Onset Of Systemic Sclerosis Research Articles

Clinical and laboratory features dependent on age at onset in Japanese systemic sclerosis

To clarify those clinical characteristics dependent on patient age at onset of Japanese systemic sclerosis (SSc). A total of 329 SSc patients treated at Kanazawa University Hospital were enrolled in the study and subsequently categorized into four subgroups depending on age at SSc onset: childhood-onset, young-onset, normal age-onset, and late-onset. The clinical features at the first visit were compared between groups. Factors that correlated with age at onset were also analyzed. The childhood-onset subgroup was characterized by a higher male:female ratio, higher anti-topoisomerase I antibody (Ab) and anti-U3 RNP Ab levels, a higher frequency of pitting scars, and a lower frequency of anticentromere Ab and interstitial lung disease (ILD). The young-onset patients had an increased frequency of anti-U1 RNP Ab and anti-U3 RNP Ab, overlap with other connective tissue diseases, digital ulcers, and pitting scars and a reduced frequency of anticentromere Ab. Patients with late-onset SSc showed a shorter disease duration and an increased frequency of anti-RNA polymerase Ab. Multiple regression analysis showed that anti-topoisomerase I Ab, anti-U1 RNP Ab, pitting scars, and long disease duration were associated with onset at a younger age, whereas anticentromere Ab and ILD were associated with onset at an older age. The clinical phenotype of SSc in Japanese patients showed a tendency to be dependent on age at onset.

Biological ageing is a key determinant in systemic sclerosis

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation and fibrosis of the skin and internal organs, occurring mainly in females. Although a lot of progress has been made in the discovery of genetic risk factors for SSc, environmental factors triggering onset of SSc have not been identified. This provides a foundation for the involvement of processes related to biological ageing to trigger SSc onset and perpetuation in the genetically susceptible host. Consequently, we have investigated key determinants of biological ageing, namely telomere attrition and the role of telosome proteins in the pathology of systemic sclerosis and how it impacts on individual leukocyte cell subsets. Epigenetic processes, such as telomere attrition have been implicated in SSc [1]. The length of telomeric DNA repeats shortens during replicative ageing of peripheral blood lymphocytes. This process is exacerbated by psychological, sociological and biological determinants [2,3]. As a consequence, telomere length reflects the “miles on the clock” of a given cell type. Proteinaceous components of the associatedtelosome arecomplicit in the sensing, signaling and repair of DNA damage [3]. These have a critical role inprotectingthe cell from excessive DNA damage, by facilitating cellular senescence and apoptosis. This study aimed to evaluate telosome biologyin an independent, clinically well-defined SSc cohorts. Moreover, we aimed to investigate whether there are differences in telomere attrition between different immune cell subsets and if these differences are accompanied by changes in expression of genes involved in telomere functioning.

Cancer in Italian Patients with Systemic Sclerosis

The association between cancer and systemic sclerosis (SSc) is known, although the underlying mechanisms remain unclear and epidemiological data is conflicting. Since no data exist on cancer in Italian SSc, we examined the frequency and characteristics of cancer in an Italian cohort of SSc patients to examine whether clinical and/or laboratory SSc-specific features represent a risk for developing malignancies in these patients. A retrospective chart review was carried out of 112 Italian SSc patients of whom 109 were women 3 and were men, aged 63±13 years; 81 patients had limited SSc, 25 had diffuse SSc and 6 had sine scleroderma SSc. Fifteen cancers were found in 14 patients. The majority (60%) occurred after SSc onset (average 16 years), 40% occurred before the onset of SSc (average 14 years). The most frequent was breast cancer (prevalence: 4.5%, relative prevalence:33.3%), followed by uterine cancer and lymphomas (prevalence: 2.7%, relative prevalence: 20% each). Lung cancer was not observed. Cancers were unrelated with SSc type, autoantibodies, organ involvement and treatments. In conclusion, clinical features do not seem to be linked with the risk of developing cancer in SSc patients. Interestingly, and in contrast with published data, no lung cancer was present in our patients, although lung involvement was observed in the majority of them. This finding, consistent with a lower prevalence of lung cancer in the Italian female general population, and the absence of associations between SSc-specific features and cancer, suggests that genetic and environmental factors might play a pivotal role in cancer risk in these patients.

Malignancies in Italian Patients with Systemic Sclerosis Positive for Anti-RNA Polymerase III Antibodies

To evaluate the frequency of malignancies in Italian patients with systemic sclerosis (SSc) and anti-RNA polymerase III (RNAP III), antitopoisomerase I (topo I), or anticentromere antibodies (ACA); and to characterize the temporal relationship between the 2 diseases, in order to confirm data suggesting a close temporal relationship between the onset of SSc and malignancy in American patients with anti-RNAP III antibodies. From a cohort of 466 consecutive SSc patients, 360 Italians with isolated positivity for anti-RNAP III (n = 16), anti-topo I (n = 101), or ACA (n = 243) were identified. Malignancy cases were divided according to their relationship with SSc onset into 3 categories: preceding, synchronous with, or metachronous to the onset of SSc (diagnosed more than 6 months before; 6 months before to 12 months after; and more than 12 months after onset of SSc, respectively). Malignancies were more frequent in the anti-RNAP III group (7/16 patients), than in the anti-topo I (11/101) and ACA groups (21/243) (p < 0.001). This difference was accounted for by the number of patients with cancer synchronous to the onset of SSc (3/16 in the anti-RNAP III group vs 0/101 in the anti-topo I and 1/243 in the ACA group; p < 0.001), whereas neither the number of malignancies preceding nor those metachronous to the onset of SSc was significantly different between the groups. In a cohort of Italian patients with SSc we observed a significant association between malignancies synchronous to SSc onset and positivity for anti-RNAP III antibodies, similar to that described in American patients with SSc.

Myopathies related to systemic sclerosis: a case–control study of associated clinical and immunological features

Objective: Little is known about systemic sclerosis (SSc)-related myopathy. We aimed to compare the clinical and immunological features of SSc patients with or without associated myopathy.Methods: Forty SSc patients with myopathy, defined by myalgia or muscle weakness associated with creatine kinase (CK) more than five times the upper limit range or myopathic electromyography (EMG) or abnormal myopathology, were identified from the records of four French hospital centres. For each patient, we selected two SSc controls matched for cutaneous SSc form, sex, age at SSc onset, and disease duration. We performed a case–control study testing clinical and immunological SSc-related features for association with myopathy by conditional logistic regression.Results: Muscle and SSc features of patients with myopathy did not differ significantly among the four centres of origin. Only four (10%) patients with SSc-associated myopathy had anti-polymyositis-scleroderma (PM-Scl) antibodies. Case–control univariate analysis revealed that reduced forced vital capacity (FVC) [odds ratio (OR) 3.0, 95% confidence interval (CI) 1.3–34.9], heart involvement, defined as clinical congestive heart failure, left ventricular ejection fraction (LVEF) < 60%, arrhythmia or conductive abnormalities (OR 2.9, 95% CI 1.3–6.5), and scleroderma renal crisis (OR 3.0, 95% CI 1.3–34.9) were significantly more frequent in patients with myopathy than in controls. Two autoantibodies were more frequent in patients with myopathy: anti-PM-Scl (OR 5.0, 95% CI 1.1–23.9) and anti-RNP (OR 6.9, 95% CI 1.1–64.4). Multivariate analysis retained two variables associated positively with myopathy [reduced FVC (OR 3.1, 95% CI 1.3–9.8) and heart involvement (OR 2.5, 95% CI 1.1–7.1)], while anti-centromere antibodies were associated negatively (OR 0.11, 95% CI 0.03–0.53).Conclusion: Heart monitoring of SSc patients with myopathy should be undertaken regularly because of the association of myocardial and skeletal myopathies in such patients.

Life Events and Psychoeducation in Patients with Systemic Sclerosis

Objective: The purpose of this study was to assess the impact of psychological/psychoeducational assessment in pa-tients with systemic sclerosis (SSc). Methods: A diagnostic interview was undertaken in order to investigate any tem-poral connection between an adverse life event and the first appearance of SSc. Following this, the rheumatologist's assessment of subsequent changes in the SSc were noted. The psychoeducation we did, as an adjunct to conventional thoracic duct lymphatic drainage therapy (TDD), started in Dec. 2002, and the primary end point was an improvement in clinical outcome at 1 month after entry. Results: The patients with SSc in the study showed higher percentages of lower education (69.2%) and working class (63.5%), and reported that the most common life event in adults was di-vorce or separation from spouse, while in adolescent was difficult home conditions. A favourable response was noted in all patients who participated in the study; Remission was achieved in 35, while 17 showed some improvement. Conclusions: We conclude that life events were causally related to the onset of SSc and psychoeducation combinated with conventional TDD led to a remission in the majority of patients.

Serologic Profile and Mortality Rates of Scleroderma Renal Crisis in Italy

To analyze clinical and serological characteristics of subjects with scleroderma renal crisis (SRC) in Italian patients with systemic sclerosis (SSc). A retrospective analysis of medical records from 9 Italian rheumatologic referral centers was carried out. All patients with SRC and an available serum sample at the time of crisis were included. Antinuclear antibodies (ANA) by indirect immunofluorescence, anti-topoisomerase (topo) I by enzyme-linked assay (ELISA), anti-RNA polymerases (RNAP) by ELISA for the subunit III, and immunoprecipitation (IP) were performed. Forty-six cases (38 female; 40 diffuse cutaneous SSc) were identified. Mean age at SSc and SRC onset was 52.8 years +/- 13.2 and 55.4 years +/- 11.8, respectively. ANA were present in 44 patients (96%). Anti-topo I antibodies were detected in 30 (65%), anti-RNAP I-III in 7 (15%). No differences emerged between these 2 groups for their main clinical characteristics. The proportion of patients in the anti-RNAP I-III group developing SRC early (< 18 mo) in the course of SSc was significantly higher (p = 0.03). Cumulative survival rates were 64%, 53%, and 35% at 1, 2, and 10 years of followup, respectively. Survival rates of SSc patients significantly differed according to their autoantibody profile, being lower in the anti-topo I than in the anti-RNAP I-III group (p = 0.034). SRC is a rare manifestation of SSc in Italy but it is still associated with severe prognosis. Anti-topo I reactivity was more frequent than anti-RNAP I-III in our patients with SRC and was associated with delayed onset and high mortality rates.

Clinical Features of Scleroderma Patients With or Without Prior or Current Ischemic Digital Ulcers: Post-Hoc Analysis of a Nationwide Multicenter Cohort (ItinérAIR-Sclérodermie)

Digital ulcers are the most frequent vascular manifestations of systemic sclerosis (SSc). Clinical features of patients with prior or current digital ulcers have not been extensively described. This cross-sectional analysis of a large multicenter cohort compared the characteristics of SSc patients with prior or current digital ulcers with those never affected. Patients with prior/current digital ulcers or never affected were identified in the cohort of SSc patients enrolled in the French ItinérAIR-Sclérodermie registry. Rodnan skin scores, pulmonary function test results, and clinical and immunological data were analyzed to identify digital ulcerassociated clinical features. Of 599 SSc patients, 317 had prior or current digital ulcers. These patients were more frequently male, with impaired diffusing capacity for carbon monoxide (DLCO), and higher Rodnan skin scores than patients never affected by digital ulcers. In a multivariate analysis, male gender, early onset of SSc, increased duration of SSc, high Rodnan skin score, and presence of anti-topoisomerase I antibodies (anti-topo I) were associated with prior or current digital ulcers. Comparison of patients with current digital ulcers versus patients never affected indicated that affected patients had increased duration of SSc, impaired DLCO, increased Rodnan score, and younger age at onset of SSc. Male patients with early onset SSc, more severe skin fibrosis, impaired DLCO, and anti-topo I were most likely to exhibit prior or current digital ulcers. Confirmation of these results in a prospective longitudinal study may enable identification of patients at greatest risk of developing digital ulcers, facilitating management of this disabling complication.

Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis: contribution to severe gastrointestinal tract dysmotility

Objective:Patients with systemic sclerosis (SSc) complicated by severe gastrointestinal tract (GIT) dysmotility at an early stage are difficult to treat and mortality is high. To clarify the pathogenesis of GIT...

Watermelon stomach in systemic sclerosis: its incidence and management

To date, there are no large endoscopic studies in systemic sclerosis (SSc), and both prevalence and characteristics of watermelon stomach in SSc have not been determined. To determine the prevalence, clinical presentation, endoscopic appearance, therapy success and long-term outcome in SSc patients with watermelon stomach and make predictions about which SSc patients are at risk for watermelon stomach. Patients and methods From 1990 to 2008, 264 patients were seen for evaluation of SSc. Data were collected as regards patients' characteristics, time of watermelon stomach onset, features, therapy and outcome of watermelon stomach. Fifteen SSc patients (5.7%) exhibited watermelon stomach. SSc onset preceded watermelon stomach manifestations in 13 patients (86.7%). Most patients (86.7%) presented with iron-deficiency anaemia, two other patients experienced gastrointestinal haemorrhage. Gastroscopy disclosed typical 'watermelon stomach' characterized by prominent, erythematous stripes, radiating in a spoke-like fashion from the antrum to the pylorus. All patients received conservative therapy; because of deterioration of watermelon stomach, eight patients (53.3%) underwent endoscopic procedures. During follow-up, five patients (33.3%) exhibited recurrences of watermelon stomach. Our series indicates that watermelon stomach should be considered when unexplained iron-deficiency anaemia occurs in SSc patients. Moreover, because watermelon stomach may be the first manifestation of SSc, patients with unexplained watermelon stomach should systematically undergo physical examination and autoantibody testing to detect the underlying SSc.

Incidence of lymphoma in systemic sclerosis: a retrospective analysis of 218 Hungarian patients with systemic sclerosis

Recent results suggest that B cells may have multiple pathogenic roles in systemic sclerosis (SSc) and there may be increased incidence of B cell lymphomas in SSc. Here, we assessed the prevalence of lymphomas in a large SSc cohort. We analyzed data of 218 Hungarian patients undergoing follow-ups in our institutions between 1995 and 2007. During this follow-up period, there were three SSc patients, who eventually developed B cell lymphoma. The first case is a woman with diffuse cutaneous form of SSc (dcSSc) including pulmonary, cardiac, gastrointestinal, and renal manifestations and anti-topoisomerase I antibody positivity. B cell chronic lymphocytic leukemia (B-CLL) with Zap70 expression (Rai I stage) developed 2 years after the onset of SSc. The second case is a woman with dcSSc presenting with pulmonary, cardiac, and gastroesophageal manifestations. Twenty-one months after disease onset, a chronic small lymphocytic B cell non-Hodgkin's lymphoma was diagnosed from retroperitoneal lymph nodes. Our third case is a woman with dcSSc and no internal organ manifestations. She also developed Zap70-positive B-CLL, stage Rai I 9 months after the onset of SSc. Thus, there were three cases of B cell lymphoma among our 218 SSc patients (1.38%). The association of scleroderma and non-Hodgkin's lymphoma may be a rather uncommon feature; however, the incidence of lymphoma among Hungarian SSc patients may be 1.9-2.5 times higher than that in the general population. In our three patients, B cell lymphoma developed within 2 years after the onset of SSc. Altered B cell function implicated in the pathogenesis of SSc may lead to the development of lymphoid malignancies.

Sclerosing skin disorders in association with multiple sclerosis. Coincidence, underlying autoimmune pathology or interferon induced?

Objectives:To describe and analyse the manifestation of sclerosing skin disorders in patients with multiple sclerosis (MS).Case reports:We describe three patients with relapsing-remitting MS who developed skin sclerosis while receiving interferon...

Autopsy case of systemic sclerosis with severe pulmonary hypertension

We report an autopsy case of a 60-year-old Japanese woman who died 27 years after the onset of systemic sclerosis and 4 years after the diagnosis of pulmonary arterial hypertension. Oral administration of bosentan was effective in improving her dyspnea but had to be stopped because of drug eruption along with fever and eosinophilia. During hospitalization for the treatment of multiple skin ulcers and gangrene, she suddenly complained of severe respiratory difficulty, followed by bradycardia, unconsciousness and cardiopulmonary arrest. The autopsy revealed concentric intimal proliferation and marked luminal obstruction in many small- and medium-sized vessels of the lungs. In addition to right ventricular hypertrophy and dilatation, similar vascular changes were also present in the myocardial tissue and the atrioventricular node. In our patient, these marked vascular changes caused pulmonary hypertension followed by the severe right heart failure. The vascular changes in the atrioventricular node were suspected as the cause of a fatal arrhythmia leading to sudden death.

The X chromosome and systemic sclerosis

Similar to the majority of autoimmune rheumatic diseases, systemic sclerosis is characterized by a striking female predominance superimposed on a predisposing genetic background. At least two genetic mechanisms have been proposed that play a role in susceptibility to systemic sclerosis; firstly the maintenance of immune tolerance via genes on the X chromosomes and, secondly, fetal microchimerism. Based on these lines of evidence, experimental efforts have been most recently dedicated to investigating the role of X chromosome abnormalities (i.e. monosomy rates and inactivation patterns) in autoimmunity. We will review herein the most recent data on the role of the X chromosome in systemic sclerosis onset and discuss the potential implications. Women with systemic sclerosis manifest an enhanced rate of X monosomic cells in peripheral blood compared with healthy age-matched women. Furthermore, a severely skewed X chromosome inactivation pattern is found in women with systemic sclerosis. These observations, reproduced in other female-predominant autoimmune diseases, strongly support the role of the X chromosome in conferring susceptibility to tolerance breakdown and open novel scenarios to emphasize the unknown etiopathogenesis of systemic sclerosis. The implications of these findings will be discussed.

Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement

Background: Isolated pulmonary hypertension (iPHT) is a near‐fatal consequence of systemic sclerosis (SSc); in female patients, the risk of its development is increased during the post‐menopausal period, when the protective effects of oestrogens on the endothelium decrease. In many animal and human models, hormone replacement therapy (HRT) and oestrogen administration proved efficacious in counteracting many mechanisms that might be implicated in the pathogenesis of iPHT. Accordingly, it has been hypothesized that HRT might help to prevent the development of iPHT.Methods: A retrospective cohort study was conducted on 61 SSc patients with the limited cutaneous form of the disease and no sign of pulmonary hypertension on echocardiogram (pulmonary artery pressure, PAP>35 mmHg) at the time of menopause. All the patients had to be stably treated with calcium‐channel blockers and not to have risk factors for secondary PHT throughout the duration of the observational period.Results: Twenty patients (32.8%) received HRT for a mean of 6.7±3.7 years. None of these patients developed iPHT after a mean of 7.2±3.5 years from menopause, whereas eight out of 41 patients not receiving HRT (19.5%) developed iPHT after a similar time period (7.5±3.9 years, p = 0.032). These rates were not explained by differences between the two groups with respect to autoantibodies, age, age at onset of SSc, diffusing capacity of the lung for carbon monoxide (DLCO) at menopause, or duration of therapy with calcium‐channel blockers.Conclusion: HRT administration may be effective in SSc post‐menopausal women, preventing the development of iPHT.

Association between systemic sclerosis and breast cancer: eight new cases and review of the literature

Several studies have demonstrated an increased frequency of cancer in patients with systemic sclerosis (SSc), specially lung and breast cancers. The pathogenesis of the association between SSc and cancer is not fully established. The aim of this study was to describe new cases of the association between SSc and breast cancer and to perform a review of the literature. We retrospectively studied the medical files of eight patients followed in our institution for SSc and breast cancer. We analyzed them with data available in the literature for a total of 46 patients. Cutaneous extension of SSc was clearly mentioned in 17 cases: the SSc was limited in 10 cases and diffuse in 7 cases The median age at the diagnosis of cancer was 54 years (range: 40-71). The median duration between SSc onset and breast cancer diagnosis was 11.5 months (range: 0-288). The duration between SSc onset and breast cancer diagnosis was < or = 12 months in 27 of 44 patients (61.4%), and in 11 (25%) of them the diagnosis of both diseases was made simultaneously. It was clearly mentioned for 35 patients whether the diagnosis of breast cancer was made before or after the onset of SSc. The diagnosis of breast cancer was made before SSc onset in 17 of 35 patients (48.6%) and after SSc onset in 18 of 35 patients (51.4%). For 33 patients, the follow-up was available: 18 (54.5%) died, 11 (33.3%) of them within the 1st year after the diagnosis of the cancer. For none of the patients did the anticancer treatment improve the SSc. The close temporal relationship between SSc onset and breast cancer diagnosis is highly suggestive of a pathophysiological link. SSc is probably not a paraneoplastic disease since the anticancer treatment has no influence on the evolution of SSc. However, it can be suggested that SSc could be a disease facilitating breast cancer and/or metastases development.

Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis.

Microvascular lesions are a predominant feature in systemic sclerosis (SSc) and seem to play a central pathogenetic role. Recently, we graded scleroderma microangiopathy by nailfold videocapillaroscopy (NVC) into three NVC patterns (early, active and late). The aim of the present study was to confirm, in a larger number of SSc patients, the presence of three patterns of microvascular damage, and to detect any possible relationship between these patterns and both specific serum autoantibodies and the subsets of cutaneous involvement. Two hundred and forty-one consecutive patients (227 women and 14 men) affected by SSc were recruited. One hundred and forty-eight patients were affected by limited cutaneous SSc (lSSc) and 93 patients by diffuse cutaneous SSc (dSSc). The ages at onset of Raynaud's phenomenon (RP) and SSc, the durations of RP and SSc, ANA and antitopoisomerase I (anti-Scl70) and anticentromere (ACA) antibodies were investigated in all patients. The SSc patients were subdivided on the basis of the NVC pattern into three groups. A statistically significant correlation was found between the NVC patterns and the durations of both RP and SSc (P<0.001). Enlarged and giant capillaries, together with haemorrhages, constituted the earliest NVC finding in SSc (early NVC pattern). These abnormalities were mostly expressed in the active NVC pattern. Loss of capillaries, ramified capillaries and vascular architectural disorganization were increased in the late NVC pattern. Age and the duration of both RP and SSc were lower in 24 patients complaining of RP alone. Anti-Scl70 antibodies were statistically less frequent in the early vs both the active and the late NVC pattern, whereas no significant correlation was found between the presence of anti-Scl70 antibodies and the duration of either RP or SSc. ACA positivity was more frequent in patients with longer RP duration. Patients with lSSc had shorter SSc duration and showed the early or active NVC pattern more frequently. Conversely, patients with dSSc showed longer disease duration and mostly showed the late NVC pattern. NVC is an appropriate tool for differential diagnosis between primary and secondary RP through the clear recognition of the early NVC scleroderma pattern. This study confirms, in a large number of SSc patients, the existence of three distinct NVC patterns that might reflect the evolution of SSc microangiopathy. The presence of anti-Scl70 antibodies seems be related to earlier expression of the active and late NVC patterns of SSc microvascular damage. The presence of ACA seems to be related to delayed expression of the late NVC pattern.

Disfunção erétil em homens com esclerose sistêmica

O objetivo deste trabalho é analisar a prevalência da disfunção erétil (DE) e a utilidade do Índice Internacional de Função Erétil (IIFE) na investigação da DE em pacientes com esclerose sistêmica (ES). Quinze homens com ES foram questionados acerca dos sintomas da DE e submetidos ao questionário de IIFE. Seus prontuários foram revisados para identificar outras possíveis causas da DE. Os pacientes estudados eram predominantemente caucasóides e tinham ES difusa. DE foi referida por 67% dos pacientes, iniciando-se, em média, 29 meses após o início da ES; quatro pacientes relataram início concomitante da DE e da ES. O diagnóstico da DE pelo IIFE e por interrogação direta foi concordante em todos os pacientes. Não foi encontrada associação nítida entre DE e extensão do envolvimento cutâneo, envolvimento visceral, drogas, escore cutâneo total e duração da doença. Cinco pacientes com DE também tinham outras causas de impotência. A DE afeta um grande porcentual de homens acometidos por esclerose sistêmica e o IIFE pode ser um instrumento válido em sua avaliação. A alta incidência da DE em jovens com ES e a eventual concomitância do início da ES e da DE enfatizam a necessidade de estudos posteriores sobre uma provável relação causal.

Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis.

To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1alpha and MIP-1beta in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP-1alpha, and MIP-1beta were significantly elevated in patients with SSc compared with normal controls. Elevated serum levels of MCP-1 and MIP-1alpha significantly correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular endothelial cells in the sclerotic skin of SSc patients, but not expressed in any control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells and endothelial cells significantly correlated with earlier onset of SSc. Thus, MCP-1, MIP-1alpha and MIP-1beta may be involved in the disease process, possibly by augmenting leucocyte migration into the affected tissues in SSc. Furthermore, MCP-1 and MIP-1alpha may play an important role in the development of pulmonary fibrosis in SSc.

Correlates of the disability index of the health assessment questionnaire: a measure of functional impairment in systemic sclerosis.

To evaluate functional impairment in systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma at the time of entry into a trial of a therapeutic intervention (D-penicillamine). The 20-item Disability Index of the Health Assessment Questionnaire (HAQ-DI) was administered to 134 patients as they entered a multicenter trial of high-dose versus low-dose D-penicillamine. All patients had diffuse SSc of < 18 months' duration. SSc patients who had severe organ system involvement and recent renal crisis and who were receiving prednisone > 10 mg/day were excluded from entry. Logistic regression modeling was used to examine the relationship of HAQ-DI scores to SSc skin and organ system involvement. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to estimate effects. The mean (+/-SD) HAQ-DI score at entry was 1.04 +/- 0.67. Fifty-three percent of patients had HAQ-DI scores > or = 1.0 (signifying moderate-to-severe functional impairment). Multivariate logistic regression demonstrated that impaired fist closure > or = 23 mm (OR 4.24, 95% CI 1.68-10.70), reduced handspread < or = 175 mm (OR 4.5, 95% CI 1.80-11.24), joint tenderness count > or = 1.0 (OR 2.93, 95% CI 1.16-7.40), age > or = 43 years (OR 2.44, 95% CI 1.01-5.95), platelet count > or = 330,000/mm3 (OR 2.30, 95% CI 0.96-5.57), and female sex (OR 2.43, 95% CI 0.77-7.73) were the most important correlates of HAQ-DI scores > or = 1.0. Increased HAQ-DI scores at baseline were correlated with reduced fist closure, reduced hand-spread, elevated platelet count, presence of tender joints, older age, and female sex. The most important contributor to functional impairment was hand dysfunction. Even within the first 18 months after SSc onset, moderate-severe functional impairment (HAQ-DI scores > or = 1.0) was frequent (53%) in this group of diffuse SSc patients. In early diffuse SSc, the self-administered HAQ-DI is therefore a valuable assessment of function that correlates with objective physical and laboratory measures of SSc disease involvement. Abnormal HAQ-DI scores may support patient claims of functional impairment, help to focus physician attention on implementing measures to reduce functional impairment, and be useful in reflecting the disease course over time.