Katsuhiro Nishioka

Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice

OBJECTIVE To investigate the roles of interleukin-6 (IL-6) in the pathogenesis of rheumatoid arthritis (RA) by studying its effect on murine collagen-induced arthritis (CIA). METHODS IL-6-deficient (IL-6-/-) mice with a genetic background of susceptibility to CIA were generated by backcrossing them with DBA/1J mice for 8 generations. Clinical and immunologic features were compared between these mice and IL-6 wild-type (IL-6+/+) littermates with CIA. RESULTS Serum IL-6 levels increased during the development of CIA in IL-6+/+ mice. Two prominent peaks were observed. The first was coincident with the onset of arthritis, and the second one was observed during exacerbation of the disease. The onset of arthritis in IL-6-/- mice was delayed for 2 weeks compared with that in IL-6+/+ mice, and the severity of arthritis, as indicated by the arthritis score, remained significantly lower in IL-6-/- mice during the entire followup period (14 weeks), although all IL-6-/- mice developed definite arthritis as did the IL-6+/+ mice. Histologic severity was also reduced in IL-6-/- mice. In addition, radiologic changes such as osteopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL-6-/- mice were reduced to about half those in IL-6+/+ mice. In addition, enhanced production of IL-4 and IL-10 in response to concanavalin A stimulation was observed in IL-6-/- mice. CONCLUSION IL-6 plays an important role in the development of CIA, and both suppression of specific immune responses to CII and a tendency to a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL-6-/- mice. These findings suggest that blockade of IL-6 might be beneficial in the treatment of RA.

Remission of the Renal Involvement in a Patient with Primary Sjo¨gren’s Syndrome (SS) after Pulse High-Dose Corticosteroid Infusion Therapy

Abstract: We report the case of a young female patient with primary Sjo¨gren’s syndrome (SS). In addition to sicca symptoms she also suffered from progressive renal insufficiency and renal tubular acidosis (RTA). She was treated with three sets of pulse high-dose corticosteroid infusion and subsequent low-dose corticosteroid oral administration. When the efficacy was evaluated about 6 months after the start of the therapy, dramatic improvements were seen with no adverse effects, not only in laboratory tests but also histopathologically, as indicated by the repeat kidney biopsy. This suggests that renal involvements of SS might be reversible in some cases, and that there might be a clinical benefit of pulse high-dose corticosteroid infusion therapy in SS with progressive renal involvement.

Enhanced expression and DNA binding activity of two CCAAT/enhancer‐binding protein isoforms, C/EBPβ and C/EBPδ, in rheumatoid synovium

OBJECTIVE To investigate the activation and expression of CCAAT/enhancer-binding proteins (C/EBP), especially C/EBPbeta and -delta, in rheumatoid synovium, and their pathogenic implications in rheumatoid arthritis (RA). METHODS The activation of C/EBPbeta and -delta was assessed in synovial tissues from patients with RA by electrophoretic mobility shift assay (EMSA); DNA binding activity of C/EBPs was evaluated by measuring EMSA band density. The expression and distribution of C/EBPbeta and -delta in synovial tissues were examined by immunohistochemistry analysis. As a control, synovial tissues from patients with osteoarthritis (OA) were studied. RESULTS Enhanced DNA binding activity of C/EBPbeta and -delta, 2 major members of the C/EBP family, was detected in synovial tissues from RA patients, while synovial tissues from the patients with OA showed only faint or marginal activity (mean +/- SEM arbitrary units [AU] RA 23.3 +/- 11.7 in RA versus 4.5 +/- 1.3 in OA; P < 0.05). Moreover, the binding activities of the C/EBP proteins were correlated with both serum C-reactive protein levels (r = 0.62, P < 0.05) and synovial interleukin-6 messenger RNA levels (r = 0.60, P < 0.05). In immunohistochemistry studies, C/EBPbeta and -delta were detected predominantly in the rheumatoid synovial lining cells (both CD14+ and CD14- cells). CONCLUSION C/EBPbeta and -delta may contribute to the pathology of rheumatoid synovitis.

Suboptimal Clinical Response to Anti-tumor Necrosis Factor alpha (TNFa) Antibody Therapy in a Patient with Severe Rheumatoid Arthritis and Lymphadenopathy: CASE REPORT

3Centcor, Inc., Malvern, PA, USA This concerns a patient with severe rheumatoid arthritis (RA) and lymphadenopathy (LA) who showed suboptimal clinical response to antitumor necrosis factor alpha (TNFa) antibody (Ab), cA2 therapy. The assessment of TNFaand IL-6 mRNA expression in the swollen lymphnode (LN) of the patient by reverse transcription, polymerase chain reaction (RT-PCR) before cA2 treatment, showed only enhanced IL-6 production, but not TNFa. Moreover, cA2 failed to inhibit in-vitro spontaneous IL-6 production in the LN block culture from the patient. Taken together, these results indicate that IL-6 production in the swollen LNs of the patient might not depend on TNFa. This might partly cause suboptimal clinical response to anti-TNFaAb therapy in the patient.