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An automatic inspection system for antinuclear autoantibodies (ANA) testing can be divided into HEp-2 cell detection, fluorescence pattern classification and computer aided diagnosis phases. This paper presented a multi-staged segmentation method for automatically detecting outlines of fluorescence cells in Indirect immunofluorescence (IIF) images. The similarity-based watershed algorithm performed the marker to prevent over-segmentation. This paper evaluated 2305 autoantibody fluorescence patterns with manual sketched outlines (including 456 diffuse patterns, 417 peripheral patterns, 719 coarse speckled patterns, 55 fine speckled patterns, 517 discrete speckled patterns and 141 nucleolar patterns) from 44 IIF images. The experimental results revealed that the proposed method can practically outline fluorescence cells from IIF images.

Objective To determine spontaneous and activation-induced apoptosis of peripheral blood lymphocytes (PBLs) from patients with active untreated adult-onset Still's disease (AOSD) and to examine the role of interleukin-18 (IL-18) involved in the apoptosis related to this disease. Methods The percentages of spontaneous and IL-18–stimulated apoptotic lymphocytes in peripheral blood of 20 patients with active untreated AOSD, 20 with active untreated systemic lupus erythematosus (SLE), and 20 healthy controls were determined using annexin V/propidium iodide staining and flow cytometry. Serum IL-18 levels were measured using enzyme-linked immunosorbent assay. The transcripts of caspase 3 gene and apoptosis-regulating genes, including Fas, FasL, Bcl-2, and p53 in IL-18–treated peripheral blood mononuclear cells (PBMCs) from 8 AOSD patients, 4 SLE patients, and 4 healthy controls, were examined by real-time quantitative polymerase chain reaction. Results Significantly higher percentages of spontaneous and IL-18–stimulated apoptotic PBLs were found in patients with active untreated AOSD and those with active untreated SLE than in healthy controls. The percentages of spontaneous and IL-18–stimulated apoptotic lymphocytes correlated positively with clinical activity scores and serum IL-18 levels for AOSD patients and SLE patients. The percentages of spontaneous and activation-induced apoptotic PBLs significantly declined, paralleling clinical remission and the decrease in serum IL-18 levels after effective therapy in AOSD patients. Up-regulation of FasL and p53 transcripts was demonstrated in IL-18–treated PBMCs from AOSD patients and SLE patients in a dose-dependent manner. Conclusion The increased apoptosis of PBLs from AOSD patients may be associated with the effect of IL-18 through up-regulation of FasL and p53 transcripts.

Background: Little is known about the differences in the immunopathogenesis between elderly-onset rheumatoid arthritis (EORA) and younger-onset RA (YORA) and the factors responsible for their clinical characteristics. Objective: It was the aim of this study to investigate proinflammatory cytokines of EORA patients and compare them with those of YORA patients. Methods: Serum levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were determined by cytometric bead array in 86 patients with active EORA, in 76 patients with active YORA and in 30 healthy controls. Disease activity of RA was assessed using the 28-joint disease activity score. Erosion scores were recorded using a modified version of the Sharp method. Levels of anti-cyclic citrullinated peptide antibodies were determined by ELISA, and levels of rheumatoid factor-IgM and C-reactive protein were measured by nephelometry. Results: A higher proportion of men and a higher frequency of acute onset with constitutional symptoms and comorbidities were observed in EORA compared with YORA patients. Increased levels of serum IL-1β, IL-6, TNF-α, IFN-γ and IL-8 were positively correlated with the 28-joint disease activity score, and elevated levels of IL-1β and TNF-α were positively correlated with erosion scores for both groups of RA patients. Significantly higher IL-6 levels and lower TNF-α levels were found in EORA compared with YORA patients. Higher levels of serum IL-6 were found in EORA patients with polymyalgia rheumatica-like symptoms than in those without and were also noted in male patients with EORA compared with female patients. Multivariate analysis showed that high levels of TNF-α were associated with the occurrence of constitutional symptoms, and high levels of IL-1β were associated with the presence of anti-cyclic citrullinated peptide antibodies in EORA patients. Conclusion: EORA patients appear to have differences in clinical characteristics and the patterns of proinflammatory cytokines when compared with YORA patients.

Plant-thorn synovitis is an uncommon cause of arthritis and has not been reported in Asian countries. Zanthoxylum ailanthoides, an aromatic plant distributed in East Asia, is used as a spice in Taiwan. We reported a case of acute monoarthritis over the third metacarpo-phalangeal joint of the right hand after an injury by the thorn of the Zanthoxylum ailanthoides. A thorn foreign body of 2.7 mm in length was detected in the joint by high-resolution ultrasonography and led to a surgical synovectomy. The patient recovered completely after synovectomy. Plant-thorn synovitis is easily negligible. Early diagnosis is difficult and frequently delayed. The removal of thorn by synovectomy is the only curative treatment for plant-thorn synovitis. Compared to CT and MRI, ultrasonography is inexpensive, nonradioactive, repeatable, and easily accessible. It could detect foreign bodies that are smaller than 0.5 mm. High-resolution ultrasonography is a useful tool for detecting plant thorn and could promote early diagnosis.

Data on the disease course and ultimate outcome of adult-onset Still's disease (AOSD) are limited. We analyzed the clinical manifestations, disease course, and complications of patients with AOSD in Taiwan.A retrospective cohort design with prospective follow-up was used. Eighty two patients with AOSD diagnosed between 1983 and 2003 were evaluated. Their clinical features and laboratory findings at presentation, disease course, and complications were analyzed.Fifty nine patients (72%) were female and 55 (67.1%) were aged between 16-35 years at onset. The most common clinical manifestations were fever (100%), articular symptoms (100%), evanescent rash (87%), and sore throat (84%). Dermatographism was noted in 59% of patients. Elevation of erythrocyte sedimentation rate and C-reactive protein, which were significantly correlated with disease activity score (both p0.01) occurred in more than 90% of AOSD patients. Elevation of serum ferritin, which was significantly correlated with disease activity score and hepatic enzyme levels, was present in 91% of patients. Polycyclic systemic course was the most common (45%), followed by monocyclic systemic course (34%); only 20% of patients progressed to chronic arthropathy.The multisystemic involvement and various patterns of disease course in this series illustrate the heterogenic nature of AOSD. Serum ferritin levels can be used as a marker for monitoring disease activity in AOSD.

To investigate concentrations of proinflammatory cytokines in the sera and their mRNA expression in biopsy specimens of evanescent rash and synovitis from patients with active untreated adult onset Still's disease (AOSD).We measured serum levels of interleukin 6 (IL-6), IL-8, and tumor necrosis factor (TNF-alpha) by immunochemiluminescence method and serum IL-18 levels by ELISA in 50 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls. Multivariate analysis was used to evaluate the correlation between serum cytokine levels and disease activity and clinical features of AOSD. We also evaluated the expression of cytokine transcripts by real-time quantitative polymerase chain reaction in biopsy specimens of evanescent rash and synovitis from 12 patients with active untreated AOSD.Significantly higher levels of IL-6, IL-8, IL-18, and TNF-alpha in sera were found in patients with active untreated AOSD compared to healthy controls. Serum levels of IL-6 and IL-18 correlated well with clinical activity score of AOSD patients. Multiple logistic regression analysis showed that serum IL-6 level was a possible predictor for the occurrence of evanescent rash (p = 0.0593), serum IL-8 level was a significant predictor of persistent arthritis, and serum IL-18 level predicted occurrence of liver dysfunction. The levels of mRNA expression of IL-6, IL-18, and IL-8 were significantly higher in the biopsy tissue of Still's rash from AOSD patients compared with those in controls. Levels of mRNA expression of IL-18, IL-8, and TNF-alpha were significantly higher in the synovial membranes of AOSD patients compared with those in osteoarthritis controls. Significantly lower levels of TNF-alpha and IL-8 were found in the sera and in the synovial membranes of AOSD patients compared with those in RA patients. AOSD patients who had a chronic articular course had significantly higher levels of serum IL-8 compared with those who had a monocyclic systemic course.Significantly higher levels of IL-6, IL-8, IL-18, and TNF-alpha were seen in both sera and pathological tissues of patients with active AOSD. The associations between levels of cytokine profile and distinct clinical manifestations and various patterns of disease course suggest the heterogeneity of pathogenesis in AOSD.

Objective: To determine the type 1 T helper (Th1)/type 2 T helper (Th2) balance in the peripheral blood (PB) and pathological tissues of patients with active untreated adult onset Still's disease (AOSD). Methods: The percentages of interferon γ (IFNγ)- and interleukin (IL)4-producing Th cells in the PB of 20 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls were determined by intracellular staining and flow cytometry. Serum levels of IL18 and soluble IL2 receptor were measured by enzyme linked immunosorbent assay. Levels of IFNγ and IL4 messenger (m) RNA expression were examined by real time quantitative polymerase chain reaction in biopsy specimens of evanescent rash and synovitis from 8 patients with AOSD. Results: Significantly higher IFNγ-producing Th cells and Th1/Th2 ratio in PB were found in patients with AOSD than in healthy controls. Percentages of IFNγ-producing Th cells and Th1/Th2 ratio in PB correlated significantly with clinical activity score and serum IL18 levels in patients with AOSD. Increased ratio of Th1/Th2 cytokine transcripts was seen in the biopsy specimens of evanescent rash and synovitis from patients with AOSD compared with normal skin controls and patients with OA. Th cell cytokine pattern in PB and cytokine mRNA expression in synovium were similar for patients with AOSD and with RA. After 3 months' treatment, clinical remission was associated with a marked decrease in the percentages of cytokine-producing Th1 cells, but not of the Th2 cells. Conclusion: A predominance of Th1 cytokine may precipitate the pathogenesis of AOSD.

Etanercept (Enbrel), a recombinant tumor necrosis factor receptor fusion protein, has been shown to be effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate (MTX) and MTX alone in Taiwanese patients with active RA.In this double-blind study, 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were randomized to receive either etanercept 25 mg (n = 29) or placebo (n = 29) by subcutaneous injection twice weekly over a period of 12 weeks. The primary endpoint was the reduction of tender and swollen joint counts by 20% (ACR 20), 50% (ACR 50), and 70% (ACR 70) as determined by the American College of Rheumatology criteria at the 12th week.The addition of etanercept to MTX resulted in a greater reduction in the number of tender (7.00 vs 2.45, p = 0.012) and swollen joints (8.55 vs 3.86, p = 0.017), and in serum levels of C-reactive protein (1.26 mg/dL vs 0.45 mg/dL, p = 0.014) compared to MTX alone after 12 weeks of therapy. In addition, the global assessment of disease activity by both physicians and patients, duration of morning stiffness, pain visual analog scale score, and Health Assessment Questionnaire were all improved by etanercept plus MTX therapy. Results for the overall improvement in disease activity assessed by ACR 20 (90% vs 34%), ACR 50 (66% vs 10%) and ACR 70 (24% vs 0%) all favored the etanercept plus MTX group. However, the adverse events were comparable between the 2 treatment groups.Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA.

Methotrexate pneumonitis is an unpredictable and life-threatening side effect of methotrexate therapy. Early diagnosis, cessation of methotrexate, and treatment with corticosteroids and/or cyclophosphamide are important in the management of patients with methotrexate pneumonitis. Methotrexate pneumonitis has not been reported in patients of Chinese ethnicity. We report a case of methotrexate pneumonitis in a Taiwan patient with rheumatoid arthritis who presented with acute nonproductive cough, dyspnea, fever, severe hypoxemia, and rapid progression to respiratory failure. Chest roentgenogram demonstrated bilateral diffuse interstitial and alveolar infiltration. Thoracoscopic biopsy with wedge resection of the upper lobe of the right lung was performed and the histologic findings of the biopsy specimen were consistent with bronchiolitis obliterans with organizing pneumonia. Rapid improvement of methotrexate pneumonitis was achieved after pulse therapies of methylprednisolone and cyclophosphamide and daily use of prednisolone.

Protein-losing gastroenteropathy is a rare complication in autoimmune diseases, especially in Sjögren's syndrome. We report two cases of primary Sjögren's syndrome, one in a 37-year-old female and another in a 50-year-old female, both of whom presented with peripheral edema. Protein-losing gastroenteropathies of the stomach and small intestine in the first patient and of the small intestine only in the second patient were demonstrated by abdominal Tc-99m labeled albumin abdominal scintigraphy and pathologic findings. Results of gastrointestinal tract biopsies from both patients showed chronic inflammatory cell infiltrations without lymphangiectasis or vasculitis. The patients were successfully treated with corticosteroids. Results of follow-up Tc-99m labeled albumin scintigraphy were well correlated with clinical improvement and the increase in serum albumin. Sjögren's syndrome should be considered as a cause of protein-losing enteropathy. Tc-99m labeled albumin abdominal scintigraphy is helpful in diagnosing the condition, locating the protein-losing sites, and monitoring the treatment outcome, especially in cases where protein loss occurs in the stomach.

In most patients with progressive systemic sclerosis the esophagus is affected. Reflux symptoms are most frequent whilst dysphagia also occurs. The radionuclide esophageal transit study is a sensitive screening test for esophageal dysfunction. In this study, we evaluated the esophageal motility of patients with progressive systemic sclerosis using a solid-phase radionuclide esophageal study.Thirty-two patients with progressive systemic sclerosis and 30 normal volunteers were studied with solid-phase radionuclide esophageal study. Each subject was placed in a supine position above a gamma camera linked to a computer and was given a 4-mL bolus of solid gelatin containing 1 mCi of Tc-99m phytate. Data were acquired in the list mode.Twenty-nine of the 32 patients (91%) had abnormal findings from the study.The radionuclide esophageal transit study can be regarded as a useful tool for evaluating the esophageal function in patients with progressive systemic sclerosis and in the follow-up of treatment.

Joint Bone Spine - In Press.Proof corrected by the author Available online since dimanche 22 juin 2014

Autoimmune disease is a disorder of immune system due to the over-reaction of lymphocytes against one's own body tissues. Anti-Nuclear Antibody (ANA) is an autoantibody produced by the immune system directed against the self body tissues or cells, which plays an important role in the diagnosis of autoimmune diseases. Indirect ImmunoFluorescence (IIF) method with HEp-2 cells provides the major screening method to detect ANA for the diagnosis of autoimmune diseases. Fluorescence patterns at present are usually examined laboriously by experienced physicians through manually inspecting the slides with the help of a microscope, which usually suffers from inter-observer variability that limits its reproducibility. Previous researches only provided simple segmentation methods and criterions for cell segmentation and recognition, but a fully automatic framework for the segmentation and recognition of HEp-2 cells had never been reported before. This study proposes a method based on the watershed algorithm to automatically detect the HEp-2 cells with different patterns. The experimental results show that the segmentation performance of the proposed method is satisfactory when evaluated with percent volume overlap (PVO: 89%). The classification performance using a SVM classifier designed based on the features calculated from the segmented cells achieves an average accuracy of 96.90%, which outperforms other methods presented in previous studies. The proposed method can be used to develop a computer-aided system to assist the physicians in the diagnosis of auto-immune diseases.

Myeloid cell leukemia-1 (Mcl-1, Mcl-1L) is an anti-apoptotic protein of the Bcl-2 family that acts as a critical molecule in apoptosis control. Mcl-1 pre-mRNA can undergo alternative splicing to yield the short isoform, Mcl-1S, which resembles BH3-only pro-apoptotic proteins and induces apoptosis. Overexpression of Mcl-1 may play a role in various human tumors, and Mcl-1 may serve as a target in cancer therapy. In this study, we found an imbalance between the expression levels of Mcl-1L and Mcl-1S in the skin basal cell carcinoma (BCC) cell line when compared with primary keratinocytes. We showed that overexpression of Mcl-1S induces apoptosis in BCC cells. Finally, we showed that Mcl-1 antisense morpholino oligonucleotides (AMOs) can specifically target Mcl-1 pre-mRNA and shift the splicing pattern from Mcl-1L to Mcl-1S mRNA and protein. This shift increases the level of pro-apoptotic Mcl-1S and reduces the level of anti-apoptotic Mcl-1L, which induces apoptosis in BCC cells and AGS cells, a human gastric adenocarcinoma epithelial cell line. Thus, this report provides a strategy for cancer therapy in which AMOs change the alternative splicing pattern of Mcl-1 pre-mRNA and thereby induce apoptosis.

Sarcoidosis is a granulomatous multisystem disorder that rarely involves muscle. Although characteristic ultrasound features of nodular-type muscular sarcoidosis have been reported, observations for such lesions at different disease stages are limited. We report ultrasonographic findings for nodular-type muscular sarcoidosis at 3 months and 1 year after the onset of disease in the left medial gastrocnemius muscle of a 35-year-old woman. A hypoechoic mass was initially detected in the involved muscle, and central echogenicity appeared later. It is, therefore, considered that ultrasonography can be a valuable tool in detecting and following up nodular-type muscular sarcoidosis lesions.

Introduction The goal of this study was to investigate (1) the associations of rheumatoid arthritis (RA)-related inflammation or rheumatoid factor/anti-cyclic citrullinated peptide (anti-CCP) positivity with lipid profiles and insulin resistance (IR), (2) the effects of biologic therapy on lipid profiles and IR, and (3) potential predictors for the presence of subclinical atherosclerosis. Methods Serum levels of lipid profiles were determined by enzymatic methods in 32 adalimumab-treated patients, 16 etanercept-treated patients, 24 tocilizumab-treated patients, and 20 biologic-naïve patients. Atherogenic index, which corresponds to the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C), was calculated. IR was measured by homeostasis model assessment. Pro-inflammatory cytokine levels were examined by enzyme-linked immunosorbent assay. Common carotid artery intima-media thickness was determined by using sonography. Results There was an inverse correlation between disease activity (disease activity score for 28 joints, or DAS28) and low-density lipoprotein cholesterol (LDL-C) levels (r = −0.226, P