Cheng-De Yang

Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease : a retrospective cohort study

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer’s definition or Bohan–Peter’s classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan–Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239–14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO2, higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation.

Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus.

The purpose of this study is to describe the etiology, characteristics and outcomes of central nervous system (CNS) infections in patients with systemic lupus erythematosus (SLE), while also identifying prognostic and risk factors. Thirty-eight SLE patients with CNS infections were identified from review of all charts of patients with SLE hospitalized from January 1995 to June 2005. These patients were divided into 3 groups, i.e., Mycobacterium tuberculosis (TB), non-TB bacterial and fungal infection groups. Of the 38 SLE cases with CNS infections, TB was identified in 19 patients, Listeria monocytogenes in 3 patients, Klebsiella pneumoniae in 1 patient, Staphylococcus aureus in 1 patient, Gram’s stain positive bacteria in 1 patient, Cryptococcus neoformans in 12 patients, and Aspergillus fumigatus in 1 patient. The rate of unfavorable outcome in patients with fungal infection was lower than in patients with TB (P=0.028) and non-TB bacterial CNS infections (P=0.046). SLE patients with TB or fungal CNS infections had a more insidious or atypical clinical presentation. Compared to SLE patients without CNS infections, those with CNS infections were more likely to have low serum albumin levels (P=0.048) and have been receiving higher doses of prednisolone at the onset of CNS infection (P=0.015) or higher mean doses of prednisolone within the previous year (P=0.039). In conclusion, low levels of serum albumin and higher doses of received prednisolone are important risk factors for the development of CNS infections in SLE patients.

Clinical features and prognosis of adult-onset still's disease: 61 cases from China.

Objective. To describe the onset, clinical features, prognostic factors, and treatment of adult-onset Still’s disease (AOSD) in cases from China. Methods. Sixty-one Chinese patients with AOSD were analyzed retrospectively. Results. Common clinical features were fever (100.0%), rash (88.5%), and arthritis (82.0%). The laboratory findings were as follows: leukocytosis (83.6%), increased erythrocyte sedimentation rate (100.0%), elevated transaminase concentrations (23.0%), elevated ferritin levels (79.6%), negative antinuclear antibody (88.5%), and negative rheumatoid factor (88.5%). Of the 61 patients, 44.3% exhibited a monocyclic disease pattern, 29.5% experienced disease relapse at least once, 16.4% exhibited chronic articular course, and 9.8% died; most deaths were due to pulmonary infection and respiratory failure. Based on the disease course, we divided the 61 patients into 2 groups: those with favorable outcome (cyclic disease course, n = 45) and unfavorable outcome (chronic disease course or death, n = 16). We analyzed the prognostic factors for the 2 groups, and found that pleuritis, interstitial pneumonia, elevated ferritin levels, and failure of fever to subside after 3 days of prednisolone at 1 mg/kg/day were unfavorable prognostic factors for patients with AOSD. Conclusion. Patients with AOSD had complex symptoms with no specific laboratory findings. Our results indicate that AOSD is not a relatively benign disease, especially in cases that are refractory to high doses of prednisone.

Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases

IntroductionGlomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is largely unknown. Although several studies have reported the association of antiphospholipid antibodies (aPL) with GMT, the relation between GMT and aPL remains controversial. Previous studies have demonstrated that some aPL could bind to several hemostatic and fibrinolytic proteases that share homologous enzymatic domains. Of the protease-reactive aPL, some can inhibit the anticoagulant activity of activated protein C and the fibrinolytic function of plasmin, and hinder the antithrombin inactivation of thrombin. The purpose of this study was to investigate the prevalence of GMT in LN patients and examine the relation between the aPL profiles (including some protease-reactive aPL) and GMT.MethodsRenal biopsy specimens were examined for the presence of glomerular microthrombi. Plasma samples from 25 LN patients with GMT (LN-GMT group) and 99 LN patients without GMT (LN-non-GMT group) were tested for lupus anticoagulant and antibodies against cardiolipin, β2 glycoprotein I, plasmin, thrombin, tissue plasminogen activator, and annexin II.ResultsThe prevalence of GMT in LN patients was 20.2%. Compared with the LN-non-GMT group, the LN-GMT group had an elevated systemic lupus erythematosus disease activity index; elevated renal tissue injury activity and chronicity indices; elevated serum creatinine, blood urea nitrogen, and proteinuria levels; a lower serum C3 level and much intense glomerular C3, C1q staining; and a higher frequency of hypertension (P < 0.05 for all). Additionally, the detection rate of lupus anticoagulant, immunoglobulin G (IgG) anti-β2 glycoprotein I and anti-thrombin antibodies were higher in the LN-GMT group than in the LN-non-GMT group (P < 0.05 for all). No statistical differences were found in the detection rates of IgG anti-cardiolipin, plasmin, tissue plasminogen activator, or annexin II antibodies (P > 0.05 for all). No detectable difference in IgM autoantibodies to the above antigens was observed between the two groups.ConclusionsGMT occurs in approximately 20.2% of LN patients. Patients with GMT have severer renal tissue injuries and poorer renal functions than patients without GMT. The lupus anticoagulant and antibodies against β2 glycoprotein I and thrombin may play a role in GMT.

The levels of macrophage migration inhibitory factor as an indicator of disease activity and severity in adult-onset Still's disease

OBJECTIVES This study investigated the levels of macrophage migration inhibitory factor (MIF) in adult-onset Stills disease (AOSD) and explored the role of this pro-inflammatory cytokine in the systemic inflammation of AOSD. DESIGN AND METHODS Serum MIF levels were measured by ELISA in patients with AOSD and controls. Intracellular MIF production by peripheral blood leukocytes was detected by three-color flow cytometry. RESULTS Serum MIF levels were significantly increased in patients with AOSD. Serum MIF levels were significantly higher in AOSD patients with sore throat, myalgias, splenomegaly, or pleuritis, and were closely correlated with clinical disease severity and activity. Examined by flow cytometry, the intracellular MIF levels in monocytes and T-lymphocytes from AOSD patients were significantly higher than those from healthy subjects. CONCLUSION These data represent the first demonstration of increased MIF expression in AOSD, and suggest that MIF may be an important marker for disease evaluation and monitoring.

Hemophagocytic syndrome as one of main manifestations in untreated systemic lupus erythematosus: two case reports and literature review

Hemophagocytic syndrome (HPS) is an unusual but fatal disorder characterized by pancytopenia and activation of macrophages. We describe two cases of untreated systemic lupus erythematosus (SLE) with HPS that presented as one of the manifestations of SLE. The onset of HPS was after parturition for one patient, and after abortion for the other. Bone marrow examination revealed severe hemophagocytosis in both patients. One patient responded to pulsed methylprednisone alone, and the other responded to pulsed methylprednisone plus intravenous immunoglobulin (IVIG). We believe accurate diagnosis, intensive therapy, and sufficient supportive cares are essential in improving patients’ prognosis.

Anti-class a scavenger receptor autoantibodies from systemic lupus erythematosus patients impair phagocytic clearance of apoptotic cells by macrophages in vitro

IntroductionInadequate clearance of apoptotic cells by macrophages is one of the reasons for the breakdown of self-tolerance. Class A scavenger receptors, macrophage receptor with collagenous structure (MARCO) and scavenger receptor A (SR-A), which are expressed on macrophages, play important roles in the uptake of apoptotic cells. A previous study reported the presence of the anti-MARCO antibody in lupus-prone mice and systemic lupus erythematosus (SLE) patients. The purpose of this study was to investigate the prevalence of anti-class A scavenger receptor antibodies in patients with various autoimmune diseases, in particular SLE, and the functional implication of those autoantibodies in the phagocytic clearance of apoptotic cells by macrophages.MethodsPurified recombinant scavenger receptor cysteine-rich (SRCR) polypeptide (ligand-binding domain of MARCO) and recombinant SR-A were used as antigens. By using enzyme-linked immunosorbent assay, the anti-SRCR and anti-SR-A antibodies were detected in the sera of untreated patients with SLE (n = 65), rheumatoid arthritis (n = 65), primary Sjögren syndrome (n = 25), and healthy blood donors (n = 85). The effect of IgG purified from SLE patients or healthy controls on the phagocytosis of apoptotic cells by macrophages was measured by the flow cytometry assay.ResultsAnti-SRCR antibodies were present in patients with SLE (18.5%) and rheumatoid arthritis (3.1%), but not in those with primary Sjögren syndrome. Anti-SR-A antibodies were present in patients with SLE (33.8%), rheumatoid arthritis (13.8%), and primary Sjögren syndrome (12.0%). IgG from SLE patients positive for anti-SRCR or anti-SR-A antibodies showed a higher inhibition rate on binding of apoptotic cells to macrophages than IgG from healthy controls (both P < 0.05). IgG from SLE patients positive for both anti-SRCR and anti-SR-A antibodies showed a significantly higher inhibition rate on ingestion of apoptotic by macrophages than IgG from healthy controls (P < 0.05).ConclusionsOur results indicated that autoantibodies to class A scavenger receptors might contribute to the breakdown of self-tolerance by impairing the clearance of apoptotic debris and play a role in the pathogenesis of autoimmune disease, especially in SLE.

Some Plasmin-Induced Antibodies Bind to Cardiolipin, Display Lupus Anticoagulant Activity and Induce Fetal Loss in Mice

The combined presence of anti-phospholipid Ab (aPL), thrombosis, and/or fetal loss is recognized as the antiphospholipid syndrome (APS). aPL include anti-cardiolipin Ab (aCL) and/or lupus anticoagulants (LAC, detected as Ig that prolong certain in vitro phospholipid (PL)-restricted blood clotting tests); both aCL and LAC are the diagnostic Ab for APS. Studies show that aPL represent a heterogeneous group of Ab, which recognize various PL, PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found that five of seven patient-derived IgG monoclonal aCL react with thrombin, activated protein C, and plasmin. All three proteins are trypsin-like serine proteases (SP), and are highly homologous in their catalytic domains. Importantly, among these SP autoantigens, the reactive aCL bind to plasmin with the highest affinity, suggesting that plasmin may serve as a major driving autoantigen for some aCL in ∼30% of APS patients who are positive for IgG anti-plasmin Ab. To test this hypothesis, we immunized BALB/c mice with human plasmin and analyzed immune sera for aCL activity and reactivity with relevant SP. We found that some immune sera displayed aCL activity and/or bound to test SP. Subsequently, eight mAb were obtained and studied. The results revealed that one mAb displayed the aCL and the LAC activities and induced fetal loss when injected into pregnant mice. Immunohistological analyses of placentas revealed extensive deposits of activated C3 components. Combined, these data demonstrate that plasmin may serve as a driving Ag for some pathogenic aPL.

The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression

Introduction. Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined. Methods. Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN. Results. Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium. Conclusion. As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.Introduction. Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined. Methods. Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN. Results. Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium. Conclusion. As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.

New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus

IntroductionGlucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.MethodsSixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.ResultsMIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.ConclusionsOur results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.