A case of pityriasis rubra pilaris associated with rapidly progressive finger joint destruction]

A 40-year-old female noticed edema of the lower limbs in March 1995. Nephrotic syndrome due to membranous nephropathy was diagnosed and administration of high-dose corticosteroids resulted in incomplete remission. Progressively enlarging, red scaling skin lesions developed concomitantly from the scalp to the extremities. Pityriasis rubra pilaris (PRP) was diagnosed in 1996 in the Department of Dermatology at Sapporo Medical University hospital. Various treatments proved ineffective. Arthritis of the finger joints developed in July 1999, and proteinuria recurred in April 2000. She was admitted to our department in August 2000. Physical examination on admission revealed marked swelling of both distal interphalangeal (DIP) joints and the right fourth proximal interphalangeal (PIP) joint. Results of testing for antinuclear antibody, rheumatoid factor, and HLA-B27 were all negative. Radiography of the hands revealed destruction of the DIP and PIP joints where MRI indicated the presence of synovitis. Bone scintigraphy demonstrated accumulation in bilateral metatarso-phalangeal joints and the left sacroiliac joint. Arthritis associated with PRP was diagnosed, as both PRP and psoriasis represent keratinizing disorders of the skin and clinical features in the present case resembled those of psoriatic arthritis. Despite administration of high-dose corticosteroids, destruction of finger joints progressed rapidly. Administration of cyclosporine in April 2002 improved arthritic symptoms. Cases of PRP accompanied by arthritis need to be accumulated to allow analysis of the pathogenesis and clinical picture of this association.     

A review of pityriasis rubra pilaris and rheumatologic associations

Pityriasis rubra pilaris (PRP) is a rare group of hyperkeratotic, papulosquamous disease that can be acquired or inherited. There have been reported cases of rheumatologic associations, mainly arthritis and dermatomyositis. In this review article, we will explore the clinical presentation and classification, rheumatologic associations and treatment modalities of PRP. In addition, we will also report a case of PRP with seronegative arthritis.     

A case of mixed connective tissue disease with microscopic polyarteritis nodosa associated with perinuclear-antineutrophil cytoplasmic antibody and anti-glomerular basement membrane]

A 46-year-old female was admitted to our hospital due to general fatigue, systemic edema and dyspnea with history of systemic sclerosis (SSc). The patient was diagnosed as mixed connective tissue disease (MCTD) based on Raynaud phenomenon, a high anti-RNP antibody level and clinical symptoms and laboratory findings suggesting SSc, dermatomyositis (DM) and systemic lupus erythematosus (SLE). After the admission, both alveolar hemorrhage and a rapidly progressive glomerulonephritis (RPGN) also developed and laboratory findings showed a positive remark of myeloperoxydase-antineutrophil cytoplasmic antibody (MPO-ANCA) and anti-glomerular basement membrane (GBM) antibody. She was therefore re-diagnosed as microscopic polyarteritis nodosa (microscopic PAN) combined with MCTD and treatment with high dose prednisolone and steroid pulse therapy dramatically improved general conditions and lung symptoms, but maintenance dialysis was persistent because of irreversible renal failure. However, 3 months after the admission, she died of acute exacerbation of interstitial pneumonitis that was unresponsive to steroid pulse therapy. Autopsy revealed interstitial pneumonitis with alveolar hemorrhage and crescentic glomerulonephritis (CrGN), in which immunofluorescent microscopy showed no deposition in agreement with pauciimmune type. The histological findings supported the diagnosis; primary microscopic PAN combined with MCTD, which is a quite rare case, to our knowledge. Furthermore, co-existence of MPO ANCA and anti-GBM antibody, clinical and histological findings of the case also lead us to reconsider the relevance of these antibodies to pathogenesis and/or categories of microscopic PAN and Goodpasture's syndrome.     

Autoimmune hepatitis associated with mixed connective tissue disease: report of a case and a review of the literature]

A case is reported of a 29 year old female who had autoimmune hepatitis associated with mixed connective tissue disease (MCTD). The patient developed MCTD at the age of 19, and was treated with prednisolone. Liver dysfunction developed 7 years later, which exacerbated shortly after the patient suffered intrauterine fetal death during the second trimester of pregnancy. Laboratory data showed negative anti-hepatitis C antibody and hepatitis B antigen, but positive anti-smooth muscle antibody. A liver biopsy showed chronic active hepatitis. Referring to the criteria we diagnosed her as having autoimmune hepatitis. Although hepatomegaly is sometimes observed in MCTD patients, only 5 cases of autoimmune hepatitis associated with MCTD have been reported in the past. In our case, it is of note that autoimmune hepatitis developed while symptoms of MCTD were in remission, and that autoimmune hepatitis exacerbated with the emergence of anti-smooth muscle antibody following the termination of pregnancy.     

Cold-induced reversible brain ischemia in mixed connective tissue disease, a case report]

A 19-year-old woman with long-standing mixed connective tissue disease was admitted for dizziness. We examined cerebral blood flow quantitation using 99mTc-hexamethylpropyleneamine oxime (HMPAO) and single photon emission computed tomography (SPECT) at rest and after cold pressor test. Mean cerebral blood flow reduced remarkably when she complained dizziness and showed peripheral Raynaud's phenomenon after cold exposure. We concluded cold-induced reversible brain ischemia was the reason of dizziness. Our finding suggests brain Raynaud's phenomenon. Further studies are necessary to clarify this phenomenon.     

A case of mixed connective tissue disease successfully treated for hemophagocytic syndrome with intermittent intravenous injection of cyclophosphamide]

A 52 year-old woman noticed general fatigue, polyarthralgia, and muscle weakness of lower extremities in October 2001. In December, she felt difficulty in walking due to muscle weakness. In January 2002, she admitted another hospital because of dyspnea on exertion and edema of lower extremities. Laboratory test revealed leukocytopenia, the elevation of creatine kinase and positive anti-U1-RNP antibodies. Her chest computed tomography (CT) showed severe interstitial pneumonia. Cardiac echogram revealed that she had pericardial effusion and pulmonary hypertension. Then she was transferred to Keio University Hospital and she was diagnosed as having mixed connective tissue disease (MCTD) manifestating myositis, interstitial pneumonia, pulmonary hypertension and pericarditis. Prednisolone (PSL) 60mg daily following to methylprednisolone (mPSL) pulse therapy was begun and her symptoms were gradually improved. In middle of February, she complained of high fever over 39.0 degrees C. Bacterial culture tests were negative and laboratory data indicated pancytopenia and a high level of serum ferritin. Bone marrow aspiration revealed hemophagocytosis in bone marrow specimens and she was diagnosed as having hemophagocytic syndrome associated with MCTD. mPSL pulse therapy was not effective and intermittent cyclophosphamide pulse therapy (IV-CY) was performed resulting in improvement of the symptoms. This case suggested the effectiveness of IV-CY therapy in patients with corticosteroid-resistant HPS associated with connective tissue diseases.     

Fibroblast growth factors in connective tissue disease associated interstitial lung disease.

Fibrosis is a major cause of morbidity and mortality in chronic inflammatory diseases, especially interstitial pulmonary disorders. Fibroproliferation is an important part of this fibrotic response, and is mediated largely through growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) I and tumour necrosis factor-alpha (TNF-alpha). Although there is some evidence implicating these cytokines in fibrotic disorders, strong evidence in vivo is almost nonexistent. In order to ascertain the role that these factors play in inflammatory lung disorders associated with connective tissue diseases, alveolar mononuclear cells have been obtained from subjects by bronchoalveolar lavage and assessed for the spontaneous release of fibroblast growth factors. The study population consisted of subjects with a variety of different connective tissue disorders, both with and without inflammatory pulmonary complications. It was found that lavage cells spontaneously secreted fibroblast growth factor activity over 24 h with maximum activity detected at 6 to 12 h. Growth factor activity could be detected in most subjects with connective tissue disease-associated inflammatory lung disease and some normal subjects, but the amount of growth factor activity was much higher in the former than in the latter. By means of antibody depletion experiments all growth factor activity from lavage cells of normal patients was attributable to TNF-alpha while patients with interstitial lung disease secreted large amounts of PDGF and fibronectin in addition to TNF-alpha. Approximately 40-50% of the total released growth factor activity could be accounted for by PDGF, and 100% by the combination of PDGF, TNF-alpha and fibronectin. While TNF-alpha is released from the bronchoalveolar lavage cells of many subjects, in addition, many patients with interstitial lung disease also release spontaneously, large amounts of fibroblast growth factor activity attributable to PDGF and fibronectin.     

Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension

We investigated the clinical characteristics and immunoserological alterations in patients with mixed connective tissue disease (MCTD) associated with pulmonary arterial hypertension (PAH). Anti-U1RNP autoantibodies, anti-endothelial cell antibodies (AECA) and serum thrombomodulin (TM) as well as von Willebrand factor antigen (vWFAg) concentrations were measured in 25 patients with MCTD associated with PAH and in 154 MCTD patients without PAH. The results showed that the probability of survival was lower in MCTD patients with PAH than in the 154 MCTD-non-PAH patients (5-year survival rate in MCTD with PAH: 73%, versus 96% in MCTD-non-PAH; P < 0.01). AECA were more frequently present in the sera of MCTD patients with PAH than in MCTD-non-PAH (P < 0.001). Serum TM and vWFAg levels were higher in MCTD-PAH patients than in MCTD-non-PAH patients (TM: P < 0.001; vWFAg: P < 0.001). Significant correlation was noticed between the quantity of AECA and TM level (r = 0.466) as well as the quantity of AECA and vWFAg level (r = 0.550). In conclusion, our results suggest that in MCTD the presence of AECA and endothelial cell activation may play a role in the development of PAH and in the maintenance of obliterative vascular processes.     

KL-6在结缔组织病合并间质性肺病诊断中的应用价值

目的：探讨KL-6在结缔组织病合并间质性肺病诊断中的应用价值。 方法：本实验收集自2016年1月至2017年12月就诊于新疆维吾尔自治区人民医院风湿免疫科并确诊的CTD-ILD患者50例,单纯CTD患者46例。记录患者年龄、性别、诊断、肺功能。使用ELISA法测定血清中KL-6水平。所有数据处理均采用SPSS20软件包,其中计量资料统计采用t检验及Mann-Whitney检验,计数资料统计采用χ2检验,临界值用ROC曲线分析,危险因素分析采用Logistic回归检验,P<0.05为差异具有统计学意义。结果：本实验共纳入96例患者,其中CTD-ILD患者50例,CTD患者 46例,CTD-ILD血清KL-6浓度平均值为（1 962.1±1 329.4）mg/L,明显高于CTD组（259.4±435.1）mg/L,对比组间存在显著差异（P=0.000）,血清KL-6水平与FVC%、FEV1%及TLcoSB%呈负相关。ROC分析其诊断ILD最佳临界值为500 mg/L,其敏感度为82.0%,特异度为89.1%,曲线下面积为0.877。结论：血清KL-6是诊断ILD的重要诊断工具,同时可能也是检测CTD-ILD活动的重要血清标志物。     

Nucleoporin p62 antibodies in a case of mixed connective tissue disease

Mixed connective tissue disease is an overlap syndrome characterized by features of different systemic autoimmune diseases and a high titer of U1-snRNP antibodies. We examine here the autoantibodies to nucleoporin p62 in a severe case of mixed connective tissue disease in a young male patient. Thus far, p62 antibodies have mainly been described in cases of primary biliary cirrhosis. We speculate that the presence of p62 antibodies is an indication of a poor prognosis in connective tissue disorders.     

Differential isotype recognition of two centromere associated polypeptides by immunoblotting in connective tissue disease.

On investigating the immunoblotting profile of 65 systemic sclerosis patients, a 140 kD polypeptide was recognised by sera from 16, when immunoblotted against a nuclear-enriched K562 cell sonicate. All 16 sera contained anticentromere antibodies (ACA) detected by immunofluorescence (IF) and 15 of 16 also recognized a 19 kD polypeptide on immunoblotting. Two ACA positive sera failed to recognize the 140 kD polypeptide but one of these recognized the 19 kD polypeptide. The 140 kD polypeptide identified a group with more limited skin involvement (P less than 0.05) and all 16 had Raynaud's phenomenon. The sera from three of 100 systemic lupus erythematosus (SLE) patients also recognized both polypeptides. On investigating the isotype specificity, the 140 kD polypeptide was strongly detected by an IgM autoantibody and the 19 kD polypeptide by an IgG autoantibody.     

A confocal microscopy study of anticytoskeletal antibody activity in patients with connective tissue disease.

The significance of the presence of antibodies to cytoskeleton proteins in patients with connective tissue diseases is not clear, as there is a high level of these antibodies in healthy controls. In an attempt to improve the visualization of the immunofluorescence binding pattern of autoantibodies to cytoskeletal structures in cultured fibroblasts, we have used confocal microscopy. Of the 256 serum samples tested, 155 (61%) WERE reactive with cytoplasmic structures. These reactive samples could be divided into seven patterns of binding, as determined by double-blind examination of single-section confocal images. While confirming the results of previous immunofluorescence studies which have shown that autoantibodies that bind to filamentous structures in the cytoplasm of cultured cells are common in patients with connective tissue diseases, we were able to identify three patterns of cytoskeletal binding which may be useful as an adjunct to other tests for the diagnosis of some connective tissue diseases, in particular systemic sclerosis (scleroderma) and rheumatoid arthritis/Sjogren's syndrome. None of the seven patterns was exclusive to a particular disease. We conclude that confocal microscopy may be of limited use as an adjunct to other serological assays in the diagnosis of some forms of connective tissue disease.     

Derailed B cell homeostasis in patients with mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19 + CD27-IgD + CD38^high); (2) naive B cells (CD19 + CD27-IgD + CD38^low); (3) non-switched memory B cells (CD19 + CD27 + IgD+); (4) switched memory B cells (CD19 + CD27 + IgD-); (5) double negative (DN) memory B cells (CD19 + CD27-IgD-) and (6) plasma cells (CD19 + CD27^highIgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27^high B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.     

A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations

Deletions encompassing TAK1‐binding protein 2 (TAB2) associated with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole‐exome sequencing (WES) disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C‐terminal zinc finger domain essential for activation of TAK1 (TGFβ‐activated kinase 1)‐dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers‐Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development.     

A case of vasculitis syndrome associated with epididymitis]

A case of vasculitis syndrome associated with epididymitis is reported. A 56-year-old male presented with the sudden left testicular pain and fever. He came to the department of urology in our hospital, and was treated with antibiotics and anti-tuberculous drugs. However, the testicular pain was not relieved as well as the fever. In January 5, 1993, he was admitted. He had lost 6 kg. Physical examination revealed pyrexia and blood pressure of 150/91 mmHg. Laboratory finding revealed leukocytosis, thrombocytosis, and erythrocyte sedimentation rate of 100 mm/hr. On serological examination, the C-reactive protein was positive. We suspected this case as a polyarteritis nodosa, then he was given prednisolone. On January 20, 1993, left orchidectomy and spermatic cord biopsy was performed and non-necrotizing vasculitis was found. On August 10, cyclophoaphamide was added and his symptom disappeared. Although polyarteritis nodosa is well known as the vasculitis affecting the epididymis, it was rare that initial manifestation was testicular pain. In this case necrotizing vasculitis was not proven, but we diagnosed this case as a vasculitis in which the initial symptom was the epididymitis.