Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study.

OBJECTIVE: To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs. METHODS: A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application. RESULTS: At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (- 1.68; 95% CI - 1.46, - 1.90; P < 0.0001), as well as at study end (- 2.24; 95% CI - 2.01, - 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed. CONCLUSION: Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.

Circulating P- and L-selectin and T-lymphocyte activation and patients with autoimmune rheumatic diseases.

Circulating levels of P- and L-selectins and the degree of T-lymphocyte activation were assessed by enzyme-linked immunosorbent assays in 75 selected patients with rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) at various clinical stages, and in 40 healthy blood donors matched for age and gender. Mean levels of P-selectin were significantly higher than normal in RA (lower in patients with clinical remission) and SSc (higher in patients with early-onset diffuse disease), but not in SLE. In contrast, mean L-selectin levels were significantly higher than normal in SLE (no correlation to the degree of disease activity), but not in RA or SSc. Mean levels of soluble interleukin-2 receptors (sIL-2R), reflecting mainly T-lymphocyte activation, in patients with active RA, SSc and SLE were almost double the normal level; however, correlations between individual levels of circulating P- or L-selectins and sIL-2R within groups revealed a strong positive correlation only between L-selectin and sIL-2R (r = 0.66, p<0.001), and only in patients with SLE. Given the different expression of P- and L-selectins, these findings indicate a distinct pattern of immune cell activation in chronic diseases that share an overactivation of T-lymphocytes. The possible clinical value of quantitation of circulating P-selectin in patients with RA and SSc on the one hand, and L-selectin in patients with SLE on the other, should be investigated by prospective studies.

An unusual panniculitis appearing in the winter with good response to tetracycline.

Cold panniculitis is a form of physical panniculitis due to exposure of skin to severe cold. It usually appears on the cheeks of infants and children. It has also been reported on the thighs and buttocks of young females. Its clinical manifestations include red, cold, indurated plaques or nodules which appear one to three days after exposure to low temperatures and resolve spontaneously within several weeks without scarring. The histopathological picture shows a perivascular infiltrate of lymphoid and histiocytic cells at the dermal-subcutaneous junction in the early phase of the reaction (1). After 48 to 72 hours, a well developed panniculitis appears. We report an unusual case of an adult female patient with recurrent panniculitis on her legs appearing in the winter but without any preceding repeated or prolonged exposure to cold. She responded dramatically to oral tetracycline. This drug was successful as a prophylactic agent as well.

Effects of 2-chlorodeoxyadenosine and gold sodium thiomalate on human bcl-2 gene expression.

Aberrant expression of apoptosis-related genes, including the "cell death suppressor gene" bcl-2, may play an important pathogenetic role in cancer and autoimmune diseases, In vivo upregulation of bcl-2 mRNA in synovial lining cells of patients with rheumatoid arthritis but not in patients with osteoarthritis has been recently found. In the present study we investigated whether agents exerting beneficial effects in patients with rheumatoid arthritis, namely the long used Gold Sodium Thiomalate (GST) and the novel immunosuppressive, purine analogue 2-chlorodeoxyadenosine (2-CdA), a lymphocyte apoptosis-inducing agent interfere directly with induction of bcl-2 mRNA expression. The phytohemagglutinin (PHA)-induced in vitro proliferation of normal human peripheral blood lymphocytes was significantly inhibited by non-toxic concentrations of 2-CdA and GST which are within the range of in vivo plasma concentrations in patients receiving the respective treatment. Using mRNA dot-blot analysis and hybridization with an IL-2-specific probe we found that GST, similarly to dexamethasone that served as control, suppressed the PHA-induced IL-2 mRNA accumulation dose-dependently. In contrast, 2-CdA (0.1 microgram/ml) at concentrations that inhibit by 80-90% the PHA-induced proliferative responses of lymphocytes did not affect IL-2 mRNA accumulation. Hybridization with a bcl-2-specific probe showed that the activation-induced accumulation and kinetics of bcl-2 mRNA were not changed in the presence of a wide range of concentrations of either GST or 2-CdA. Similarly, the mRNA accumulation of the "house-keeping" control gene beta-action remained unchanged by both agents. These findings indicate that biosynthesis of bcl-2 is not specifically affected by GST and CdA, suggesting that the immunomodulating effects of these agents, including their efficacy in suppressing chronic arthritis, are not related with a bcl-2-dependent mechanism.

Increased levels of intercellular adhesion molecule-1 in the serum of patients with systemic lupus erythematosus.

Intercellular adhesion molecule-1 (ICAM-1) is a membrane-bound molecule that is primarily involved in cell-cell adhesive interactions of the immune system. The levels of soluble ICAM-1 (s-ICAM-1) shed into the circulation were studied in the sera of patients with systemic lupus erythematosus (SLE) by an enzyme linked immunosorbent assay. Serum concentrations of s-ICAM-1 were significantly increased in 61 patients with SLE compared to 51 controls (mean +/- SEM: 564 +/- 30 versus 348 +/- 17 ng/ml, p < 0.0001) and 41% of patients had higher serum levels than the normal cut off value of 584 ng/ml. Among the various clinical manifestations, skin involvement was significantly associated with high serum levels of s-ICAM-1. Individual values of serum s-ICAM-1 concentrations in patients with SLE correlated significantly with two different disease activity indices, as well as with the erythrocyte sedimentation rate and serum levels of soluble interleukin-2 receptors, but not with serum levels of anti-dsDNA antibodies or C4. No significant differences in s-ICAM-1 levels were found between patients receiving immunomodulatory treatment and those who were not. These findings suggest that s-ICAM-1 measurement may serve as an additional serologic marker of disease activity in patients with SLE. Further studies to determine whether increased s-ICAM-1 shedding has any pathogenetic significance or biological role in SLE are warranted.