A case of nodular scleroderma

Nodular scleroderma is a rare complication of systemic sclerosis; the pathogenetic implications are still unknown, although many factors are supposed to play a role in lesion development. We report the case of a young woman suffering from systemic sclerosis, who developed nodular lesions during therapeutic management with D-penicillamine and plasmapheresis. In order to better understand the essence of this disease, we examined all the possible pathogenetic mechanisms that could be implicated in nodular lesion development.     

Cutaneous concerns of scleroderma patients

The clinical features of facial and oral involvement in scleroderma are striking. We conducted a survey of patients with systemic sclerosis (scleroderma). The purpose of our study was to ascertain what was most bothersome aesthetically to scleroderma patients. We also looked at the differences between age groups and genders. The survey was mailed to 1,000 individuals who subscribe to a national lay group organization. We received 303 completed surveys indicating the patient's age, gender, age at onset of disease, and a checklist of 14 physical variables involving the central face and non-face. The respondents were asked to rate their level of concern [on a scale of great (1) -moderate (2) -little (3) -none (4)] in regards to 14 different physical variables. The respondents consisted of 92% females and 8% males. The mean age was 59 years +/- 13 (SD), and the median age was 60. The mean and median age at diagnosis was 45 years +/- 15 (SD). The percentage of respondents expressing concern for specific features was the following: for thin lips (73%), mouth furrows (80%), loss of facial lines (68%), and a smaller, tighter mouth (77%). There was less concern over the non-face features. The percentage of respondents expressing no concern was the following: for absence of sweating (57%), skin darkening (50%), nail dystrophy (57%), and skin atrophy (63%). There was a highly statistically significant difference (p<0.0001) between those respondents concerned with central face features vs. non-face features. With advancing age and longer disease duration, there was increased concern over the aforementioned central face features (p<0.0001). The vast majority of patients with systemic sclerosis have great concerns over changing facial features, and this worsens with age.     

Nodular scleroderma in systemic sclerosis under D-penicillamine therapy.

A case of systemic sclerosis (SS) which developed keloidal lesions (nodular scleroderma) on the chest during D-penicillamine (DPC) therapy is reported. The 36-year-old woman showed rapidly progressing skin sclerosis with lung and esophageal involvement, and DPC was started at the age of 38. Skin sclerosis as a whole had improved to some extent, when keloidal nodules developed on the upper chest at the age of 44. Since there were no other findings suggestive of adverse reactions caused by DPC, we speculate that activation of the fibroblasts in these lesions occurred despite the suppressive effect of DPC.     

Presence of eosinophilia in progressive systemic sclerosis and localized scleroderma

Summary Recent studies on eosinophilic fasciitis have lead to this investigation of eosinophilia in progressive systemic sclerosis and localized scleroderma.Eosinophilia (eosinophilic count >300/cmm) was found in ten of 63 progressive systemic sclerosis patients (15.8%) and in two of nine localized scleroderma cases (22.2%). In patients with progressive systemic sclerosis eosinophilia was found occasionally in six cases; it was transitory, but frequent in three cases; it was constant and very high in one case. In patients with localized scleroderma eosinophilia was found occasionally in one case and frequent, but not constant, in the other one.The possible influence of drugs could be excluded in five cases: three progressive systemic sclerosis cases and two affected with localized scleroderma.Therefore, it is possible to confirm that eosinophilia is not a distinctive sign of eosinophilic fasciitis in patients suffering from scleroderma-like syndromes.While eosinophilia is related to inflammation in eosinophilic fasciitis, eosinophilia and disease activity could not be correlated in our patients with PSS.Recently, it has been suggested that eosinophilia might be an unfavorable prognostic criterion in progressive systemic sclerosis. Our data does not allow confirmation of this assumption.     

Epidemiology and pathogenesis of scleroderma

Scleroderma is a heterogenous connective tissue disorder characterized by fibrosis of the skin, with or without internal organ involvement. The aetiology of scleroderma may involve both environmental and genetic factors. Abnormalities involving the immune system, vascular tissue and extracellular matrix have been demonstrated. Recent research has focused on microchimerism as a risk factor for the development of scleroderma. This article reviews the epidemiology and pathogenesis of this disorder.     

Fatal scleroderma renal crisis caused by gastrointestinal bleeding in a patient with scleroderma, Sjögren''s syndrome and primary biliary cirrhosis overlap

A 57‐year‐old female patient presented with a long history of overlapping autoimmune disease, including limited cutaneous systemic sclerosis, Sjögren's syndrome and primary biliary cirrhosis. Another unusual finding was that the mild skin involvement (limited cutaneous systemic sclerosis, subcutaneous calcinosis) was combined with serious internal organ involvement, including honeycombing and finally scleroderma renal crisis. The most important finding was, that two decades later she developed severe telangiectasia of the gastrointestinal and urinary tract. Furthermore, a specific type of vascular malformation, i.e. gastric watermelon stomach was also found. The chronic gastrointestinal bleeding primarily derived from a watermelon stomach caused protein overload, which provoked the onset of the scleroderma renal crisis that finally led to the patient's death.     

HLA in systemic scleroderma (PSS) and familial scleroderma

HLA in systemic scleroderma (PSS), including three familial cases, is reported. Three families in which one sister developed PSS and another sister suffered from either PSS (family 1), mixed connective tissue disease (MCTD) (family 2), or Sjögren's syndrome (SjS) (family 3) were described. The elder sister in family 1 died of respiratory insufficiency caused by scleroderma lung. The sisters in family 2 both had SjS, anti SS-A antibodies, and HLA A2-Bw55-Cwl-DRw8 haplotype in common. The elder sister with PSS in family 3 also had SjS and Hashimoto's thyroiditis. HLA in 28 PSS patients including these 3 familial cases were analyzed with 4 MCTD and 4 generalized morphea patients. HLA A2, Bw46, DR2, DRw8, DRw6 and DQw1 antigens were more frequently found in the PSS patients than in the controls. HLA DRw6 was the only antigen that was positive in common in the 3 familial cases. In those patients with anti topoisomerase I antibodies, HLA DR2 antigen was found more frequently than in the controls. Some, but not all, of these results were similar to the previous reports on HLA in PSS. Further investigations on more patients and the other members of these families would be necessary to clarify the significance of these results.     

Scleroderma

ABSTRACT: Scleroderma presents a formidable therapeutic challenge for both the physician and the patient. Over the years many medications and interventions have been reported to be beneficial in scleroderma. With equal regularity, however, when put to the test of the randomized controlled trial, many of these same medications have subsequently been shown to be ineffective. This is true for both the localized and systemic forms of the disease. Two of the most recent additions to this inauspicious list for systemic sclerosis include D-penicillamine and methotrexate. At the very least these outcomes should point to our deficiencies in understanding the pathogenesis of this unusual disorder. It should raise the possibility that collagen and inflammatory or immune cells are not good therapeutic targets and new targets should be sought. Despite the scope of these problems and the lack of definitive therapy, there is a great deal an individual physician can do to help a patient living with scleroderma. This article presents management approaches to patients with either localized or systemic scleroderma.     

系统性硬皮病患者血浆肾上腺髓质素及内皮素水平的测定

目的:探讨肾上腺髓质素(ADM)和内皮素(ET)在系统性硬皮病(SSc)发病中的作用。方法:采用放免法测定28例SSc患者和20名健康人的血浆ADM和ET-1水平。结果:SSc患者血浆ADM水平为(222.26±48.64)pg/mL,高于正常对照组(89.07±13.00)pg/mL,两组间比较,差异有显著性(P<0.01);SSc伴肺动脉高压者其血浆中ADM水平(254.73±39.36)pg/mL明显高于不伴肺动脉高压者(206.88±45.64)pg/mL,二者之间差异有显著性(P<0.01)。SSc患者血浆ET-1水平为(196.45±65.20)pg/mL,高于正常对照组(54.17±11.70)pg/mL,两组间比较,差异有显著性(P<0.01);SSc伴肺动脉高压者其血浆中ET-1水平(273.19±48.97)pg/mL明显高于不伴肺动脉高压者(160.11±31.17)pg/mL,二者之间差异有显著性(P<0.01)。血浆中ADM和ET-1水平呈正相关(r=0.5148,P<0.01)。结论:ADM和ET与SSc关系密切,可能在SSc发病和防治中具有重要的生理及病理学意义。     

Oligosaccharide modification by N‐acetylglucosaminyltransferase‐V in macrophages are involved in pathogenesis of bleomycin‐induced scleroderma

Oligosaccharide modification by N‐acetylglucosaminyltransferase‐V (GnT‐V), which catalyses the formation of β1,6 GlcNAc (N‐acetylglucosamine) branches on N‐glycans, is associated with various pathologies, such as cancer metastasis, multiple sclerosis and liver fibrosis. In this study, we demonstrated the involvement of GnT‐V in the pathophysiology of scleroderma. High expression of GnT‐V was observed in infiltrating cells in skin section samples from systemic and localized patients with scleroderma. Most of the infiltrating cells were T cells and macrophages, most of which were CD163⁺ M2 macrophages. To determine the role of GnT‐V in scleroderma, we next investigated skin sclerosis in GnT‐V knockout (MGAT5^?/?) mice. Expression of GnT‐V was also elevated in bleomycin (BLM)‐injected sclerotic skin, and MGAT5^?/? mice were resistant to BLM‐induced skin sclerosis with reduced collagen type 1 α1 content, suggesting the biological significance of GnT‐V in skin sclerosis. Furthermore, the number of CD163⁺ M2 macrophages and CD3‐positive T cells in BLM‐induced skin sclerosis was significantly fewer in MGAT5^?/? mice. In bone marrow‐derived macrophages (BMDMs), IL‐4‐induced expressions of Fizz1 and Ym1 were significantly reduced in MGAT5^?/? mice‐derived BMDMs. Taken together, these results suggest the induction of GnT‐V in skin sclerosis progression is possibly dependent on increased numbers of M2 macrophages in the skin, which are important for tissue fibrosis and remodelling.     

Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients

In this study, we determined the adiponectin expression in the serum and lesional skin of patients with scleroderma (SSc). Serum adiponectin concentrations were measured in 32 patients with SSc, 10 patients with SLE, 12 patients with dermatomyositis patients and 13 healthy subjects with specific enzyme-linked immunosorbent assays. Adiponectin mRNA was determined in skin tissues of five patients with diffuse cutaneous SSc (dcSSc), seven patients with limited cutaneous SSc (lcSSc) and seven healthy subjects with real-time polymerase chain reaction. There was a significant reduction in serum adiponectin levels in patients with dcSSc. SSc patients with decreased serum adiponectin levels had higher total skin thickness score and higher incidence of pulmonary fibrosis. Adiponectin mRNA levels in skin tissues from patients with dcSSc were also reduced. Serum adiponectin levels may be a useful biomarker for fibrotic condition in patients with SSc. Clarifying the role of adiponectin in collagen diseases may lead to further understanding of the pathogenesis and new therapeutic approach.     

系统性硬皮病的治疗进展

系统性硬皮病是一种以皮肤及各系统胶原纤维硬化为特征的结缔组织疾病,本病目前尚无特殊疗法,获取良好的治疗效果,是临床医师期待解决的实际问题。为此,本文简要综述并分析当前国内外缓解该病的治疗方法(如血管活性剂,结缔组织抑制剂。免疫抑制剂的应用)并介绍新的治疗手段,如自体干细胞移植等。     

结节性硬皮病

报告1例结节性硬皮病,患者在诊断为系统性硬皮病4年后,胸、背部出现瘢痕疙瘩样皮损,根据病史和组织病理学改变诊断为结节性硬皮病。该型硬皮病多继发于系统性硬皮病,治疗困难。     

High plasminogen activator inhibitor type 2 expression is a hallmark of scleroderma fibroblasts in vitro

Systemic scleroderma is a chronic disease, which leads to fibrosis of the skin and internal organs. Fibroblasts obtained from patients with this disease demonstrate an activated state in culture. We, in this study, report strong, constitutive overexpression of plasminogen activator inhibitor type-2 (PAI-2) in scleroderma fibroblasts and demonstrate that this induction observed at the mRNA and protein level is dependent on serum addition. Induced PAI-2 protein levels were restricted to the non-glycosylated 47-kDa form, which is located intracellularly. Induction was stable for at least 12 passages. No modulation by fibrogenic cytokines--for example, transforming growth factor-beta1 or connective tissue growth factor--or by antagonizing IL-1 receptors was observed. The data indicate that scleroderma fibroblasts are more sensitive to the induction of PAI-2 expression than control fibroblasts by a presently unknown factor in serum.     

A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset

BACKGROUND: Several uncontrolled studies in systemic sclerosis have shown that D-penicillamine may cause improvement in skin sclerosis, decrease the rate of new visceral organ involvement, and improve overall survival. OBJECTIVES: To undertake a single-centre retrospective randomly selected cohort study to examine the effects of D-penicillamine treatment on skin and visceral organ involvement in patients with rapidly progressive systemic sclerosis of recent onset. METHODS: Eighty-four patients with diffuse cutaneous systemic sclerosis who had received D-penicillamine within 24 months of clinically detectable onset of skin sclerosis were randomly selected from the systemic sclerosis cohort followed at the Scleroderma Center of Thomas Jefferson University. Employing a previously described severity scale, disease severity and skin involvement were compared from initiation of D-penicillamine to end of study and a correlated matched t-test was used to establish statistical significance. RESULTS: At a mean+/-SD duration of D-penicillamine therapy of 29.2+/-5.5 months and at a median dose of 750 mg per day statistically significant improvement in skin (P<0.01) and cardiac, pulmonary and renal involvement (P<0.05) was observed. At last follow-up, 17 (20%) patients were still receiving D-penicillamine, 25 (30%) had discontinued it owing to disease improvement, and 18 (21%) had discontinued it owing to side-effects. CONCLUSIONS: In a population of patients with diffuse cutaneous systemic sclerosis, with progressive disease of recent onset, D-penicillamine treatment at a median dose of 750 mg per day caused a statistically significant reduction in skin involvement and improvement of renal, cardiac and pulmonary involvement.     

Serum levels of manganese superoxide dismutase in patients with localized scleroderma

The objective was to determine the serum levels of manganese superoxide dismutase (Mn SOD) in patients with localized scleroderma and investigate their clinical significance in this disease. Serum samples from 15 patients with localized scleroderma and 20 healthy volunteers were examined by a specific enzyme-linked immunosorbent assay. Serum levels of Mn SOD were significantly higher in patients with generalized morphea than those in healthy individuals. And the patients with elevated serum Mn SOD levels had significantly larger number of sclerotic lesions and significantly higher serum levels of soluble interleukin-2 receptor than those without it. These results suggested that the serum levels of this enzyme may be a serological marker for the disease activity and the extent of skin involvement in this disease.     

Acute exacerbation of systemic scleroderma in Borrelia burgdorferi infection

In recent years a possible aetiological connection between skin sclerosis and an infection with Borrelia burgdorferi has been discussed, but this association has not yet been reported for systemic scleroderma. Several treatment modalities are suggested for systemic scleroderma, but no treatment has yet been found to alter the overall course of the disease. This report describes a 61-year-old woman with Raynaud's phenomenon, nail-fold changes and circulating anticentromere antibodies, who showed an abrupt onset of erythemas and doughy swellings involving the face and upper trunk, followed by thickening and induration of the skin mimicking diffuse systemic scleroderma. Laboratory tests including enzyme-linked immunosorbent assay (ELISA), immunoblot and urine polymerase chain reaction (PCR) showed an infection with B. burgdorferi sensu lato that was successfully treated with intravenous ceftriaxone, an antibiotic recommended for Lyme borreliosis. Fourteen days after the end of treatment the skin was no longer stiff and indurated and had returned to its normal predisease state. This case suggests that Lyme disease should be considered in atypical cases of skin sclerosis in patients predisposed to the development of systemic scleroderma.     

Antifibrogenic effects of C‐C chemokine receptor type 2 antagonist in a bleomycin‐induced scleroderma model

There have been several studies on the role of the monocyte chemotactic protein‐1/C‐C chemokine receptor type 2 (CCR2) signalling pathway in fibrotic diseases, which identified the blockade of this pathway as a potential therapeutic target for treating fibrosis. We examined the efficacy of CCR2 antagonist (RS‐504393) in a mouse model of scleroderma induced by bleomycin. RS‐504393 was administered via intradermal injection 6 hours prior to bleomycin injection, in the same sites. Histopathological examination showed that RS‐504393 treatment suppressed dermal fibrosis and decreased dermal thickness. The numbers of mast cells and myofibroblasts in the skin of RS‐504393–treated mice were significantly lower compared with those in PBS‐treated mice. Moreover, the amount of collagen in the skin of RS‐504393–treated mice was significantly lower compared with that in the PBS‐treated mice. Additionally, mRNA levels of TGF‐β1 and collagen I alpha 1 in sclerotic skin were significantly decreased by RS‐504393, and semiquantitative histopathological scoring of the lungs showed inhibition of fibrosis in RS‐504393–treated mice. The amount of collagen in the lung of the RS‐504393–treated mice was lower compared with that in the PBS‐treated mice. These data suggest that CCR2 antagonist RS‐504393 may be a therapeutic agent for human scleroderma.     

Soluble CD4 and CD8 in serum from patients with localized scleroderma

Localized scleroderma has been shown to be accompanied by various immunologic abnormalities. To obtain functional information on activated CD4+ or CD8+ T cells, we studied the levels of soluble CD4 (sCD4) and soluble CD8 (sCD8) in serum from patients with localized scleroderma. Serum samples were examined by enzyme-linked immunosorbent assay. The samples were obtained from 49 patients in the following three subgroups: 15 patients with generalized morphea, 22 with linear scleroderma, and 12 with morphea. The levels of sCD4 and sCD8 were significantly elevated in patients with generalized morphea. Furthermore, these patients showed significantly higher levels of sCD4 than those with systemic sclerosis (SSc). The frequency of positivity for IgG anti-single-stranded DNA (ssDNA) antibody was significantly higher in localized scleroderma patients with elevated sCD4 levels than in patients with normal sCD4 levels. The frequency of positivity for antinuclear antibodies, IgM antihistone antibodies, IgG anti-ssDNA antibody and rheumatoid factor, and elevated sCD23 levels were significantly higher in localized scleroderma patients with elevated sCD8 levels than in patients with normal sCD8 levels. Our findings suggest that both CD4+ and CD8+ T cells are activated in vivo in generalized morphea and that the immunologic events in generalized morphea are different from those in SSc.