Faculty Bibliography

BACKGROUND: Tight control of disease activity is the recommended target of therapy for rheumatoid arthritis (RA). OBJECTIVES: To determine the outcome of RA with respect to disease activity and the rate of remission, as measured by the DAS-28, in a real-world inception cohort. METHODS: We conducted an observational cross-sectional study of a single-center real-world inception cohort of 101 consecutive patients being treated for RA in 2009-2010 in a rheumatology outpatient clinic. Patients were managed at the discretion of the attending rheumatologist with the goal of achieving remission. DAS-28 scores were calculated and analyzed by clinical and treatment variables derived from the medical files. RESULTS: Mean patient age was 58.6 +/- 13.4 years and mean duration of disease 10.7 +/- 7.9years. Disease remission (DAS-28 < 2.6) was achieved in 26.7% of patients and low disease activity (> 2 .6 DAS-28 < 3.2) in 17%. Monotherapy with a conventional disease-modifying anti-rheumatic drug (C-DMARD, 21% of patients at last follow-up) was associated with a significantly lower mean DAS-28 score and C-reactive protein level than combined C-DMARD treatment (79% of patients), and with shorter disease duration than combined treatment with C-DMARDs or C-DMARD(s)+biological DMARD (40% of patients). Rheumatoid factor and anti-cyclic citrullinated peptide positivity had no effect on DAS-28 scores. Time from diagnosis was inversely correlated with DAS-28 scores. CONCLUSIONS: The achievement of low disease activity and remission in a significant portion of our inception cohort of patients with RA suggests that the treat-to-target strategy is feasible and effective in routine clinical practice.

Objective. Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating beta2-glycoprotein I (beta2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined. Methods. Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies. Results. uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 +/- 0.1 vs 1.9 +/- 0.05 ng/ml (P < 0.0001), 6.6 +/- 0.3 vs 2.1 +/- 0.2 ng/ml (P < 0.0001) and 435 +/- 34 vs 220 +/- 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 +/- 0.1 vs 1.9 +/- 0.05 ng/ml; P = 0.0086, 6.2 +/- 1.4 vs 2.2 +/- 0.7 ng/ml; P = 0.147 and 412 +/- 61 vs 260 +/- 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region. Conclusion. Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.

OBJECTIVE: To determine the association between inflammatory markers and mortality in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective cohort analysis of 143 patients with SLE followed between 1991 and 2010 in a Lupus Clinic in Israel. High sensitivity CRP (hsCRP) level and ESR were recorded at baseline. We compared outcomes of patients with elevation of either ESR or hsCRP to outcomes of patients without any elevation of inflammatory markers at start of follow-up. Risk factors for mortality were identified using univariate and multivariate analyses (Cox regression analysis). RESULTS: Of the 143 patients, 93 patients had an inflammatory marker and 50 had no inflammatory marker. There were no differences between the two groups in terms of lupus criteria, disease activity parameters or damage index. Survival was lower for patients in the inflammatory group, 24 deaths of 93 patients (25.8%), 1393 patients-years, versus five deaths of 50 patients (10%), 692 patient-years, in the non-inflammatory group, log rank P=0.031. On multivariate analysis, inflammatory markers at baseline remained an independent risk factor for death, hazard ratio 2.72 (95% CI, 1.3-7.2). CONCLUSIONS: SLE patients with elevation of inflammatory markers at baseline are at higher risk of death.

A case is presented of Capnocytophaga bacteraemia, in a juvenile chronic arthritis (JCA) patient receiving steroids, methotrexate and rituximab. This Gram-negative bacillus commonly found in dog saliva has been described to cause illness in immune compromised hosts such as oncology patients, those receiving cytotoxic or biological drugs, alcoholics or postsplenectomy. To the best of our knowledge, this is the first report of Capnocytophaga bacteraemia following rituximab treatment.

OBJECTIVE: Defective expression of Ras guanil releasing protein-1 (RasGRP-1) and increased apoptosis have been reported in lymphocytes from SLE patients. Whether these aberrations are correlated and linked to disease activity has not been elucidated. METHODS: Expression of normal 90 kDa RasGRP-1, its most prevalent 86 kDa isoform and full PARP-1 116 kDa and its cleavage fragment 84 kDa were determined in whole protein lysates of peripheral blood mononuclear cells (PBMC) in correlation with mitogen activated protein kinase (MAPK) activity and SLE clinical status in a large group of SLE patients during 1 year follow-up. RESULTS: Expression of normal 90 kDa RasGRP-1 was comparable in patients and controls. However, SLE patients demonstrated a constitutively increased 86 kDa/90 kDA ratio (p < 0.01) and decreased full poly (ADP-ribose) polymerase protein-1 (PARP-1) expression (p < 0.002) compared with controls who were disease-independent. A remission in disease activity was associated with decreased RasGRP-1 expression. Expression of 84 kDa PARP-1 cleavage fragment was found in 15% of patients but in none of the controls. In addition, expression of PARP-1 correlated positively with normal 90 kDa RasGRP-1 expression and negatively with the RasGRP-1 86 kDa/90 kDA ratio. CONCLUSIONS: These data suggest that constitutive aberrant expression of PARP-1 and RasGRP-1 ratio may act in concert to impair survival of lymphocytes in SLE patients.

OBJECTIVES: Anti-beta2 glycoprotein 1 (a-beta2GP1) was added to the criteria for antiphospholipid syndrome (APS) in 2005. However, its clinical significance with respect to complications of pregnancy is not well established. The aim of this study was to evaluate the association of laboratory findings of a-beta2GP1 with events of thromboembolism or obstetric complications (pregnancy loss, placental dysfunction, intrauterine growth restriction, preeclampsia, fetal death, and preterm delivery) in women with clinical and laboratory evidence of APS. METHODS: A retrospective cohort design was used. Ninety-one patients (total 394 pregnancies) referred to a tertiary medical center for evaluation of clinical features consistent with APS were divided into three groups: group A (n = 34), two positive tests for anticardiolipin (ACL) or lupus anticoagulant (LAC), in accordance with original APS classification (1998); group B (n = 18), two positive tests for a-beta2GP1, in accordance with the revised APS criteria; and group C (n = 39), only one positive test for ACL or LAC. RESULTS: Of the 52 women with APS (group A or B), 36 had primary disease, and 16 had secondary disease. On comparison of the groups, group B was characterized by a significantly higher rate of complicated pregnancy (83.3%) than groups A (47.1%) and C (76.9%), P = 0.007, and a higher rate of fetal loss (72.2%) than groups A + C (28.8%, P = 0.001). CONCLUSIONS: The findings suggest that the revised APS criteria are preferable to the original classification for the prediction of complicated pregnancy.

BACKGROUND: Aberrant signalling along the p21ras/MAP kinase pathway has been demonstrated in systemic lupus erythematosus (SLE). OBJECTIVE: To determine whether expression and activity of the MAP kinases ERK and JNK reflect disease activity in patients with SLE. METHODS: Blood samples of 42 outpatients with SLE were prospectively collected during four consecutive visits. The control group included 20 healthy subjects. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Expression of total ERK and JNK kinases and their active forms (pERK and pJNK) was determined in whole protein lysates of peripheral blood mononuclear cells. RESULTS: The mean levels of the active kinases pERK and pJNK were significantly increased in patients with active disease (SLEDAI 4-20) as compared with patients with inactive disease (SLEDAI 0-3), p = 0.04, as well as with healthy controls, p = 0.03 and p = 0.003 for pERK and pJNK, respectively. The percentage of activated forms of ERK and JNK of the total expression of these MAP kinases was also gradually increased, reaching 50% for pERK and >40% for pJNK in patients with SLE with moderate-to-severe disease (SLEDAI 7-20), p = 0.005, p = 0.005 and p = 0.02, p = 0.05 as compared with controls and inactive patients, respectively. A decrease of more than three SLEDAI points was associated with a significant reduction in the expression of both total and activated forms of ERK and JNK, p = 0.03, p = 0.01, respectively. CONCLUSIONS: The results show that ERK and JNK activity reflects disease activity in patients with SLE. These MAP kinases may serve as additional tools for the evaluation of disease activity and management of these patients.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of cytokines, apoptosis, and B- and T-cell functions. The tolerogenic peptide, hCDR1 (Edratide), ameliorated the clinical manifestations of murine lupus via down-regulation of pro-inflammatory cytokines and apoptosis, up-regulation of the immunosuppressive cytokine TGF-beta, and the induction of regulatory T-cells. In the present study, gene expression was determined in peripheral blood mononuclear cells of 9 lupus patients that were treated for 26 weeks with either hCDR1 (five patients), or placebo (four patients). Disease activity was assessed by SLEDAI-2K and the BILAG scores. Treatment with hCDR1 significantly down-regulated the mRNA expression of the pathogenic cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-10, of BLyS (B-lymphocyte stimulator) and of the pro-apoptotic molecules caspase-3 and caspase-8. In contrast, the treatment up-regulated in vivo gene expression of both TGF-beta and FoxP3. Furthermore, hCDR1 treatment resulted in a significant decrease in SLEDAI-2K (from 8.0+/-2.45 to 4.4+/-1.67; P=0.02) and BILAG (from 8.2+/-2.7 to 3.6+/-2.9; P=0.03) scores. Thus, the tolerogenic peptide hCDR1, immunomodulates, in vivo, the expression of genes that play a role in SLE, consequently restoring the global immune dysregulation of lupus patients. Hence, hCDR1 has a potential role as a novel disease-specific treatment for lupus patients.

The association of the antiphospholipid syndrome with malignancy has been extensively reported. Raynaud's phenomenon has also been reported to be associated with various malignancies. In this report, we describe two patients who presented with severe digital ischemia mimicking Raynaud's phenomenon. The patients were found to have antiphospholipid syndrome, and upon extensive evaluation, a diagnosis of a malignancy was made. This report highlights the importance of malignancy workup in patients with severe digital ischemia associated with antiphospholipid syndrome.

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS: . Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.