Deng-Ho Yang

Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus

OBJECTIVE SLE is an autoimmune disorder characterized by abnormal complement activation. Numerous new biomarkers have recently been used to diagnose or monitor disease activity in patients with SLE. We checked the levels of erythrocyte-bound C4d (E-C4d), an activation-derived fragment of C4 that is deposited on the erythrocytes, under different conditions of SLE in order to correlate these levels with disease activity. METHODS We conducted a cross-sectional investigation of three groups of patients: (i) 63 patients with SLE; (ii) 43 patients with other diseases; and (iii) 26 healthy controls. Erythrocytes were analysed by flow cytometry to determine the levels of E-C4d. RESULTS We found a significant elevation in the mean levels of E-C4d in SLE patients compared with patients with other diseases or healthy controls. In SLE patients, the levels of E-C4d were correlated with the SLEDAI and inversely correlated with serum C3/C4 levels. In the subgroup of SLE patients with haemolytic anaemia (HA), a significantly higher level of E-C4d was observed than that in SLE patients without HA. However, in SLE patients with HA, there was no correlation between the levels of E-C4d and other markers of disease activity, including SLEDAI and levels of anti-dsDNA, C3 and C4. CONCLUSION E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA.

Advanced glycation end products induce T cell apoptosis: Involvement of oxidative stress, caspase and the mitochondrial pathway

Accumulation of advanced glycation end products (AGEs) is a hallmark in aged people. T cells play important roles in maintaining homeostasis of immune function. This study investigated the effects of AGEs-bovine serum albumin (AGEs) in human T cells. Incubation of Jurkat and several immortalized T cell lines with AGEs resulted in cell death dose-dependently. AGEs-induced cell death was partially but significantly blocked by neutralizing antibodies recognizing receptor of AGEs. In addition to detecting DNA nick, simultaneous stainings of annexin V with 7-amino-actinomycin D further confirmed the apoptotic nature of cell death. AGEs also caused apoptosis in purified T cells. Although AGEs-induced apoptosis could be blocked by the pan-caspase inhibitor, Ala-Asp-fluomethyl ketone (Z-VAD-fmk), there was no activation of caspase-3, -5, -8 and -9. AGEs caused mitochondrial outer membrane permeabilization and this process was prevented by an antioxidant or Z-VAD-fmk. Furthermore, AGEs treatment led to translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. Altogether, this report demonstrated that AGEs induced T cell apoptosis in an oxidative stress-associated and caspase-dependent manner with involvement of the mitochondrial pathway. It is likely that AGEs-induced T cell apoptosis may play a role in T cell homeostasis in ageing.

Etanercept as a rescue agent in patient with adult onset Still’s disease complicated with congestive heart failure

Adult onset Still’s disease (AOSD) is an uncommon disorder of unknown cause. The clinical symptoms of AOSD are a spiking fever, a typical rash, arthralgia or arthritis, sore throat, lymphadenopathy, and splenomegaly. Pleuropulmonary and cardiac involvement are rare. We report a patient with a two-year history of AOSD with myocarditis refractory to cyclosporine and glucocorticoid. Significant congestive heart failure due to left ventricle dysfunction and hyperferritinemia developed during the hospital course. After therapy with etanercept, the patient’s clinical manifestations recovered and she regained normal left ventricular systolic function.

Useful biomarkers for assessment of hepatitis C virus infection-associated autoimmune disorders

During the course of chronic hepatitis C virus (HCV) infection, various extrahepatic manifestations of autoimmune disorders may occur, including arthralgia/arthritis, sicca complex, purpura, cutaneous ulcer, and thyroid dysfunction. In addition, the prevalence of circulating autoantibodies is high among patients with HCV infection. Commonly detected autoantibodies in HCV-infected patients include rheumatoid factor, antinuclear antibody, anti-SSA/anti-SSB antibody, cryoglobulin, antineutrophil cytoplasmic antibody, anti-smooth muscle antibody, anti-liver and anti-thyroid autoantibodies. These autoantibodies may be associated with underlying autoimmune disorders or liver inflammation in HCV infection. A possible reason for antibody production is overactivation and proliferation of B lymphocytes, via the interaction with the surface protein of HCV. Because immunotherapy can cause HCV flare-up or liver damage, overdiagnosis of HCV-related autoimmune symptoms as primary autoimmune disorders should be avoided. This review describes biomarkers that are useful in clinically evaluating autoimmune manifestations and disorders associated with HCV infection.

Significantly Higher Percentage of Circulating CD27high Plasma Cells in Systemic Lupus Erythematosus Patients with Infection than with Disease Flare-Up

Purpose To distinguish lupus flare-up from infection in systemic lupus erythematosus (SLE), we analyze the expression of circulating CD27high plasma cells in SLE patients with and without infection, in comparison to non-SLE patients with infection. Materials and Methods The percentage of circulating CD27high plasma cells was measured by flow cytometry in the following four groups: 36 SLE patients without infection, 23 SLE patients with infection, eight non-SLE patients with infection, and 26 healthy controls. Results The frequency of CD27high plasma cells had a correlation with the SLE disease activity index (SLEDAI) (r = 0.866, p < 0.05), level of anti-dsDNA (r = 0.886, p < 0.05), C3 (r = - 0.392, p < 0.05), and C4 (r = - 0.337, p < 0.05) in SLE patients without infection, but there was no correlation with disease activity in SLE patients with infection. Among three groups in particular-SLE without infection, SLE with infection, and non-SLE with infection-the percentages of CD27high plasma cells were elevated. The percentage of CD27high plasma cells was higher in SLE patients with infection, when compared to SLE patients without infection. Conclusion The percentage of CD27high plasma cells is a biomarker for disease activity of SLE without infection, under correlation with SLEDAI, anti-dsDNA, and C3 and C4 level. However, when the SLE patients have an infection, the percentage of CD27high plasma cells is not an adequate biomarker for the survey of disease activity. The percentage of CD27high plasma cells may serve as a potential parameter to distinguish a lupus flare-up from infection.

Peripheral Arthritis Caused by Mycobacterium avium-intracellulare in a Patient With Ankylosing Spondylitis

To the Editor: We read with interest the report by Lee who described an unusual case of Mycobacteria avium complex (MAC)-induced pleurisy in a patient with amyopathic dermatomyositis and interstitial lung disease following prolonged immunosuppressive therapy. We would like to present a patient with a two-year history of ankylosing spondylitis (AS) who developed Mycobacterium avium-intracellulare arthritis of the left ankle after immunosuppressive therapy. In March 2006, a 33-year-old Asian male was diagnosed with AS after he presented with lower back pain that had persisted for more than 3 months, with bilateral grade III sacroiliitis and positive HLA-B27. Thereafter, he started to receive therapy consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) and sulfasalazine. Four months before his admission, pain and swelling with tenderness over the left ankle occurred, and he visited a clinic for an examination. At the clinic, he received an increased dosage of NSAIDs and sulfasalazine under the suspicion of AS flare up with peripheral arthritis. After one month, the arthritis with low-grade fever persisted. Treatment with methotrexate was commenced to control the peripheral arthritis, and this treatment was combined with NSAIDs and sulfasalazine. After 3 months, swelling over the left ankle with limitation of movement and intermittent lowgrade fever was still noted. He was admitted to our hospital for further survey of monoarthritis. There was swelling and local heat with tenderness over the left ankle but no significant signs of arthritis in the other joints. The patient denied having history of pulmonary tuberculosis and other medical illness. A complete blood count revealed 6360 WBC/ mm, 76% neutrophils, 24% lymphocytes, 13 g/dL hematoglobin, 180,000 platelets/mm, an erythrocyte sedimentation ratio 100 mm/h (N 25), and 7.48 mg/dL C-reactive protein (N 0.5). Liver and renal function tests were both normal. An immunologic study revealed the patient to be negative for rheumatoid factor and antinuclear antibody. Bacterial and TB cultures from sputum were negative. Serologic tests for viruses, including CMV, EBV and HIV, were also negative. A chest x-ray was normal. Plain film of the left ankle showed mild sclerotic change of the subtalar joint with bony erosion of the calcaneus, suggesting inflammatory arthritis. Magnetic resonance imaging (MRI) revealed synovial thickening with several hypointense nodules in the talus, subtalar joint, and around the posterior tibialis tendon on T1weighted images; these nodules showed hyperintensity on T2-weighted images. The MRI diagnosis of septic arthritis with abscesses was suggested. Subsequently, 1 mL turbid synovial fluid was aspired under ultrasound-guided arthrocentesis. Although initial bacterial culture and acid-fast stain for tuberculosis of the synovial fluid were negative, surgical debridement and biopsy of the left ankle was still performed under the suspicion of septic arthritis. The pathologic tests revealed acute necrotizing inflammation with multiple foci of calcification of soft tissue surrounding granulomas and a few multinucleated giant cells. One month later, M. aviumintracellulare was identified from a soft tissue culture. The patient was treated with 1000 mg clarithromycin, 800 mg ethambutol, and 300 mg rifabutin daily and has shown a good clinical response. Extraspinal manifestations in patients with AS include peripheral arthritis, enthesitis, acute anterior uveitis, and pulmonary and cardiac involvement. Approximately 10% of the patients have significant peripheral arthritis. The pathogens in nontuberculosis mycobacterial (NTM) infections include MAC, M. fortuitum, M. kansasii, M. mariunum, and M. xenopi with a prevalence rate of 1.8 cases per 100,000. The most common type of NTM is MAC. Most patients with MAC infection have pulmonary or disseminated diseases. Most NTM pulmonary infections give rise to variable chest radiographic findings with positive sputum and blood cultures. Rarely, patients have only skeletal involvement and there are no significant systemic symptoms. MRI or computed tomography may help to localize lesions. In immunocompromised subjects, such as HIV-positive patients or these receiving immunosuppressive treatments, there appears to be an increased risk of developing this opportunistic infection. NTM septic arthritis can occur in those patients with rheumatic diseases, including systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, because these patients receive immunosuppressive drug treatment over a long term. These immunosuppressive drugs include azathoprine, oral corticosteroids, intra-articular corticosteroids, cyclosporine, and biologic agents. Our patient is receiving long-term medication of sulfasalazine. Sulfasalazine has many anti-inflammatory and immunosuppressive properties including inhibition of prostaglandin and leukotriene synthesis, free radical scavenging, immunosuppressive activity, impairment of white cell adhesion and function, inhibition of cytokine synthesis. This case seems to be an increased risk of developing this opportunistic infection due to receiving immunosuppressive treatments. However, no M. avium-intracellulare was detected in the initial culture of synovial fluid aspirate. Significant pulmonary symptoms or image finding were not found in our case. A synovial biopsy was required to confirm the infection. In patients with AS, peripheral arthritis including that of the knees, wrists, ankles and feet, can develop during the course of the disease. The indolent nature of tuberculous bone and joint disease may lead to delayed or missed diagnosis because rheumatologists easily suspect AS flare with peripheral arthritis.

Remitting seronegative symmetrical synovitis with pitting edema following acute intracranial hemorrhage

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is an unusual inflammatory arthritis with unknown pathogenic mechanism, and is characterized by an acute onset of symmetrical synovitis with pitting edema of the hands or feet. Numerous diseases are associated with RS3PE, including neoplasia, infection, Parkinson’s disease, and other rheumatic diseases. Neoplasia is the most common condition associated with RS3PE. We report a case of RS3PE that occurred following acute intracranial hemorrhage in an 80-year-old man with a 20-year history of hypertension.

Predictive Value of erythrocyte-bound C4d to erythrocyte-complement Receptor Type 1 Ratio in Lupus Disease Activity

Objective: Erythrocyte-bound C4d (E-C4d) and erythrocyte-complement receptor type 1 (E-CR1) are both novel biomarkers to diagnose systemic lupus erythematosus (SLE) and to monitor disease activity. This study aimed at determining the ratio of E-C4d to E-CR1 (E-C4d/E-CR1) using mouse monoclonal antibody CR1-2B11 and correlating the clinical association of this ratio with disease activity of SLE. Methods: This study included 6 SLE patients, and their blood samples were collected before and after immunosuppressive therapy. E-C4d and E-CR1 levels were measured using indirect immunofluorescence and flow cytometry on the same day as the blood drawing, and the E-C4d/E-CR1 ratios were calculated from the values obtained. Results: The mean of the E-C4d/E-CR1 ratio was significantly decreased in SLE patients after immunosuppressive therapy (12.93±1.9 vs. 3.52±0.9, p＜0.05). Three of the 6 SLE patients showed decreased ratios when their active disease stabilized after adequate treatment respectively (19.23 to 1.01, 5.47 to 1.25, and 13.16 to 2.40). Conclusion: The reciprocal change in E-C4d and E-CR1 levels is important in SLE patients. The E-C4d/E-CR1 ratio assessed with CR1-2B11 could be a good biomarker to predict disease activity and may be helpful in formulating a therapeutic strategy in SLE.