Activation of PI3K is a key step of intracellular signaling involved in many cellular functions. PI3K inhibitors have shown anti-rheumatic effects on arthritis model in mice. PI3K is a potential therapeutic target of rheumatoid arthritis

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  Over production of interleukin (IL)-15 and IL-17 was observed in synovial fluids of rheumatoid arthritis (RA) patients. IL-15 activates T cells and induces IL-17 production whereas IL-17 stimulates synoviocytes to release several mediators of inflammation including IL-6, TNF-α, IL-8, and CCL2. Thus, it is presumed that IL-15 and IL-17 play important roles in the pathogenesis of RA. Based on these results, we investigated a new anti-rheumatic drug targets IL-15 and IL-17 and found a new pyrazoleanilide derivative, Y-320 that inhibits IL-15-induced IL-17 production by T cells at 10-nM order. Therapeutic treatment with Y-320 (0.3 to 3 mg/kg orally) significantly inhibited the progression of arthritis and joint destruction in type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 inhibited the elevation of IL-17 mRNA expression in the joint of CIA mice. Concomitant treatment with Y-320 and anti-mouse TNF-α antibody showed a synergistic effect in mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, a small molecule inhibitor for IL-17 production, is a candidate for the new class of orally active anti-rheumatic drug.

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  Nuclear factor kappa B (NF-κB) is an inducible transcription factor that is activated through intracellular signal transduction pathways. Its target genes include those that are responsible for immuno-inflammatory responses, apoptosis inhibitors, growth promoting factors, virus-encoded proteins involved in viral replication, and self-regulatory proteins for NF-κB actions. Thus, it has been reported that NF-κB plays major roles in the pathogenesis of cancer, leukemia, autoimmune diseases such as rheumatoid arthritis, and AIDS. On the other hand, it has been revealed that some drugs that are effective in the treatment of rheumatoid arthritis have actually inhibitory activities of NF-κB actions. In this review, we have attempted to analyze various pathological steps of rheumatoid arthritis especially by depicting the steps that involve NF-κB. We also discuss possible therapeutic strategies with NF-κB as a major target.

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  FR167653 is a potent inhibitor of p38 MAP Kinase and inhibits TNF-α and IL-1β production in inflammatory cells. In this study we investigated the effect of FR167653 on CIA.
  CIA rats were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection and after the onset of arthritis in the prophylactic and therapeutic treatment groups, respectively. The hind paw swelling, radiolographic and histologic scores, and osteoclast number were evaluated. Serum and tissue cytokine levels were assessed by ELISA. Flow cytometric analysis of T-lymphocytes from bone marrow was also performed. The effect of FR167653 on in vitro osteoclast formation induced by sRANKL and TNF-α was examined. Hind paw swelling occurred in CIA rats but not in the prophylactic treatment group. Therapeutic treatment also significantly reduced the paw swelling. The mean radiographic, histologic score, and osteoclast number of the treatment group were significantly lower than those of CIA rats without treatment. FR167653 treatment reduced serum TNF-α and IL-1β levels, ankle IL-1β concentration, and CD4-CD8a+ T-cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNF-α in vitro.
  FR167653 prevented the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAP Kinase is a potential therapeutic target for rheumatoid arthritis.

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  Inflammatory cytokine cascade plays a pivotal role in the pathogenesis of rheumatoid arthritis. Recently, a novel human cytokine, interleukin-32, was reported to induce TNF-α. Interleukin-32 is expressed mainly in lymphoid tissues and leukocytes, but also in stimulated epithelial cells and synovial fibroblasts. Although the interleukin-32 receptor has not been reported, interleukin-32 can induce other inflammatory cytokines, such as TNF-α, interleukin-1β, and interleukin-6 from monocytes/macrophages in vitro and in vivo, and synergizes with signals from pattern-recognition receptors. Notably, in the inflamed synovial tissues from rheumatoid arthritis patients, interleukin-32 is prominently expressed and correlates with the severity of arthritis and the expression of other cytokines, including TNF-α and interleukin-1. In experimental mice models of arthritis, joint injection of interleukin-32 induces joint inflammation, and overexpression of interleukin-32β in haematopoietic cells exacerbates collagen-induced arthritis. Herein, interleukin-32 plays an important role in the pathogenesis of rheumatoid arthritis.

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  RANK ligand (RANKL) is a key mediator of osteoclast formation, function, and survival. Therefore, RANKL is thought to be responsible for osteoclast-mediated bone resorption in a broad range of disorders such as postmenopausal osteoporosis and cancer-induced bone disease. Moreover, RANKL has been implicated as a primary mediator of bone erosions, a hallmark of rheumatoid arthritis (RA). Denosumab is a fully human monoclonal antibody. This antibody binds to RANKL with high affinity and specificity, and inhibits RANKL-RANK interaction, mimicking the endogenous effects of osteoprotegerin (OPG), a soluble RANKL decoy receptor. Clinical trial data support the continued development of denosumab for the inhibition of bone erosions in RA.

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  Objective : To examine clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) in RA. Methods : Hundred fifteen patients with polyarthralgia (89 females, 26 males) were recruited, and subjected for the study. We studied anti-CCP antibody, ESR, CRP, IgM-RF, IgG-RF, RAPA, MMP-3, CARF, C1q-IC, Stage, Class, Joint score, Sharp score, KL-6, SP-D, chest CT. Results : Anti-CCP antibody test had high specificity (93.5%). In RA with positive anti-CCP antibody, Sharp score (10.9±22.4) was higher than those with negative anti-CCP (1.7±1.8), and may serve as a prognostic marker of joint destruction (P<0.05). Anti-CCP antibody in RA with interstitial pneumonia is higher (84.5±36.4 U/mL) than those without interstitial pneumonia (52.6±44.7 U/mL) (P<0.05). Conclusion : Anti-CCP antibody is useful for diagnosis of RA, and could be a specific marker of joint destruction. Further investigation is necessary to clarify the relation of anti-CCP antibody with organ involvement and activity of RA.

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  The patient was a 33 year female. In 2001, she was diagnosed with systemic lupus erythematosus (SLE) and treated with prednisolone and ciclosporin. In May 2006, she noticed slight muscle weakness in the bilateral lower limbs. In July of the same year, she experienced gait difficulty and was admitted to our hospital because of fatigue, appetite loss, fever and disorientation. Soon afterwards, she had a fit of general convulsion and suffered from urinary retention and fecal incontinence. A brain magnetic resonance image revealed atrophy of the thoracic cord in T2 weighted images, and cerebrospinal fluid examination showed high total protein and interleukin-6 concentration, indicating complication of lupus myelitis as well as cerebral involvement. Steroid pulse and oral prednisolone treatment resulted in ameriolation of cerebral complications such as disorientation and convulsion, but muscle weakness and paresthesia in the lower limbs and urinary retention persisted. Cyclophosphamide pulse therapy was started and resulted in a marked recovery from muscle weakness, paresthesia and urinary retention, and she could discharge. We conclude that steroid and cyclophasphamide pulse therapy for a SLE patient with CNS lupus and lupus myelitisis is effective for ameriolation of symptoms such as disorientation, convulsion, urinary retension, fecal incontinence, muscle weakness and paresthesia in the lower limbs as well as elevated level of serum anti-ribosomal P antibody.

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