Objective
Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as ...biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA–positive patients are associated with disease severity and/or progression from very early SSc to definite SSc.
Methods
IgG ACA–positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud’s phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement.
Results
Six hundred twenty‐five IgG ACA–positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 95% confidence interval 1.8–3.7) and IgM ACAs (odds ratio 1.8 95% confidence interval 1.3–2.3) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow‐up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 95% confidence interval 1.7–10.7).
Conclusion
ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc.
Objective
Hematopoietic stem cell transplantation (HSCT) and cyclophosphamide (CYC) are treatment options for progressive systemic sclerosis associated with interstitial lung disease (SSc‐ILD). The ...aims of our retrospective observational study were to evaluate: 1) the evolution of SSc‐ILD in SSc patients treated with HSCT (assessed by high‐resolution computed tomography HRCT; a group of patients treated with CYC was included as frame of reference); 2) how results of pulmonary function tests (PFTs) are associated with HRCT findings; and 3) which factors predict ILD reduction.
Methods
We semiquantitatively scored total ILD extent, reticulations, and ground‐glass opacities (GGO) scores at baseline and at the 1‐year HRCTs of SSc patients treated with HSCT or CYC. Linear association between changes in HRCT scores and PFT results and predictors of ILD improvement were studied.
Results
We included 51 patients (those treated with HSCT n = 20 and those treated with CYC n = 31). The mean change in total ILD score was –5.1% (95% confidence interval 95% CI –10.2, 0.0) in the HSCT treatment group (P = 0.050), and –1.0% (95% CI –4.3, 2.3) in the CYC treatment group (P = 0.535). For all patients, the evolution of HRCT scores was weakly associated with relative changes in PFT results. In univariate logistic regression, higher ground‐glass opacities, higher total ILD, and lower single‐breath diffusing capacity for carbon monoxide scores at baseline predicted improvement of ILD extent after treatment, but a multivariable model could not be built to assess independency of predictors.
Conclusion
One year after treatment with HSCT, a nonsignificant but clear reduction of SSc‐ILD extent was observed. Changes in PFT results were associated with changes in HRCT scores but the correlation was weak and cannot be considered conclusive.
Objective
Anti–topoisomerase I (anti–topo I) autoantibodies in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the ...relationship between anti–topo I antibody response and disease course has not yet been fully evaluated. This study was undertaken to gain insight into the association between characteristics of the anti–topo I antibody response and clinical disease course in SSc patients positive for anti–topo I antibodies.
Methods
Levels of anti–topo I IgG, anti–topo I IgM, and anti–topo I IgA were assessed in consecutive serum samples obtained from patients at baseline who were positive for anti–topo I IgG in the Leiden Combined Care In Systemic Sclerosis (CCISS) cohort. One‐year disease progression was defined by a relevant increase in modified Rodnan skin thickness score (MRSS), decline in pulmonary function, development of digital ulcers, renal crisis, and pulmonary hypertension, and/or mortality. Validation was performed in SSc patients who were positive for anti–topo I from the Oslo University Hospital and University Hospital Zurich.
Results
Of the 103 patients with anti–topo I IgG in the CCISS cohort, clinical data were available to assess 1‐year disease progression in 81 patients. Of these 81 patients, 23 (28%) had disease progression. At baseline, patients with disease progression were significantly more often anti–topo I IgM–positive than those who did not experience disease progression (21 91% of 23 versus 33 57% of 58; P < 0.01). This finding was confirmed in the independent validation samples.
Conclusion
In SSc patients who were anti–topo I IgG–positive, presence of anti–topo I IgM, which might be considered as a surrogate for an ongoing autoreactive B cell immune response, is associated with disease progression.
Objective
Microangiopathy and dysregulation of the immune system play important roles in the pathogenesis of systemic sclerosis (SSc). Factors that trigger vascular injury in SSc have not been ...elucidated so far. We undertook this study to evaluate whether sex or expression of specific antinuclear autoantibodies might associate with the degree of microangiopathy through performance of a systematic review that summarizes what is known about these associations.
Methods
A standardized search of PubMed, Embase, Web of Science, and the Cochrane Library were performed to identify studies that described autoantibodies in SSc patients and microangiopathy and, for the second search, those that described sex and microangiopathy.
Results
We included 11 studies that described the relationship between SSc‐specific autoantibodies and microangiopathy and 6 studies that reported on the association between sex and microangiopathy. Contradictory results were found on the association between SSc‐specific autoantibodies and microangiopathy, and no association was found between sex and microangiopathy based on the current literature.
Conclusion
Based on this review of the literature, we can conclude that sex does not seem to influence degree of microangiopathy in SSc, while results on association between SSc‐specific autoantibodies and degree of microangiopathy were inconclusive.
Objective
To assess the use, satisfaction, needs, and preferences regarding physical therapy (PT) in patients with systemic sclerosis (SSc).
Methods
A total of 405 SSc patients, treated in the Leiden ...University Medical Center multidisciplinary care program and fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 SSc criteria, received a questionnaire containing 37 questions on use and satisfaction regarding PT over a 2‐year period, and their needs and preferences for future PT.
Results
A total of 204 SSc patients (median age 63 years, 81% female) completed the questionnaire. One hundred twenty‐eight patients (63%) had used or were using PT in a primary care setting. For 39% of patients not using PT, lack of referral or lack of knowledge was the reason for not using it. The most frequently reported active treatments were muscle‐strengthening (n = 92 72%), range of motion (n = 77 60%), and aerobic exercises (n = 72 56%). Specific SSc hand‐ and mouth‐opening exercises were reported by 20 (15%) and 7 (6%) patients, respectively. Manual treatment (massage or passive mobilization) was reported by 83 patients (65%). The mean ± SD satisfaction score (range 0–10) was 8.2 ± 1.6. Regarding patients' needs, 96 patients (47%) of the total group wanted to receive more information concerning PT, and 128 (63%) wanted to continue, start, or restart PT in the near future, with 56 of the 128 patients (44%) favoring individual treatment on a continuous basis.
Conclusion
We observed a significant variation in the use and content of PT for SSc patients in a primary care setting. Our results suggest potential underuse of PT care, in particular for hand and oral dysfunction, and underpin the need for initiatives to improve the quality and accessibility of PT care for SSc patients.
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.
In the present study, we aimed to evaluate whole-body insulin sensitivity in systemic sclerosis (SSc) patients and to compare the results with controls with no autoimmune rheumatic disease (non-ARD) ...and with patients affected by rheumatoid arthritis (RA).
In all patients and controls, oral glucose tolerance test (OGTT) was performed according to the World Health Organization (WHO) recommendations. Plasma glucose and insulin concentrations were measured at time 0 and then after 30, 60, 90, and 120 minutes. Whole-body insulin sensitivity (ISI), insulinogenic index (IGI), oral disposition index (ODI), and insulin resistance (HOMA-IR) were estimated accordingly.
A total of 41 SSc patients were evaluated and, for comparison, 41 individuals with RA and 82 non-ARD control patients were recruited. OGTT yielded a proportion of normotolerant individuals among SSc patients higher than in RA controls (p = 0.040) but lower than in the non-ARD group (p = 0.028). The ISI was significantly higher in SSc patients compared with RA controls (p <0.001) and with non-ARD patients (p <0.001). Significant differences emerged also when analysing the HOMA-IR, which was lower in SSc patients than in RA (p <0.001) and non-ARD (p <0.001) groups. Additionally, IGI was lower in SSc patients compared with RA (p = 0.011) and with non-ARD controls (p <0.001), whereas ODI was not significantly different between groups.
Interestingly, we found that SSc patients are more insulin sensitive than those with RA and even than individuals without inflammatory diseases. In contrast, no significant difference was found in terms of β-cell function.
To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis (SSc) among ...international experts. In addition, to determine factors that might influence agreement.
Level of agreement (10-point scale: 0 = not at all, 10 = completely agree) and local drug availability (yes/no) were assessed using an online survey. The Web link to the survey was shared with 481 unique e-mail addresses and SSc networks (Scleroderma Clinical Trials Consortium, Australian Scleroderma Interest Group, International Systemic Sclerosis Inception Cohort). Level of agreement was compared between subgroups stratified for participant characteristics.
In total, 263 experts participated, of whom n = 209 (79%) completed each single item. The majority were rheumatologists (n = 200, 76%) working in Europe (n = 185; 71%); 59% (n = 156) were EUSTAR members; and 57% (n = 151) had > 10 years of clinical experience. Overall level of agreement was high (mean 8.0, SD 2.5). The 3 highest mean agreements included (1) angiotensin-converting enzyme inhibitors for scleroderma renal crisis (9.2, SD 2.1); (2) blood pressure control in SSc-patients treated with corticosteroids (9.0, SD 2.2); (3) proton pump inhibitors to prevent reflux complications (9.0, SD 2.2). The 3 lowest mean agreements included (1) fluoxetine for Raynaud phenomenon (RP; 4.6, SD 2.8); (2) hematopoietic stem cell transplantation (HSCT) for severe SSc (7.1, SD 2.9); (3) phosphodiesterase inhibitors 5 for RP (7.3, SD 2.7). Agreement differed between Europe and non-Europe for the use of iloprost, bosentan, methotrexate, HSCT, and cyclophosphamide. Treatment availability could partially explain differential agreement for iloprost, bosentan, and HSCT.
In general, worldwide expert agreement on updated recommendations for treatment of SSc is high, supporting their value. Differences in agreement are partially explained by geographical area and treatment availability.
Systemic sclerosis-interstitial lung disease (SSc-ILD) is a major complication of SSc resulting in important morbidity and mortality. Next to cyclophosphamide and mycophenolate mofetil, tocilizumab ...and nintedanib have proven efficacy in the treatment of SSc-ILD. The highly variable course of SSc-ILD, the complexity in determining and predicting the progression of SSc-ILD, and the diversity of treatment options for SSc-ILD, pose many challenges for everyday clinical practice. In this review, currently available evidence for monitoring and treatment of SSc-ILD is summarized and areas where additional evidence is highly desirable are discussed.
A hallmark of disease pathogenesis of systemic sclerosis (SSc) is the presence of autoreactive B cell responses targeting nuclear proteins. Almost all SSc-patients harbour circulating antinuclear ...autoantibodies of which anti-topoisomerase 1, anti-centromere protein, anti-RNA polymerase III and anti-fibrillarin autoantibodies (ATA, ACA, ARA and AFA, respectively) are the most common and specific for SSc. In clinical practice, autoantibodies serve as diagnostic biomarkers and can aid in the identification of clinical phenotypes of the disease. However, factors driving disease progression in SSc are still poorly understood, and it is difficult to predict disease trajectories in individual patients. Moreover, treatment decisions remain rather empirical, with variable response rates in clinical trials due to patient heterogeneity. Current evidence has indicated that certain patients may benefit from B cell targeting therapies. Hence, it is important to understand the contribution of the antinuclear autoantibodies and their underlying B cell response to the disease pathogenesis of SSc.
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