihtyanova, MD, C. Fonseca, MD, C.P. Denton, PhD, FRCP, Professor of Experimental Rheumatology, UCL Centre for Rheumatology and Connective Tissue Diseases, London, UK;

Objective: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC.

Methods: ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort.

Results: Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; = 1.98 × 10), CTNND2 (rs1859082; = 5.58 × 10), HECW2 (rs16849716; = 1.2 × 10), and GPATCH2L (rs935332; = 4.92 × 10) with SRC. Further, the validation cohort showed an association between rs935332 within the region, with SRC ( = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L ( = 0.026) and glomerular expression of CTNND2 ( = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP.

Conclusion: Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.
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http://dx.doi.org/10.3899/jrheum.190945DOI Listing
November 2020

Scleroderma mimics - Clinical features and management.

Best Pract Res Clin Rheumatol 2020 02 5;34(1):101489. Epub 2020 Mar 5.

Centre for Rheumatology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK. Electronic address:

Systemic sclerosis is a severe immune-mediated rheumatic disease by virtue of its clinical impact and mortality. There are a number of other sclerosing skin diseases that should be considered in the differential diagnosis and these are important because they may require specialist investigation and management. In addition, long-term follow up of the different conditions should reflect the risk of associated complications and anticipated duration of therapy. This article reviews the clinical features of potential mimics of scleroderma (systemic sclerosis) including localised forms of scleroderma (morphoea) and other conditions that lead to skin thickening and connective tissue fibrosis or scarring.
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http://dx.doi.org/10.1016/j.berh.2020.101489DOI Listing
February 2020

Challenges in evidence-based therapy for systemic sclerosis associated interstitial lung disease.

Lancet Respir Med 2020 03 27;8(3):226-227. Epub 2020 Feb 27.

Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK.

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http://dx.doi.org/10.1016/S2213-2600(20)30012-6DOI Listing
March 2020

Improving access to digital ulcer care through nurse-led clinic: a service evaluation.

Musculoskeletal Care 2020 03 21;18(1):92-97. Epub 2020 Jan 21.

Rheumatology Department, Royal Free NHS Foundation Trust, Pond Street, London, NW3 2QG, UK.

Objective: Digital ulcers (DU) remain one of the most burdensome co-morbidities in systemic sclerosis. The objectives of the study were to describe patient-level stratification and to evaluate a nurse-led DU clinic service development.

Methods: A nurse-led digital ulcer clinic was established to identify patients with DU and manage them. Patients were recruited through scleroderma clinics, GP referrals, and self-referrals. The clinic involved patients being treated with appropriate treatment. Patients were stratified according to their DU risk level based on number and severity of ulcers. Among these, 22 patients were asked to complete a patient satisfaction survey. Data were analyzed descriptively.

Results: Seventy-five patients were seen in the clinic, 46 (61%) were 56 years of age and above. Patients were identified as high (23%), medium (51%) or low risk (26%) for development of DU. The duration of DU history was from 7 months to 40 years. Prior to attending the nurse-led DU clinic, 90% of patients had received up to six courses of antibiotics for their DU, 76% had attended A&E, and 90% had unscheduled appointments. 90% had been seen by the GP due to DU and subsequently required hospital admissions. During the nurse-led clinic follow-up, only two patients had emergency admission. All patients reported that their needs in personal care of DU were met.

Conclusion: There are a significant number of people with SSc who have DUs affecting their quality of life as well as needing more healthcare services. A dedicated specialist nurse-led DU clinic may improve overall care of patients.
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http://dx.doi.org/10.1002/msc.1433DOI Listing
March 2020

Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.

Clin Rheumatol 2020 Apr 8;39(4):1173-1179. Epub 2020 Jan 8.

Interstitial Lung Disease Unit, National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), p = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), p = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), p = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), p = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), p = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), p = 6.6 × 10). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), p = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.
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http://dx.doi.org/10.1007/s10067-019-04922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142048PMC
April 2020

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy.

Pharmacol Res Perspect 2019 12 20;7(6):e00546. Epub 2019 Nov 20.

Cidara Therapeutics, Inc San Diego CA USA.

Rezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half-life allowing once-weekly administration, front-loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep-seated infections, such as intra-abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutropenic mouse models of disseminated candidiasis, including infection caused by azole-resistant , and aspergillosis. These results contribute to a growing body of evidence demonstrating the antifungal efficacy and potential utility of rezafungin in the treatment of invasive fungal infections.
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http://dx.doi.org/10.1002/prp2.546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864408PMC
December 2019

Using Autoantibodies and Cutaneous Subset to Develop Outcome-Based Disease Classification in Systemic Sclerosis.

Arthritis Rheumatol 2020 03 28;72(3):465-476. Epub 2020 Jan 28.

UCL Division of Medicine, Royal Free Hospital, London, UK.

Objective: To describe the associations between autoantibodies, clinical presentation, and outcomes among patients with systemic sclerosis (SSc) in order to develop a novel SSc classification scheme that would incorporate both antibodies and the cutaneous disease subset as criteria.

Methods: Demographic and clinical characteristics, including cutaneous subset, time of disease and organ complication onset, and autoantibody specificities, were determined in a cohort of SSc subjects. Survival analysis was used to assess the effect of the autoantibodies on organ disease and death.

Results: The study included 1,325 subjects. Among the antibody/skin disease subsets, anticentromere antibody-positive patients with limited cutaneous SSc (lcSSc) (n = 374) had the highest 20-year survival (65.3%), lowest incidence of clinically significant pulmonary fibrosis (PF) (8.5%) and scleroderma renal crisis (SRC) (0.3%), and lowest incidence of cardiac SSc (4.9%), whereas the frequency of pulmonary hypertension (PH) was similar to the mean value in the SSc cohort overall. The anti-Scl-70+ groups of patients with lcSSc (n = 138) and patients with diffuse cutaneous SSc (dcSSc) (n = 149) had the highest incidence of clinically significant PF (86.1% and 84%, respectively, at 15 years). Anti-Scl-70+ patients with dcSSc had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years. In contrast, in anti-Scl-70+ patients with lcSSc, other complications were rare, and these patients demonstrated the lowest incidence of PH (6.9%) and second highest survival (61.8%) at 20 years. Anti-RNA polymerase antibody-positive SSc patients (n = 147) had the highest incidence of SRC (28.1%) at 20 years. The anti-U3 RNP+ SSc group (n = 56) had the highest incidence of PH (33.8%) and cardiac SSc (13.2%) at 20 years. Among lcSSc patients with other autoantibodies (n = 295), the risk of SRC and cardiac SSc was low at 20 years (2.7% and 2.4%, respectively), while the frequencies of other outcomes were similar to the mean values in the full SSc cohort. Patients with dcSSc who were positive for other autoantibodies (n = 166) had a poor prognosis, demonstrating the second lowest survival (33.6%) and frequent organ complications.

Conclusion: These findings highlight the importance of autoantibodies, cutaneous subset, and disease duration when assessing morbidity and mortality in patients with SSc. Our novel classification scheme may improve disease monitoring and benefit future clinical trial designs in SSc.
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http://dx.doi.org/10.1002/art.41153DOI Listing
March 2020

Erratum for Lakota et al., "Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data".

Antimicrob Agents Chemother 2019 04 27;63(4). Epub 2019 Mar 27.

Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.

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http://dx.doi.org/10.1128/AAC.00333-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437527PMC
April 2019

Elevated kynurenine levels in diffuse cutaneous and anti-RNA polymerase III positive systemic sclerosis.

Clin Immunol 2019 02 14;199:18-24. Epub 2019 Feb 14.

Royal Free Hospital, Centre for Rheumatology and Connective Tissue Diseases, UCL, London, UK. Electronic address:

Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.
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http://dx.doi.org/10.1016/j.clim.2018.12.009DOI Listing
February 2019

Patient-reported outcome instruments for assessing Raynaud's phenomenon in systemic sclerosis: A SCTC Vascular Working Group Report.

J Scleroderma Relat Disord 2018 Oct 24;3(3):249-252. Epub 2018 May 24.

Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester.

The episodic nature of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) has led to a reliance on patient-reported outcome (PRO) instruments such as the Raynaud's Condition Score (RCS) diary. Little is known about the utilisation in routine clinical practice and health professional attitudes towards existing PRO instruments for assessing SSc-RP. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (SCTC-VWG, n=28) were invited to participate in a survey gauging attitudes towards the RCS diary and the perceived need for novel PRO instruments for assessing SSc-RP. Nineteen SCTC-VWG members (68% response rate) from academic units based in North America (n=9), Europe (n=8), South America (n=1) and Australasia (n=1) took part in the survey. There was broad consensus that RCS diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of RP, habituation to RP symptoms, evolution of RP symptom characteristics with progressive obliterative microangiopathy, patient coping strategies, respondent burden and placebo effect. There was consensus that limitations of the RCS diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel PRO instrument for assessing SSc-RP should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the RCS diary have been identified along with concerns that such factors might impede drug development programs for SSc-RP. There is support within the systemic sclerosis community for the development of a novel PRO instrument for assessing SSc-RP.
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http://dx.doi.org/10.1177/2397198318774307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350902PMC
October 2018

Autoimmunity and immunodeficiency at the crossroad: autoimmune disorders as the presenting feature of selective IgM deficiency.

BMJ Case Rep 2019 Jan 3;12(1). Epub 2019 Jan 3.

Department of Experimental Rheumatology, Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UK.

Selective immunoglobulin M deficiency (sIgMD) is an immunodeficiency with undefined pathogenesis and commonly presenting with recurrent infections. The European Society for Immunodeficiencies Registry defines sIgMD as a serum IgM level repeatedly below 2 SD of normal with normal levels of serum IgA, IgG and IgG subclasses, normal vaccination responses, absence of T-cell defects and absence of causative external factors. Rarely it can also be associated with autoimmune diseases. Here we describe a patient with primary sIgMD; who presented with multiple autoimmune diseases without a history of recurrent infections and we provide a short literature review on sIgMD and autoimmune diseases.
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http://dx.doi.org/10.1136/bcr-2017-223180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326303PMC
January 2019

Functional and phenotypic heterogeneity of Th17 cells in health and disease.

Eur J Clin Invest 2019 Jan 1;49(1):e13032. Epub 2018 Nov 1.

William Harvey Research Institute, Queen Mary University of London, London, UK.

Background: Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro-inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear.

Design: In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL-17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases.

Results: The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis.

Conclusion: This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.
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http://dx.doi.org/10.1111/eci.13032DOI Listing
January 2019

European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis.

Rheumatology (Oxford) 2019 02;58(2):254-259

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, UK.

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort.

Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software.

Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score.

Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.
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http://dx.doi.org/10.1093/rheumatology/key271DOI Listing
February 2019

Severe gangrene in a patient with anti-RNP positive limited cutaneous systemic sclerosis/rheumatoid arthritis overlap syndrome caused by vasculopathy and vasculitis.

Eur J Rheumatol 2018 Dec 20;5(4):269-271. Epub 2018 Jun 20.

Department of Rheumatology, Whipps Cross University Hospital, London, UK.

In this paper, we describe a case of a male patient with anti-U1RNP positive limited cutaneous systemic sclerosis/rheumatoid arthritis overlap syndrome, who presented acutely with rapidly progressive digital ischemia, which lead to extensive gangrene. Management with conventional vasodilator therapy was unsuccessful. There were constitutional symptoms and a marked inflammatory response in the absence of evidence of infection, implying a component of vasculitis underlying the presentation. Treatment with immunosuppression and intravenous immunoglobulin led to resolution of the inflammatory process with no further progression of tissue necrosis. Here we discuss pertinent issues raised by the case, including the management of digital ischemia and gangrene in this context and the relevance of the anti-U1RNP in systemic sclerosis overlap syndromes.
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http://dx.doi.org/10.5152/eurjrheum.2018.17177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267747PMC
December 2018

Reliability of digital ulcer definitions as proposed by the UK Scleroderma Study Group: A challenge for clinical trial design.

J Scleroderma Relat Disord 2018 Jun 27;3(2):170-174. Epub 2018 Mar 27.

Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Introduction: The reliability of clinician grading of systemic sclerosis-related digital ulcers has been reported to be poor to moderate at best, which has important implications for clinical trial design. The aim of this study was to examine the reliability of new proposed UK Scleroderma Study Group digital ulcer definitions among UK clinicians with an interest in systemic sclerosis.

Methods: Raters graded (through a custom-built interface) 90 images (80 unique and 10 repeat) of a range of digital lesions collected from patients with systemic sclerosis. Lesions were graded on an ordinal scale of severity: 'no ulcer', 'healed ulcer' or 'digital ulcer'.

Results: A total of 23 clinicians - 18 rheumatologists, 3 dermatologists, 1 hand surgeon and 1 specialist rheumatology nurse - completed the study. A total of 2070 (1840 unique + 230 repeat) image gradings were obtained. For intra-rater reliability, across all images, the overall weighted kappa coefficient was high (0.71) and was moderate (0.55) when averaged across individual raters. Overall inter-rater reliability was poor (0.15).

Conclusion: Although our proposed digital ulcer definitions had high intra-rater reliability, the overall inter-rater reliability was poor. Our study highlights the challenges of digital ulcer assessment by clinicians with an interest in systemic sclerosis and provides a number of useful insights for future clinical trial design. Further research is warranted to improve the reliability of digital ulcer definition/rating as an outcome measure in clinical trials, including examining the role for objective measurement techniques, and the development of digital ulcer patient-reported outcome measures.
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http://dx.doi.org/10.1177/2397198318764796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986081PMC
June 2018

Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis.

Ann Rheum Dis 2018 09 31;77(9):1362-1371. Epub 2018 May 31.

Genentech, South San Francisco, California, USA.

Objectives: Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment-the faSScinate study-in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.

Methods: We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.

Results: The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.

Conclusions: We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.

Trial Registration Number: NCT01532869; Post-results.
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http://dx.doi.org/10.1136/annrheumdis-2018-213031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104680PMC
September 2018

Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata.

Antimicrob Agents Chemother 2018 06 25;62(6). Epub 2018 May 25.

Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against and species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log CFU reductions from baseline for and were calculated for each rezafungin regimen. At the MIC for and , a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC values for and based on contemporary surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to or .
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http://dx.doi.org/10.1128/AAC.02614-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971579PMC
June 2018

Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data.

Antimicrob Agents Chemother 2018 06 25;62(6). Epub 2018 May 25.

Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent activity against and , including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.
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http://dx.doi.org/10.1128/AAC.02603-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971566PMC
June 2018

Distinctive clinical phenotype of anti-centromere antibody-positive diffuse systemic sclerosis.

Rheumatol Adv Pract 2018 7;2(1):rky002. Epub 2018 Mar 7.

Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Hospital, London, UK.

Objectives: The aim was to define clinical characteristics and long-term survival of patients with dcSSc and positive ACA.

Methods: We identified all cases of ACA SSc in our cohort ( = 1313). Those with dcSSc (ACA diffuse) were compared with representative groups of consecutive ACA patients with limited subset (ACA limited) and ACA dcSSc (non-ACA diffuse).

Results: Thirty-five patients (2.7%) were ACA diffuse. The peak modified Rodnan skin score was not significantly different between the dcSSc subgroups, but it occurred later in the disease course in ACA diffuse (88.54 30.65 months,  < 0.001). Patterns of organ involvement were different between the groups. ACA diffuse had a higher incidence of interstitial lung disease than ACA limited (22.86 4.43%,  = 0.001), but lower than non-ACA diffuse (41.18%,  = 0.042). More patients developed pulmonary hypertension in the ACA diffuse group (28.5 12.0% ACA limited or 12.0% non-ACA diffuse), although this was attributable to the longer follow-up in these patients. The cumulative incidence of pulmonary hypertension was not different from the other two groups. The incidence of cardiac involvement was similar between the dcSSc groups, and scleroderma renal crisis was more frequent in the non-ACA diffuse group. Survival in ACA patients was similar in both subsets, whereas non-ACA diffuse had higher mortality.

Conclusion: ACA dcSSc is uncommon and has a distinct clinical phenotype, with a more insidious onset of skin and organ involvement. Even in dcSSc, ACA appears protective for organ-based complications, namely interstitial lung disease and scleroderma renal crisis, and is associated with a better survival than expected in dcSSc.
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http://dx.doi.org/10.1093/rap/rky002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649979PMC
March 2018

Development of systemic sclerosis in transgender females: a case series and review of the literature.

Clin Exp Rheumatol 2018 Jul-Aug;36 Suppl 113(4):50-52. Epub 2018 Feb 19.

Centre for Rheumatology and Connective Tissue Diseases, University College London, UK.

Objectives: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease with a female predominance. The reason for the female predilection in SSc may relate to the difference in hormones between the genders. There are no current data on the influence male-to-female sex transition may have in the development of SSc. We report three patients who developed SSc after initiating the transgender process, and review current literature in regards to transgender patients with connective tissue disease (CTD).

Methods: We describe the clinical features and disease course of three transgender patients who developed SSc after their transition from male-to-female, who presented to our centre. Two additional transgender cases de- scribed in the literature with CTD were included in this review.

Results: All three patients developed SSc after having started the hormonal therapy required to transition. Two patients had surgical procedures preceding their diagnosis of SSc. Antibody profile, time of onset and disease features differed among our patients. Hormonal therapies were continued in all patients and they received the standard therapy for SSc. One patient died from complications of her disease. Only two cases describing the development of CTD in transgender patients were identified in the literature and both of these patients were diagnosed with systemic lupus erythematosus (SLE).

Conclusions: This case series suggests that the hormonal modification as part of gender transition may be relevant in development of SSc. No further conclusions can be drawn on the continuation or not of HT.
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January 2019