Machine learning predicts stem cell transplant response in severe scleroderma.

OBJECTIVE: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. METHODS: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). RESULTS: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. CONCLUSIONS: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.

Using Autoantibodies and Cutaneous Subset to Develop Outcome-Based Disease Classification in Systemic Sclerosis.

OBJECTIVE: To describe the associations between autoantibodies, clinical presentation, and outcomes among patients with systemic sclerosis (SSc) in order to develop a novel SSc classification scheme that would incorporate both antibodies and the cutaneous disease subset as criteria. METHODS: Demographic and clinical characteristics, including cutaneous subset, time of disease and organ complication onset, and autoantibody specificities, were determined in a cohort of SSc subjects. Survival analysis was used to assess the effect of the autoantibodies on organ disease and death. RESULTS: The study included 1,325 subjects. Among the antibody/skin disease subsets, anticentromere antibody-positive patients with limited cutaneous SSc (lcSSc) (n = 374) had the highest 20-year survival (65.3%), lowest incidence of clinically significant pulmonary fibrosis (PF) (8.5%) and scleroderma renal crisis (SRC) (0.3%), and lowest incidence of cardiac SSc (4.9%), whereas the frequency of pulmonary hypertension (PH) was similar to the mean value in the SSc cohort overall. The anti-Scl-70+ groups of patients with lcSSc (n = 138) and patients with diffuse cutaneous SSc (dcSSc) (n = 149) had the highest incidence of clinically significant PF (86.1% and 84%, respectively, at 15 years). Anti-Scl-70+ patients with dcSSc had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years. In contrast, in anti-Scl-70+ patients with lcSSc, other complications were rare, and these patients demonstrated the lowest incidence of PH (6.9%) and second highest survival (61.8%) at 20 years. Anti-RNA polymerase antibody-positive SSc patients (n = 147) had the highest incidence of SRC (28.1%) at 20 years. The anti-U3 RNP+ SSc group (n = 56) had the highest incidence of PH (33.8%) and cardiac SSc (13.2%) at 20 years. Among lcSSc patients with other autoantibodies (n = 295), the risk of SRC and cardiac SSc was low at 20 years (2.7% and 2.4%, respectively), while the frequencies of other outcomes were similar to the mean values in the full SSc cohort. Patients with dcSSc who were positive for other autoantibodies (n = 166) had a poor prognosis, demonstrating the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: These findings highlight the importance of autoantibodies, cutaneous subset, and disease duration when assessing morbidity and mortality in patients with SSc. Our novel classification scheme may improve disease monitoring and benefit future clinical trial designs in SSc.

Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences.

OBJECTIVES: To compare a cohort of patients with systemic sclerosis sine scleroderma (ssSSc) vs. patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Forty-five patients with ssSSc and 186 patients with lcSSc were investigated. Demographic, clinical and immunologic features and survival were compared. RESULTS: There were no significant differences between ssSSc and lcSSc in gender, age at onset and interval between onset and diagnosis. ssSSc patients fulfilled the ACR criteria for SSc less than lcSSc patients (13%/77%, p<0.0001). There were no significant differences in articular involvement, myopathy, tendon friction rubs and gastrointestinal, pulmonary, cardiac and renal involvements. There was a trend to higher prevalence of pulmonary arterial hypertension (PAH) in ssSSc patients (29%/19%) but not reach significant difference. The prevalence of antinuclear and anticentromere antibodies and slow capilaroscopic pattern was similar. Sicca syndrome (13%/30%; p=0.024), digital ulcers (16%/50%; p<0.0001), calcinosis (11%/26%; p=0.047) and acroosteolysis (0% /10%; p=0.028) were more frequently in lcSSc. Survival at 5, 10, and 15 yr was not different in ssSSc and lcSSc patients (100%/98%, 100%/98%, and 92%/89%, respectively). CONCLUSIONS: ssSSc and lcSSc patients share demographic, clinical and immunologic features. Survival is also similar in both groups. Differences are mainly due to peripheral vascular manifestations. However, despite great similarities, we believe that ssSSc patients should be considered as a different subset in order to avoid misdiagnosis. ssSSc patients should be truly differentiated from early SSc using sensitive and specific studies looking for any asymptomatic organ involvement.

The Belgian Systemic Sclerosis Cohort: correlations between disease severity scores, cutaneous subsets, and autoantibody profile.

OBJECTIVE: To report baseline and followup data on the first 438 patients with systemic sclerosis (SSc) included in the Belgian Systemic Sclerosis Cohort. METHODS: According to LeRoy and Medsger's classification, 73 patients with limited SSc (lSSc), 279 with limited cutaneous SSc (lcSSc), and 86 with diffuse cutaneous SSc (dcSSc) were included. History was collected and clinical examination, blood tests, and paraclinical investigations were repeated. The Disease Activity Score (DAS) and Disease Severity Score (DSS) of several organ systems were computed. An organ system was considered to demonstrate SSc if the corresponding DSS was ≥ 1. RESULTS: At baseline, patients with dcSSc had more general, joint/tendon, muscle, gastrointestinal, and kidney involvement. Mean DLCO was below normal in patients with lSSc, indicating unsuspected lung involvement. Patients with anti-Scl-70 had more vascular, skin, joint/tendon, and lung involvement. Patients with anti-RNA polymerase III had more skin and joint/tendon involvement compared to patients with anticentromere. Time to death was statistically shorter for patients with dcSSc. New-onset lung disease was the most common complication over time. No changes in DAS were observed. By contrast, the general and the skin DSS worsened in patients with lcSSc and lSSc, respectively. Fifteen percent of patients with lSSc shifted to lcSSc at Month 30, but neither serology nor capillaroscopy findings at baseline were helpful in identifying those at risk. CONCLUSION: Our data indicate that the DSS can be used to define organ involvement in SSc. Differences can be seen between subsets classified not only according to cutaneous subtypes but also to autoantibody profile.

Scleroderma and CREST syndrome: a case report in dentistry.

CREST syndrome is part of the heterogeneous scleroderma group of autoimmune diseases that cause thickening, hardening and tightening of the connective tissue in different parts of the body, and it may lead to complex disorders. CREST syndrome is characterized by the coexistence of calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactily and telangectasia. A 72-year-old caucasian woman is referred to the S. Gerardo Hospital of Monza, with a chief complaint of oral pain and difficulties in deglutition and eating, associated with denture instability and difficulties to fit it. She had been previously diagnosed with Raynaud's phenomenon, and afterwards with CREST syndrome. Extra-oral examination underlined taut, thickened and rigid skin, pallid-red irregular maculae all over the face, telangiectasias and acrocyanosis. Intra-oral examination showed no alteration of the mucosa, but we can observe tongue rigidity and some speckled red alternating with white spots on the hard palate and in the vestibule. We undermitted the patient the dental treatment of Sjogren's syndrome. The management of the Sjogren's syndrome is symptomatic and empirical, and involves the use of saliva secretion stimulators, salivary substitutes and coadjuvants. Dental treatment and prophylaxis are important to prevent the consequences of xerostomia, such as rampant caries, based on the administration of topical fluoride in toothpastes and rinses, and supplemented by fluoride gels and varnishes. Instruction and reinforcement of oral hygiene, along with frequent dental assessment and management by the dentist are essential measures to preserve the oral health of those affected with CREST syndrome in progression to SS, complicated with Sjogren's syndrome.

[Classification criteria of scleroderma]. / Critères de classification des sclérodermies.

Classification criteria of scleroderma aim to delineate the different clinical forms of the disease, which are associated with different prognoses. The basic classification between localized and systemic scleroderma remains pertinent. Among the former, the problems are essentially esthetic or sometimes functional; but the second may yield many other problems which are pertinent to function but also to life, owing to the involvement of body organs, including lungs, heart, digestive tract, kidneys and locomotor system. Overall, the quality of life of scleroderma patients is often poor. The patients are subclassified according to the skin involvement. Those patients with systemic scleroderma involving the trunk are classified as "Cutaneous diffuse systemic scleroderma"; the association of Raynaud's phenomenon, capillaroscopic abnormalities and specific autoantibodies defines "limited systemic scleroderma"; among the latter patients, those with distal skin involvement are classified "Cutaneous limited systemic sclerosis". The old term "CREST" tends to be abandoned due to its lack of specificity.

Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

Classification of systemic sclerosis. Visions and reality.

Systemic sclerosis, scleroderma (SSc) is a disabling condition that shortens life expectancy. Disease heterogeneity and difficulties separating SSc from SSc-like conditions make classification an important issue. Limited cutaneous and diffuse cutaneous SSc, with different severity and survival, have been recognized for several years as distinct subsets. Some authors have suggested an intermediate cutaneous form with intermediate survival. This issue remains unsettled, however. The technique of capillaroscopy is helpful as an adjunct diagnostic tool to separate idiopathic Raynaud's phenomenon from SSc. Digitized video-capillaroscopy is developing as a powerful new method to assess individual capillaries over time. Using the simpler techniques of video-capillaroscopy, different patterns have been described and named 'early', 'active', 'late' and 'slow'. The value of nailfold video-capillaroscopy to distinguish different subsets or provide prognostic information for use in daily practice remains to be assessed. The features of CREST (calcinosis, Raynaud's, oesophagus dysmotility, sclerodactyly, telangiectasias) are not confined to single subsets of SSc. There is no convincing evidence of any advantage for distinguishing the limited, intermediate and diffuse forms of SSc rather than only the limited and diffuse forms.