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Objective: This studied investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PFF) in patients with systemic sclerosis-associated interstitial lung disease (ILD) receiving treatment., Method: Participants of Scleroderma Lung Study (SLS) II, which compared mycophenolate (MMF) versus cyclophosphamide (CYC) for SSc-ILD, who had blood samples at baseline and 12-months were included. Levels for C-reactive protein (CRP), interleukin (IL)-6, chemokine ligand 4 (CXCL4), chemokine ligand 18 (CCL18) and Krebs von den Lungen 6 (KL-6) were measured, and a logistic regression model evaluated relationships between changes in these biomarkers and the development of PPF by 24 months., Results: Ninety-two of the 142 randomized participants had longitudinal biomarker measurements and the required clinical outcome data, with 19 (21%) meeting criteria for PPF. In the whole cohort, changes in KL-6 levels were significantly correlated with PPF. KL-6 increased in patients who developed PPF and decreased in patients who did not (Mean change 365.68 [SD 434.41]) vs -207.45 [SD 670.26]; P<0.001). In the MMF alone arm, changes in CRP and CXCL4 were also significantly correlated with PPF. When added to an existing prediction model based on baseline factors associated with PPF in this cohort (sex, baseline reflux severity and CXCL4 levels), the change in KL-6 remained significantly associated with PFF (OR 1.4; P=0.0002)., Conclusion: Changes in the circulating levels of KL-6 after treatment with MMF or CYC predicted PPF, even after adjusting for baseline factors associated with PPF. Measuring longitudinal KL-6 in patients with SSc-ILD may improve how we personalize therapy in SSc-ILD., (This article is protected by copyright. All rights reserved.)

Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation., Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs)., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations., Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: To characterize disease manifestations in Hispanic American patients with systemic sclerosis (SSc) in comparison with non-Hispanic White and Black patients., Methods: Longitudinal clinical characteristics were collected prospectively in the Genetics versus Environment in Scleroderma Outcome Study cohort. All patients fulfilled the classification criteria for SSc and had a disease duration less than five years at enrollment., Results: A cohort of 427 patients, consisting of 124 Hispanic, 220 non-Hispanic White, and 83 non-Hispanic Black participants were examined. At enrollment, Hispanic patients were significantly younger but had longer disease duration, higher frequency of U1-RNP positivity as well as concurrent systemic lupus erythematosus (SLE) diagnosis, and lower income and educational levels in comparison to non-Hispanic White patients. Compared with non-Hispanic Black patients, Hispanic patients had more frequently limited cutaneous involvement and anticentromere antibodies. In the longitudinal analysis, Hispanic patients had significantly lower forced vital capacity percents predicted (point estimate, -9.3%; P < 0.001) than non-Hispanic White but not Black patients. Hispanic patients had similar longitudinal modified Rodnan Skin Scores like non-Hispanic White patients but lower measurements than non-Hispanic Black patients (point estimate, -3.2; P = 0.029). Hispanic patients had significantly higher serially obtained perceived functional disability scores than White patients (point estimate, 0.29; P < 0.001). Hispanic patients also had higher mortality rates than White Americans even after adjustment for age, gender, and socioeconomic statuses., Conclusion: Hispanic patients have higher likelihood of having U1-RNP positivity and SLE overlap, more severe restrictive lung disease, as well as higher rate of mortality than non-Hispanic White patients., (© 2024 American College of Rheumatology.)

Objective: The modified Health Assessment Questionnaire (M-HAQ) is a well-established patient-reported outcome measure in systemic sclerosis (SSc) studies that reflects how a patient functions in several categories of activities of daily living. This study analyzed clinical, demographic, and socioeconomic factors that predict M-HAQ scores over time., Methods: This study included 388 patients with baseline M-HAQ scores from the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) early disease cohort with a mean disease duration of 2.5 years, mean follow-up time of 3.9 years, and median follow-up of 7.2 years. A total of 1,950 M-HAQ measurements were analyzed. Baseline disease characteristics were recorded, and the association of these characteristics with the M-HAQ score was analyzed at baseline and longitudinally., Results: Lower income and education levels, older age, and more severe skin involvement at enrollment were independent predictors of worse perceived functional disability over time (i.e., higher longitudinal M-HAQ levels). Higher longitudinal modified Rodnan skin scores correlated with higher M-HAQ scores, whereas higher longitudinal forced vital capacity percentage predicted values correlated with lower M-HAQ scores over time (P < 0.001 for both univariable and multivariable analyses). Moreover, higher baseline M-HAQ scores predicted higher mortality (hazard ratio 1.29, 95% confidence interval 1.09-1.52, P = 0.003)., Conclusion: This large, longitudinal study of early disease SSc demonstrates that severity of skin disease and socioeconomic factors such as educational level and income are important predictors of perceived functional disability in SSc., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc)., Methods: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality., Results: Of the 447 SSc patients in the GENISOS cohort at the time of analysis, 377 (84.3%) had available baseline blood neutrophil and lymphocyte counts. Higher baseline neutrophil count and NLR predicted lower serially obtained FVC% (b = -4.74, P = 0.009 and b = -2.68, P = 0.028, respectively) and higher serially obtained MRSS (b = 4.07, P < 0.001 and b = 2.32, P < 0.001, respectively). Longitudinal neutrophil and NLR measurements also significantly correlated with lower concurrently obtained FVC% measurements and higher concurrently obtained MRSS. Baseline neutrophil count and NLR predicted increased risk of long-term mortality, even after adjustment for baseline demographic and clinical factors (hazard ratio [HR] 1.42, P = 0.02 and HR 1.48, P < 0.001, respectively). The predictive significance of higher baseline neutrophil count and NLR for declining FVC% and increased long-term mortality was confirmed in the SLS II., Conclusion: Higher blood neutrophil count and NLR are predictive of more severe disease course and increased mortality, indicating that these easily obtainable laboratory studies might be a reflection of pathologic immune processes in SSc., (© 2022 American College of Rheumatology.)

Objective: Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently 3 versions of the BFNE with strong demonstrated measurement properties: two 8-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients., Methods: Participants were 1,010 patients with SSc enrolled in the Scleroderma Patient-Centered Intervention Network cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson's product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively., Results: Confirmatory factor analysis demonstrated that 1-factor models fit acceptably well for the 12-item BFNE-II, the 8-item BFNE-S, and the 8-item BFNE-8. Additionally, all Cronbach's alphas demonstrated excellent internal consistency reliability (BFNE-II = 0.98, BFNE-S = 0.97, BFNE-8 = 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education., Conclusion: Psychometric support was found for all 3 versions of the BFNE, although the longer 12-item BFNE-II did not improve measurement compared to the shorter 8-item versions (BFNE-S and BFNE-8). Of these 2, the BFNE-S has been more widely studied, with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc., (© 2018, American College of Rheumatology.)

Objective: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs)., Methods: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT., Results: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02)., Conclusion: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc., (© 2016, American College of Rheumatology.)

Objective: There are currently no validated outcome measures to assess calcinosis severity in systemic sclerosis (SSc; scleroderma). We sought to develop and validate a novel radiographic scoring system for calcinosis affecting the hands of SSc patients for potential use in future clinical trials., Methods: Following a 1-hour teleconference training session, 12 investigators (8 rheumatologists, 1 dermatologist, and 3 radiologists) scored 12 hand radiographs in random order using 2 scoring systems (termed “simple” and “complex”) and re-scored 2 randomly assigned radiographs after a minimum of 24 hours. Interrater and intrarater reliability were assessed using a weighted kappa coefficient for the simple system (κ), and an intraclass correlation coefficient (ICC) for the complex system (ICC <0.4 for poor, 0.4–0.7 for moderate, and >0.7 for excellent)., Results: Mean time to complete the complex scoring system was significantly longer than the simple scoring system (4.0 versus 0.4 minutes; P < 0.0001). Overall interrater reliability for the simple scoring system was poor (κ = 0.39, 95% confidence interval [95% CI] 0.1–0.52) but improved if dichotomized as mild/moderate versus severe (κ = 0.51, 95% CI 0.26–0.7). Interrater reliability was excellent for the complex scoring system (ICC 0.89, 95% CI 0.86–0.92). Intrarater reliability was moderate for the simple scoring system (κ = 0.67, 95% CI 0.37–0.96) but almost perfect for the complex scoring system (ICC 0.93, 95% CI 0.89–0.97)., Conclusion: We developed a novel radiographic scoring system that accounts for the area coverage, density, and anatomic location of calcinosis affecting the hands in patients with SSc. This scoring system is feasible with excellent reliability and should undergo further validation testing for use in clinical trials.

Objective: Despite being a common problem in systemic sclerosis (SSc; scleroderma), the extant literature on pain has primarily focused on biomedical correlates, or bivariate relationships with a few psychological characteristics. There is a need to investigate the more heuristic biopsychosocial model, which incorporates the simultaneous contributions of medical, psychological, and social variables in understanding pain., Methods: Patients with SSc (n = 333) received clinical examinations and completed self-report surveys at enrollment in the Genetics versus Environment in Scleroderma Outcome Study. Latent profile analysis was used to derive biopsychosocial profiles of patients using skin thickening, percent predicted forced vital lung capacity, perceived physical health, health worry, mental health, and social support. The profiles were examined in relation to pain and pain medication usage., Results: A 3-profile solution provided the best fit to the data. Based on the biopsychosocial indicators, the profiles were characterized as managing (n = 217), resilient (n = 86), and distressed (n = 30). Between-group differences for pain emerged, with the distressed group, whose disease was less severe than the resilient group, reporting the highest pain and the greatest utilization of pain medication., Conclusion: Clinicians should consider biopsychosocial characteristics as contributing factors to the experience of pain in patients with SSc. Patients who are similar to those in the distressed profile may be at an increased risk for pain and would likely benefit from a referral to a behavioral health or other ancillary service provider for pain management, rather than relying solely on pharmacologic therapies., (Copyright © 2014 by the American College of Rheumatology.)

Objective: There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort., Methods: First, the CRP levels were compared between baseline samples of 266 SSc patients enrolled in the Genetics Versus Environment in Scleroderma Outcome Study cohort and 97 unaffected matched controls. Subsequently, the correlation between CRP levels and concomitantly obtained markers of disease severity was assessed. Serially obtained % predicted forced vital capacity (FVC) was used to examine the long-term ILD progression. The predictive significance of CRP level was investigated by a joint analysis of longitudinal measurements (serial FVCs up to 13 years) and survival data. This approach allowed inclusion of all 1,016 FVC measurements and accounted for survival dependency., Results: We confirmed that baseline CRP levels were higher in SSc patients than controls. CRP levels were associated with absence of anticentromere antibodies and correlated with the concomitant severity of lung, skin, and joint involvement. More importantly, higher baseline CRP levels were associated with shorter survival (P < 0.001) and predicted the long-term decline in FVC independent of potential confounders (age at baseline, sex, ethnicity, disease type, current smoking, body mass index, topoisomerase status, and treatment with immunosuppressive agents) in the multivariable model (P = 0.006)., Conclusion: Baseline CRP levels are predictive of long-term ILD progression. CRP level might aid clinicians in identifying patients that require more intensive monitoring and treatment., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Illness behaviors (cognitive, affective, and behavioral reactions) among individuals with systemic sclerosis (SSc; scleroderma) are of clinical concern due to relationships between these behaviors and physical and mental quality of life, such as pain and symptoms of depression. Self-report measures with good psychometric properties can aid in the accurate assessment of illness behavior. The Illness Behavior Questionnaire (IBQ) was designed to measure abnormal illness behaviors; however, despite its longstanding use, there is disagreement regarding its subscales. The goal of the present study was to evaluate the validity of the IBQ in a cohort of patients with SSc., Methods: Patients with SSc (n = 278) completed the IBQ at enrollment into the Genetics Versus Environment in Scleroderma Outcome Study. Structural validity of previously derived factor solutions was investigated using confirmatory factor analysis. Exploratory factor analysis was utilized to derive SSc-specific subscales., Results: None of the previously derived structural models were supported for SSc patients. Exploratory factor analysis supported an SSc-specific factor structure with 5 subscales. Validity analyses suggested that the subscales were generally independent of disease severity, but were correlated with other health outcomes (i.e., fatigue, pain, disability, social support, and mental health)., Conclusion: The proposed subscales are recommended for use in SSc, and can be utilized to capture illness behavior that may be of clinical concern., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome-wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants., Methods: Overall, 502 AS patients were examined, consisting of 312 patients who had first-degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK-Oxford cohort. The frequencies of AS susceptibility loci in IL-23R, IL1R2, ANTXR2, ERAP-1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag single-nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size., Results: HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward higher frequency in the multiplex cases (P = 0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined., Conclusion: HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Birth order has been valuable in revealing the role of environmental influences on the risk of developing certain diseases such as allergy and atopy. In addition, pregnancy has profound effects on the immune system such as short-term effects that permit fetal survival as well as longer-term effects that could influence late-onset diseases. In order to better evaluate these influences, we studied the association of birth order and gravidity/parity as risk factors for systemic sclerosis (SSc; scleroderma)., Methods: Data regarding SSc cases and their unaffected sibling controls were obtained from the Scleroderma Family Registry and DNA Repository. The case-sibling design was used to minimize confounding due to differences in age, race, ethnicity, or calendar time. The gravidity/parity analysis was based on sibships with at least one SSc-affected and one unaffected sister., Results: Birth order was examined in 974 sibships, comparing SSc cases (n = 987) with their unaffected siblings (n = 3,088). The risk of scleroderma increased with increasing birth order (odds ratio [OR] 1.25, 95% confidence interval [95% CI] 1.06-1.50 for birth order 2-5; OR 2.22, 95% CI 1.57-3.15 for birth order 6-9; and OR 3.53, 95% CI 1.68-7.45 for birth order 10-15). Gravidity/parity was analyzed in 168 sibships (256 unaffected sisters, 172 SSc cases). We found an association between a history of one or more pregnancies and SSc (OR 2.8)., Conclusion: Birth order and pregnancy were independently associated with a higher risk of developing SSc. These findings suggest that immune development in early childhood and/or pregnancy-associated events, including but not limited to microchimerism, plays a role in SSc susceptibility.