Systemic Sclerosis Cases Research Articles

Systemic sclerosis and cancer in the UK: An epidemiological analysis using the Clinical Practice Research Datalink.

Cancer can cause mortality in systemic sclerosis (SSc). We investigated the association between cancer and SSc using the Clinical Practice Research Datalink (CPRD). A validated case-ascertainment strategy identified SSc patients in the CPRD. A cohort study design examined cancer occurrence following SSc, with SSc patients matched to six non-SSc comparators by age, sex and GP-practice. Prevalent and incident cases of SSc were analysed separately. Descriptive statistics and Cox analyses determined hazard ratios for cancer occurrence. A case-control study (matched 1:6) examined cancer occurrence prior to SSc. From 10.1 million individuals in CPRD, 1,588 of cases of SSc were identified. Two hundred and six cancers followed SSc diagnosis (116 in prevalent and 90 in incident cohort). Commonest cancers were mucocutaneous (4.5%), lung (2.1%) and breast (1.9%). The proportion of SSc patients developing cancer was significantly higher than non-SSc in both incident (11.2% vs 9.7%, p= 0.02) and prevalent cohorts (14.8% vs 12.1%, p= 0.03); particularly for lung cancer (2.6% vs 0.9% in prevalent cohort, p< 0.001). Overall incidence of cancer in the SSc groups was 17.6/1000 person years, compared with 13.9/1000 person years in non-SSc group. The adjusted hazard ratios for cancer was 1.41 (95% CI 1.14-1.75) and 1.32 (95% CI 1.04-1.67) for prevalent and incident SSc respectively. No increased risk of cancer prior to SSc diagnosis was identified in case-control study. We have identified an increased risk of cancer diagnosis following, but not before, SSc diagnosis. Our findings could support screening recommendations for cancer in SSc.

Epidemiology of systemic sclerosis in Quebec, Canada: a population-based study

Systemic sclerosis (SSc) is a systemic life-threatening autoimmune rheumatic disease. We aimed to assess the incidence, prevalence, mortality and spatiotemporal trends of SSc in Quebec, Canada with stratification by sex and age. SSc cases were identified from Quebec populational databases from 1989 to 2019. Negative Binomial (NB) Generalized Linear Models were used for age-standardized incidence rates (ASIR) analyses and NB random walk for prevalence and mortality. A Poisson Besag-York-Mollié regression model was used for spatial analysis. 8180 incident SSc cases were identified between 1996 and 2019 with an average age of 57.3±16.3 years. The overall ASIR was 4.14/100,000 person-years (95%, Confidence Interval (CI) 4.05-4.24) with a 4:1 female predominance. ASIR increased steadily over time with an Average Annual Percent Change (AAPC) of 3.94% (95% CI 3.49-4.38). While the highest incidence rates were in those aged 60-79 years old among females and >80 years old among males, the highest AAPC (∼10%) was seen in children. Standarized incidence ratios varied geographically between 0.52 to 1.64. The average prevalence was 28.96/100,000 persons (95% CI 28.72-29.20). The Standardized Mortality Ratio (SMR) decreased from 4.18 (95% CI 3.64-4.76) in 1996 to 2.69 (95% CI 2.42-2.98) in 2019. Females had a greater SMR until 2007 and males thereafter. The highest SMR was in children and young adults [31.2 (95% CI 8.39-79.82) in the 0-19-year age group]. We showed an increasing trend in SSc incidence and prevalence and a decline in SMR over a 25-year period in Quebec. An uneven geographic distribution of SSc incidence was demonstrated. National Scleroderma Foundation, Canadian Dermatology Foundation/Canadian Institutes of Health Research.

Clinical features of patients with systemic sclerosis positive for anti-SS-A antibody: a cohort study of 156 patients

BackgroundAnti-SS-A/Ro antibody (anti-SSA), the diagnostic marker of Sjögren’s syndrome (SS), is often detected in systemic sclerosis (SSc). Some patients are diagnosed with SSc/SS overlap syndromes, while there are anti-SSA-positive SSc cases without SS. In this study, we investigated the clinical characteristics of SSc with anti-SSA and clarified the clinical impact of this antibody in SSc.MethodsA retrospective chart review was conducted of 156 patients with SSc at Yokohama City University Hospital from 2018 to 2021. Clinical data, laboratory data, imaging, and autoantibody positivity status were collected and analysed to assess the association between these variables and anti-SSA using multivariable logistic regression analysis.ResultsThis cohort included 18 men and 138 women with SSc (median age, 69.0 years). Thirty-nine patients had diffuse cutaneous SSc (dcSSc) (25%), and 117 patients had limited cutaneous SSc (75%). Forty-four patients were anti-SSA-positive. Among them, 24 fulfilled the SS criteria. Multivariable logistic regression revealed that anti-SSA was statistically associated with interstitial lung disease (ILD; odds ratio [OR] = 2.67; 95% confidence interval [CI], 1.14–6.3; P = 0.024). Meanwhile, anti-SSA positivity tended to increase the development of digital ulcer (OR = 2.18; 95% CI, 0.99–4.82, P = 0.054). In the comparative analysis of the autoantibody single-positive and anti-SSA/SSc-specific autoantibody double-positive groups, the anti-SSA single-positive group showed a significantly increased risk of ILD (OR = 12.1; 95% CI, 2.13-140.57; P = 0.003). Furthermore, patients with SSc and anti-SSA indicated that anti-SSA-positive SSc without SS was strongly associated with dcSSc when compared to that in patients with SS (OR = 6.45; 95% CI, 1.23–32.60; P = 0.024).ConclusionsAnti-SSA positivity increases the risk of organ involvement, such as ILD, in patients with SSc. Additionally, the anti-SSA-positive SSc without SS population may have more severe skin fibrosis than others. Anti-SSA may be a potential marker of ILD and skin severity in SSc.

Journey into the Esophageal Complications: Decoding Systemic Sclerosis with Cutting-Edge Endoscopy, Manometry, and Ambulatory pH-Study.

Systemic Sclerosis (SSc) is a rare connective tissue disorder characterized by autoimmunity, fibrosis, and vasculopathy that affects the skin and internal organs, including the gastrointestinal tract, particularly the esophagus. This article highlights the characteristics and clinical symptoms of esophageal involvement in patients with SSc. This study was conducted between November 2022 to August 2023, including 26 already diagnosed cases of SSc in the Department of Rheumatology and Rehabilitation and Kurdistan Center for Gastroenterology and Hepatology-Sulaymaniyah, Iraq. Esophageal involvement was investigated using esophageal manometry, esophagogastroduodenoscopy (EGD), and 24-hour impedance-pH monitoring. Females were significantly predominant (P = 0.019) regarding the symptoms; 76.9% of the patients had heart burn, 76.9% dysphagia, 73.1% water brush, and 69.2% regurgitation. In total, 69.2% of the patients showed erosive gastrointestinal reflux disease (GERD) on EGD, 76.9% had decreased lower esophageal sphincter pressure (DLESP) and decreased distal esophageal peristaltic contractions (DDEPC) on esophageal manometry, and 84.6% had reflux on pH monitoring. Raynaud's phenomenon is the most common and typically the earliest clinical manifestation of SSc. The presence of erosive GERD was found to significantly increase the risk of developing dysphagia (B = 4.725, P = 0.014, OR = 3.482) and regurgitation (B = 3.521, P = 0.006, OR = 4.030). It is crucial to take gender-specific considerations into account when diagnosing and managing esophageal complications in patients with systemic sclerosis (SSc). Additionally, employing various diagnostic assessments to detect esophageal involvement during SSc is essential. Erosive GERD has been identified as a risk factor that contributes to the development of dysphagia and regurgitation in individuals with SSc.

P134 Developing a potential composite pharmacodynamic serum marker of skin severity in systemic sclerosis

Abstract Background/Aims Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients. Methods COMP (DCMP0, R&amp;D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n = 33) and MODERNISE (n = 37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n = 36). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA results. Results Serum concentration positively correlated with mRSS for COMP and TNC, particularly in early dcSSc patients (COMP, r = 0.10, p = 0.05; TNC, r = 0.13, p = 0.03). No significant correlation was observed for COL4A1 (r = 0.03, p = 0.34). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Confirming previous results multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins (r = 0.15, p = 0.009). mRSS = 9.896 + 0.01719(COMP) - 0.006481(COL4A1) - 0.002318(TNC). Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p = 0.16), COL4A1 (p = 0.32), TNC (p = 0.15) and a lower composite biomarker score (p = 0.22) with increasing treatment duration in early dcSSc cases (Table 1). Conclusion Our results confirm this novel three-protein composite serum marker predicts skin severity in SSc better than each individual analyte. After further validation, this blood-based approach may help evaluate treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker. Disclosure E. Roblin: None. K.E.N. Clark: None. C. Beesley: None. V.H. Ong: None. C.P. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

Platelet-rich plasma for the treatment of scleroderma-associated ulcers: a single-center experience and literature review

Systemic sclerosis (SS) is a complex connective tissue disease characterized by vasculopathy and progressive fibrosis, primarily considered an autoimmune disorder. SS can affect multiple organs and tissues, including the skin, respiratory, gastrointestinal, genitourinary, cardiovascular, and musculoskeletal systems. Skin involvement is common, and SS-related ulcers, especially digital ulcers, occur in roughly 50% of patients. These ulcers not only cause pain but also significantly impact patients' quality of life, and in severe cases, they can lead to infection, gangrene, and amputation. The search for novel therapies for scleroderma-related ulcers remains an ongoing research area. Platelet-rich plasma (PRP) has been investigated as a potential treatment for difficult-to-heal ulcers, including diabetic, pressure, and vascular ulcers. In this study, we share our experience in treating scleroderma ulcers with PRP. Ten patients with confirmed SS and chronic skin ulcers lasting at least six weeks, which had not responded to conventional treatments, were selected for the study. Homologous PRP gel was prepared and applied once a week for up to eight weeks. The ulcers were documented photographically before and after PRP treatment, and pain levels were assessed using a visual analog scale (VAS). We also conducted a systematic review of the literature focusing on the use of PRP in the setting of SS. The results from our casuistry showed that the ten patients, including eight females and two males with a median age of 52.5 years, had ulcer sizes ranging from 0.78 cm2 to 28.26 cm2. The ulcers were located on fingers, legs, and heels, and they were associated with various forms of SS, including limited and diffuse cutaneous involvement. Raynaud's phenomenon was prevalent, and two patients exhibited organ involvement. The average ulcer size at the end of PRP treatment decreased significantly, with a 78% reduction in ulcered area. Pain levels also markedly improved, as indicated by a reduction in VAS scores. With regards to systematic revision of literature, we retrieved 45 cases of SS treated with PRP-based therapeutic regimes. However, only a minority of them (n=16) underwent PRP treatment for the treatment of SS-related ulcers. An improvement in wound size and pain has been documented in all cases. Taken together, these data highlight the potential benefits of using homologous PRP in the treatment of scleroderma ulcers, emphasizing its positive impact on ulcer size reduction and pain relief.

Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome.

To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance. We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electronic medical records. PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs. Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement.

ERASMUS SYNDROME: AN INTERFACE BETWEEN ENVIRONMENT AND AUTOIMMUNITY

Introduction: Erasmus Syndrome (ES) is a rare condition in which Systemic Sclerosis (SSc) is caused by exposure to silica. The term Erasmus Syndrome was coined after cases of SSc were found among gold miners in South Africa. In India, there is a paucity of such reported cases which might be more due to unawareness of the entity rather than low prevalence. Though the treatment remains the same, ES provides a template for the study of interactions between the environment and our immune system. Case: We present the case of a male patient diagnosed with systemic sclerosis, who was referred to the Rheumatology Clinic of our institution, and which on further evaluation revealed the cause as occupational silica exposure thus changing the diagnosis to ES. Conclusion: We conclude that ES represents an interaction of the environment and the human immune system, with the environment being the factor in the earlier and more severe progression of the disease. We also underline the importance of awareness of this entity among clinicians and of taking a proper history, especially the occupational history of any patient of SSc.

The Autoantibody Array Assay: A Novel Autoantibody Detection Method.

Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune collagen diseases. Specific autoantibodies are known to be involved in their pathogeneses, each presenting with a different clinical manifestation. Although immunoprecipitation is the gold standard method for detecting autoantibodies, it is difficult to perform in all cases owing to the use of radioisotopes. In this study, we developed a new detection method for SSc and DM autoantibodies (A-cube) using cell-free protein synthesis and examined its validity. Proteins were synthesized using wheat germ cell-free protein synthesis. A total of 100 cases of SSc, 50 cases of DM, and 82 healthy controls were examined. The validity of the method was examined by a comparison with existing test results. Anti-centromere antibody, anti-topoisomerase I antibody, anti-RNA polymerase III antibody, anti-U1RNP anti-body, anti-Jo-1 antibody, anti-TIF1γ antibody, anti-Mi-2 antibody, and anti-ARS antibody were tested for. The results suggested that A-cube is comparable with existing testing methods or has a high sensitivity or specificity. In addition, there was a case in which the diagnosis was reconsidered using the A-cube. The quality of the A-cube was ensured, and its usefulness for a comprehensive analysis was demonstrated. The A-cube can therefore contribute to the clinical assessment and treatment of SSc and DM.

A significant implication of intronic SNP (rs11246213) of IRF7 gene with disease susceptibility in Kashmiri (North-Indian) patients with Systemic Sclerosis

ObjectiveA study was undertaken to investigate whether the Interferon regulatory factor (IRF7) genomic region is involved in the pathogenesis of Systemic sclerosis (SSc). MethodsWe selected two single nucleotide polymorphisms (SNPs) of IRF7, namely rs11246213 which is an intronic variant, and rs1061501 located on the promoter for genotyping. Confirmed 100 cases were tested against 100 controls for IRF7 polymorphism study by Polymerase chain reaction-restriction length polymorphism method (PCR-RFLP) method. ResultsThe mean age of SSc patients were 36.87 ± 9.4 years; 90 females and 10 males (F:M 9:1); they were 52 (52 %) limited and 48 (48 %) diffuse subtypes. The distribution of SNP rs11246213 by genotypes (GG, AG, and AA) and by allele (G, A) was significantly different between the SSc and the control group (p ≤0.0001 for genotypes; p = 0.0002 for allele). A higher frequency of AG genotypes of rs11246213 (OR = 3.5; p < 0.0001) was observed in SSc cases than those in controls. Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs11246213 both were found higher in dc SSc than those of lc SSc subtype. Furthermore, the allele G frequency was associated with interstitial lung disease (OR = 5.21; p ≤0.001) and anti-topo I positivity (OR = 2.82; p = 0.005). However, the genotypic and allelic distribution of rs1061501 among the cases and controls was found to be non-significant. ConclusionA significant association of the IRF7 (rs11246213) variant allele with clinical variables may serve as a novel biomarker for the severity of SSc and hence bear important clinical implications.

Molecular typing of HLA-class II alleles reveals an association with autoantibodies and disease subsets of systemic sclerosis in a North Indian (Kashmir) population

To identify specific human leukocyte antigen (HLA)-Class II (DRB/DQB1/DPB1) alleles associated with systemic sclerosis (SSc) and to explore their relation with SSc autoantibodies, clinical manifestations, and disease subsets. HLA-class II alleles (DRB1/DRB3/DRB4/DRB5/DQB1) were determined by DNA typing in 80 SSc cases and 60 matched controls and HLA-DPB1 in 40 SSc patients and 30 controls by allele-specific-polymerase chain reaction with sequence-specific primers (PCR-SSP). The mean age of SSc patients was 36.9 ± 9.4 years; 76 females and 4 males (F:M 19:1) and a disease duration of 5.3 ± 3.3 years, they were 43(53.7%) limited and 37(46.2%) diffuse subtypes. SSc was significantly associated with DRB1*11, DRB1*01, DQB1*04, and DQB1*03*03 in a >4-fold manner, whereas DPB1*04 had a >7-fold increased risk compared to controls. There was a strong association between DRB1*11 (p = 0.04), DQB1*03*03 (p = 0.005), and DPB1*13 (p = 0.009) with anti-topoisomerase I (anti-topoI) whereas the frequency of DRB1*01 (p < 0.0001) was increased in patients with anti-centromere (ACA) positive SSc compared those negative (56% vs 25%; p < 0.0001). DRB1*03, DRB1*15, and DQB1*03*01 were SSc protective alleles in patients with positive ACA. Anti-topo I was associated with interstitial lung disease (ILD) (p < 0.01), whereas ACA with pulmonary arterial hypertension (PAH) (p = 0.01) and protection against ILD (p < 0.001). In addition, HLA-DRB1*03, DQB1*03*01and DPB1*03 were more frequent in patients with ILD than in patients without. Associations between specific HLA-class II alleles with certain SSc-specific autoantibodies (anti-topo I and ACA) were identified. Specific HLA associations with clinical and serological subtypes could serve as biomarkers of disease severity and progression in SSc.

OA30 Systemic sclerosis and cancer in the UK: an epidemiological analysis using the Clinical Practice Research Datalink

Abstract Background/Aims After cardiopulmonary disease, cancer accounts for the highest proportion of deaths in systemic sclerosis (SSc), exceeding deaths attributed to renal disease and/or infection. Few population-based studies have assessed the burden of cancer in SSc. The present study investigated the association between cancer and SSc using the Clinical Practice Research Datalink (CPRD). Methods A validated case ascertainment strategy using combinations of diagnostic Read codes was applied to identify SSc patients in the CPRD with &amp;gt;12 months of data within the time period 01/01/1998 to 31/12/2017. A cohort study design examined cancer occurrence following a diagnosis of SSc. Patients with SSc were matched to six non-SSc comparators by age, sex and GP practice using incident density sampling. Prevalent and incident cases of SSc were analysed separately. Information on date and type of diagnosis of cancer was recorded. Descriptive statistics and Cox analyses determined hazard ratios for cancer occurrence. Results From 10.1 million individuals in the CPRD, 1,588 of cases of SSc were identified (85.3% female). We identified 206 cancers that occurred following a diagnosis of SSc (116 in prevalent cohort and 90 amongst incident cohort) (Table). The three commonest cancers were mucocutaneous (4.5%), lung (2.1%) and breast (1.9%). Lung cancer was significantly more common in SSc (Table). Incidence of cancer was higher in SSc (17 vs. 13.8 per 1000 person years) with adjusted hazard ratios of 1.41 (95% CI 1.14-1.75) for prevalent cases and 1.32 (95% CI 1.04-1.67) for incident SSc cases. We did not identify a strong relationship between cancer occurrence and SSc onset. Incidence of cancer increased with age at SSc diagnosis and was higher in males. Death from any cause at 6 months was higher in patients with SSc and cancer. Conclusion We have identified an increased risk of cancer occurrence (primarily mucocutaneous and lung) in patients with SSc from the UK, particularly amongst males and patients with higher age at SSc diagnosis. These findings could support screening recommendations for cancer in SSc. Disclosure J.D. Pauling: Consultancies; Astra Zenaca, Janssen, Permeatus Inc., Sojournix Pharma, Boehringer Ingelheim. Honoraria; Janssen. Member of speakers’ bureau; Janssen. J. Snowball: None. N. McHugh: None. A. McGrogan: None.

Incidence and prevalence of systemic sclerosis in Thailand in year 2017-2020: a database from the Ministry of Public Health.

A better understanding of the epidemiological profile of systemic sclerosis (SSc) in Thais could improve care, human resource deployment, and public health budgeting. We aimed to determine the incidence and prevalence of SSc in Thailand between 2017 and 2020. A descriptive epidemiological study was performed using the Information and Communication Technology Center, Ministry of Public Health database, comprising all types of healthcare providers during the study period. Demographic data of patients having a primary diagnosis of M34 systemic sclerosis and over 18 years of age between 2017 and 2020 were reviewed. The incidence and prevalence of SSc were calculated as well as their respective 95% confidence intervals (CIs). The number of SSc cases in 2017 was 15,920 from a total Thai population of 65,204,797. The prevalence of SSc in 2017 was 24.4 per 100,000 populations (95% CI 24.0-24.8). The prevalence of SSc among women was 2 times greater than among men (32.7 vs. 15.8 per 100,000). The incidence of SSc was stable from 2018 to 2019 but dropped slightly in 2020 (7.2, 7.6, and 6.8 per 100,000 person-years, respectively). Most SSc cases were in northeastern Thailand (11.6, 12.1, and 11.1 per 100,000 person-years from 2018 to 2020, respectively) and the peak was between 60 and 69 years of age (24.6, 23.8, and 20.9 per 100,000 person-years from 2018 to 2020, respectively). SSc is a rare disease among Thais. The disease was commonly revealed in late middle-aged women with a peak at age 60-69 years, mainly from the northeast regions. The incidence remained stable during the study period, albeit during the emergence of the coronavirus pandemic a slight decline was recorded. Key Points • The incidence and prevalenceof systemic sclerosis (SSc) vary across ethnic populations. • There is a lack of epidemiology research of SSc since the 2013 ACR/EULAR Classification Criteria for Scleroderma was adopted among Thais included Asia-Pacific population as the population has some different clinical features than those reported among Caucasians. • SSc is a rare connective disease among Thaisand commonly presents in late middle-aged group of both genders,mainly in Thailand's northern and northeastern regions. • When compare to the epidemiology of SSc in Asia-Pacific, the prevalence of SSc in Thais was higher than among East Asians and the Indian population and the incidence of SSc among Thais was greater than the other Asia-Pacific population including Australian.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

Identification and validation of key immune-related genes with promising diagnostic and predictive value in systemic sclerosis

AimsTo screen and confirm key immune-related genes (IRGs) with diagnostic and predictive value in systemic sclerosis (SSc) and provide potential therapeutic targets for patients with SSc. Materials and methodsIn Gene Expression Omnibus database (GEO), four datasets of gene expression profiling related to SSc were downloaded and used for the analysis in this study. After differential analysis of SSc cases and controls in GSE130955, the differentially expressed genes (DEGs) were overlapped with IRGs to obtain the immune-related differentially expressed genes (IR-DEGs) in SSc. In addition, functional annotation and pathway enrichment of IR-DEGs were conducted. The protein-protein interaction network (PPI) was constructed to identify key IR-DEGs. Using GSE58095, GSE181549 and GSE130953, the diagnostic and predictive abilities for the key IR-DEGs in SSc were validated. Finally, the screened key genes were confirmed in skin derived bleomycin (BLM)-induced SSc mice by Real-time PCR. Key findingsNGFR, TNFSF13B, FCER1G, GIMAP5, TYROBP and CSF1R may have important or very high diagnostic value for SSc. TYROBP and TNFSF13B had moderate and mild predictive value respectively in SSc patients after treatment. Real-time PCR assay further confirmed that the expressions of Ngfr, Tyrobp, Csf1r, Fcer1g and Gimap5 were significantly higher in skin of BLM-induced SSc mice than that in controls. SignificanceThe key IR-DEGs, including NGFR, TNFSF13B, TYROBP, CSF1R, FCER1G and GIMAP5, may become auxiliary diagnostic indicators and potential biomarkers for SSc. Moreover, TNFSF13B and TYROBP could have good prospects as predictive indicators in SSc patients that accepted cyclophosphamide or transplantation therapy.

Damage Trajectories in Systemic Sclerosis Using Group-Based Trajectory Modeling.

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive organ damage, which can be measured using the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). We aimed to identify whether distinct trajectories of damage accrual exist and to determine which variables are associated with different trajectory groups. Incident cases of SSc (<2 years) were identified in the Australian Scleroderma Interest Group and Canadian Scleroderma Research Group prospective registries. Group-based trajectory modeling was used to identify SCTC-DI trajectories over the cohort's first 5 annual visits. Baseline variables associated with trajectory membership in a univariate analysis were examined in multivariable models. A total of 410 patients were included. Three trajectory groups were identified: low (54.6%), medium (36.2%), and high (10.3%) damage. Patients with faster damage accrual had higher baseline SCTC-DI scores. Older age (odds ratio [OR] 1.57 [95% confidence interval (95% CI) 1.18-2.10]), male sex (OR 2.55 [95% CI 1.10-5.88]), diffuse disease (OR 6.7 [95% CI 2.57-17.48]), tendon friction rubs (OR 5.4 [95% CI 1.86-15.66]), and elevated C-reactive protein level (OR 1.98 [95% CI 1.49-2.63]) increased the odds of being in the high-damage group versus the reference (low damage), whereas White ethnicity (OR 0.31 [95% CI 0.12-0.75]) and anticentromere antibodies (OR 0.24 [95% CI 0.07-0.77]) decreased the odds. We identified 3 trajectories of damage accrual in a combined incident SSc cohort. Several characteristics increased the odds of belonging to worse trajectories. These findings may be helpful in recognizing patients in whom early aggressive treatment is necessary.

Review of systemic sclerosis and antineutrophil cytoplasmic antibody vasculitis overlap: Using autoantibodies for a personalised medicine approach.

Both antineutrophil cytoplasmic antibody-associated vasculitis and systemic sclerosis are rare autoimmune diseases. Both have the potential for significant multi-organ involvement, and both carry high morbidity and mortality. Disease-specific autoantibodies in these conditions allow for risk stratification for organ-based complications, and for personalised therapeutic strategies. The concomitant presentation of antineutrophil cytoplasmic antibody-associated vasculitis and systemic sclerosis is rare, and only reported in up to 1.3% of systemic sclerosis cases. These patients present more frequently with anti-myeloperoxidase and anti-topoisomerase antibody profiles, with increased incidence of interstitial lung disease and renal involvement than would be expected in either disease independently. Appreciating the role of the autoantibodies in each disease state, and where they overlap, allows for the potential of a more personalised approach to managing these complex patients.

Development of severe fingertip ulcers, pulmonary hypertension, and scleroderma renal crisis in a patient with systemic sclerosis and anti‐PL12 antibodies

A 50-year-old Japanese woman with limited cutaneous-type SSc presented with severe gangrene in the fingertips of the hands and hypertension, tested positive for anti-PL-12 antibodies. She was diagnosed with acute heart failure owing to scleroderma renal crisis and pulmonary arterial hypertension. Therapeutic agents for pulmonary arterial hypertension were also effective for the digital gangrene. A 50-year-old Japanese woman received prednisolone treatment (2.5 mg/2 days) for systemic sclerosis (SSc) and interstitial pneumonia for approximately 15 years. She suddenly developed severe pain, cold sensation, and digital cyanosis and was treated with intravenous alprostadil (10 μg/day). Two days later, she presented with acute exacerbations of hepatic (aspartate aminotransferase, 4400 IU/L; alanine aminotransferase, 1997 IU/L), renal (creatinine, 2.14 mg/dl), and respiratory (blood oxygen saturation, 77% on room air) functions. Upon admission to the hospital, she presented with increased blood pressure (160/80 mmHg), and within a week developed severe gangrene in the second-to-fifth fingertips of the right hand and the second and fourth fingertips of the left hand (Figure 1A). A modified Rodnan skin score of 2, Raynaud's phenomenon, and nailfold bleeding were observed. Scleroderma was noted only in the extremities and was confirmed by histopathological examination of the forearm lesions. The patient tested positive for anti-nuclear (40×, cytoplasmic), aminoacyl-tRNA synthetase (ARS, 170 index), and PL-12 antibodies,1 but tested negative for anti-topoisomerase 1, centromere, RNA polymerase III, ribonucleoprotein, cardiolipin, anti-cardiolipin β2-glycoprotein I complex, lupus anticoagulant, and myeloperoxidase antineutrophil cytoplasmic antibodies. The findings from lung perfusion scintigraphy were normal. Computed tomography showed mild interstitial pneumonia. The trans-tricuspid pressure gradient (assessed by echocardiography), mean pulmonary arterial pressure, and levels of N-terminal prohormone of brain natriuretic peptide all showed marked elevation to 65 mmHg (normal, <35 mmHg), 50 mmHg (<25 mmHg), and 62,991 pg/ml, respectively. The patient was diagnosed with limited cutaneous-type SSc with anti-PL12 antibodies, acute heart failure, and congestive liver failure, owing to scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH). The cardiac, renal, and hepatic functions of the patient improved after 5 days of treatment with continuous hemodiafiltration and a combination of an angiotensin-converting enzyme inhibitor and a Ca-channel antagonist. Endothelin receptor antagonist, phosphodiesterase-type 5 inhibitor, and selective prostacyclin receptor agonist were systemically administered (Figure 1B), and absolute ethanol and a sucrose povidone-iodine ointment were topically applied on the gangrenous fingertips. Seven months later, re-epithelialization in the fingertips was observed (Figure 1C). Anti-synthetase syndrome is often associated with the development of specific clinical symptoms, such as Raynaud's phenomenon, mechanic's hands, polyarthritis, interstitial pneumonia, and myositis.2 Anti-ARS antibodies, including anti-PL12 antibodies, are typically specific to polymyositis/dermatomyositis. The frequency of SSc in patients positive for anti-ARS antibodies is relatively low (3.6%).2 A few cases of SSc with anti-PL12 antibodies have been reported. However, there are no reported cases of this condition with digital gangrene, PAH, and SRC. Generally, SRC or PAH develops in SSc patients with anti-RNA polymerase III or anti-centromere antibodies, respectively.3, 4 Therapeutic agents for PAH are often effective for the concurrent treatment of digital ulcers and gangrene in patients with SSc.5 In this case, we prevented the progression of gangrene and achieved cure through a combination treatment with multiple anti-PAH agents. This approach may be useful for the treatment of patients with SSc who develop refractory digital ulcers and/or gangrene. Approval of the research protocol: N/A. Informed consent: Acquired. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. The authors declare no conflicts of interest.

Understanding the value of non-specific abnormal capillary dilations in presence of Raynaud’s phenomenon: a detailed capillaroscopic analysis

BackgroundNailfold videocapillaroscopy (NVC) non-specific abnormalities may be present in subjects with isolated Raynaud’s phenomenon (RP) before the potential transition to systemic sclerosis (SSc) specific microvascular alterations (‘scleroderma pattern’). This study...

Kidney transplantation in systemic sclerosis: Advances in graft, disease, and patient outcome.

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by vascular abnormalities, tissue fibrosis, and inflammation. Renal disease occurring in patients with SSc may have a variable clinicopathological picture. However, the most specific renal condition associated with this disease is the scleroderma renal crisis (SRC), characterized by acute onset of renal failure and severe hypertension. SRC develops in about 20% of cases of SSc, especially in those patients with diffuse cutaneous disease. The prognosis of this condition is often negative, with a rapid progression to end-stage renal disease (ESRD). The advent of the antihypertensive angiotensin-converting enzyme inhibitors in 1980 was associated with a significant improvement in patients’ survival and recovery of renal function. However, the prognosis of these patients can still be improved. The dialytic condition is associated with early death, and mortality is significantly higher than among patients undergoing renal replacement therapy (RRT) due to other conditions. Patients with SRC who show no signs of renal functional recovery despite timely blood pressure control are candidates for kidney transplantation (KT). In this review, we reported the most recent advances in KT in patients with ESRD due to SSc, with a particular overview of the risk of disease recurrence after transplantation and the evolution of other disease manifestations.