Anti-PM/Scl Antibody-positive Systemic Sclerosis Complicated by Multiple Organ Involvement

A 40-year-old Japanese woman developed malignant-phase hypertension complicated by thrombotic microangiopathy, progressing to end-stage renal disease. Five years later, she was diagnosed with pulmonary arterial hypertension and interstitial pneumonia. Despite a lack of overt skin sclerosis, nucleolar staining in our indirect immunofluorescence analysis and nailfold capillaroscopy facilitated the diagnosis of anti-PM/Scl antibody-positive systemic sclerosis. We observed the persistent presence of anti-PM/Scl antibodies throughout the clinical course, suggesting that her kidney disease was scleroderma renal crisis. Anti-PM/Scl antibodies can be associated with multiple organ diseases. Careful attention to a patient''s antinuclear antibody pattern and dermatological findings may help clarify the etiology of undiagnosed diseases.     

Determination of procollagen type I carboxyterminal propeptide in Japanese patients with systemic sclerosis

Our objective was to clarify the relationship between the serum levels of procollagen type I carboxyterminal propeptide (PICP) and the extent of skin sclerosis or pulmonary fibrosis in patients with systemic sclerosis (SSc). Thirty-eight SSc patients and 36 control subjects were examined for serum PICP levels using enzyme-linked immunosorbent assay. SSc patients were divided into two subgroups according to the grade of skin sclerosis. Mean PICP level in the SSc patients was significantly higher than that in the normal controls. In 53% of the SSc patients, the serum PICP levels were elevated more than 3 SD above the mean control value. The SSc patients with elevated serum PICP levels showed a high incidence of pulmonary fibrosis of diffuse skin sclerosis compared to those with normal PICP levels. Moreover, in 17 patients with pulmonary fibrosis there was an increase in the percentage of patients with elevated PICP levels in the group with diffuse SSc compared to that in the limited SSc group. Furthermore, there was a significant negative correlation between PICP levels and partial pressure of arterial oxygen levels (r=−0.744). We conclude that serum PICP levels may be a useful parameter for the evaluation of skin sclerosis and pulmonary fibrosis of SSc patients.     

Causes and prevalence of inadequate pulmonary function testing among patients with systemic sclerosis

Introduction

Spirometry is a screening tool for evaluating the degree of restrictive lung disease in systemic sclerosis (SSc). Observations indicated that some patients could not complete the test. The aim of the study was to identify the prevalence, causes and clinical predictors of an inadequate pulmonary function test (PFT) in SSc.

Material and methods

A cross-sectional study was performed among SSc patients over 18 years old followed up at Srinagarind Hospital, Khon Kaen, Thailand, during January 2006–December 2012. The adequacy of the PFT was based on the acceptable blow criteria as set out by the American Thoracic Society and the European Respiratory Society 2005 Standardizations of Spirometry.

Results

Two hundred and forty-nine patients were included (female to male ratio was 2 : 1). The mean age at performing PFT was 51.4 ±11.1 years (range: 19.6–79.5). Median duration of disease at performing PFT was 2 years (IQR: 0.6–4.4). Inadequate PFT occurred in 73 cases (prevalence 29.3%: 95% CI: 23.6–35.0); the majority (60 cases; 82.2%) had an expiration time < 6 s and the others were due to plateau < 1 s (11 cases; 15%), air leak around mouth piece (1 case; 1.4%) and hesitation (1 case; 1.4%). Thirteen of 73 (17.8%) had an unusable graph with the overall prevalence of 5.2% (95% CI: 2.4–8.0). The factor associated with inadequate PFT was docy mass index (BMI) < 18.5 kg/m² (OR = 2.17: 95% CI: 1.49–3.17); the same factor was associated with an unusable graph, which was confirmed by the multivariate analysis (OR = 5.21; 95% CI: 1.60–16.95).

Conclusions

One-third of Thai SSc patients had an inadequate pulmonary function test – the majority because of inadequate time for expiring. Low BMI influenced the effectiveness of the test, leading to an incomplete graph for evaluating lung disease in SSc.     

Epstein–Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti‐DNA

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities – anti‐dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two‐thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two‐thirds of SLE patients reacted to a large spectrum of self‐molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein–Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.     

系统性硬化症动物模型

系统性硬化症是一种自身免疫病,以多系统纤维化、小血管病变、血清自身抗体阳性为主要特点。目前其病因尚未十分清楚,越来越多的证据显示可能有血管病变、炎性反应、纤维化、自身免疫四大机制参与并相互作用。在研究系统性硬化症的发病机制、探索新药治疗效果时需要用到动物模型来模拟病理生理过程,而每一种模型都有其特点却又不完美。本文将根据建模方法分类介绍一些经典的和创新的模型,以及它们各自的特点、应用价值,为研究者选择最合适的动物模型提供帮助。     

Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

OBJECTIVE:

To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice.

METHODS:

Skin fibroblasts that were isolated from three systemic scleroderma (SSc) patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM). Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I) procollagen (COL1A1), alpha 1 (III) procollagen (COL3A1), matrix metalloproteinase (MMP)-1 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d) was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson''s trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA). Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR.

RESULTS:

Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3).

CONCLUSION:

Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc mouse model, in part due to a reduction in ET-1.     

The Dilemma of Breast Cancer Treatment and Existing Collagen Vascular Disease: A Case of Scleroderma and Review of the Literature

Collagen vascular diseases present a treatment dilemma for patients with breast cancer. Due to the potential for severe, acute, and late complications of radiation therapy, a history of collagen vascular disease (CVD) is a relative contraindication to breast‐conserving treatment. We present a case of early stage breast cancer in a patient with severe scleroderma treated with breast‐conserving surgery without radiation and a brief review of the published literature regarding the therapeutic approach to the patient with CVD and breast cancer.     

Localized scleroderma and regional inflammatory myopathy

Inflammatory myopathy is rare in localized scleroderma. We report 2 new cases of regional inflammatory myopathy associated with localized scleroderma and review 10 reported cases of localized scleroderma associated with an inflammatory myopathy with regional muscle involvement, more often in the upper extremities. Serum creatine kinase was mildly elevated or normal. Histopathology often showed perimysial inflammation and plasma cell infiltration. These cases demonstrate that inflammatory myopathy should be considered in patients with localized scleroderma and regional muscle weakness, pain or atrophy. Muscle biopsy can confirm the diagnosis of myositis, which if identified, will require anti-inflammatory and/or immunosuppressive therapy.