Naomi Ichikawa

IL‐17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti‐TNF‐α antibody: A novel mechanism of osteoclastogenesis by IL‐17

IL‐17 is a proinflammatory cytokine crucial for osteoclastic bone resorption in the presence of osteoblasts or synoviocytes in rheumatoid arthritis. However, the role of IL‐17 in osteoclastogenesis from human monocytes alone remains unclear. Here, we investigated the role of IL‐17 in osteoclastogenesis from human monocytes alone and the direct effect of infliximab on the osteoclastogenesis induced by IL‐17. Human peripheral blood mononuclear cells (PBMC) were cultured for 3 days with M‐CSF. After non‐adherent cells were removed, IL‐17 was added with either infliximab or osteoprotegerin (OPG). Seven days later, adherent cells were stained for vitronectin receptor. On the other hand, CD11b‐positive monocytes purified from PBMC were also cultured and stained as described above. CD11b‐positive cells were cultured with TNF‐α and receptor activator of NF‐κB ligand (RANKL). In the cultures of both adherent cells and CD11b‐positive cells, IL‐17 dose‐dependently induced osteoclastogenesis in the absence of soluble‐RANKL. OPG or infliximab inhibited IL‐17‐induced osteoclastogenesis. Interestingly, in the culture of CD11b‐positive cells, the osteoclastogenesis was more potently inhibited by infliximab than by OPG. TNF‐α and RANKL synergistically induced osteoclastogenesis. The present study clearly demonstrated the novel mechanism by which IL‐17 directly induces osteoclastogenesis from human monocytes alone. In addition, infliximab potently inhibits the osteoclastogenesis directly induced by IL‐17. J. Cell. Biochem. 108: 947–955, 2009.

Incidence of serious respiratory infections in patients with rheumatoid arthritis treated with tocilizumab.

We aimed to demonstrate the incidence of serious respiratory infections in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) monotherapy. We analyzed the incidence of serious respiratory infections in 601 RA patients enrolled in TCZ clinical trials and their extension studies (TCZ cohort) and in 601 age- and sex-standardized RA patients treated in daily clinical practice at Tokyo Women’s Medical University (IORRA subsample cohort). The rates of serious respiratory infections were 1.77 per 100 patient-years from 1999 to 2008 in the TCZ cohort and 0.53 per 100 patient-years from 2000 to 2009 in the IORRA subsample cohort. With the IORRA subsample cohort regarded as a standard population, the standardized incidence ratio (SIR) of serious respiratory infection in the TCZ cohort was 3.64 [95% confidence interval (CI) 2.56–5.01], standardized for age and sex; 2.35 (95% CI 1.66–3.24), standardized for age sex, and corticosteroid use; 1.85 (95% CI 1.30–2.55), standardized for age sex, and pre-existing pulmonary involvement; and 2.41 (95% CI 1.68–3.34) standardized for age sex, and disease activity. The risk of serious respiratory infection in the TCZ cohort was approximately double that in the IORRA subsample cohort after standardizing for corticosteroid use, pre-existing pulmonary involvement, or disease activity. This is comparable to the risk reported when tumor necrosis factor (TNF) inhibitors are used.

Effect of Genetic Polymorphisms on Development of Gout

Objective. To validate the association between genetic polymorphisms and gout in Japanese patients, and to investigate the cumulative effects of multiple genetic factors on the development of gout. Methods. Subjects were 153 Japanese male patients with gout and 532 male controls. The genotypes of 11 polymorphisms in the 10 genes that have been indicated to be associated with serum uric acid levels or gout were determined. The cumulative effects of the genetic polymorphisms were investigated using a weighted genotype risk score (wGRS) based on the number of risk alleles and the OR for gout. A model to discriminate between patients with gout and controls was constructed by incorporating the wGRS and clinical factors. C statistics method was applied to evaluate the capability of the model to discriminate gout patients from controls. Results. Seven polymorphisms were shown to be associated with gout. The mean wGRS was significantly higher in patients with gout (15.2 ± 2.01) compared to controls (13.4 ± 2.10; p < 0.0001). The C statistic for the model using genetic information alone was 0.72, while the C statistic was 0.81 for the full model that incorporated all genetic and clinical factors. Conclusion. Accumulation of multiple genetic factors is associated with the development of gout. A prediction model for gout that incorporates genetic and clinical factors may be useful for identifying individuals who are at risk of gout.

T-cell leukemia translocation-associated gene (TCTA) protein is required for human osteoclastogenesis☆

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-kappaB ligand (RANKL), TNFalpha, IL-6, IL-17 and IFNgamma. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in resorbing bone. Here, our objective was to identify novel proteins expressed in synovial tissues of RA that regulate human osteoclastogenesis. Proteins were purified from synovial tissues of patients with RA, using gel filtration chromatography, ion-exchange chromatography, reverse-aspect HPLC, and mass spectrometry. We evaluated the effects of the purified fractions on human osteoclastogenesis induced by RANKL and M-CSF. We determined the amino acid sequences showing inhibitory activity on human osteoclastogenesis. In addition, we synthesized novel peptides from the molecule including the amino acid sequences. Then, we evaluated the effects of the peptides and antibodies against the molecule on human osteoclastogenesis from monocytes and mature osteoclasts, and on pit formation by mature osteoclasts using Osteologic discs. We examined the effect of the peptide on the expression of both mRNA and protein of NFATc1. We also examined the effect of RANKL on the expression of mRNA of the molecule on osteoclasts and macrophages. We identified a small peptide including Gly-Gln-Asn (GQN) with inhibitory activity on human osteoclastogenesis. We then found that GQN is included in the amino acid sequence of the extra-cellular domain of TCTA protein, which is expressed ubiquitously in normal human tissues, but whose function has not been clarified. We designed novel peptides, including GQN, from the sequence of TCTA protein. One of these peptides (29-mer), but not a scrambled peptide for the 29-mer peptide, potently inhibited RANKL-induced human osteoclastogenesis. The peptide also inhibited pit formation of mature human osteoclasts and suppressed the formation of large osteoclasts in the culture of mature osteoclasts. Furthermore, polyclonal antibodies against TCTA protein suppressed the formation of large osteoclasts in the cultures of both monocytes and mature osteoclasts, supporting our hypothesis. Peptide A did not significantly inhibit the expression of both mRNA and protein of NFATc1 in osteoclasts. Our novel peptide and polyclonal antibodies against the peptide inhibited human osteoclastogenesis and the function of mature osteoclasts, preventing cellular fusion by TCTA protein and a putative counterpart molecule.

Performance of hands and feet radiographs in differentiation of psoriatic arthritis from rheumatoid arthritis

The purpose of this study was to determine useful radiographic findings for differentiating psoriatic arthritis (PsA) from rheumatoid factor (RF)‐positive or ‐negative rheumatoid arthritis (RA) in Japanese patients.

Comorbidities in Patients with Gout

Gout is one of the most important diseases associated with hyperuricemia. Gout is characterized by acute monoarthritis with frequent flares. Some patients with gout have gouty tophi that are composed of monosodium urate crystals and inflammatory cells. In addition to tophi, gout is associated with various comorbidities such as obesity, hypertension, abnormal lipid metabolism, renal dysfunction, and urolithiasis. We examined the associations of the presence of tophi and comorbidities with demographic and disease characteristic data of gout patients. Subjects were 422 male patients with gout who visited our outpatient clinic. The patients’ background data and laboratory data at the first visit were collected from patient records. We investigated the relationship between comorbidities and characteristics of patients using multiple regression models. The age of gout onset was 44 ± 13 years. The duration of gout at the first visit was 6 ± 8 years. Five percent of subjects had tophi. The presence of tophi was significantly associated with the duration of gout and maximum serum uric acid (SUA), indicating a close association of tophi with urate deposition. Reduced estimated glomerular filtration rate was associated with older age of onset, longer duration of gout, and higher levels of maximum SUA, indicating that sustained hyperuricemia relates with renal impairment of gout. Urolithiasis did not associate with gout duration and maximum SUA. The increased frequency of hypertension was associated with the duration of gout, suggesting that poor control of gout is one of the causes of hypertension. This study provides useful information for gout management and patient education.

Antiphospholipid syndrome with complete abdominal aorta occlusion and chondritis

Abstract We report a case of a 42-year-old man with antiphospholipid syndrome (APS) with chondritis. He presented with preceding insidious progressive occlusion of the bilateral common iliac arteries extending to the lower two-thirds of the abdominal aorta. Active thrombotic events developed concurrent with the onset of chondritis, and resulted in massive thromboses in multiple organs and renal dysfunction. Both conditions responded well to combined intravenous high-dose methylprednisolone and anticoagulation therapy. The inflammatory component of his disease may have played a major role in the pathogenesis of thrombosis given the concurrent active inflammation from his chondritis.

Immune thrombocytopenic purpura associated with rheumatoid arthritis- a report of five cases and review of the literature

Abstract Immune thrombocytopenic purpura (ITP) associated with rheumatoid arthritis (RA) is relatively rare. We describe five cases of RA with ITP. In all five patients, platelet counts were low, platelet-associated IgG levels were elevated, and bone marrow aspiration showed megakaryocytosis. Glucocorticoid therapy was effective in three cases, but the other two cases required immunosuppressants or intravenous γ-globulin in addition to glucocorticoid. We review the reported cases of RA with ITP and discuss the pathophysiology and differential diagnosis of thrombocytopenia in RA.