Aberrant activation of the type I interferon system may contribute to the pathogenesis of anti-melanoma differentiation-associated gene 5 dermatomyositis

Dermatomyositis (DM) is a rare condition which causes inflammation in the skin and muscles. There are different subtypes of DM, which are defined by genetic differences. One subtype of DM, characterised by a gene called anti-melanoma differentiation-associated gene 5 (anti-MDA5 DM), is linked to an extremely high risk of interstitial lung disease (ILD). In Asia, 10-48% of DM patients have this type of DM. This study, from China, aimed to explore the role of certain proteins, together known as the type 1 interferon system, in development of this type of DM. Patients with anti-MDA5 DM were studied and compared with patients who suffered from other variations of DM. The levels of specific proteins in the blood (inflammatory cytokines, B cell activating factor or ‘BAFF’, Krebs von den Lungen-6) and in skin lesions (STAT1, ISG15 and MxA) were tested. The levels of the protein plasma IFN-α was much higher in anti-MDA5 DM patients than those of other DM subtypes. Skin biopsies from anti-MDA5 DM patients were characterized by the strong expressions of (presence of) STAT1, ISG15, and MxA proteins. In the anti-MDA5 DM/ILD patients with high IFN-α production, there was a relationship between IFN-α and BAFF levels. In addition, the higher levels of BAFF paralleled to the higher concentrations of KL-6. This study confirms the abnormal activation of type I IFN protein system in anti-MDA5 DM. Overproduction of IFN-α linked with BAFF may be implicated in the development of ILD.     

IgG autoantibody reactivity against bullous pemphigoid (BP) 180 and BP230 in elderly patients with pruritic dermatoses

Background  Pruritic dermatoses of the elderly often pose a diagnostic and therapeutic challenge. Specifically, a prodromal phase of bullous pemphigoid (BP) has to be considered in patients with pruritic lesions of polymorphic appearance. These conditions frequently do not fulfil all the clinical, histological and immunopathological criteria for establishing the diagnosis of BP.
Objectives  To investigate IgG reactivity against the autoantigens of BP, BP180 and BP230, by enzyme-linked immunosorbent assay, in elderly patients affected with various pruritic disorders who had never experienced clinically apparent blisters.
Methods  The sera of 15 elderly patients with pruritic disorders (group I) were tested for IgG reactivity against BP180 and BP230. Also included were 30 patients with full-blown BP (group II) and 25 age-matched patients with immediate-type allergic reactions (group III).
Results  Thirty-three per cent of the patients with pruritic disorders (group I) showed IgG against BP230 and/or BP180: four of 15 patients had IgG against BP230 while two of the 15 group I patients were BP180 reactive. All the BP sera (group II) showed IgG reactivity against BP180 and/or BP230. Notably, two of 25 control sera (group III) showed IgG reactivity against either BP180 or BP230.
Conclusions  The present findings suggest that IgG reactivity against BP230 (i.e. the COOH terminus), and to a lesser extent against BP180, is a common finding in pruritic disorders of the elderly with a wide clinical spectrum. IgG-mediated autoimmunity against the intracellular BP230 may facilitate a chronic, inflammatory response eventually leading to full-blown BP which is presumably associated with IgG against BP180.     

Prevalence and antigen specificity of anti-histone antibodies in patients with polymyositis/dermatomyositis

Anti-histone antibodies have been detected in the sera of patients with various autoimmune diseases. The existence of anti-histone antibodies in patients with polymyositis/dermatomyositis, however, has not been reported. We found anti-histone antibodies in eight (17%) of 46 sera from patients with polymyositis/dermatomyositis by an enzyme-linked immunosorbent assay. One serum was positive for both IgG anti-histone antibodies and IgM anti-histone antibodies. Six sera were positive only for IgG anti-histone antibodies. One serum was positive only for IgM anti-histone antibodies. An indirect immunofluorescence analysis using HEp-2 cells as the substrate showed that all sera positive for anti-histone antibodies produced homogeneous nuclear fluorescence. This immunofluorescence pattern disappeared after absorption of anti-histone activity with total histones. An immunoblotting analysis demonstrated that the anti-histone antibodies were predominantly directed against histone H1 in all seven sera with IgG anti-histone antibodies. Weak reactivity with H2B and H4 were also found in three sera from the patients with polymyositis/dermatomyositis. Sera from two patients with polymyositis/dermatomyositis displayed anti-H2A and H3 activity. One of the two sera showed IgM anti-histone antibodies in the enzyme-linked immunosorbent assay reacted with H1, H2A, H2B, H3, and H4, whereas the other serum reacted with no fractions of total histones. The activity of anti-histone antibodies disappeared in immunoblotting after absorption with total histones. All of the patients with anti-histone antibodies were free from lung fibrosis or internal malignancies. Thus, our data indicate that the presence of anti-histone antibodies is classified as one of the serologic abnormalities observed in polymyositis/dermatomyositis.     

Amyopathic dermatomyositis (dermatomyositis sine myositis) and cutaneous dermatomyositis with mild muscle disease

We report on one patient suffering from amyopathic dermatomyositis, and two patients with transient or mild muscle involvement, respectively. The rare subset of amyopathic dermatomyositis is characterized by benign clinical course and prognosis. Leading cutaneous symptoms are heliotropic rash, periorbital violaceous-red erythema and edema, erythematous lichenoid plaques at the dorsum of the hands and fingers, hyperkeratotic, hyperesthetic eponychium, nailfold capillary abnormalities and the skin histology, while itching and photosensitivity are optional features. On the other hand, clinical or laboratory evidence of muscle involvement is absent for at least 2 years. The two patients with transient or mild muscle involvement point to transitional forms between amyopathic and classical dermatomyositis. As differential diagnosis lupus erythematosus, (photo)contact eczema, lichen planus, psoriasis, seborrhoic dermatitis and atopic dermatitis, as well as polymorphic light eruption and erythroderma, should be considered. Association with internal malignancy is rare, but is to be excluded. Waiting, hydroxychlorochine and systemic glucocorticoids are the steps of treatment, depending on the clinical course.     

Characterization of the anti-BP180 autoantibody reactivity profile and epitope mapping in bullous pemphigoid patients

Bullous pemphigoid is a subepidermal bullous disease of skin and mucosae associated with autoantibodies to BP180. To characterize the humoral response to BP180, we generated a random BP180 epitope library displayed on lambda bacteriophage. After validation of the library by epitope mapping of three BP180-specific monoclonal antibodies, 15 novel or known BP180 epitopes were identified using 10 bullous pemphigoid serum samples. Fifty-seven bullous pemphigoid and 81 control sera were then assayed against the selected epitopes. Thirty-one out of 57 (54%) bullous pemphigoid sera reacted with at least an additional antigenic site other than the NC16A, within the extracellular (37%) and intracellular (28%) domains of BP180. In addition, the reactivity with extracellular epitopes of BP180 contained within the residue stretches 508-541 and 1331-1404 appeared to be related to the presence of both skin and mucosal involvement. Finally, a preliminary analysis of the epitope pattern in the disease course indicated that bullous pemphigoid patients exhibit a specific reactivity pattern, and that binding to intracellular epitopes of BP180, in addition to NC16A, may be detectable at an early clinical stage. Our findings provide novel insights into the pathophysiology of bullous pemphigoid and show the potential of the utilized approach as a tool for a rapid diagnosis of bullous pemphigoid patients and their management.     

Mannose binding lectin (MBL) polymorphisms associated with low MBL production in patients with dermatomyositis

One theory for the pathophysiology of photosensitive autoimmune skin diseases is that photoinduction of tumor necrosis factor alpha (TNFalpha) secretion leads to keratinocyte apoptosis and translocation of previously sequestered cellular antigens that then activate the immune system. We previously found an association of the overproducing TNFalpha-308 A variant with adult dermatomyositis and with subacute cutaneous lupus erythematosus. Here we focused on mannose binding lectin (MBL), which is one of several proteins involved in clearance of apoptotic cells and could thereby lessen photosensitive autoimmunity. We examined three variant MBL polymorphisms associated with decreased MBL protein (Asp54, Glu57, and the LX promoter polymorphism) in adult dermatomyositis, subacute cutaneous lupus erythematosus, and discoid lupus, and controls. The variant Asp54 allele was positively associated with adult dermatomyositis in a dose-responsive fashion (p=0.0004), as was the Glu57 allele (p=0.004). None of the three variant MBL alleles considered individually was significantly associated with either subacute cutaneous lupus erythematosus or discoid lupus. In adult dermatomyositis patients homozygous for the wild-type TNFalpha-308G allele (GG), i.e., presumably without elevated TNFalpha production, 69% had at least two of the MBL polymorphisms, versus 20% of healthy GG controls (p=0.0011). Combinations of low-producing MBL variants were over-represented in adult dermatomyositis in a dose-responsive fashion (p=0.0002). In adult dermatomyositis patients with one variant TNFalpha-308 A allele (GA), 46% had at least two MBL polymorphisms, versus 7% of GA controls (p=0.0077). Thus, low-producing MBL genes are very strongly associated with adult dermatomyositis. Our model is that genetic polymorphisms leading to overproduction of apoptotic keratinocytes and then impaired clearance of these cells contribute to the pathogenesis of adult dermatomyositis, a photoinduced autoimmune skin disease.     

Prevalence of 52-kd and 60-kd Ro/SS-A autoantibodies in Japanese patients with polymyositis/dermatomyositis

To determine the prevalence of 52-kd and 60-kd Ro/SS-A antibodies in Japanese patients with polymyositis/dermatomyositis, we examined serum samples from 61 patients with PM/DM, 10 patients with primary Sj?gren's syndrome, and 25 healthy control subjects. Six serum samples possessed anti-Ro/SS-A antibodies and were positive for anti-Ro52, anti-Ro60, or both. Two reacted with both Ro52 and Ro60, and 4 reacted with Ro52 alone. The results suggest that Ro52 is the main antigen of anti-Ro/SS-A antibodies in patients with polymyositis/dermatomyositis and that its coexistence with other defined antibodies suggests the existence of a subgroup of patients with various serologic abnormalities.     

Cr(III) reactivity and foot dermatitis in Cr(VI) positive patients

Chromium allergy has become synonymous with Cr(VI) allergy. However, real exposure to chromium from leather products may include both Cr(III) and Cr(VI). In this study, we investigate the reactivity to both Cr(VI) and Cr(III) in consecutive patients to analyse the relation between foot eczema/leather exposure and reactivity to Cr(III). From March 2002 to December 2004, 2211 consecutive patients with suspected allergic contact dermatitis were patch tested with 0.5% potassium dichromate (Cr(VI)) and 13% chromium trichloride (Cr(III)). A total of 71 (3.2%) patients had a positive reaction to Cr(VI), of which 31 also had a positive Cr(III) reaction. No Cr(VI) negative patients had a positive reaction to Cr(III). An increased risk of foot dermatitis was found in Cr(VI) positive patients with a concomitant positive or doubtful reaction to Cr(III) compared with Cr(VI) positive patients with no reactions to Cr(III). The increased risk was not due to a higher degree of sensitivity to Cr(VI). Leather was reported most frequently as the suspected cause of chromium dermatitis (54%). However, Cr(VI) allergics having foot eczema and positive or doubtful Cr(III) reactions often had positive reactions to other shoe allergens. Thus, Cr(III) allergy is part of a multiple shoe allergy pattern.     

Prevalence of autoantibodies in patients with endemic pemphigus foliaceus (fogo selvagem)

Objective The aim of the present study was to investigate a broad spectrum of autoantibodies in patients with endemic pemphigus foliaceus (EPF)—fogo selvagem—and to determine the possible association between EPF and other autoimmune diseases.Materials and methods Indirect immunofluorescence was used to test 120 patients with EPF and 200 healthy controls for the presence of the following autoantibodies: anti-desmoglein-1 (APF), anti-neutrophil cytoplasmic (ANCA), anti-smooth muscle (SMA), anti-mitochondrial (AMA), anti-nuclear (ANA), anti-liver kidney microsomal (LKM), anti-gastric parietal cells (GPCA) and anti-thyroid microsome (TMA).Results APF antibodies were detected in 62.5% of the patients (75/120), ANA and SMA in 0.8% (1/120), and TMA in 1.6% (2/120). None of the patients was positive for ANCA, AMA, LKM or GPCA. In the control group, a positivity of 2% was observed for SMA (4/200), 1.5% for TMA (3/200), and 0.5% (1/200) for ANA and GPCA. None of the controls was positive for APF, LKM, AMA or ANCA.Conclusions The prevalence of the autoantibodies ANA, SMA, AMA, GPCA, LKM and ANCA in patients with EPF was similar to that observed in the control group. No association with clinical or laboratory manifestations of other concomitant autoimmune diseases was observed in EPF patients. These results confirm the concept that EPF is an organ-specific autoimmune disease.     

Predictive factors for anti-MDA5 antibody in patients with dermatomyositis: a retrospective multicenter study

Background and objectives : Melanoma differentiation-associated gene 5 antibody (anti-MDA5) in dermatomyositis (DM) is associated with rapidly progressive interstitial lung disease and poor prognosis. Early diagnosis is key to improving the prognosis of these patients. The aim was to confirm cutaneous characteristics in patients with anti-MDA5 dermatomyositis and to explore new diagnostic markers for the presence of anti-MDA5 (anti-MDA5⁺). Patients and Methods : A multicenter cross-sectional retrospective cohort study of 124 patients diagnosed with DM, of which 37 were anti-MDA5⁺. Demographic data, laboratory data, and clinical manifestations were collected. Results : Anti-MDA5⁺ DM is characterized by a distinct mucocutaneous phenotype that includes oral lesions, alopecia, mechanic's hands, palmar and dorsal papules, palmar erythema, vasculopathy, and skin ulceration. We found vasculopathy and digit tip involvement very frequently in anti-MDA5⁺ patients (p <0.001), being a diagnostic marker of anti-MDA5⁺ (OR, 12.355; 95% CI 2.850–79.263; p  =  0.012 and OR, 7.447; 95% CI 2.103–46.718; p  =  0.004, respectively). The presence of ulcers deserves special mention, especially in anti-MDA5⁺ patients, because in our cohort, up to 97% of the anti-MDA5⁺ patients had ulcers. Conclusions : In patients with suspected DM with digit tip involvement or vasculopathy, the presence of anti-MDA5 antibodies must be ruled out, as it may be a clinical predictor.     

98例皮肌炎患者临床分析

<正>皮肌炎(DM)是一种自身免疫性结缔组织病,该病典型症状是肌肉炎症和皮肤损害,可累及多系统病变,如肺部、关节及心脏等,部分患者还可伴发恶性肿瘤。现将我科近年收治的98例皮肌炎患者的临床资料进行回顾性分析,旨在探讨皮肌炎的首发症状、临床表现、实验室检查等特点,分析易误诊的原因和合     

皮肌炎55例回顾性临床分析

目的:探讨皮肌炎的临床特征和治疗方法。方法:对55例皮肌炎住院患者进行回顾性分析。结果:55例皮肌炎患者中女:男为2.2:1,儿童5例,40岁以上42例。成人患者中10%合并恶性肿瘤。92.1%有双眼睑紫红色水肿性斑片,58.2%有Gottron丘疹,98.2%感乏力,75.6%有肌痛和肌压痛。76.9%血清LDH升高,61.1%CK升高,39.1%基底膜带免疫球蛋白沉积。糖皮质激素联合MTX治疗20～40d病情控制。结论:40岁以上患者易合并肿瘤,肌酶中LDH敏感性最高,CK可以作为糖皮质激素减量的参考指标。糖皮质激素联合免疫抑制剂是目前治疗皮肌炎的主要方法。     

皮肌炎77例临床分析

回顾分析７７例皮肤炎病例,男女比在２１－６０岁间为１：１．９,在≤２０岁和〉６０岁为２：１。初发症状表现皮炎者５１．９％,皮炎肌炎同时发生占２６％。１８．２％出现间质性肺炎,１０．４％出现胸腔积液。