Anti-carbonic anhydrase II antibodies in systemic sclerosis: association with lung involvement

Carbonic anhydrase II (CAII) is expressed on alveolar epithelium and participates to CO2 elimination, fluid secretion and post-capillary pH regulation. CAII is overexpressed in animal models of lung fibrosis in sites of epithelial injury. Autoantibodies directed against CAII (anti-CAII) have been described in sera from patients affected by systemic sclerosis (SSc), but no study focused on their clinical associations in this disease. The aim of this study was to assess the presence of anti-CAII in sera of SSc patients and to investigate their association with lung involvement. We performed ELISA to detect anti-CAII in 34 SSc patients who underwent pulmonary function tests (PFT) and Doppler echocardiography. We found increased prevalence and significantly elevated serum levels of anti-CAII in SSc patients affected by restrictive lung disease (RLD) compared to SSc patients without lung involvement and healthy controls. These findings suggest both a possible pathogenic role of anti-CAII in the development of lung damage and a potential clinical utility as serological marker of pulmonary involvement in SSc patients.     

Anti-carbonic Anhydrase II Antibodies in Systemic Sclerosis: Association with Lung Involvement

Carbonic anhydrase II (CAII) is expressed on alveolar epithelium and participates to CO 2 elimination, fluid secretion and post-capillary pH regulation. CAII is overexpressed in animal models of lung fibrosis in sites of epithelial injury. Autoantibodies directed against CAII (anti-CAII) have been described in sera from patients affected by systemic sclerosis (SSc), but no study focused on their clinical associations in this disease. The aim of this study was to assess the presence of anti-CAII in sera of SSc patients and to investigate their association with lung involvement. We performed ELISA to detect anti-CAII in 34 SSc patients who underwent pulmonary function tests (PFT) and Doppler echocardiography. We found increased prevalence and significantly elevated serum levels of anti-CAII in SSc patients affected by restrictive lung disease (RLD) compared to SSc patients without lung involvement and healthy controls. These findings suggest both a possible pathogenic role of anti-CAII in the development of lung damage and a potential clinical utility as serological marker of pulmonary involvement in SSc patients.     

系统性硬化症肺部受累的胸部高分辨力CT表现特点分析

目的分析系统性硬化症（SSc）肺部受累时胸部高分辨力计算机体层摄影术（HRCT）表现,提高对SSc肺部损害的认识。方法选择2009年1月~2012年6月明确诊断的45例SSc患者,其中男性9例,女性36例;年龄为20~80岁,平均年龄58.50岁。回顾其胸部HRCT表现,并进行HRCT评分,对其胸部HRCT特点进行总结分析。结果胸部HRCT证实,存在间质性肺疾病患者为32例（71.1%）,其中34.4%患者（11/32）无呼吸系统症状。SSc肺部受累在HRCT图像上以磨玻璃影（81.3%）和网格影（56.3%）最为常见,分布以双下肺（71.9%）及胸膜下分布（81.3%）为主。对两侧的上中下肺野的HRCT评分进行t检验发现双侧病变差异无统计学意义（P〉0.05）,呈对称性分布。对上中下肺野的HRCT评分进行两两比较,下肺野受累最明显,中野次之,上野受累最少（P〈0.05）。在存在肺间质受累的患者中,弥漫型患者的HRCT评分（8.82±5.56）与局限型患者的评分（8.73±5.61）间差异无统计学意义（P〉0.05）。肺外胸部脏器受累包括肺动脉增宽、胸膜病变、心包积液、纵隔淋巴结肿大、食管扩张。肺动脉增宽33.3%（15/45）,弥漫型患者中肺动脉增宽的发生率与局限型患者的发生率差异无统计学意义;有雷诺现象者的肺动脉增宽的发生率高（15/34 vs 0/11;P=0.005）。结论胸部HRCT对SSs的肺、胸膜、食道、肺动脉的评估均有较高价值,其中肺间质受累是最为常见的,对称性分布、双下肺突出的间质性病变为其主要特点。     

Vascular complications of scleroderma

Systemic sclerosis (SSc) is a multiorgan disease characterized by injury to vascular wall and extensive damage of the microvessels. The injury of the vascular wall is characterized by the formation of megacapillaries and avascular areas. The reduced capillary density leads to clinical manifestations such as digital ulcers. These lesions are extremely painful and lead to substantial functional disability. Management of digital ulcers includes non-pharmacologic and pharmacologic modalities. Despite the reduced blood flow and reduced partial oxygen pressure levels, there is paradoxically no evidence for a sufficient angiogenesis in the skin of patients with SSc. Angiogenesis is strongly disturbed in SSc, as demonstrated by Nailfold Video-Capillaroscopy changes, the damage of the vessels evolves progressively from early to late stages and is characterized by different morphological aspects. Almost all patients develop Raynaud's phenomenon which, together with structural vasculopathy, results in ulceration and critical digital ischemia. Many of the severe internal organ complications of SSc are vascular, including pulmonary arterial hypertension (PAH) and scleroderma renal crisis. Structural vascular damage occurs in many vascular beds and contribute to pulmonary, renal, cardiac and gastrointestinal complications. SSc has a high case-specific mortality due to organ-based complications including PAH, lung fibrosis, renal failure and involvement of the gastrointestinal tract.     

N-TproBNP as Biomarker in Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue fibrosis affecting the skin and internal organs, fibroproliferative vasculopathy, and autoimmune activation. SSc still heralds a poor prognosis with significant morbidity and mortality. Early detection of organ involvement is critical as currently available treatments are most effective when started early. Many candidate biomarkers have been investigated in the past two decades. However, despite the enormous efforts, no accurate tool to predict the pattern of organ involvement and to assess disease activity has been yet identified. The N-terminal fragment of probrain natriuretic peptide (N-TproBNP) is a neurohormone released by ventricular myocytes in response to pressure overload. N-TproBNP is highly relevant for diagnosis, prognosis, and prediction of pulmonary arterial hypertension in SSc. Moreover, several studies support its potential benefit for cardiac assessment of scleroderma patients. Conversely, the role of N-TproBNP as surrogate marker of pulmonary fibrosis and skin involvement is much less clear. We provide an extensive review of the studies that have previously investigated the role of N-TproBNP as candidate biomarker in scleroderma manifestations, presenting also the findings of a recent study we conducted in a cohort of 87 SSc patients.     

Distinctive autoantibody profile in Mexican Mestizo systemic sclerosis patients

Systemic sclerosis (SSc) shows variable clinical expression among different ethnic groups. Herein, we describe the clinical features, prevalence of organ involvement, and autoantibody profile in Mexican Mestizo SSc patients and we compare them with patients from other ethnic groups.We included 139 SSc patients. They underwent clinical evaluation and were tested for antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-topoisomerase I, anti-RNA polymerase III, anti-U1 RNP, anti-U3 RNP, anti-U11/U12 RNP, anti-Th/To, anti-PM-Scl, anti-Ku, antinucleosome, anti-double-stranded DNA (dsDNA), anti-Sm, anti-SSA, and anti-SSB antibodies. Female predominance (93.5%) was noted; 56.8% of patients had limited cutaneous SSc; 91% had peripheral vascular involvement; 70% had joint involvement; 27% had musculoskeletal damage; 66% had gastrointestinal involvement; 41% had interstitial lung disease; 32% had pulmonary arterial hypertension (PAH); 11% had cardiac involvement; and in 1.4% renal involvement was observed. Our patients showed lower frequency of renal crisis and higher frequency of PAH than patients from other ethnic groups; also they showed higher frequency of ACA than Japanese and African American patients, higher frequency of anti-topoisomerase I than Caucasian and African American patients, higher frequency of anti-PM-Scl and anti-Ku and lower frequency of anti-RNA Pol III than the other ethnic groups. High frequencies of antinucleosome (41%) and anti-dsDNA (63%) were identified. SSc-specific autoantibody frequencies are different in our patients and in those from other ethnic groups; associations of autoantibodies with clinical manifestations are confirmed in our patients. Ethnicity and the interaction of gene and environmental factors may influence the clinical picture and autoantibody profile in SSc patients.     

Distinctive autoantibody profile in Mexican Mestizo systemic sclerosis patients

Systemic sclerosis (SSc) shows variable clinical expression among different ethnic groups. Herein, we describe the clinical features, prevalence of organ involvement, and autoantibody profile in Mexican Mestizo SSc patients and we compare them with patients from other ethnic groups.We included 139 SSc patients. They underwent clinical evaluation and were tested for antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-topoisomerase I, anti-RNA polymerase III, anti-U1 RNP, anti-U3 RNP, anti-U11/U12 RNP, anti-Th/To, anti-PM-Scl, anti-Ku, antinucleosome, anti-double-stranded DNA (dsDNA), anti-Sm, anti-SSA, and anti-SSB antibodies. Female predominance (93.5%) was noted; 56.8% of patients had limited cutaneous SSc; 91% had peripheral vascular involvement; 70% had joint involvement; 27% had musculoskeletal damage; 66% had gastrointestinal involvement; 41% had interstitial lung disease; 32% had pulmonary arterial hypertension (PAH); 11% had cardiac involvement; and in 1.4% renal involvement was observed. Our patients showed lower frequency of renal crisis and higher frequency of PAH than patients from other ethnic groups; also they showed higher frequency of ACA than Japanese and African American patients, higher frequency of anti-topoisomerase I than Caucasian and African American patients, higher frequency of anti-PM-Scl and anti-Ku and lower frequency of anti-RNA Pol III than the other ethnic groups. High frequencies of antinucleosome (41%) and anti-dsDNA (63%) were identified. SSc-specific autoantibody frequencies are different in our patients and in those from other ethnic groups; associations of autoantibodies with clinical manifestations are confirmed in our patients. Ethnicity and the interaction of gene and environmental factors may influence the clinical picture and autoantibody profile in SSc patients.     

Mucosal‐associated Invariant Cells are Deficient in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease, characterized by fibrosis of the skin and other organs, vascular impairment and deficient immune responses. Mucosal‐associated invariant T cells (MAIT) have been involved in various inflammatory and autoimmune diseases. The aims of this study were to determine the frequencies of MAIT cells in the blood of patients with systemic sclerosis (SSc) and to compare their distribution in different types of SSc. Blood samples from patients with SSc and healthy controls were examined by flow cytometer to analyse the frequencies of MAIT and γδ T cells. We demonstrate that in SSc the frequencies and absolute numbers of MAIT and γδ T cells are significantly reduced in comparison with healthy controls. MAIT and γδ T cells did not correlate with C‐reactive protein, BNP, pulmonary involvement or median skin fibrosis scale, steroid amount or disease duration. In addition, MAIT and γδ T cells decrease did not stratify with gender, interstitial lung disease or active digital ulcers. Functional studies are necessary to determine the signification of MAIT cells decrease in systemic sclerosis.     

Interstitial Lung Disease of Systemic Sclerosis

Fibrosis of the pulmonary parenchyma is a frequent and serious complication of scleroderma (systemic sclerosis, SSc), resulting in significant morbidity and mortality. During the past decade data have accumulated in support of an inflammatory process affecting the alveoli and distal airways that culminates in irreversible fibrosis in many SSc patients. Recent findings indicate the presence of lung fibroblasts with altered phenotype and biologic activity (myofibroblasts), perhaps arising from the influence of cytokines on resident lung fibroblasts. Acute-phase inflammatory cytokines such as IL-1α, TNF-α, MlP-1α, IL-8 and RANTES are increased in SSc bronchoalveolar lavage (BAL) fluid, as is thrombin, a potent mitogen for lung fibroblasts. Chronic-phase inflammatory and fibrogenic cytokines such as PDGF and TGF-β are also present in increased amounts in SSc BAL fluid. The inciting event(s) and the process(es) leading to the perpetuation of fibrosis in SSc are unknown. Treatment of SSc lung disease has been empiric and generally disappointing, and it is likely that effective treatment awaits a better understanding of the biological events that regulate collagen and other extracellular matrix synthesis.     

Epithelioid hemangioendothelioma with multiple organ involvement

Epithelioid hemangioendothelioma is a rare vascular neoplasm of uncertain malignant potential. Various reports document metastatic or concurrent epithelioid hemangioendothelioma in several sites, most commonly with combined lung and liver involvement. The concurrent involvement of multiple sites at presentation may cause diagnostic problems because epithelioid hemangioendothelioma can mimic other neoplastic processes. Although it is a chemo-resistant disease, chemotherapy is usually advised for patients with metastatic or concurrent involvement. Here we document the presentation, treatment, and outcome of two cases with concurrent involvement of the lung and liver.     

Lung involvement in systemic lupus erythematosus (SLE)--own experience

Pulmonary disorders in systemic lupus erythematosus are frequent and sometimes they are the first symptoms of the disease. SLE may cause a variety of clinical presentations and pathologic patterns, which can be difficult to diagnose. We observed 11 patients (9 women and 2 men) with pulmonary manifestations of SLE during last 18 years in our department. Mean age of patients was 47.7 +/- 13.4 years. There were no patients with drug induced SLE. Interstitial lung diseases (7/11) acute or chronic and pleural involvement (5/11) were the most frequent clinical presentation. In three cases airway disease presented as reduction of FEV1%VC index was detected. In one case "shrinking lung" syndrome was confirmed by muscle function (diaphragm relaxation time) and lung function tests. Pulmonary hypertension confirmed by echocardiography, was associated with interstitial lung disease or vasculitis. Six cases representing different lung involvement pattern of SLE were described in details.     

Increased IL-6 and IL-8 in bronchoalveolar lavage fluids (BALF) from patients with sarcoidosis: correlation with the clinical parameters

A variety of cytokines have been implicated in the pathogenesis of pulmonary sarcoidosis, but the exact roles of IL-6 and IL-8 are not yet clear. We studied these cytokine levels in BALF from patients with pulmonary sarcoidosis, idiopathic pulmonary fibrosis (IPF), systemic screlosis (SSc) with interstitial lung disease and control subjects. IL-6 and IL-8 levels were significantly elevated in sarcoidosis, IPF and SSc with interstitial lung disease compared with control subjects. Subjects with sarcoidosis had significantly increased levels of both cytokines compared with controls when the cytokine values were corrected by the total albumin content and the two cytokine levels correlated with each other (r=0.876). BALF IL-6 levels correlated with percent lymphocytes and percent CD3⁺ cells. Moreover, when sarcoidosis patients were divided into three groups, those who needed steroid therapy or had progressive disease showed increased cytokine levels in BALF over stable or improved patients. These observations suggest that locally derived IL-6 and IL-8 were increased in sarcoidosis and correlated with activity of this granulomatous lung disease.     

Glutathione S-transferase genotypes in systemic sclerosis and their association with clinical manifestations in early disease

The glutathione S-transferases (GSTs) are a family of enzymes involved in limiting oxidative damage to tissues. Null alleles for one or more of the GST enzymes, especially GSTM1, reportedly occur more frequently in patients with Sj?gren's syndrome and systemic lupus erythematosus who possess certain autoantibodies. Because systemic sclerosis (SSc) is a disease in which oxidative damage has been hypothesized to contribute both to immune dysfunction and tissue damage, we sought to determine if patients from a multi-ethnic cohort of SSc patients with early disease (< or =5 years) were more likely than ethnically-matched normal controls to have null alleles for GSTM1 (M1) and/or GSTT1 (T1), and if the null allele status correlated with any major disease features. The data show that while M1 and T1 null genotypes were not significantly increased in SSc compared to ethnically matched controls, their frequencies (especially T1 nulls) were significantly higher among SSc patients with hypertension and pulmonary involvement. This suggests that GST genotype may be a genetic factor that contributes to clinical disease expression in SSc.     

Pulmonary involvement by Niemann-Pick disease. A report of six cases

AIMS: Although pulmonary involvement is a known cause of morbidity in Niemann-Pick disease, histological features in the lung are not well characterized. The purpose of this study is to document the histological features seen in pulmonary involvement by types B and C Niemann-Pick disease and to correlate them with clinical and imaging data. METHODS AND RESULTS: Surgical lung biopsies from six patients (four with type B and two with type C disease) were reviewed and all showed diffuse endogenous lipid pneumonia, with lesser involvement of the interstitium by fibrosis and foamy macrophage accumulation. In type B disease only, there was also fine cytoplasmic vacuolation within the cytoplasm of ciliated epithelial cells. Neither disease showed foamy changes within pneumocytes. One patient had a bronchial cast removed on whole lung lavage. Electron microscopy showed abnormal lamellar inclusions within lysosomes of affected cells in type B disease. In patients with type C disease, biopsies were undertaken as part of investigations into acute respiratory failure in the context of multiorgan systemic presentation. Three patients with type B disease had clinical disease limited to the lung, all adults (mean age of 40 years) with unexplained diffuse parenchymal lung disease and mainly ground-glass shadowing on high-resolution computed tomography. CONCLUSIONS: Niemann-Pick disease should be considered for any patient with unexplained diffuse endogenous lipid pneumonia, even when disease is limited to the lungs and presentation is during adulthood.     

中国系统性硬化症患者硬皮病相关自身抗体的检测及其临床意义

目的 检测中国系统性硬化症(SSc)患者血清中硬皮病相关自身抗体-抗Sol-70抗体、抗着丝点抗体(ACA)和抗RNA多聚酶Ⅲ抗体(ARA),分析其与各种临床表现之间的关系.方法 序贯纳人入选欧洲抗风湿病联盟硬皮病实验研究组(EULAR Scleroderma Trial and Research Group,EUSTAR)的135例巾国SSc患者,分别用线性免疫印迹法、免疫双扩散法和间接免疫荧光法检测ARA、抗Scl-70抗体、ACA在患者血清中表达水平,并进一步分析自身抗体与患者各种临床表现之间的相关性.结果 在135例SSc患者中抗Sel-70、ACA、ARA的阳性率分别为49 6%、13 3%和8.9%.抗Scl-70抗体阳性组患者的病程显著短于阴性组[(71±59)个月vs(90±103)个月,P=0 041],肺问质病变的患病率亦显著高于阴性组(P=0.031),但阳性组肺动脉高压的患病率显著低于阴性组(P=0 042),修订的Rodnan皮肤硬化评分(P=0 008)、面颈部皮肤硬化(P=0.002)、肘/膝关节远端皮肤硬化(P=0.004)以及指端凹陷性瘢痕/指垫消失的发生率(P=0.01)均显著高于阴性组;ACA附性组患者的病程长于阴性组,差异具有统计学意义[(90±107)个月vs(69±64)个月,P=0.036],肺间质病变的患病率显著低于阴性组(P=0 045),IgM水平亦显著低于阴性组(P=0 045);ARA阳性组和阴性组患者的病程等各项临床指标差异均无统计学意义,但阳性组血清肌酐和尿素氨水平显著高于阴性组(P＜0.001).ACA和ARA患者各项皮肤硬化指标在阳性组和阴性组差异均尤统计学意义.结论 硬皮病特异相关的自身抗体与不同的临床表现紧密相关,检测此类抗体可能有助于SSc的诊断、脏器受累和预后评估.这些自身抗体在中国SSc患者的临床相关性可能不同于其他地区的SSc患者.

Abstract：

Objective To detect the expression of scleroderma-related autoantibodies, such as anti-Scl-70, anli-centromere antibody ( ACA)and anti-RNA polymerase Ⅲ ( ARA) , and their relationship with clinical features in Chinese systemic sclerosis (SSc) patients. Methods One hundred and thirty-five Chinese SSc patients from the clinical database of the Scleroderma Trials and Research Group proposed by European League Against Rheumatism's Scheroderma Trial and Research Group( EUSTAR) were consecutively enrolled. The expression of ARA, anti-Scl-70 and ACA were detected through linear immunoblotting, double immunodiffusion and indirect irnmunofluorescence, respectively. The relevance between the existing of autoantibodies and clinical manifestations was analyzed statistically. Results Among the 135 Chinese SSc patients, the prevalence of anti-Scl-70, ACA, ARA were 49. 6% , 13.3 % and 8.9% respectively. Patients with anti-Scl-70 antibody had significantly shorter disease course [(71 ±59) month vs (90 ± 103) month, P = 0.041] , higher proportion of interstitial lung disease ( P = 0. 031) but lower of pulmonary arterial hypertension (P =0.042). Modified Rodnan's skin score (P=0.008) and prevalence of facial and cervical cutaneous sclerosis (P = 0. 002) , distal (to elbow/knee ) cutaneous sclerosis ( P = 0. 004 ) and digital pitting scarring/disappear of digital pad were all significantly higher in anti-Scl-70 positive group. Patients with AC A had longer disease course ( P = 0. 036) , lower IgM level ( P = 0. 045) and were less prevalent of interstitial lung disease ( P =0. 045). Patients with ARA had higher serum creatinine and urea nitrogen level ( P ＜ 0.001) although otherwise features had unremarkable differences. Conclusion Scleroderma-related autoantibodies have relevance with different clinical manifestation and detection of these autoantibodies may be helpful to the diagnosis of SSc, organ involvement evaluation and predicting outcomes. The clinical relevances of autoantibodies in Chinese SSc patients may differ from other areas or races.     

Predictors of morbidity and mortality in early systemic sclerosis: Long-term follow-up data from a single-centre inception cohort

Objectives

To determine predictors of morbidity and mortality in systemic sclerosis (SSc) in a long-term follow-up of an inception cohort of early SSc patients.

Distribution and antigen specificity of anti-U1RNP antibodies in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a generalized connective tissue disease which is characterized by the presence of several autoantibodies. To determine the prevalence and antigen specificity of anti-U1RNP antibodies (anti-U1RNP) in patients with SSc, serum samples from 223 patients with SSc, 117 patients with systemic lupus erythematosus (SLE), 18 patients with mixed connective tissue disease (MCTD) and 40 healthy control subjects were examined by indirect immunofluorescent analysis (IIF), double immunodiffusion, and immunoblotting using nuclear extract of HeLa cells. Eighteen of the 223 (8%) serum samples from patients with SSc were shown to be positive for anti-U1RNP. The frequency of anti-U1RNP positivity in limited cutaneous SSc (14%) was significantly higher than that in those with diffuse cutaneous SSc (3%). Anti-Sm antibodies were detected in patients with SLE positive for anti-U1RNP, but not in those with SSc positive for anti-U1RNP or those with MCTD. Immunoblotting demonstrated that anti-70-kD antibodies were detected more often in patients with SSc positive for anti-U1RNP and in those with MCTD than in those with SLE. Furthermore, anti-U1RNP was closely correlated with pulmonary fibrosis and joint involvement in patients with SSc. These results suggest that anti-70-kD antibodies are useful in the classification of patients with anti-U1RNP.     

核不均一性胞核核糖核蛋白Ⅰ(hnRNPI)抗原表位在系统性硬化症中临床意义的研究

目的探讨核不均一性胞核核糖核蛋白I(hnRNPI)抗原表位多肽在系统性硬化症(systemic sclerosis,SSc)中的临床意义,初步建立简便快捷的ELISA检测方法,为系统性硬化症的早期诊断寻找新的临床指标。方法根据已知的hnRNPI蛋白的氨基酸序列,应用不同的蛋白质抗原表位图谱分析软件对其进行表位分析,经比对筛选后,化学合成hnRNPI短肽序列2个,分别命名为I-1_(264-292)及I-2_(441-461),作为抗原对临床上包括硬皮病在内的多种结缔组织病患者血清相应抗体进行ELISA检测,包括SSc 42例、系统性红斑狼疮(SLE)102例、干燥综合征(SS)26例、混合型结缔组织病(MCTD)16例、未分化结缔组织病(UCTD)13例,其他结缔组织病(CTD)30例、类风湿关节炎(RA)26例及正常对照54例。结果抗hnRNPI-1及抗hnRNPI-2多肽抗体在SSc组中阳性率均明显高于其他疾病组(P<0.05),在SSc中敏感性分别为47.62%及38.1%,特异性分别为93.43%及91.08%,二者之间差异无统计学意义(P>0.05)。另外,除了与SSc患者病程相关外,该二抗体均与发病年龄、临床症状、器官受累、ESR、抗Scl-70抗体、抗着丝点抗体及抗核仁抗体之间未发现有统计学意义的相关性(P>0.05)。结论I-1及I-2分别是位于hnRNPI蛋白表面的抗原表位之一,具有抗原性,其抗体对SSc的临床诊断具有较高的敏感性及特异性,且在病程早期具有更高的阳性率,有助于SSc的早期诊断。     

Systemic sclerosis (scleroderma) and malignancy]

The association of malignancy with collagen diseases has been a focus of interest. Especially, relation between dermatomyositis and malignancy is well-recognized. I reviewed here about the coexistence of SSc and malignancy in literature. I would like to raise four points as characteristics of the relationship. (1) Special attention should be paid to the patients who is late-onset, with advanced skin sclerosis (ex. Barnett III type) and male. (2) There are three generalized mechanisms of the association. The first is the predisposition of the malignancy on the basis of organ fibrosis, such as pulmonary fibrosis and lung cancer. The second is the nature of paraneoplastic syndrome. Lastly, immunological derangement inherent to SSc might cause carcinogenesis. (3) It has been documented that the interval of the onsets of SSc and breast cancer is extremely short. (4) Longstanding reflux esophagitis and Barrett's esophagus with SSc is suspected to predispose to esophageal carcinoma.