Yoshinori Nonomura

Adenoviral Transfer of Cyclin-Dependent Kinase Inhibitor Genes Suppresses Collagen-Induced Arthritis in Mice

In rheumatoid synovial tissues, synovial fibroblasts are activated by proinflammatory cytokines and proliferate to develop hyperplastic pannus tissues, which irreversibly damage the affected joints. We recently reported that the cyclin-dependent kinase inhibitors p16INK4a and p21Cip1 are not expressed in vivo in rheumatoid synovial fibroblasts, but are readily inducible in vitro. This observation was followed by the successful treatment of rat adjuvant arthritis by local p16INK4a gene transfer, showing that the inhibition of the cell cycle of the synovial cells ameliorates the arthritis. In this study, we show that another animal model of rheumatoid arthritis, murine collagen-induced arthritis, can be effectively treated by local gene transfer of p21Cip1 as well as that of p16INK4a. The anti-arthritic effects were observed even when the treatment was conducted after the arthritis had developed. Furthermore, the effects included suppression of the expression of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. Our results demonstrate that the ectopic expression of cyclin-dependent kinase inhibitors not only prevents synovial overgrowth but also ameliorates the proinflammatory milieu in the affected joints. The induction of p21Cip1 in rheumatoid synovial tissues by pharmacological agents may also be an effective strategy to treat rheumatoid arthritis.

Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis

Forced expression of a cyclin-dependent kinase inhibitor gene, p21Cip1 in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21Cip1 on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21Cip1 gene transferred. We have found that p21Cip1 gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, and matrix metalloproteinases-1 and -3. Down-regulation of IL-1R1 by p21Cip1 resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21Cip1 was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21Cip1, and inactivation of NF-κB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.

Hypoxia-induced Abrogation of Contact-dependent Inhibition of Rheumatoid Arthritis Synovial Fibroblast Proliferation

Objective. Uncontrolled proliferation of synovial fibroblasts is characteristic of the pathology of rheumatoid arthritis (RA). Since synovial tissues in the rheumatoid joints are hypoxic, we investigated how hypoxia affects RA synovial fibroblast (RASF) proliferation. Methods. RASF were cultured at 2000 cells (low density culture) or at 5000 cells (high density, growth-inhibitory confluent culture) per microtiter well under hypoxic (10%, 3%, or 1% O2) or normoxic (21% O2) conditions. Some RASF were treated with recombinant human interleukin 1 receptor antagonist (IL-1ra), anti-tumor necrosis factor-α (TNF-α)-neutralizing antibodies, anti-N-cadherin-blocking antibodies, or MG132. 3H-labeled thymidine incorporation was quantified to assess their proliferation. Total RNA and cell lysates were prepared for real-time polymerase chain reaction and Western blot analyses. Results. Hypoxia exerted no effect on proliferation of RASF cultured at low density. At high density, it abrogated contact-dependent growth inhibition of RASF, but not of human dermal fibroblasts. Addition of anti-TNF-α antibodies or IL-1ra did not affect the results. Upregulated expression of cyclin-dependent kinase inhibitor p27Kip1 was observed in the cells cultured at high density under normoxic conditions, but not under hypoxic conditions. Hypoxia decreased N-cadherin expression on RASF. Addition of anti-N-cadherin-blocking antibodies mimicked the effects of hypoxic culture; it promoted proliferation of RASF cultured at high density under normoxic conditions. This antibody treatment also downmodulated p27Kip1 expression. Conclusion. Hypoxia downregulates N-cadherin expression on RASF, and thus prevents p27Kip1 upregulation for their contact inhibition. It is likely that hypoxia in rheumatoid synovial tissues contributes to rheumatoid pathology by augmenting proliferation of synovial fibroblasts.

Two cases of acute respiratory distress syndrome resulting from adult-onset Still's disease

Abstract Adult-onset Stills disease (AOSD) is a systemic inflammatory disorder of unknown origin. Acute respiratory distress syndrome (ARDS) is a rare complication of AOSD, with only nine cases having been reported in the literature. Here, we describe two cases of AOSD complicated with ARDS that were successfully treated with immunosuppressive therapy, including corticosteroids. Although ARDS is a life-threatening complication in AOSD, early commencement of high-dose corticosteroids and mechanical ventilation improve the prognosis.

Infected abdominal aortic aneurysm caused by nontyphoid Salmonella in an immunocompromised patient with rheumatoid arthritis

Nontyphoid Salmonella strains are important pathogens commonly found worldwide, typically causing gastrointestinal illness. Here, we report a case of a 66-yearold man with an abdominal aortic infected (or so-called mycotic) aneurysm caused by Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis). He had multiple risk factors for atherosclerosis: age over 60, a long history of smoking, an 8-year history of diabetes mellitus, and a 10-year history of rheumatoid arthritis treated with low-dose corticosteroids. Although he had presented with no episode of diarrhea or abdominal pain, the abdominal aortic infected aneurysm was diagnosed by blood cultures and was carefully followed up by computed tomography. An abdominal aneurysmectomy and autogenous in situ reconstruction were successfully performed consequently. Alertness to the possibility of endovascular infection is important, even if there are no symptoms except for persistent fever, when treating Salmonella bacteremia in an immunocompromised patient, particularly when there are associated atherosclerotic risk factors.

全身性エリテマトーデスに肥厚性硬膜炎を合併し，低髄圧症候群様の頭痛・難聴を呈した1例

We report a case of systemic lupus erythematosus (SLE) complicated with hypertrophic pachymeningitis. A 34-year old woman who was diagnosed as SLE in 1985 was admitted to our hospital for a high grade fever and a headache. Laboratory findings showed increased titer of anti-double strand DNA antibody and decreased number of platelets. She complained a severe headache and hearing loss which were worsened by head-up position, resembling the symptoms of intracranial hypotension. MRI findings revealed thickened dura and she was diagnosed as hypertrophic pachymeningitis. Both clinical symptoms and laboratory findings were resolved after methyl-prednisolone pulse therapy followed by a high dose of prednisolone. Although hypertrophic pachymeningitis is a rare complication with SLE, it should be considered in SLE patients with severe headache.

Prominent splenic microcalcifications in a patient with systemic lupus erythematosus complicated by antiphospholipid syndrome.

A 40-year-old woman, with a 7-year history of systemic lupus erythematosus (SLE) associated with type V lupus nephritis, was admitted to our hospital because of worsening proteinuria. The presence of serum antiYcardiolipinA2 glycoprotein I antibody and episodes of chorea, lacunar cerebral infarction, thrombophlebitis, and acute myocardial infarction over the last 4 years led to the diagnosis of antiphospholipid syndrome. She had been receiving prednisolone, azathioprine, aspirin, and warfarin for the past 3 years. Physical examination at the time of admission revealed nail-fold thrombi, cutaneous hyperpigmentation, and livedo reticularis over the lower limbs. According to the Systemic Lupus Erythematosus Disease Activity Index 2000, SLE was inactive. A plain radiograph depicted multiple calcifications in the left upper quadrant of the abdomen (panel A, arrow); these calcifications did not change significantly 1 year later. Computed tomography revealed splenomegaly and punctate splenic calcifications (panel B). Diffuse calcifications in the splenic parenchyma have been reported in cases of tuberculosis, histoplasmosis, brucellosis, Pneumocystis jiroveci infection, and lymphoma. In the present case, these diseases were ruled out. Thrombotic splenic infarctions can also cause splenic calcifications. Splenic microcalcifications have been reported in 4 patients with long-standing SLE, and anticardiolipin antibodies were detected in 2 of these patients. Therefore, we concluded that splenic infarctions due to antiphospholipid syndrome might be responsible for the prominent calcifications observed in the present case.

Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan

Abstract Objective: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA). Methods: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI). Results: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI <3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI <0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (ΔmTSS ≤0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328–10.489) and structural remissions (OR, 4.301; 95% CI, 1.298–14.243) at month 12 after adjusting for covariates. Conclusions: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.

Allergic bronchopulmonary aspergillosis in a patient with rheumatoid arthritis under adalimumab therapy: a case report.

A 77-year-old woman with a 15-year history of rheumatoid arthritis (RA) was admitted to our hospital because of a wet cough that persisted for 1 month. The patient had been taking methotrexate (MTX) and adalimumab (ADA) for the past 3 years, and disease activity of RA was low. Discontinuation of ADA and MTX and treatment with oral levofloxacin were not effective. On admission, laboratory examinations showed eosinophilia (2539/μL), elevated serum total immunoglobulin E (538.0 IU/ml) and Aspergillus-specific immunoglobulin E levels, and Aspergillus fumigatus serum precipitins. A chest radiograph revealed multiple bilateral pulmonary shadows, and computed tomography revealed multiple consolidations. Bronchoscopic examination showed mucous plugs. Pathological examination revealed diffuse infiltration of eosinophils and fungus in the plugs. These findings led to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). A combination of prednisolone (0.5 mg/kg/day) and itraconazole (200 mg/day) was administered. After 3 months, the pulmonary consolidations resolved. To our knowledge, this is the first report of ABPA in a patient with RA treated with ADA. If patients treated with biologic disease-modifying antirheumatic drugs present with eosinophilia and pulmonary consolidations, clinicians should consider ABPA in the differential diagnosis.