Association of HLA-DQB1*0501 with scleroderma and its clinical features in Chinese population.

Specific human leukocyte antigen (HLA) DQB1 alleles confer strong susceptibility to systemic sclerosis (SSc). However, the frequencies of specific DQB1 alleles and their associations with SSc vary according to ethnicity and clinical features of SSc. The aim of this study was to profile DQB1 alleles in a Chinese population and to identify specific DQB1 alleles in association with SSc of Han Chinese. A cohort containing 213 patients with SSc and 239 gender-matched and unrelated controls was examined in the study. The HLA-DQB1 genotyping was performed with sequence-based typing (SBT) method. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts or allele carriers and disease status. Seventeen DQB1 alleles were found in the cohort. DQB1*03:03 was the most common allele in this cohort. DQB1*05:01 was significantly increased in SSc, and was strongly associated with anti-centromere autoantibodies (ACA). Compared with SSc in other ethnic populations, SSc patients of Han Chinese are distinct in association with DQB1*06:11, common in association with DQB1*05:01, but lack association with DQB1*03:01. In addition, DQB1*06:01 appeared more common in ATA-positive Chinese SSc, and marginally associated with pulmonary fibrosis, and an increased frequency of DQB1*03:03 was observed in anti-U1RNP-positive Chinese SSc patients.

STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population.

Systemic sclerosis (SSc) is an immune-mediated and complex genetic disease. An association of single-nucleotide polymorphisms (SNPs) in the STAT4 gene with SSc has been reported in European Caucasians, North Americans and Japanese. We undertook the current study to examine whether the STAT4 SNPs are also associated with susceptibility to SSc and SSc subsets in a Han Chinese population. A total of 453 Han Chinese patients with SSc and 534 healthy controls were examined in the study. The SNPs rs7574865, rs10168266 and rs3821236 of the STAT4 gene were examined with SNP TaqMan assays. The T-allele carriers of rs7574865 and rs10168266 were strongly associated with the presence of anti-topoisomerase I (ATA) and pulmonary fibrosis in SSc patients, as well as with diffuse cutaneous SSc (dcSSc). The presence of anti-centromere (ACA) and limited cutaneous SSc (lcSSc) did not show significant association with any of the examined SNPs. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc. It also revealed different genetic aspects of SSc subsets in a Han Chinese population.

Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. METHODS: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture. RESULTS: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. CONCLUSION: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians.

OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.

Development of a provisional core set of response measures for clinical trials of systemic sclerosis.

OBJECTIVE: To develop a provisional core set of response measures for clinical trials of systemic sclerosis (SSc). METHODS: The Scleroderma Clinical Trials Consortium (SCTC) conducted a structured, 3-round Delphi exercise to reach consensus on a core set of measures for clinical trials of SSc. Round 1 asked the SCTC investigators to list items in 11 pre-defined domains (skin, musculoskeletal, cardiac, pulmonary, cardio-pulmonary, gastrointestinal, renal, Raynaud phenomenon and digital ulcers, health-related quality of life and function, global health, and biomarkers) for SSc clinical trials. Round 2 asked respondents to rate the importance of the chosen items and was followed by a meeting, during which the Steering Committee discussed the feasibility, reliability, redundancy and validity of the items. Round 3 sought to obtain broader consensus on the core set measures. Members also voted on items that had data on feasibility but lacked data on reliability and validity, but may still be useful research outcome measures for future trials. RESULTS: A total of 50 SCTC investigators participated in round 1, providing 212 unique items for the 11 domains. In all, 46 (92%) participants responded in round 2 and rated 177 items. The ratings of 177 items were reviewed by the Steering Committee and 31 items from the 11 domains were judged to be appropriate for inclusion in a 1-year multi-centre clinical trial. In total, 40 SCTC investigators completed round 3 and ranked 30 of 31 items as acceptable for inclusion in the core set. The Steering Committee also proposed 14 items for a research agenda. CONCLUSION: Using a Delphi exercise, we have developed a provisional core set of measures for assessment of disease activity and severity in clinical trials of SSc.

Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis.

OBJECTIVES: Pulmonary fibrosis is a leading cause of death in systemic sclerosis (SSc). This report examines the differences at baseline and over 12 months between patients with limited versus diffuse cutaneous SSc who participated in the Scleroderma Lung Study. METHODS: SSc patients (64 limited; 94 diffuse) exhibiting dyspnoea on exertion, restrictive pulmonary function and evidence of alveolitis on bronchoalveolar lavage and/or high-resolution computed tomography (HRCT) were randomised to receive cyclophosphamide (CYC) or placebo and serially evaluated over 12 months. RESULTS: Baseline measures of alveolitis, dyspnoea and pulmonary function were similar in limited and diffuse SSc. However, differences were noted with respect to HRCT-scored fibrosis (worse in limited SSc), and to functional activity, quality of life, skin and musculoskeletal manifestations (worse in diffuse SSc) (p<0.05). When adjusted for the baseline level of fibrosis, both groups responded similarly to CYC with regard to lung function and dyspnoea (p<0.05). Cyclophosphamide was also associated with more improvement in skin score in the diffuse disease group more than in the limited disease group (p<0.05). CONCLUSIONS: After adjusting for the severity of fibrosis at baseline, CYC slowed the decline of lung volumes and improved dyspnoea equally in the limited and the diffuse SSc groups. On the other hand, diffuse SSc patients responded better than limited patients with respect to improvements in skin thickening.

Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: clinical associations.

Autoantibodies directed against the Ku autoantigen are present in systemic sclerosis (SSc) and have been associated with myositis overlap and interstitial lung disease (ILD). However, there is a paucity of data on the clinical correlates of anti-Ku antibodies in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of single-specificity anti-Ku in SSc.An international (Canada, Australia, USA, Mexico) cohort of 2140 SSc subjects was formed, demographic and clinical variables were harmonized, and sera were tested for anti-Ku using a line immunoassay. Associations between single-specificity anti-Ku antibodies (i.e., in isolation of other SSc-specific antibodies) and outcomes of interest, including myositis, ILD, and survival, were investigated.Twenty-four (1.1%) subjects had antibodies against Ku, and 13 (0.6%) had single-specificity anti-Ku antibodies. Subjects with single-specificity anti-Ku antibodies were more likely to have ILD (58% vs 34%), and to have increased creatine kinase levels (>3× normal) at baseline (11% vs 1%) and during follow-up (10% vs 2%). No difference in survival was noted in subjects with and without single-specificity anti-Ku antibodies.This is the largest cohort to date focusing on the prevalence and disease characteristics of single-specificity anti-Ku antibodies in subjects with SSc. These results need to be interpreted with caution in light of the small sample. International collaboration is key to understanding the clinical correlates of uncommon serological profiles in SSc.

The effect on memory of chronic prednisone treatment in patients with systemic disease.

There have been no systematic investigations of the effects of glucocorticoid treatment on memory in a clinical population despite experimental and clinical evidence that such treatment could cause memory disturbance. We conducted both cross-sectional and longitudinal studies. In Study 1, we administered tests of both hippocampal-dependent explicit memory and hippocampal-independent implicit memory to twenty-five prednisone-treated patients with systemic disease without CNS involvement and 25 matched clinical controls. All treated patients were taking doses of 5 to 40 mg of prednisone daily for at least 1 year. The glucocorticoid-treated group performed worse than the controls on tests of explicit memory, but the groups did not differ on the implicit memory task. Multiple regression analyses suggested that elderly patients are more susceptible to memory impairment with less protracted treatment. The results of Study 2, a prospective, longitudinal study of the effects of prednisone on memory across 3 months of therapy, suggest that even acute treatment can adversely affect memory. The observed alteration in memory was not secondary to inattention, affective disturbance, generalized global cognitive decline, or severity of disease. Results reported here, combined with previous clinical and experimental reports, indicate that the risk of memory impairment should be carefully considered before initiating treatment with glucocorticoids. Conversely, use of glucocorticoids should be considered in the differential diagnosis of memory loss. Finally, the potential benefit of anti-inflammatory treatment in Alzheimer's disease might be counterbalanced by possible iatrogenic memory impairment, at least when synthetic glucocorticoids are considered.

Epidemiologic studies of environmental agents and systemic autoimmune diseases.

Systemic lupus erythematosus and systemic scleroderma are autoimmune diseases thought to have an exogenous trigger. This review summarizes relevant case-control and cohort studies that investigated exogenous sex hormones, silica, silicone, solvents, pesticides, mercuric chloride, and hair dyes as putative risk factors for the development of these diseases. These studies indicate that estrogen replacement therapy in postmenopausal women increases the risk of developing lupus, scleroderma, and Raynaud disease, although the increase in risk is relatively modest. Oral contraceptives may also play a role in disease susceptibility in lupus but not apparently in scleroderma. Environmental endocrine modulators, in the form of pesticides, may represent another opportunity for estrogenlike effects to occur, but there is scant evidence that these agents play a role in human systemic autoimmune disease. Although exposure to silica dust increases the risk of scleroderma in men occupied in the industry, this does not explain most male scleroderma cases. When this exposure was investigated among women, no significant risk was found. Additionally, silicone in implanted devices as well as occupational exposure to silicone-containing compounds did not pose an increased risk among women for scleroderma. The role of solvent exposure has been investigated as a risk factor for scleroderma with mixed findings. One study suggested a potential role in male patients or in those individuals with Scl-70 antibody positivity either male or female. Two other studies were unable to corroborate this finding. Mercuric chloride causes antifibrillarin antibodies and immune complex glomerulonephritis in susceptible mouse strains. Antifibrillarin antibodies, but not glomerulonephritis, occur in a subset of scleroderma patients and preliminary evidence suggests that mercury levels may be higher in this group of individuals. Hair products have been studied as possibly raising the risk of developing lupus, since such products contain an aromatic amine similar to a compound known to cause drug-induced lupus. A 1986 study suggested a positive association, but two subsequent studies did not support this association.

Maternal scleroderma: placental findings and perinatal outcome.

Pregnancy after the onset of scleroderma is uncommon; therefore, placental findings and perinatal outcome have rarely been correlated. The histopathologic features of placentas from 13 pregnancies in eight women with scleroderma were recorded and correlated with the clinical features of the mother and fetus. Adverse perinatal outcome included intrauterine fetal demise in five, and previable or preterm delivery in four. A decidual vasculopathy was seen in 5 of the 13 placentas, four of which were associated with intrauterine fetal demise. Decidual blood vessels in the scleroderma patients were evaluated immunohistochemically for platelet-derived growth factor (PDGF), transforming growth factor beta1 (TGF-beta1), T-helper and T-suppressor lymphocytes, macrophages, immunoglobulin (Ig) M, and IgG, and compared with those from hypertensive and uncomplicated third-trimester pregnancies. The atherotic blood vessels in scleroderma were characterized by mural macrophages and IgM and IgG deposition and were similar to those seen in placentas from hypertensive pregnancies. CD8-positive T cells predominated in normal and hypertensive decidua compared with scleroderma, in which CD4-positive T cells were more frequent. No difference in PDGF or TGF-beta1 staining was found between scleroderma and control groups. In conclusion, decidual vasculopathy is common in scleroderma, is similar to that seen in hypertension, and is associated with poor perinatal outcome. A trend toward a reversed ratio of decidual CD4 to CD8-positive T cells is seen in scleroderma compared with hypertension and uncomplicated pregnancies. PDGF and TGF-beta1 do not appear to be involved in the pathogenesis of decidual vasculopathy in scleroderma.

Scleroderma epidemiology.

The overall incidence and prevalence rates for scleroderma in the United States appear to be stable over the past 2 decades. Age-specific incidence rates are higher in black women than in white women, and diffuse disease is more common in the black population. Risk factors for disease development include female gender and may include HLA-DQ type. Diffuse disease, older age at onset, and early internal organ involvement are risk factors for reduced survival. Genetic factors appear to play a permissive role, whereas as yet undefined environmental factors play a more direct role in disease causation.

Photopheresis and autoimmune diseases.

Although several case reports and case series suggest efficacy for photopheresis in the treatment of autoimmune diseases, few controlled studies have been conducted to test this hypothesis. After a decade of interest, multiple case reports, open trials, and one controlled study, the role of photopheresis in autoimmune disease remains to be established. Controlled multi-center trials in rheumatoid arthritis, SLE, and scleroderma may be costly but are clearly necessary for proper evaluation of this therapy.

The mineralization of elastic fibers and alterations of extracellular matrix in pseudoxanthoma elasticum. Ultrastructure, immunocytochemistry, and X-ray analysis.

Histologic paraffin sections of pseudoxanthoma elasticum (PXE)-involved skin of forearm and axilla were used for histochemistry and immunohistochemical and analytical electron microscopy to study the progressive mineralization in the dermis of patients with PXE. The von Kossa technique identified mineral deposits throughout the reticular PXE dermis. X-ray analysis revealed patterns of calcium and phosphorus deposition in the von Kossa-positive areas, and the immunohistochemical staining using monoclonal antibodies identified increased chondroitin-6-sulfate in these areas when compared with normal skin. Scanning transmission electron microscopy observation combined with X-ray dot mapping show calcium and phosphorus to be codistributed within the mineralized area. This study confirms by new methods the increase in chondroitin-6-sulfate, alterations in elastin and collagen, and a high calcium and phosphorus elemental distribution matching the mineralized area in the PXE dermis.

Assessment of kidney involvement.

Scleroderma renal crisis (SRC) represents the classic manifestation of kidney involvement in SSc. It particularly occurs in patients with early, rapidly progressive, diffuse skin involvement. Its detection requires the assessment of a few core set variables: arterial blood pressure, serum creatinine, and urinalysis. In clinical investigations SSc patients developing arterial hypertension after the disease onset (new onset hypertension) without SRC should also be reported.

Increased dermal elastic fibers in the tight skin mouse.

OBJECTIVE: The tight skin (Tsk-1) mouse has been proposed as a model for systemic sclerosis on the basis of increased accumulation of collagen and glycosaminoglycans in the skin, and by the presence of serum autoantibodies. The genetic basis of the mutation has been identified as a genomic duplication within the fibrillin-1 (Fbn-1) gene that results in a larger than normal Fbn-1 transcript, but the mechanism that leads to dermal fibrosis is unclear Fibrillin molecules associate into a polymer that is coated with elastin molecules to form elastic fibers. To further evaluate the Tsk-1 mouse model of scleroderma, we have studied elastic fibers in the skin of these mice. METHODS: Skin sections obtained from C57BL/6-TSK+ (Tsk-1) and C57BL6-pa/+ (control) mice were stained with Masson's trichrome for evaluation of collagen and Gomori's aldehyde fuchsin stain for elastic tissue. Computer assisted image analysis was performed to quantify differences in histologic sections. RESULTS: Tsk-1 mice had a highly significant increase in the percentage of elastic fibers (19.6%) in the dermis compared to control mice (7.9%) [p < 0.001]. This correlates with the findings in the skin of systemic sclerosis patients where increased elastic fibers have been observed. In addition, an increased level of dermal collagen staining was also observed in the Tsk-1 dermis (82.9%) compared with the level in normal sections (73.7%) [p < 0.01]. CONCLUSION: These data support the use of the Tsk-1 mouse as a model for the connective tissue abnormalities of human scleroderma.

Classification and epidemiology of scleroderma.

Scleroderma is classified as two separate but related entities, a localized form and a systemic form. The classification scheme for morphea presented here is that of Peterson et al, which divides morphea into five categories: plaque, generalized, bullous, linear, and deep. Using this system, these authors estimated the incidence rate of localized scleroderma to be 27 new cases per million population per year. Overall survival was similar to that of the general population. There was a preponderance of female cases (approximately 3:1) for all forms of morphea except for linear scleroderma, which had an even sex distribution. Systemic scleroderma is divided into limited and diffuse disease based on the extent of skin involvement. Recent estimates have placed the incidence rate of systemic sclerosis in the United States at 19 new cases per million adults per year, with an overall prevalence of 240/million adults. The female-to-male ratio is approximately 5:1. The prevalence of scleroderma varies by geographic region and ethnic background and is higher in the United States than in Europe or Japan. Although systemic sclerosis survival has improved over the past two decades, with 5-year survival over 80%, long-term survival is significantly lower than expected, and morbidity is considerable.

Gastric slow waves, gastrointestinal symptoms and peptides in systemic sclerosis patients.

Impaired gastric slow waves, frequent gastrointestinal (GI) symptoms and altered GI peptides have been reported in Scleroderma (SSc) patients. The aim of this study was to investigate the associations among these three important components in GI dysmotility. Seventeen fasted SSc patients underwent four channel surface electrogastrography, measuring % of normal gastric slow waves or dysrhythmia. Patients completed a questionnaire designed by us to assess demographics, upper and lower GI symptoms (symptom presence, frequency and impact on quality of life, QOL), by YES/NO, Likert Scales and Visual Analogue Scales 1-100 mm (called GI Dysmotility Questionnaire, GIDQ) and health-related QOL by SF-36. Fasting plasma vasoactive intestinal peptide (VIP) and motilin levels were measured by peptide immunoassays. There were significant correlations between percentages of gastric dysrhythmias (bradygastria or arrhythmia) and a number of major GI symptoms such as nausea, abdominal bloating and pain. The plasma level of VIP was correlated positively with % dysrhythmia but negatively with % normal slow waves. Motilin was positively correlated with slow wave coupling (coordination). No major differences were noted in the measured peptides or gastric slow waves between limited SSc and diffuse SSc. Correlations were noted between SF-36 domain scores and our GIDQ scores. In SSc patients, gastric dysrhythmias are correlated with certain GI symptoms. Correlations are also noted between plasma VIP/Motilin levels and gastric slow waves. Thus in SSc, gastric dysrhythmias may be predictive of development of certain dyspeptic symptoms. Plasma VIP may be involved in the development of dysrhythmias.

An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis.

OBJECTIVE: To identify genetic associations between allograft inflammatory factor 1 (AIF1) and systemic sclerosis (SSc), or its subsets, using a single nucleotide polymorphism (SNP) in a replicate case-control study. METHODS: The frequencies of alleles and genotypes of an SNP, rs2269475, for the AIF1 gene were examined in two large independent cohorts of SSc patients (n = 1015 total), and compared with two groups of normal controls (n = 893 total). Both cases and controls were stratified by ethnicity (Caucasian, African American and Hispanic) and by autoantibody status [anti-centromere antibodies (ACA) and anti-topoisomerase I antibody (ATA)]. RESULTS: The minor T allele and CT/TT genotype frequencies of the AIF1 SNP were not observed more frequently in SSc patients of the three ethnic groups (individually or combined) when compared with controls. On the other hand, T and CT/TT frequencies were significantly increased in ACA-positive Caucasian SSc patients, and all ACA-positive SSc patients (the three ethnic groups combined), when compared with ACA-negative SSc patients and with normal controls, with odds ratios of approximately 1.5. CONCLUSION: The data demonstrate a genetic association between AIF1 and the ACA-positive subset of SSc. This polymorphism is a non-synonymous substitution and therefore likely to represent an important functional change in AIF1. Since vascular pathology is a prominent feature in ACA-positive SSc patients, the observed association with a vasculotrophic inflammatory gene is biologically plausible and warrants further research.