Prognostic Value of Echocardiographic Coupling Metrics in Systemic Sclerosis-Associated Pulmonary Vascular Disease.

BACKGROUND: Ineffective right ventricular (RV) adaptation to increasing pulmonary arterial (PA) afterload in pulmonary vascular disease (PVD) significantly contributes to morbidity and mortality. PVD in systemic sclerosis (SSc) arises through various mechanisms, yet detecting abnormal contractile response remains challenging. Here, we examine whether echocardiographic RV-PA coupling metrics correlate with invasive pressure-volume (PV) loops, enhancing the prediction of adverse clinical outcomes in SSc-PVD patients. METHODS: Prospectively enrolled patients with SSc-PVD with paired echocardiogram and PV loops were included. Linear regression and receiver-operating curve (ROC) analysis were used to assess the relationship between tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP), fractional area change (FAC)/PASP, tissue Doppler velocity (TDI S')/PASP, RV free wall strain (RVFWS)/PASP and coupling thresholds defined by end-systolic to end-arterial elastance (Ees/Ea), obtained by the multi-beat method. The contribution of right atrial strain (RAS) to RV-PA coupling parameters was also investigated. Kaplan-Meier analysis was used to identify the relationship between coupling ratios and composite outcomes including clinical worsening, lung transplant, and death. RESULTS: 42 patients with SSc were studied with mean age 59 ± 12 years, 91% female and varying degrees of PVD: mPAP 29.5 ± 12.8 mmHg, PVR 4.7 ± 4.2 WU, PCWP 10.3 ± 4.1 mmHg. Echocardiographic coupling metrics including TAPSE/PASP, FAC/PASP, TDI S'/PASP, RVFWSglobal and RVFWSbasal/PASP, and RASreservoir/PASP were linearly associated with Ees/Ea. At cut-points obtained through ROC analysis, all ratios were predictive of RV-PA uncoupling, defined by Ees/Ea, and composite outcomes. Additionally, RASreservoir/RVFWS correlated with Ees/Ea even after adjustment for PASP, suggesting that diminished RAS further impacts RV performance and coupling. CONCLUSION: Echocardiographic RV-PA coupling ratios strongly correlate with invasive Ees/Ea and predict adverse clinical outcomes in SSc patients across the spectrum of PVD. Further, we demonstrate how RAS impacts RV performance. These findings may refine risk stratification and prognostication in this at-risk cohort.

Demographics and Clinical Features Associated with Abnormal Small Bowel Motility in Systemic Sclerosis.

OBJECTIVE: The small bowel is affected in up to 50% of systemic sclerosis (SSc) patients, and some patients experience severe complications. Our aim was to use specific statistical methods to compare demographic and clinical features of SSc patients with and without abnormal small bowel to better characterize patients at risk for this complication. METHODS: SSc patients with gastrointestinal symptoms were prospectively enrolled and underwent a scintigraphy-based whole gut transit (WGT) study. A cross-sectional analysis was performed comparing clinical features between patients with and without abnormal small bowel transit by WGT. Univariate logistic regression models and multivariable models were used to examine the relationship between clinical features and abnormal small bowel transit. RESULTS: Of 130 patients enrolled in this study, 22 had abnormal small bowel transit. SSc patients with abnormal small bowel transit were more likely to be male [Odds Ratio(OR)=3.70, Confidence Interval(CI) 1.07-12.50, p= 0.038], and have more severe cardiac involvement (OR = 3.98, CI 1.10-14.38, p= 0.035), while they were less likely to have sicca symptoms (OR = 0.30, CI 0.10-0.94, p= 0.039). In multivariable analyses, sicca symptoms (OR = 0.28, CI 0.08-0.96, p= 0.043) remained negatively associated with abnormal small bowel transit. Additionally, SSc patients with abnormal small bowel transit had higher mortality than patients with normal small bowel transit [Hazard ratio(HR)=4.57, CI 1.58-13.24, p= 0.005]. CONCLUSIONS: These findings suggest that patients with abnormal small bowel transit in SSc are more likely to be male, have more severe cardiac involvement, higher mortality, and less sicca symptoms. Recognizing this patient subgroup is essential for risk stratification and optimizing clinical care.

Color changes in the feet: a sign of autonomic symptoms in systemic sclerosis.

OBJECTIVES: Patients with autonomic dysfunction, or dysautonomia, often report discoloration of their dependent extremities, which is thought to be from venous pooling or acrocyanosis. A subset of patients with systemic sclerosis (SSc) are affected by dysautonomia but may be challenging to identify. We sought to determine whether patients with SSc who report discoloration in their feet have a higher burden of autonomic symptoms, including orthostatic, gastrointestinal (GI), urinary, secretomotor, and pupillomotor. METHODS: 167 patients with SSc completed the COMPASS-31 survey, which queries whether the patient experiences discoloration of the feet or hands. We compared the COMPASS-31 subdomain scores between SSc patients with and without foot discoloration. 79 patients with postural orthostatic tachycardia syndrome (POTS) also completed the COMPASS-31 questionnaire for comparison. RESULTS: We found that extremity discoloration is common in POTS and more often affects the feet, whereas in SSc the hands are more frequently involved. 62% of SSc patients report colour changes in their feet. These patients are more likely to have other autonomic symptoms, including orthostatic (11.7 ± 10.6 vs 8.6 ± 9.9, p= 0.06), GI (11.3 ± 4.3 vs 8.8 ± 4.3, p= 0.0003), urinary (1.4 ± 1.5 vs 0.8 ± 1.3, p= 0.002) and secretomotor (7.0 ± 3.8 vs 5.9 ± 3.8, p= 0.06) symptoms. These associations persist in a multivariable model after adjusting for potential confounders. CONCLUSION: Dependent extremity discoloration is common in dysautonomia. Patients with SSc who report colour changes in their feet are more likely to report other symptoms of autonomic dysfunction.

Causal inference using multivariate generalized linear mixed-effects models.

Dynamic prediction of causal effects under different treatment regimens is an essential problem in precision medicine. It is challenging because the actual mechanisms of treatment assignment and effects are unknown in observational studies. We propose a multivariate generalized linear mixed-effects model and a Bayesian g-computation algorithm to calculate the posterior distribution of subgroup-specific intervention benefits of dynamic treatment regimes. Unmeasured time-invariant factors are included as subject-specific random effects in the assumed joint distribution of outcomes, time-varying confounders, and treatment assignments. We identify a sequential ignorability assumption conditional on treatment assignment heterogeneity, that is, analogous to balancing the latent treatment preference due to unmeasured time-invariant factors. We present a simulation study to assess the proposed method's performance. The method is applied to observational clinical data to investigate the efficacy of continuously using mycophenolate in different subgroups of scleroderma patients.

Racial variability in immune responses only partially explains differential systemic sclerosis disease severity.

OBJECTIVE: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients. METHODS: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared. RESULTS: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%. CONCLUSIONS: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups.

The Impact of Radiation Therapy in Patients with Systemic Sclerosis and Head and Neck Cancer.

OBJECTIVE: Systemic sclerosis (SSc) is considered a relative, or in some cases, absolute contraindication for radiation therapy for various cancers; however, radiation is the standard of care and the best option for tumor control for locally advanced head and neck (H&N) cancer. We present a case series to document postradiation outcomes in patients with SSc and H&N cancer. METHODS: Patients with SSc and H&N cancer treated with radiation were identified from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center research registries. Through chart review, we identified whether patients developed predetermined acute and late side effects or changes in SSc activity from radiation. We further describe therapies used to prevent and treat radiation-induced fibrosis. RESULTS: Thirteen patients with SSc who received radiation therapy for H&N cancer were included. Five-year survival was 54%. Nine patients (69%) developed local radiation-induced skin thickening, and 7 (54%) developed reduced neck range of motion. Two patients required long-term percutaneous endoscopic gastrostomy use due to radiation therapy complications. No patients required respiratory support related to radiation therapy. Regarding SSc disease activity among the patients with established SSc before radiation therapy, none experienced interstitial lung disease progression in the postradiation period. After radiation, one patient had worsening skin disease outside the radiation field; however, this patient was within the first year of SSc, when progressive skin disease is expected. Treatment strategies to prevent radiation fibrosis included pentoxifylline, amifostine, and vitamin E, while intravenous immunoglobulin (IVIG) was used to treat it. CONCLUSION: Although some patients with SSc who received radiation for H&N cancer developed localized skin thickening and reduced neck range of motion, systemic flares of SSc were uncommon. This observational study provides evidence to support the use of radiation therapy for H&N cancer in patients with SSc when radiation is the best treatment option.

Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis.

OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. METHODS: Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. RESULTS: Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. CONCLUSION: In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Aberrant long-chain fatty acid metabolism associated with evolving systemic sclerosis-associated pulmonary arterial hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial.

BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.

Xist ribonucleoproteins promote female sex-biased autoimmunity.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course.

OBJECTIVES: We examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification. METHODS: Scleroderma cancer cases and scleroderma controls without cancer from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center were studied. Sera were assayed by Lineblot and enzyme-linked immunosorbent assay (ELISA) for autoantibodies against centromere, topoisomerase 1, RNA polymerase (POLR) 3, PM/Scl, Th/To, NOR90, U3 RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer-associated scleroderma (cancer occurring three years before and after scleroderma onset). The effects of having more than one autoantibody on cancer were further examined using random forest analysis. RESULTS: A total of 676 cases and 687 controls were studied. After adjusting for relevant covariates, anti-POLR3 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.03-2.11) and monospecific anti-Ro52 (OR 2.19, 95% CI 1.29-3.74) were associated with an increased overall cancer risk, whereas anticentromere (OR 0.69, 95% CI 0.51-0.93) and anti-U1RNP (OR 0.63, 95% CI 0.43-0.93) were associated with lower risk. When examining risk of cancer-associated scleroderma, these immune responses remained associated with increased or decreased risk: anti-POLR3 (OR 2.28, 95% CI 1.33-3.91), monospecific anti-Ro52 (OR 2.58, 95% CI 1.05-6.30), anticentromere (OR 0.39, 95% CI 0.20-0.74), and anti-U1RNP (OR 0.32, 95% CI 0.11-0.93). Anti-Ro52 plus anti-U1RNP or anti-Th/To was associated with decreased cancer risk compared with anti-Ro52 alone. CONCLUSIONS: These data suggest that five distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify the risk of cancer for scleroderma patients. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted.

Improved lung cancer clinical outcomes in patients with autoimmune rheumatic diseases.

PURPOSE: Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD. METHODS: This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients' history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes. RESULTS: ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p<0.05). Patients with ARD were more likely to be diagnosed with stage 1 lung cancer (36.8% vs 26.9%, p<0.001) and with smaller tumour size (OR: 0.76, p=0.01), controlling for sex, race and histology. Notably, lung cancer patients with ARD had a significantly prolonged median overall survival (OS) (7.11 years vs 1.7 years, p<0.001), independent of stage. CONCLUSION: Patients with ARD and lung cancer had better OS compared with their counterparts, independent of cancer stage and treatments and were less likely to have advanced stage lung cancer at diagnosis. Additional studies are needed to investigate the differential immunological anti-tumour immune activity and genomic variations in patients with and without ARD.

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Baseline predictors of disease severity in immune checkpoint inhibitor-induced inflammatory arthritis.

OBJECTIVES: To determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). METHODS: Participants were adults with rheumatologist diagnosed ICI-IA. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of IA > 6 months after ICI cessation and requirement of corticosteroids. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. RESULTS: 126 patients with ICI-IA were included; 53 patients (42%) required a csDMARD/bDMARD. In univariate logistic regressions, higher CDAI, tenosynovitis, longer symptom duration before first rheumatology visit, and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; there was a trend toward those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration, and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4/PD-1 therapy and steroid use at baseline were associated with a higher risk of persistent IA. CONCLUSION: Higher levels of disease activity, tenosynovitis, and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-IA, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial steroid dose, earlier rheumatology referral, and adoption of immunosuppression beyond steroids to improve outcomes.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

Construct validity and reliability of the assessment of systemic sclerosis-associated raynaud's phenomenon (ASRAP) questionnaire.

OBJECTIVES: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic sclerosis-associated RAynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1-week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. RESULTS: Four hundred and twenty SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, p< 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, p< 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, p< 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (p< 0.05 for all comparisons). There was excellent repeatability at 1-week amongst patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, p< 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77 respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53-7.81, p= 0.029) was estimated. CONCLUSION: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

Preventative Care in Scleroderma: What Is the Best Approach to Vaccination?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. There are multiple complications inherent to SSc and its management. One of these complications is increased infection risk, which can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have lower vaccination rates and decreased vaccine seroconversion secondary to immunosuppressive medications compared with the general population. The purpose of this review is to provide clinicians with an approach to vaccinations in SSc.

Preventative Care in Scleroderma: What Is the Best Approach to Bone Health and Cancer Screening?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. Lesser known complications inherent to SSc, such as malignancies and osteoporosis, can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have a greater risk of developing malignancies than the general population. In addition, they are more likely to be vitamin D deficient and are at great risk of osteoporosis-related fractures. However, these complications can be addressed through preventative measures. The purpose of this review is to provide clinicians with an approach to bone health and cancer screening in SSc.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.