TNF-α antagonists beyond approved indications: stories of success and prospects for the future.

Tumour necrosis factor alpha (TNF-α) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-α may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Over the past decade pharmaceutical agents directed against TNF-α (infliximab, adalimumab and etanercept) have been widely and successfully employed for the management of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and inflammatory bowel disease, whereas two novel anti-TNF-α agents, golimumab and certolimumab pegol, recently entered the market for the treatment of RA, AS, Crohn's disease and psoriasis. Encouraged by the positive results obtained from the use of TNF-α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-α in the pathogenesis of numerous disorders, anti-TNF-α agents have been considered for the management of diseases other than the ones they were initially approved for. Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of TNF-α blockers had been less than favourable, in other cases of non-infectious inflammatory conditions the response to TNF-α inhibition had been fairly beneficial. More specifically, according to well-documented clinical trials, anti-TNF-α agents exhibited favourable results in Behçet's disease, non-infectious ocular inflammation, pyoderma gangrenosum and hidradenitis suppurativa. In this review we discuss the successful outcomes as well as the prospects for the future from the off-label use of TNF-α antagonists.

Increased expression of CD154 (CD40L) on stimulated T-cells from patients with psoriatic arthritis.

OBJECTIVES: CD40L is a costimulatory molecule and an early activation marker of T-lymphocytes. Based on the hypothesis that activated T-cells may play a role in the pathogenesis of psoriatic arthritis (PsA), we evaluated the level of CD40L expression on T-cells from patients with PsA. METHODS: We analysed 12 patients with PsA, six patients with rheumatoid arthritis (RA) and four healthy volunteers. T-cell surface expression of CD40L was evaluated using two-colour flow cytometry in (i) the resting state and (ii) following stimulation with phorbol myristate acetate/ionomycin, with or without ciclosporin (CsA)-mediated inhibition. RESULTS: Expression of CD40L was significantly increased on activated T-cells from patients with PsA, particularly those with active disease, when compared with normal individuals and patients with RA (mean percentages of CD3+ CD40L+ cells: 23.74, 11.59 and 9.57% for patients with active PsA, patients with RA and healthy volunteers, respectively). CsA-mediated inhibition of CD40L induction was equally effective in all study groups. CONCLUSION: CD40L is overexpressed on T-cells from patients with active PsA. This may indicate a role for CD40L in PsA pathogenesis. Larger-scale studies are warranted to address these issues.

Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease.

OBJECTIVE: To find an effective, safe immunosuppressive regimen as an alternative to cyclophosphamide (Cy) for the treatment of clinically evident diffuse scleroderma (dSSc)-associated alveolitis of recent onset. METHODS: Five consecutive patients with dSSc and recent-onset alveolitis were enrolled and treated with mycophenolate mofetil (MMF) and small (< or =10 mg/day) doses of predinisolone in this open-label trial. One patient with long-standing fibrosing alveolitis was later added to our cohort. Pulmonary function tests [carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC)], pulmonary high-resolution computed tomography (HRCT) scans and clinical assessment were performed before and at specified time-points after enrolment. Cases of significant infections, leucopenia and abdominal pain were recorded. RESULTS: After 4-6 months of MMF therapy, DLCO improved significantly compared with pre-treatment (mean DLCO 75.4% vs 64.2% of predicted value, respectively, P = 0.033). Values of FVC also improved, with the difference almost reaching levels of statistical significance (mean FVC 76.2% vs 65.6% of predicted value, P = 0.057). Ground glass opacities cleared in three of four patients with recent-onset alveolitis and were reduced in one patient after 6-8 months of treatment. Breathlessness and cough improved by 3 months. A possible treatment failure was seen in one patient. However, in five patients functional and clinical improvement was sustained during the study period. No adverse events were recorded in this ongoing clinical trial. CONCLUSION: Our preliminary data suggest that in patients with dSSc and recent, clinically apparent alveolitis, early treatment with MMF and small doses of corticosteroids (CS) may represent an effective, well-tolerated and safe alternative therapy.

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.