Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors.

CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non-small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8(+) T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer.

Adalimumab in the management of Behçet's disease.

Behçet's disease (BD) is a relapsing, systemic, inflammatory disorder that affects various organ systems. Most of the manifestations of BD are self-limiting, but ocular attacks are an exception. Gastrointestinal tract, central nervous system, and cardiovascular system manifestations are relatively infrequent but may be resistant to conventional immunosuppressive treatment and therefore life-threatening. Tumor necrosis factor alpha antagonists are increasingly being used in patients whose BD is inadequately controlled by standard immunosuppressive regimens. Most of the current experience regarding the treatment of refractory BD involves the use of infliximab; however, adalimumab has also been successfully used in cases of BD refractory to both conventional therapy and infliximab. Compared with infliximab, adalimumab offers several other advantages, such as the ability to self-administer at home, better patient compliance, and an improved side effect profile. Here, we review clinical experience of the use of adalimumab to treat the serious manifestations of BD. Adalimumab is a promising drug for the treatment of BD, and its randomized, prospective study in a large number of patients is warranted to fully determine its efficacy in the refractory BD setting.

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.

INTRODUCTION: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. RESULTS: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). CONCLUSIONS: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies.

BACKGROUND: Recent observational studies have suggested that use of statins reduces mortality in patients suffering from chronic obstructive pulmonary disease. However, no meta-analysis has reported the pooled hazard ratio of statins to all-cause mortality. METHODS: We searched for eligible articles using five databases. We included randomized controlled trials and cohort studies written in English using original data reporting the hazard ratio of statins to all-cause, cardiovascular-related, cancer-related, or respiratory-related mortality. A fixed model with the confidence interval method was used. Publication bias was evaluated by funnel plot and Begg's test, and was corrected using Duval's trim and fill method. Sensitivity analyses were also conducted. RESULTS: We included 10 out of 128 articles. The pooled hazard ratio of statins to all-cause mortality involving 16269 patients was 0.81 (95% CI: 0.75-0.86, P < 0.001) with moderate heterogeneity (I2 = 52%, P = 0.032). The sensitivity analysis and funnel plot suggested the existence of publication bias. After three possibly unpublished cohorts were imputed, the pooled hazard ratio of 0.83 (95% CI: 0.78-0.88, P < 0.001) still suggested a favorable prognosis in statin-treated patients. The pooled hazard ratio of statins to cardiovascular-related, cancer-related, and respiratory-related mortality were 0.52 (95% CI: 0.27-1.01, P = 0.052), 0.57 (95% CI: 0.32-1.01, P = 0.056), and 0.55 (95% CI: 0.43-0.78, P < 0.001), respectively, although these results were not conclusive as we could not find a sufficient number of original studies dealing with those forms of mortality. CONCLUSIONS: The use of statins for patients suffering from chronic obstructive pulmonary disease may reduce all-cause mortality. This conclusion should be re-evaluated by a registered large-scale randomized controlled trial.

Gastrointestinal manifestations of Behçet's disease in Japan: a study of 43 patients.

We analyzed the clinical gastrointestinal (GI) characteristics of Behçet's disease (BD) patients in Japan. We retrospectively reviewed the clinical charts of 412 patients who fulfilled the 1987 Japanese criteria for BD and were treated in two university hospitals from July 1991 to December 2007. Forty-three patients (10.4 %) had BD-related GI lesions, which were shown by imaging examinations. Median age at BD diagnosis and onset of GI episodes were 29.6 and 31.0 years, respectively. The patients suffered from abdominal pain (30/43) and GI bleeding (18/43), while they had lower frequency of eye involvement and higher incidence of arthritis and vascular involvement than BD patients without GI lesions. The lesions were prevalent in the ileum (32/43) followed by cecum (21/43) and esophagus (9/43). The patients were treated with mesalazine and sulfasalazine (41/43), corticosteroids (32/43), immunosuppressants (13/43), and infliximab for 7 patients having refractory lesions, while 10 patients had surgical operation. Two patients died due to non-GI events during the observation. The diagnosis of BD was often difficult because of lack of eye involvement. Surgery is required for some patients in spite of intensive immunosuppressive therapies. Appropriate use of anti-TNF agents may be promising for the GI involvement.

Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1-dependent and heme oxygenase 1-independent pathways.

OBJECTIVE: Reducing inflammation and osteoclastogenesis by heme oxygenase 1 (HO-1) induction could be beneficial in the treatment of rheumatoid arthritis (RA). However, the function of HO-1 in bone metabolism remains unclear. This study was undertaken to clarify the effects of HO-1 and its repressor Bach1 in osteoclastogenesis. METHODS: In vitro osteoclastogenesis was compared in Bach1-deficient and wild-type mice. Osteoclasts (OCs) were generated from bone marrow-derived macrophages by stimulation with macrophage colony-stimulating factor and RANKL. Osteoclastogenesis was assessed by tartrate-resistant acid phosphatase staining and expression of OC-related genes. Intracellular signal pathways in OC precursors were also assessed. HO-1 short hairpin RNA (shRNA) was transduced into Bach1(-/-) mouse bone marrow-derived macrophages to examine the role of HO-1 in osteoclastogenesis. In vivo inflammatory bone loss was evaluated by local injection of tumor necrosis factor α (TNFα) into calvaria. RESULTS: Transcription of HO-1 was down-regulated by stimulation with RANKL in the early stage of OC differentiation. Bach1(-/-) mouse bone marrow-derived macrophages were partially resistant to the RANKL-dependent HO-1 reduction and showed impaired osteoclastogenesis, which was associated with reduced expression of RANK and components of the downstream TNF receptor-associated factor 6/c-Fos/NF-ATc1 pathway as well as reduced expression of Blimp1. Treatment with HO-1 shRNA increased the number of OCs and expression of OC-related genes except for the Blimp1 gene during in vitro osteoclastogenesis from Bach1(-/-) mouse bone marrow-derived macrophages. TNFα-induced bone destruction was reduced in Bach1(-/-) mice in vivo. CONCLUSION: The present findings demonstrate that Bach1 regulates osteoclastogenesis under inflammatory conditions, via both HO-1-dependent and HO-1-independent mechanisms. Bach1 may be worthy of consideration as a target for treatment of inflammatory bone loss in diseases including RA.

Characteristics of vascular involvement in Behçet's disease in Japan: a retrospective cohort study.

OBJECTIVES: We analysed the clinical vascular characteristics of Behçet's disease (BD) patients in Japan. METHODS: We retrospectively reviewed the clinical charts of 412 patients who fulfilled the 1987 Japanese criteria for BD and were treated in two University hospitals from July 1991 to December 2007. Patients with superficial thrombophlebitis were excluded, since it is categorised as a skin manifestation according to the Japanese criteria. RESULTS: Twenty-six patients (6%) had large-vessel involvement. Mean ages at BD diagnosis and onset of vascular episodes were 39.7 and 41.6 years, respectively. Males predominated (62%). Arterial and venous lesions were found in 8 (31%) and 21 patients (81%), respectively, including 3 (12%) with both types. Pulmonary artery occlusion was the most common arterial lesion (n=5, 19%), followed by ascending aortic aneurysm (n=2, 8%). Limb deep vein thrombosis was the leading venous lesion (n=20, 77%). Cardiac complications (angina pectoris/aortic regurgitation) occurred in two patients. Gastrointestinal involvement was more frequent than in patients without vascular involvement (p<0.001); ocular involvement was less frequent (p<0.05). Only 3 patients (12%) required surgery. Patients received prednisone and immunosuppressants, including infliximab, for vascular and/or concurrent gastrointestinal involvement. Nine patients received warfarin, without bleeding complications. One patient died during the observation period, 4 days after surgery for an aortic aneurysm. CONCLUSIONS: Frequency of vascular involvement in BD in Japan is lower than in other ethnic populations. Although one patient died during the observation, there was no fatal haemoptysis, even in patients receiving warfarin.

Expression of heme oxygenase-1 in human leukemic cells and its regulation by transcriptional repressor Bach1.

Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or gamma-interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy.

Therapeutic angiogenesis in patients with systemic sclerosis by autologous transplantation of bone-marrow-derived cells.

We examined the efficacy and safety of autologous transplantation of bone-marrow-derived cells in patients with intractable ulcers caused by systemic sclerosis. Eight patients with ulcers resistant to treatment were enrolled. Bone marrow cells were gathered from the bilateral iliac crests with multiple repositioning bone marrow needles, and bone-marrow-derived mononuclear cells were isolated and injected into skeletal muscles of the ischemic limb. Visual analog scale (VAS), Sclerosis Health Assessment Questionnaire (SHAQ), modified Rodnan total skin score (mTSS), and the size and depth of the ulcer were examined. Thermography, capillaroscopy, intra-arterial digital subtraction angiography (IA-DSA), and laser Doppler flowmetry were also examined before and after transplantation. In all patients, reduction of ulcer size and improvement of VAS were observed after treatment. Elevation of surface temperature, increase of blood flow volume, and new capillaries of the nail bed were also found after our treatment. There were no major adverse effects of this treatment. Autologous transplantation of bone-marrow-derived cells was shown to be a novel and useful approach to intractable ulcers in systemic sclerosis.

Neurological manifestations of Behçet's disease in Japan: a study of 54 patients.

The type and frequency of neurological manifestations of Behçet's disease (BD) vary with ethnicity. We analyzed the neurological manifestations of BD in Japanese patients. All patients undergoing treatment at one of the two Yokohama City University hospitals from July 1991 to December 2007 and who fulfilled the Japanese criteria for BD revised in 1987 were studied retrospectively by chart review. Patients had been neurologically assessed by neurologists. We recorded neurological signs and symptoms, magnetic resonance imaging or computed tomography findings, and results of cerebrospinal fluid examinations from the records of each patient. We studied 412 patients with BD, of whom 54 (13%) had neurological involvement (neuro-Behçet's disease: NB). NB patients included a significantly higher proportion of males (61%) than non-NB patients (42%, P = 0.009). The majority of patients (n = 38, 70%) had acute parenchymal NB, 15 (28%) had chronic progressive parenchymal NB, and 1 (2%) had the non-parenchymal type. Headache and fever were more frequently reported by patients with acute parenchymal NB. Personality changes, sphincter disturbances, involuntary movements, and ataxia occurred predominantly in patients with chronic progressive parenchymal NB. Lesions were distributed throughout the CNS, but mainly in the brainstem, white matter, and basal ganglia. Analysis of end-point clinical outcomes revealed a poor prognosis for patients with chronic progressive NB. In Japan, most NB patients have the parenchymal type, and male gender is a predisposing factor. Because of the unfavorable prognosis associated with chronic progressive NB, development of effective therapies are urgently needed.

Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions.

Heme oxygenase (HO)-1, a heme-degrading enzyme inducible by various stimuli, plays a key role in the regulation of inflammatory response in monocytes/macrophages. The serum HO-1 level is remarkably increased in patients with secondary hemophagocytic syndrome (HPS) or adult-onset Still's disease. We measured serum HO-1 levels in patients with a variety of hematological diseases, including secondary HPS, by means of ELISA. Serum HO-1 levels were significantly higher in 22 patients with HPS (134.7 +/- 116.2 ng/mL, P < 0.0001) at diagnosis than in 80 patients with other hematological diseases. The most effective cutoff point between HPS and other conditions was 14.5 ng/mL, with 100.0% sensitivity and 96.3% specificity. In HPS patients, the serum HO-1 levels showed the highest correlation with serum ferritin (r = 0.682, P = 0.0005), which reflects the disease activity of HPS. Moreover, both HO-1 and ferritin levels were reduced in parallel after successful treatment in patients with HPS, irrespective of underlying diseases. However, HO-1 levels were not elevated in patients with other causes of hyperferritinemia. These data demonstrate that serum HO-1 can distinguish secondary HPS from other hematological diseases, including those associated with hyperferritinemia.

Multiple extra-articular synovial cysts complicated with rheumatoid arthritis.

Multiple extra-articular synovial cysts (MESC) are rarely complicated with various rheumatic diseases. We here first report a rheumatoid arthritis (RA) patient with MESC, which were extensively analyzed by a series of imaging techniques including fluorine-18-2-fluoro-D: -glucose positron emission tomography ((18)F-FDG-PET), magnetic resonance imaging (MRI), and ultrasonography. FDG uptakes in joint lesions with MESC were much higher than those reported in typical lesions of RA, suggesting that marked joint inflammation is implicated in the development of MESC.

Screening of tuberculosis by interferon-gamma assay before biologic therapy for rheumatoid arthritis.

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-gamma secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-gamma secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

Heme oxygenase 1 attenuates the development of atopic dermatitis-like lesions in mice: implications for human disease.

BACKGROUND: Oxidative stress has been implicated in the exacerbation of atopic dermatitis (AD). OBJECTIVE: We sought to investigate the pathophysiologic roles of inducible antioxidant heme oxygenase (HO) 1 in the development of AD. METHODS: Serum HO-1 levels of patients with AD (n = 100) and age-matched healthy control subjects (n = 72) were determined by means of ELISA. The relationships between serum HO-1 levels and clinical severities, laboratory parameters, and cytokines/chemokines were assessed. Skin lesions of patients with AD and psoriasis were analyzed by means of immunohistochemistry. A murine AD model, DS-Nh, was used to further investigate localization and function of HO-1. Evaluation of symptoms, serum IgE and IL-18 levels, immunoblotting results, and histologic analyses of skin were performed. The effect of intraperitoneally administered hemin, a potent HO-1 inducer, or zinc protoporphyrin IX, an inhibitor of HO, was monitored. RESULTS: Serum HO-1 levels were significantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1-expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Immunofluorescence of mouse skin lesions revealed that HO-1-positive cells were macrophages and dendritic cells. Treatment with hemin, but not with zinc protoporphyrin IX, attenuated the development of the skin lesions in DS-Nh mice and reduced serum IL-18 levels. CONCLUSION: HO-1 levels were increased in sera and skin lesions of patients with AD. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction offers a promising therapeutic strategy for AD.

RanBPM, Muskelin, p48EMLP, p44CTLH, and the armadillo-repeat proteins ARMC8alpha and ARMC8beta are components of the CTLH complex.

Ran-binding protein in microtubule organising centre (RanBPM) was originally isolated as a protein that binds to the small GTPase Ran. Recently our group and other groups reported that RanBPM was associated with several proteins and composed a large protein complex. Here, we used tandem MS with an antibody against RanBPM to purify this complex from a soluble extract of HEK293 cells: we identified Muskelin, p48EMLP, p44CTLH, and the novel armadillo-repeat proteins ARMC8alpha and ARMC8beta as components. In RanBPM, Muskelin, p48EMLP, and p44CTLH we found LisH/CTLH motifs, which are present in proteins involved in microtubule dynamics, cell migration, nucleokinesis, and chromosome segregation. We renamed the 20S large protein complex the CTLH complex. The N-terminal 364 amino acids of ARMC8alpha and ARMC8beta were completely conserved, suggesting that these proteins are probably alternatively spliced products from the same gene. We confirmed the in vivo association of each component by co-immunoprecipitation assays with Cos-7 cells in which these components were exogenously overexpressed. A pull-down assay with bacterially-expressed Twa1 revealed binding of each in vitro-translated component to Twa1. Finally, we confirmed the cellular localization of these proteins. Taken together, our results reveal that RanBPM, ARMC8alpha, ARMC8beta, Muskelin, p48EMLP, and p44CTLH form complexes in cells.

Tumor necrosis factor alpha acceleration of inflammatory responses by down-regulating heme oxygenase 1 in human peripheral monocytes.

OBJECTIVE: To examine the interaction between heme oxygenase 1 (HO-1), a stress-induced antiinflammatory protein, and tumor necrosis factor alpha (TNFalpha) in human peripheral blood monocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors or from patients with rheumatoid arthritis (RA) receiving the anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody infliximab. CD14+ cells were isolated by magnetic cell sorting, cultured with TNFalpha or auranofin, and transfected with a plasmid encoding HO-1 or an HO-1-specific small interfering RNA vector. Protein and messenger RNA (mRNA) levels were examined by immunoblotting and real-time polymerase chain reaction. Cytokine levels in culture supernatants were measured by enzyme-linked immunosorbent assay. HO-1 gene transcription was evaluated using a luciferase reporter gene assay. Actinomycin D and cycloheximide were used to monitor the stability of mRNA and protein. RESULTS: HO-1 is constitutively expressed by CD14+ PBMCs from healthy donors. TNFalpha suppressed HO-1 expression by accelerating the decay of mRNA without affecting gene transcription or protein stability. Forced expression or selective knock-down of the HO-1 gene expression resulted in down-regulation or up-regulation, respectively, of proinflammatory cytokine synthesis by monocytes. Treatment with infliximab significantly increased HO-1 mRNA levels and reduced TNFalpha synthesis by PBMCs from RA patients. CONCLUSION: TNFalpha accelerated inflammatory responses by down-regulating HO-1 expression in human monocytes. TNF antagonists may block this TNF-dependent suppression of HO-1 expression, resulting in an amelioration of inflammation.

Systemic sclerosis and pseudomesotheliomatous adenocarcinoma of the lung.

A 55-year-old man, diagnosed with systemic sclerosis (SSc) for 20 years, was admitted to our hospital for exertional dyspnea and pleural effusion. Computed tomography scan and cytological findings of the pleural fluid suggested malignant mesothelioma. In the postmortem examination, the tumor was pathologically diagnosed as pseudomesotheliomatous adenocarcinoma (PMA) of the lung, classified into pleomorphic carcinoma with adenocarcinoma component according to the new World Health Organization guidelines. This is the first case report of SSc with PMA.

Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis.

OBJECTIVE: To examine the expression and pathogenetic roles of heme oxygenase 1 (HO-1), an inducible heme-degrading enzyme with antiinflammatory properties, in rheumatoid arthritis (RA). METHODS: HO-1 expression in synovial tissue from patients with RA, patients with osteoarthritis, and patients with noninflammatory joint diseases was determined by immunoblotting and immunohistochemistry. Effects of various agents, such as hemin (a chemical inducer of HO-1), small interfering RNA (siRNA) specific for HO-1, HO-1 expression vector, and antirheumatic agents, on HO-1 expression in RA synovial cell lines were analyzed by real-time reverse transcription-polymerase chain reaction (PCR) and immunoblotting. Cytokine synthesis was evaluated by real-time PCR and enzyme-linked immunosorbent assay. RESULTS: HO-1 was expressed more abundantly in the lesions of synovial tissue from patients with RA than in those from the other patient groups. Hemin, auranofin, and HO-1 expression vector induced HO-1 and reduced expression of tumor necrosis factor alpha (TNFalpha) messenger RNA, lipopolysaccharide (LPS)-induced secretion of interleukin-6 (IL-6) and IL-8, and expression of cyclooxygenase 2 in the synovial cell lines. Treatment with HO-1-specific siRNA augmented the synthesis of TNFalpha, IL-6, and IL-8 and canceled the suppressive effects of auranofin on TNFalpha secretion. When hemoglobin, as a scavenger of carbon monoxide, was added to auranofin-treated synovial cell lines, LPS-dependent production of IL-6 and IL-8 was increased. CONCLUSION: Our data demonstrate that HO-1 is expressed in RA synovial tissues and plays a regulatory role in the development of inflammation. The pharmacologic effects of auranofin depend, in part, on the levels of HO-1, suggesting that HO-1 induction is a novel therapeutic strategy for RA.