Occupation as a gendered-role and outcome in systemic sclerosis.

Objective: Sex and gender are of growing scientific interest in disease onset and course. While sex differences have been shown to exist in systemic sclerosis, there is a paucity of data on gender. Our objective was to examine the association between occupation, a gender-related role and outcomes in systemic sclerosis. Methods: An occupation score ranging from 0 to 100, with lower scores representing occupations traditionally held by men and higher scores traditionally held by women, was constructed using the National Occupational Classification 2016 and data from Statistics Canada. Subjects in the Canadian Scleroderma Research Group registry were assigned an occupation score based on self-reported occupation. Multivariate models, adjusted for sex, age, smoking and education were used to estimate the independent effect of occupation score on systemic sclerosis outcomes. Results: We included 1104 subjects, of which 961 were females (87%) and 143 (13%) males. There were differences between females versus males: disease duration (9.9 vs 7.6 years, p = 0.002), diffuse disease (35% vs 54%, p < 0.001), interstitial lung disease (28% vs 37%, p = 0.021) and pulmonary hypertension (10% vs 4%, p = 0.033), but not pain, response to treatment and mortality. The median occupation scores differed between females and males (84.3 (interquartile range 56.8, 89.4) vs 24.9 (4.3, 54.1), p < 0.001). The Spearman correlation between sex and occupation score was 0.44, indicating a weak correlation. In adjusted analyses, occupation score was not an independent predictor of disease subset (diffuse vs limited), interstitial lung disease, pulmonary hypertension, pain, response to treatment or mortality. Conclusion: We did not find independent associations between an occupation score, a gender-related role and outcomes in systemic sclerosis. These results should be interpreted with caution as occupation may be a poor measure of gender. Future research using a validated measure of gender will be needed to generate robust data on the effect of gender in systemic sclerosis.

Prediction of damage trajectories in systemic sclerosis using group-based trajectory modelling.

OBJECTIVES: Damage accrual in SSc can be tracked using the Scleroderma Clinical Trials Consortium Damage Index (DI). Our goal was to develop a prediction model for damage accrual in SSc patients with early disease. METHODS: Using patients with <2 years disease duration from Canada and Australia as a derivation cohort, and from the Netherlands as a validation cohort, we used group-based trajectory modelling (GBTM) to determine 'good' and 'bad' latent damage trajectories. We developed a prediction model from this analysis and applied it to patients from derivation and validation cohorts. We plotted the actual DI trajectories of the patients predicted to be in 'good' or 'bad' groups. RESULTS: We found that the actual trajectories of damage accumulation for lcSSc and dcSSc were very different, so we studied each subset separately. GBTM found two distinct trajectories in lcSSc and three in dcSSc. We collapsed the two worse trajectories in the dcSSc into one group and developed a prediction model for inclusion in either 'good' or 'bad' trajectories. The performance of models using only baseline DI and sex was excellent with ROC AUC of 0.9313 for lcSSc and 0.9027 for dcSSc. Using this model, we determined whether patients would fall into 'good' or 'bad' trajectory groups and then plotted their actual trajectories which showed clear differences between the predicted 'good' and 'bad' cases in both derivation and validation cohorts. CONCLUSIONS: A simple model using only cutaneous subset, baseline DI and sex can predict damage accumulation in early SSc.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

NT-proBNP, hs-cTnT, and CRP predict the risk of cardiopulmonary outcomes in systemic sclerosis: Findings from the Canadian Scleroderma Research Group.

Objective: The aim of this study was to determine the independent value of N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein to predict onset of cardiopulmonary disease in a large, multi-center systemic sclerosis cohort followed prospectively. Methods: Subjects from the Canadian Scleroderma Research Group registry with data on N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were identified. Outcomes of interest were death, systolic dysfunction (left ventricular ejection fraction < 50% or medications for heart failure), pulmonary arterial hypertension by right heart catheterization, pulmonary hypertension by cardiac echocardiography (systolic pulmonary artery pressures ⩾ 45 mmHg), arrhythmias (pacemaker/implantable cardiac defibrillator or anti-arrhythmic medications), and interstitial lung disease. Multivariate Cox proportional hazard models were generated for each outcome. Results: A total of 675 subjects were included with a mean follow-up of 3.0 ± 1.8 years. Subjects were predominantly women (88.4%) with mean age of 58.2 ± 11.3 years and mean disease duration of 13.7 ± 9.1 years. One hundred and one (101, 15%) subjects died during follow-up, 37 (6.4 %) developed systolic dysfunction, 18 (2.9%) arrhythmias, 34 (5.1%) pulmonary arterial hypertension, 43 (7.3%) pulmonary hypertension, and 48 (12.3%) interstitial lung disease. In multivariate analyses, elevated levels of N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were associated with increased risk of death, while elevated levels of N-terminal pro b-type natriuretic peptide and C-reactive protein were associated with increased risk of developing pulmonary hypertension. Conclusion: In systemic sclerosis, N-terminal pro b-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein have independent predictive value for death and pulmonary hypertension. A larger study would be required to determine the predictive value of these biomarkers for less common systemic sclerosis outcomes.

Associations between the Composite Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS), survival and other disease measures.

OBJECTIVE: Diffuse cutaneous systemic sclerosis (dcSSc) is a multifaceted disease for which the Composite Response Index in dcSSc (CRISS) was developed as a global outcome measure. We aimed to further validate the CRISS by examining its association with other disease measures, patient reported quality of life (QoL), and mortality. METHODS: DcSSc patients with ≤5 year disease duration were recruited from multinational registries. CRISS improvers (score ≥0.6) and non-improvers (score <0.6) were identified after one year. Median changes in European Scleroderma Group Activity Index (EScSG-AI), Medsger Disease Severity Scale (DSS), Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), and Short Form 36 physical component score (SF-36 PCS) after one year was compared between CRISS groups. Kaplan Meier and adjusted Cox analyses compared SCTC-DI damage accrual and mortality between CRISS groups. RESULTS: Of 212 patients, 68 (32.1%) were CRISS improvers. CRISS improvers had improved median EScSG-AI (-1.1 points [IQR -2.6, -0.3] vs. 0 [-1.1, 1.0], p<0.001), DSS (-1 [-3, 1] vs. 0 [-2, 2], p = 0.015), and SF-36 PCS (+3.6 [-1.0, 8.9] vs. -0.3 [-5.9, 4.5], p<0.001) compared to non-improvers. CRISS improvers were less likely to accumulate damage on the SCTC-DI (hazard ratio [95% confidence interval] 0.68 [0.47, 0.96]) adjusting for age, sex, disease duration, and immunosuppression use. CRISS improvers had a trend towards better survival. CONCLUSION: CRISS improvers had more favourable changes in measures of disease activity, disease severity, and QoL compared to non-improvers. These findings support the construct validity of a CRISS outcome after one year in early dcSSc.

Influenza Vaccine Hesitancy and Its Determinants Among Rheumatology Patients.

OBJECTIVE: Patients with rheumatic disease (RD) have an increased risk of influenza and its complications. Despite inactivated influenza vaccine (IIV) recommendations, IIV uptake in patients with RD is suboptimal, a problem of increasing importance in the COVID-19 era. We estimated the frequency of IIV hesitancy and associated factors among Canadian patients with RD. METHODS: A cross-sectional vaccine hesitancy survey was completed by rheumatology clinic patients (November 2019 to January 2020). Patients rated their likelihood of receiving the influenza vaccine (scale of 0-10). We categorized these as follows: likely to refuse (scale of 0-2), uncertain (scale of 3-7), or likely to accept (scale of 8-10). Multivariate logistical regression was used to evaluate factors associated with vaccine hesitancy. RESULTS: A total of 282 patients (63.5% of those approached) completed the survey, with 165 (58.5%) being likely to accept, 67 (23.8%) being likely to refuse, and 50 (17.7%) uncertain. Uncertain patients were younger and more likely to be employed than those in the other two groups. No previous influenza vaccination (odds ratio [OR] 36.6, 95% confidence interval [CI] 5.3-252.9), belief that vaccination should not be mandatory (OR 0.1, 95% CI 0.0-0.7), unwillingness to take time off work to be vaccinated (OR 6.8, 95% CI 1.5-30.6), and distrust in pharmaceutical companies (OR 41.0, 95% CI 5.6-301.5) predicted likeliness to refuse. Reluctance to pay for vaccination (OR 2.8, 95% CI 1.1-7.5) and no previous influenza vaccination (OR 18.9, 95% CI 3.3-109.7) predicted uncertainty. CONCLUSION: More than 40% of rheumatology patients are either likely to refuse or uncertain about receiving IIV. This contributes to suboptimal vaccine coverage in this population. Interventions addressing these concerns are needed, particularly in the COVID-19 era.

Association between autoantibodies in systemic sclerosis and cancer in a national registry.

OBJECTIVE: A close temporal relationship between SSc onset and cancer has been reported in anti-RNA polymerase III-positive patients. We investigated the association between cancer and other SSc autoantibodies in a national SSc registry. METHODS: SSc patients enrolled in the Canadian Scleroderma Research Group registry from 2004 to 2019 were characterized according to autoantibodies to centromere, topoisomerase I/Scl70, RNA polymerase III, fibrillarin, Th/To (hPOP1), PM/Scl, Ku, NOR90, Ro52/TRIM21 and U1RNP. Logistic regression was used to examine the association between a close cancer-SSc interval and autoantibody status, adjusted for age, sex, race and smoking history. RESULTS: Of 1698 SSc patients, 1481 (87%) had available autoantibody data. Cancer was diagnosed within 2, 3 and 5 years of the first non-Raynaud manifestation in 1.3%, 2.1% and 3.5% of patients. The most frequent cancers diagnosed within 2 years were breast (33%), gynaecological (19%) and haematological (14%) cancers. The risk of cancer within 2 years was increased among anti-topoisomerase I [odds ratio (OR) 3.43, 95% CI: 1.04, 10.05] and anti-U1-RNP-positive patients (OR 5.54, 95% CI: 1.16, 20.40), but not with anti-RNA polymerase III. None of the anti-fibrillarin, Th/To, PM/Scl, Ku and NOR90-positive patients had cancer within 2 years. Patients with anti-centromere or none of the tested autoantibodies had numerically lower risks of developing cancer within two years. CONCLUSION: Synchronous cancer was rare in this large cohort of predominantly female and White SSc patients. The risk of cancer within 2 years was increased among anti-topoisomerase I and anti-U1-RNP-positive patients. Screening strategies guided by autoantibodies require further careful consideration.

Agreement Between Physician Evaluation and the Composite Response Index in Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: Diffuse cutaneous systemic sclerosis (SSc) is a highly heterogeneous disease. A provisionally approved Composite Response Index in diffuse cutaneous SSc (CRISS) was developed as a 1-year outcome measure for clinical trials. Our goal was to further validate the CRISS by examining agreement between CRISS definitions for improved/non-improved with physicians' evaluation of disease. METHODS: Patient profiles from a large observational cohort were created for 50 random diffuse cutaneous SSc patients of <5 years disease duration with improved CRISS scores after 1 year and 50 with non-improved CRISS scores. Profiles described disease features used during the initial CRISS development at baseline and at 1 year. Each profile was independently rated by 3 expert physicians. Majority opinion determined whether a patient was improved or not improved, and kappa agreement with the CRISS cutoff of 0.6 was calculated. RESULTS: Patients had mean ± SD disease duration of 2.2 ± 1.3 years. There was substantial agreement between the physician majority opinion about each case and the CRISS (κ = 0.76 [95% confidence interval (95% CI) 0.64-0.88]). The agreement between each individual physician opinion and the CRISS was also substantial (κ = 0.70 [95% CI 0.62-0.78]). All CRISS non-improvers were also rated as non-improved by physician majority; however, 12 CRISS improvers were rated as non-improved by physicians. CONCLUSION: There was substantial agreement between the dichotomous CRISS rating and physician assessment of diffuse cutaneous SSc patients after 1 year. This supports the use of a CRISS cutoff at 0.6 for improvement versus non-improvement, although the CRISS tended to rate more patients as improved than did physicians.

Immunosuppression does not prevent severe gastrointestinal tract involvement in systemic sclerosis.

OBJECTIVES: We aimed to test the hypothesis that exposure to immunosuppression in early systemic sclerosis (SSc) could modify the risk of developing new onset severe gastrointestinal (GIT) involvement. METHODS: A total of 762 subjects with <3 years of disease duration and without severe GIT disease at baseline study visit were identified from combined longitudinal cohort data from the Canadian Scleroderma Research Group (CSRG) and Australian Scleroderma Interest Group (ASIG). The primary exposure was ever use of methotrexate, cyclophosphamide, mycophenolate mofetil and/or azathioprine during the study period. Severe GIT disease was defined as: 1-malabsorption, 2-hyperalimentation, 3-pseudo-obstruction, and/or 4-≥10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. The change in the hazard of severe GIT disease due to exposure was estimated using a marginal structural Cox proportional hazards model fit by inverse probability of treatment weights (IPTW) to address potential confounding. RESULTS: Study subjects were 81.5% female, had a mean age of 53.7±13.0 years and mean disease duration at baseline of 1.4±0.8 years. During a mean follow-up of 4.0±2.6 years, severe GIT involvement developed in 11.6% of the 319 subjects exposed to immunosuppression and in 6.8% of the 443 unexposed subjects. In an IPTW-adjusted analysis, exposure to immunosuppression was not associated with severe GIT disease (weighted hazard ratio 0.91, 95% confidence interval 0.52-1.58). CONCLUSIONS: In this large inception SSc cohort, the risk of severe GIT involvement was not modified by exposure to immunosuppression.

Association between gastroprotective agents and risk of incident interstitial lung disease in systemic sclerosis.

OBJECTIVES: Although interstitial lung disease (ILD) occurs in over half of systemic sclerosis (SSc) patients and represents a leading cause of mortality, there are currently no preventative strategies. We evaluated if gastroprotective agents were associated with a lower incident risk of SSc-ILD. METHODS: An SSc cohort without clinically apparent ILD at baseline was constructed from the Canadian Scleroderma Research Group registry. The primary exposure was any use of gastroprotective agents. Treatment with promotility agents was assessed as a secondary exposure. Time to development of clinically apparent ILD was compared between exposed and unexposed person-time, using a multivariable marginal structural Cox model incorporating inverse probability of treatment weights to address time-varying confounding. RESULTS: In total, 798 subjects met inclusion criteria. At cohort entry, median disease duration was 7.6 (IQR 3.9-15.6) years. During a median 4.4 (IQR 2.6-7.2) years of follow-up, 158 new ILD cases were diagnosed, for a crude incidence of 4.4 (95% CI 3.8-5.1) events per 100 person-years. Most (2085, 73.4%) person-visits were exposed to gastroprotective agents, 579 (20.4%) were exposed to promotility agents, and 554 (19.5%) were exposed to both agents. The marginal structural weighted hazard ratio (HR) for incident ILD related to gastroprotective agents was 0.86 (95% CI 0.52-1.41). When exposure was defined as treatment with promotility agents, the weighted adjusted HR was 0.79 (95% CI: 0.35-1.77). CONCLUSION: In this large retrospective cohort study, we were unable to demonstrate a protective role for gastroprotective and promotility agents in preventing clinically apparent SSc-ILD.

Long term outcomes of the French ASTIS systemic sclerosis cohort using the global rank composite score.

Two randomised trials (ASTIS, SCOT) of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) versus monthly Cyclophosphamide for severe Systemic Sclerosis (SSc) patients used similar inclusion criteria, but different primary endpoints: event-free-survival (EFS) at 24 months in ASTIS versus the global rank composite score (GRCS) at 54 months in SCOT. Here we analysed the French ASTIS cohort (n = 49) outcome using the same GRCS endpoint as reported in SCOT. All patients, randomised to AHSCT (n = 26) or Cyclophosphamide (n = 23), were evaluated for the non-parametric GRCS endpoint based on: death, EFS, forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 60 months. Secondary endpoints were: EFS, overall survival (OS), HAQ DI and organ status. In intention-to-treat analysis, the GRCS demonstrated superiority for AHSCT (median: 9 versus -19, p = 0.018), mRSS (Δ mRSS: -16 versus -9, p = 0.02), and HAQ-DI (ΔHAQ-DI: -0.89 versus -0.2, p = 0.05) with no significant difference in OS, EFS, lung, heart and kidney function between the groups. In conclusion, this study demonstrates long term benefits of non-myeloablative AHSCT when assessed by the five longitudinal measures within GRCS affording direct primary endpoint comparison between ASTIS and SCOT.

Trigeminal neuralgia in systemic sclerosis.

OBJECTIVES: Although trigeminal neuralgia (TN) has been associated with systemic sclerosis (SSc), there is a paucity of evidence and pathophysiological processes remain unknown. We undertook a nested case-control study to identify associations between TN and SSc in a large multi-centered cohort and identify possible pathophysiological links. METHODS: Data were derived from a longitudinal cohort of 1652 SSc subjects. Cases with a physician-reported diagnosis of TN were identified at baseline visit (prevalent) and during follow-up (incident). Each case was matched on study visit to four SSc patients without TN. Sociodemographic, clinical and serological characteristics of cases and controls were compared. RESULTS: At enrolment, 43/1652 (2.6%) subjects had a history of TN. During follow-up, an additional 36 subjects developed TN over 6193 person-years of observation (incidence rate 5.8 per 1000 person-years). Cases were identified and matched to 172 and 144 controls, respectively. Compared to controls, prevalent cases had more inflammatory myositis (24.4% versus 5.2%, p<0.001) and inflammatory arthritis (46.5% versus 30.2%, p = 0.043). Incident cases also had more inflammatory myositis (19.4% versus. 6.3%, p = 0.033) and inflammatory arthritis (50.0% versus. 16.2%, p<0.001) compared to controls. There was a trend towards more interstitial lung disease in prevalent (32.6% versus 23.8%, p = 0.241) and incident (55.6% versus 40.6%, p = 0.105) cases compared to controls. CONCLUSION: This study provides novel evidence for a clinical association linking TN, inflammatory myositis, inflammatory arthritis and possibly interstitial lung disease. In addition to ischemia, we propose that TN in SSc could also be a consequence of inflammatory and possibly fibrotic processes.

A multimodal intervention increases influenza vaccine uptake in rheumatoid arthritis.

Annual influenza vaccination is recommended for patients with rheumatoid arthritis (RA), but coverage is suboptimal. We assessed the impact of an implementation strategy in enhancing vaccination uptake in RA. We evaluated a multimodal implementation strategy at rheumatology clinics that included 3 approaches: patient recalls, a nurse providing vaccines, and physician reminders. We compared patient-reported vaccination rates after implementation with those reported before the implementation strategy in a nonequivalent control group. In multivariate analyses, we assessed factors potentially associated with influenza vaccine uptake. One hundred and sixteen RA patients were vaccinated during the intervention. The influenza vaccination rate in RA increased from 48.5% (65/136) before implementation to 62.6% (67/107) after implementation (difference of 14.1, 95% CI 1.5, 26.1). In multivariate analyses, older age, biologics use, and physician recommendation for vaccination were associated with influenza vaccine uptake. A multimodal intervention was associated with increased influenza vaccine coverage among RA patients. Older patients and those on biologics were more likely to be immunized against influenza. Physician's recommendations are important to promote vaccine coverage. Key Points • Despite current recommendations, influenza vaccine uptake among rheumatoid arthritis (RA) patients is suboptimal. • A multimodal implementation strategy facilitating access to influenza vaccine and raising awareness through vaccination reminders improved immunization uptake in RA. • Physicians play a key role in promoting annual seasonal influenza vaccination. • The reasons for vaccine hesitancy in RA should be addressed to reach a vaccination target of 80% required to reduce the burden of this preventable infection.

Association of Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis With Marked Improvement in Health-Related Quality of Life.

OBJECTIVE: To quantify the magnitude, domains, and duration of change in health-related quality of life (HRQoL) in patients with systemic sclerosis (SSc) who underwent autologous hematopoietic stem cell transplantation (HSCT) as compared to SSc patients with similar characteristics who did not undergo autologous HSCT. METHODS: The study was designed as a retrospective study comparing SSc patients who underwent autologous HSCT and SSc patients who met the criteria for transplantation but were treated with conventional care. Outcomes included scores on the 36-item Short Form (SF-36) health survey and the Health Assessment Questionnaire (HAQ) and its disease-specific symptom scales. Differences in scores between the groups were compared using linear models, adjusting for baseline scores and inverse probability of treatment and censoring weights. RESULTS: In total, 41 SSc patients who underwent autologous HSCT and 65 SSc patients treated with conventional care were compared. In marginal linear weighted models, the SF-36 physical component summary score was a mean ± SEM 7.02 ± 1.94 points higher at the first annual visit (P = 0.001) and 14.40 ± 6.16 points higher at the seventh annual visit (P = 0.03) in patients treated with autologous HSCT compared to the conventional care group. HAQ scores were significantly better in the autologous HSCT group compared to the conventional care group during follow-up (mean ± SEM difference from baseline -0.57 ± 0.13 [P < 0.001] at the first annual visit and -0.94 ± 0.49 [P = 0.07] at the seventh annual visit). There were no differences in the SF-36 mental component summary scores between the 2 groups either at baseline or during follow-up. CONCLUSION: This study provides robust complementary HRQoL data, including overall and event-free survival data, to expand on the standard repertoire of biomedical variables, thus potentially supporting the physical benefits of autologous HSCT in patients with SSc.

Immunosuppressive treatment in diffuse cutaneous systemic sclerosis is associated with an improved composite response index (CRISS).

BACKGROUND: Outcomes of therapeutic studies in diffuse cutaneous systemic sclerosis (dcSSc) have mainly been measured for specific organs, particularly the skin and lungs. A new composite response index in dcSSc (CRISS) has been developed for clinical trials. The goal of this study was to determine whether, in an observational dcSSc cohort, immunosuppression was associated with global disease improvement measured with the CRISS. METHODS: We conducted a retrospective cohort study in a multi-centered SSc registry comparing 47 patients newly exposed to immunosuppression for ≥ 1 year to 254 unexposed patients. Inverse probability of treatment weighting (IPTW) was performed to create comparable exposed and unexposed groups by balancing for age, sex, disease duration, modified Rodnan skin score (mRSS), forced vital capacity, patient and physician global assessments, and Health Assessment Questionnaire score. A CRISS score ≥ 0.6 at 1 year was defined as improvement. RESULTS: Exposed patients had shorter disease duration (5.5 versus 11.7 years, p < 0.01), more interstitial lung disease (67.4% versus 40.3%, p < 0.01), and worse physician global severity scores (4.2 versus 2.5 points, p < 0.01) compared to unexposed patients. Improvement in CRISS scores was more common in exposed patients after IPTW (odds ratio 1.85, 95% confidence interval 1.11, 3.09). Of the individual CRISS variables, only mean patient global assessment scores were significantly better among exposed than unexposed patients (- 0.4 versus 0 points, p = 0.03) while other variables including mRSS were similar. CONCLUSION: Using a composite response measure, immunosuppression was associated with better outcomes at 1 year in a dcSSc cohort. These results provide real-world data that align with clinical trials to support our current use of immunosuppression.

Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis.

OBJECTIVE: We sought to develop the first Damage Index (DI) in systemic sclerosis (SSc). METHODS: The conceptual definition of 'damage' in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort. RESULTS: Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort. CONCLUSIONS: Through the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality.

OBJECTIVES: To examine the incidence, predictors and outcomes associated with severe gastrointestinal (GI) disease in a large inception SSc cohort. METHODS: SSc subjects with <2 years of disease duration were identified from two multicentre cohorts. Severe GI disease was defined as: malabsorption, hyperalimentation, pseudo-obstruction and/or ⩾10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. Kaplan-Meier, multivariate logistic regression and Cox proportional hazard analyses were performed to determine the cumulative incidence rate, independent clinical correlates and mortality rate associated with severe GI disease. A longitudinal mixed model was used to assess the impact of severe GI disease on the Short Form Health Survey. RESULTS: In this inception SSc cohort, the probability of developing severe GI disease was estimated at 9.1% at 2 years and 16.0% at 4 years. In multivariate analysis, severe GI disease was associated with inflammatory myositis (odds ratio 4.68, 95% CI 1.65, 13.24), telangiectasias (odds ratio 2.45, 95% CI 1.19, 5.04) and modified Rodnan skin score (odds ratio 1.03, 95% CI 1.01, 1.07). Severe GI disease was associated with a >2-fold increase in the risk of death (hazard ratio 2.27, 95% CI 1.27, 4.09) and worse health-related quality of life [Short Form Health Survey physical (ß = -2.37, P = 0.02) and mental (ß = -2.86, P = 0.01) component summary scores]. CONCLUSION: Severe GI disease is common in early SSc and is associated with significant morbidity and increased mortality. More research is needed to understand, prevent and mitigate severe GI disease in SSc.

Determinants of health-related quality of life in a multinational systemic sclerosis inception cohort.

OBJECTIVES: To evaluate health-related quality of life (HRQoL) and its determinants in a systemic sclerosis (SSc) multinational inception cohort. We performed a meta-analysis of data from individual countries, and compared the meta-analysis to individual country results by pooling data from each of the countries. METHODS: SSc patients within 2 years of disease onset were recruited from 5 countries participating in the International Systemic Sclerosis Inception Cohort (INSYNC). Data from each country's database were exported for analysis using a harmonised platform. HRQoL was assessed using the Medical Outcomes Short Form-36 (SF-36). Multivariate linear regression assessed associations between HRQoL and predictors in cohorts separately and meta-analyzed to generate pooled estimates. The analyses were repeated using individual patient data. RESULTS: Of the 637 SSc patients recruited, the majority was female (80.2%-83.3%), aged between 52.4-56.7 years with limited cutaneous disease subtype (48.6%-66.7%). HRQoL scores were lower for SSc patients than the general population (SF-36 physical component summary (PCS) score (36.4-39.6), mental component summary (MCS) score (41.0-46.4)). Determinants of SF-36 PCS by meta-analysis included increasing age (ß=-0.1, 95%CI -0.2, -0.01), diffuse cutaneous disease subtype (ß=-8.4, 95%CI -10.6, -6.3), and pulmonary arterial hypertension (ß=-10.9, 95%CI -16.6, -5.3). Increasing age (ß=0.09, 95%CI 0.0, 0.18) was the only variable associated with SF-36 MCS. Analyses using individual patient data revealed similar results to those of the meta-analysis of cohort data. CONCLUSIONS: Our study provides estimates of HRQoL in a large inception SSc cohort and provides evidence that individual patient data analysis is valid in the INSYNC dataset.

Treatment of small intestinal bacterial overgrowth in systemic sclerosis: a systematic review.

Objectives: Almost all patients with SSc have gastrointestinal manifestations. Small intestinal bacterial overgrowth (SIBO) occurs in 30-60% of patients and leads to malnutrition and impaired quality of life. Recent systematic reviews have reported efficacy of treatments for SIBO, but these are not specific to patients with SSc. We conducted a systematic review of the evidence for all possible SIBO treatments in the SSc population. Methods: The following databases were searched: MEDLINE, EMBASE and the Cochrane Library, from database inception to 1 January 2017. All evidence for all possible SIBO treatments including antibiotics, prokinetics, probiotics and alternative treatments was included. Treatment outcomes included symptomatic relief or demonstrated SIBO eradication. Results: Of 5295 articles, five non-randomized studies were reviewed with a total of 78 SSc patients with SIBO. One trial assessed octreotide while the remaining four trials investigated the effectiveness of ciprofloxacin, rifaximin, norfloxacin and metronidazole, and the combination of amoxicillin, ciprofloxacin and metronidazole. Studies were generally of low quality and most were un-controlled. Conclusion: Data indicate that, for some SSc patients, antibiotics can eradicate SIBO. There is a paucity of data reporting the effectiveness of either prokinetics or probiotics in SSc.