Acute transverse myelitis and antiphospholipid antibodies in lupus. No evidence for anticoagulation.

Current views suggest that prothrombotic properties of antiphospholipid antibodies (aPL) have a role in the development of acute transverse myelitis (ATM) in patients with systemic lupus erythematosus (SLE). Consequently, empiric anticoagulation may be included in these patients' treatment. We performed a systemic review of the literature to explore the clinical value of the presence of aPL in patients with lupus myelitis and the possible effectiveness of anticoagulation. We analyzed clinical and laboratory data extracted from published cases of SLE-associated ATM, fulfilling the Transverse Myelitis Consortium Working Group diagnostic criteria, that provided information on aPL. We report on a total of 70 patients. aPL, detected upon ATM onset in 54% of patients, neither predicted the involvement of the thoracic part of the spine, which has been postulated to reflect a predominantly thrombosis-induced injury, nor correlated with relapsing ATM, additional lupus CNS manifestations, or worse clinical outcome. An unfavorable outcome could be predicted by paralysis (P=0.02) and abnormal CSF findings at presentation (P=0.02). Whilst all patients received major immunosuppressive regimens, severe neurologic impairment (estimated Expanded Disability Status Scale score>7) was found primarily in aPL-negative patients (P=0.03). Anticoagulation was more frequently applied in aPL-positive patients (P=0.04), but any additional therapeutic effect was not evident. Detection of circulating aPL at ATM onset appears unreliable to suggest a thrombotic cause and perhaps not enough to dictate therapeutic anticoagulation. Registry creation of ATM in patients with SLE is needed to obtain more definite answers on the role of aPL in this condition.

Glutamate levels and activity of the T cell voltage-gated potassium Kv1.3 channel in patients with systemic lupus erythematosus.

OBJECTIVE: Alterations in glutamate homeostasis and Kv1.3 voltage-gated potassium channel function have been independently associated with T cell dysfunction, whereas selective blockade of Kv1.3 channels inhibits T cell activation and improves T cell-mediated manifestations in animal models of autoimmunity. Because low extracellular glutamate concentrations enhance the activity of this channel in normal T cells ex vivo, we undertook this study to examine serum glutamate concentrations and Kv1.3 channel activity in patients with systemic lupus erythematosus (SLE). METHODS: We used high-performance liquid chromatography for glutamate measurements, and we used the whole-cell patch-clamp technique for electrophysiologic studies performed in freshly isolated, noncultured peripheral T cells. RESULTS: Mean +/- SD serum concentrations of glutamate were lower in patients with either clinically quiescent SLE (77 +/- 27 microM [n = 18]) or active SLE (61 +/- 36 microM [n = 16]) than in healthy controls (166 +/- 64 microM [n = 24]) (both P < 0.0001). The intrinsic gating properties of the Kv1.3 channels in lupus T cells were found to be comparable with those in healthy control-derived T cells. Notably, electrophysiologic data from SLE patient-derived T cells exposed to extracellular glutamate concentrations similar to their respective serum levels (50 microM) demonstrated Kv1.3 current responses enhanced by almost 20% (P < 0.01) compared with those subsequently obtained from the same cell in the presence of glutamate concentrations within control serum levels (200 microM). CONCLUSION: Based on the key role of Kv1.3 channel activity in lymphocyte physiology, an enhancing in vivo effect of low serum glutamate concentrations on the functional activity of this channel may contribute to lupus T cell hyperactivity. Studies to further elucidate Kv1.3 responses in SLE, as well as the possible pathogenetic role of this unsuspected metabolic abnormality, may have therapeutic implications for SLE patients.

CD40L overexpression on T cells and monocytes from patients with systemic lupus erythematosus is resistant to calcineurin inhibition.

To explore the regulatory defects underlying the overexpression of CD40 ligand (CD40L, CD154) in human lupus we studied the effects of cyclosporin-A (CsA), which blocks Ca2+/calcineurin-dependent CD40L gene expression, on peripheral blood-derived T cells and monocytes. In contrast to control subjects, CsA failed to inhibit the prolonged CD40L expression observed in vitro on anti-CD3-activated lupus T cells. Resistance to CsA was not restricted to CD4+ or CD8+ T cell subsets and was disease activity-independent. Experiments assessing the effects of dexamethasone on CD40L expression, as well as of CsA on the early activation marker CD69 expression and on surface CD40L cleavage, confirmed the unique regulation of CD40L in lupus T cells. On the other hand, co-culture with anti-CD3-activated T cells caused surface CD40L expression on monocytes, which was not an Fc receptor-mediated event. Lupus monocytes clearly overexpressed CD40L comparing to healthy and disease-control monocytes, and, similarly to lupus T cells, displayed a prominent resistance to CsA inhibitory effects. These findings indicate that, besides Ca2+/calcineurin-dependent mechanisms, other pathways are involved in the dysregulation of CD40L in SLE immune cells, dissection of which may have important therapeutic implications.

Effect of infliximab on sight-threatening panuveitis in Behçet's disease.

Permanent loss of vision resulting from relapsing ocular inflammation occurs frequently in patients with Behçet's disease, despite intensive, chronic immunosuppressive therapy. Since tumour necrosis factor (TNF) might have an important pathogenetic role in Behçet's disease, we decided to give a single infusion of infliximab-a monoclonal antibody against TNF-to five patients with relapsing panuveitis, at the immediate onset of last relapse. Remission of ocular inflammation was evident within the first 24 h, and complete suppression was seen 7 days after treatment in all patients. No side-effects were noted. We suggest that infliximab is a rapid and effective new therapy for sight-threatening ocular inflammation in Behçet's disease.