Cardiovascular disease and serum defensin levels in systemic lupus erythematosus.

OBJECTIVES: To analyse if defensins, immunomodulatory peptides involved in angiogenesis and elevated in the sera of systemic lupus erythematosus (SLE) patients, relate to cardiovascular disease in SLE. METHODS: Serum levels of the defensins human beta defensin 2 (hBD2) and human neutrophil peptide (HNP) of 72 SLE patients were determined by ELISA at baseline. Cardiovascular risk factors and the occurrence of cardiovascular events (CVE: stroke, claudication, angina pectoris, myocardial infarction) were recorded over 6 years. Intima media thickness of the carotid arteries (CIMT) was measured by ultrasound in 42 patients at baseline and at 4 years. Normally distributed log-transformed defensin levels (log-hBD2 and log-HNP) were used for statistical analysis. RESULTS: SLE patients who experienced a CVE had significantly higher log-hBD2 values and a likelihood-ratio for CVE of 2.23 when levels increased above 3.3 log(ng/ml). Using binary logistic regression analysis, log-hBD2 significantly contributed to a model also incorporating the number of traditional cardiovascular risk factors (dyslipidemia, hypertension, positive family history, age, smoking) as explanatory variables for the incidence of cardiovascular events. Moreover, SLE patients with progressive CIMT showed increased log-hBD2 and log-HNP values. Both defensin-levels also showed some correlation to the plaque stadium at baseline (hBD2: r2 0.10; HNP r2 0.12). Neither log-hBD2 nor log-HNP were correlated to traditional cardiovascular risk factors. CONCLUSIONS: HNP and especially hBD2 may be indicators of progressive cardiovascular disease in SLE.

Elevated levels of human beta-defensin 2 and human neutrophil peptides in systemic lupus erythematosus.

OBJECTIVE: Defensins are immunomodulatory peptides and components of the innate immune response. They have been shown to be modulated in various disease states and in response to inflammatory stimuli. Recently, alpha-defensins have been implicated in the pathogenesis of autoimmune diseases. In order to explore whether these defensins may have a role in the pathogenesis of systemic lupus erythematosus (SLE), we sought to determine whether altered expression can be found in SLE patients. MATERIAL AND METHODS: Serum and EDTA-blood of 50 SLE patients who fulfilled the American College of Rheumatology (ACR) criteria (aged 41.4 ± 13.3 years) and 28 age- and sex-matched healthy controls were collected. Real-time polymerase chain reaction with gene-specific primers for human neutrophil peptides (HNPs), human beta-defensin 2 and 3 (hBD2, 3) in isolated polymorphonuclear cells and enzyme-linked immunosorbent assay (ELISA) in serum samples were performed. Results of SLE patients were compared with the control group and correlated to routine laboratory parameters, clinical data and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: SLE patients were predominantly female (90%) with a mean SLEDAI of 5.7 ± 6.1. In sera, patients displayed higher amounts of hBD2 and HNPs when compared with healthy controls. Furthermore, hBD2 correlated with levels of anti-dsDNA antibodies, erythrocyte count and the SLEDAI. Elevated values were observed in patients with myositis (n = 4). Serum HNPs on the other hand correlated with the neutrophil count and was elevated in patients with a rash (n = 7). Lupus patients suffering from transverse myelitis (n = 3) had raised serum-values of both HNPs and hBD2. While no mRNA of hBD2 or hBD3 was detected in polymorphonuclear cells, HNP mRNA was found in both healthy controls and patients without significant difference. Lupus nephritis and rash were associated with higher amounts of HNP mRNA, and the relative amount of copies correlated positively with the SLEDAI and negatively with C3 measurements. CONCLUSIONS: Serum levels of hBD2 and HNPs are elevated in SLE. The correlations of hBD2 and HNPs to established disease activity parameters and distinct clinical situations suggest that innate immune mechanisms are activated. Defensins may be involved in SLE pathogenesis.

Expression of CD57 on CD8+ T lymphocytes of patients with Wegener's granulomatosis and microscopic polyangiitis: evidence for continuous activation of CD8+ cells.

OBJECTIVES: To gain insight into the immune pathogenesis of Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), the prevalence of circulating CD8+ T lymphocytes expressing CD57 as a marker for previous activation was analyzed. METHODS: Receptor expression of CD57 was measured in CD8+ T cells of patients with active disease (n=5) by cytofluorometry and compared with expression in patients in remission (n=80) and in age-matched healthy donors (n=34). The results were compared to clinical parameters including severity and duration of the disease. RESULTS: CD8+CD57+ were detected in patients with WG and MPA and in healthy donors as well and increased considerably with age. Compared to age-matched healthy donors, the prevalence of CD8+CD57+ was increased in the younger patients (up to 40 y). In most patients a high percentage of CD8+CD57+ coincided with severe disease and multiple organ involvement, while low CD8+CD57+ percentage was seen in patients with limited disease or in patients in complete remission. In patients with smoldering disease, the percentage of CD8+CD57+ increased with time. High numbers of CD8+CD57+ correlated with low CD4:CD8 ratio. CONCLUSIONS: In patients with WG and MPA a population of CD8+CD57+ expand, identifying terminally differentiated CD8+ cells. The prevalence of CD57+ cells was related to the course of disease. So far, the function of CD57 on CD8+ cells is not understood. However, these cells might produce certain cytokines, which play a role in the pathogenesis of AAV. The data support the hypothesis that CD8+ T cells are activated in the context of primary vasculitides.

T lymphocytes in patients with primary vasculitis: expansion of CD8+ T cells with the propensity to activate polymorphonuclear neutrophils.

OBJECTIVES: To gain insight into the immune pathogenesis of primary ANCA-associated vasculitides, the prevalence of circulating T lymphocytes expressing CD11b as a marker for activation was analysed in patients with WG or microscopic polyangiitis. METHODS; Receptor expression and IFNgamma synthesis were measured in T cells of patients with active disease by cytofluorometry and compared with expression in patients in remission and in healthy donors. RESULTS: During active disease, a small but conspicuous population of CD8+CD28+CD11b+ was found which produced IFNgamma. In healthy donors and in patients in remission or undergoing immunosuppressive therapy, CD11b was exclusively associated with CD8+CD28- cells, the latter being more frequent in patients with long-lasting or severe disease. In vitro experiments confirmed that CD11b is up-regulated when T cells are activated. After multiple rounds of restimulation, the CD11b expression persists whereas CD28 expression is lost, compatible with the notion that CD8+CD28+CD11b+ represents a transient phenotype in the course of T-cell activation. The IFNgamma-producing T cells activated polymorphonuclear neutrophils (PMN) to express MHC class II, thus generating the same PMN phenotype as in patients with active ANCA-associated vasculitis. A similar PMN phenotype could be generated by cultivation with supernatants of activated T cells or by IFNgamma alone, but not by antibodies to proteinase 3. CONCLUSIONS: In active primary vasculitis, a small population of CD8+ T cells, identified by the expression of CD11b, expands, producing IFNgamma. These T cells could activate PMN, thus generating a long-living and potentially destructive PMN phenotype.

First clinical trials of a new heteropolymer technology agent in normal healthy volunteers and patients with systemic lupus erythematosus: safety and proof of principle of the antigen-heteropolymer ETI-104.

BACKGROUND: The heteropolymer technology was developed to remove pathogens from the circulation. OBJECTIVES: To evaluate the safety and tolerability of a single administration and to establish proof of principle for ETI-104 in normal healthy volunteers (NHV) and patients with systemic lupus erythematosus (SLE) METHODS: The drug was given intravenously to 11 NHV and six patients with SLE. Over 28 days, vital signs were noted, a haematological and chemical analysis of blood and urine was carried out, and adverse events were recorded. CR1 receptor numbers, the ability of antigen based heteropolymers to bind to red blood cells (RBCs), and the clearance of high avidity and total anti-dsDNA antibodies were measured by Farr assays and FACS analysis. RESULTS: No safety measure differed significantly from normal in both groups; no drug related serious adverse events occurred. ETI-104 rapidly bound to RBCs in NHV and patients with SLE. Binding of the drug to RBCs of patients with SLE also caused a rapid reduction of circulating anti-dsDNA antibodies in the plasma 15 minutes after administration, with a maximum reduction of 55% (range 43-62). At 28 days statistically significant decreases were maintained in three patients, while in the other three the values had returned to baseline levels. CONCLUSION: These clinical trials established the safety and the proof of principle of the new immunoconjugate ETI-104. This provides the basis for further development of this technology for numerous indications-for example, therapeutic options for autoimmune diseases or viral and bacterial infections.

Simple method of documenting metatarsus adductus.

A simple, accurate, and inexpensive method of documenting metatarsus adductus involves taking photocopies of the foot in the weightbearing position. Subsequently, treatment progress can be assessed objectively by reviewing serial photocopies. Some caution is urged because the strength of the glass copying surface of photocopying machines is unknown.

Early complications in the operative treatment of ankle fractures. Influence of delay before operation.

We have reviewed the early complications of 121 surgically treated closed ankle fractures; the complication rate was 30%, with 14 major and 22 minor complications. Fractures with skin blisters or abrasions had more than double the overall complication rate. Fracture-dislocations had three times as many major complications as simple fractures, and those not fixed within 24 hours had a 44% major complication rate compared to 5.3% in those operated upon as emergencies. Patients transferred from another medical facility had high complication rates, especially if they had fracture-dislocations. We conclude that operative treatment of ankle fractures must be delivered in a timely fashion, especially in severe fractures. We would caution against the practice of transferring patients with serious ankle fractures before completion of definitive care.

Biomechanical analysis of the Chiari pelvic osteotomy. Preserving hip abductor strength.

Although the Chiari osteotomy is usually effective in reducing pain, many patients are left with a long-term limp. The postoperative limp can at times be caused by hip abductors that have strength insufficient to counteract the torque from body weight during single-leg stance. To study how the surgical technique affects the hip abductor muscles, a biomechanical model was developed that computes the postsurgery pelvic geometry and the resulting hip abductor torque given three surgical parameters: angulation of the osteotomy, distance of medical displacement, and angle of internal rotation. The computer simulations of the Chiari osteotomy showed that some sets of surgical parameters conserve abductor torque while others greatly reduce it. Simulated surgeries with high angulation and large medial displacement reduce gluteus medius abductor torque by up to 65%. Therefore, this combination of surgical parameters may account for some instances of the postoperative limp. In the model, high angulation reduces the length of the gluteus medius and is the primary cause of reduced abductor strength. Simulated horizontal osteotomies (0 degrees to 10 degrees) were found to best conserve both muscle length and abductor torque.

Established hip dislocations in children with cerebral palsy.

Hip dislocation in children with cerebral palsy is caused by a combination of factors, including spastic muscle imbalance, persistent fetal femoral geometry, acetabular dysplasia, and flexion-adduction contracture. The incidence of dislocation correlates with the severity of the spasticity, and the prevalence is close to 50% in neurologically immature, spastic quadriplegic children. Successful hip reductions improve muscular balance, provide satisfactory reduction of the femoral head, and establish good pelvic coverage. In 31 occurrences of established hip dislocation in 24 patients, the most successful operations used a combined procedure consisting of soft-tissue release, open reduction, femoral varus derotation and shortening osteotomy, and pelvic osteotomy.