Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan.

OBJECTIVE: Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. METHODS: We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. RESULTS: A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. CONCLUSIONS: The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.

Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept.

We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

The role of homocysteine as a significant risk factor for white matter lesions in Japanese women with rheumatoid arthritis.

The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy in rheumatoid arthritis patients. Based on brain magnetic resonance imaging findings, 65 rheumatoid arthritis patients were divided into 2 groups: WML-positive group (61 +/- 6 years, mean +/- SD; n = 25) and WML-negative group (60 +/- 7 years, n = 40). The level of metabolic parameters was assessed by total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and homocysteine (tHcy). The duration of rheumatoid arthritis was longer in the WML-positive group than in the WML-negative group (P < .05). Plasma levels of triglyceride was higher whereas high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < .05 and P < .01, respectively). Fasting plasma glucose (P < .05) and tHcy (<.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the tHcy (odds ratio, 1.35; 95% confidence interval, 1.12-1.63; P < .0001). Our findings indicate that the presence of WML was associated with the tHcy in Japanese patients with rheumatoid arthritis.

The role of histamine H1 receptor and H2 receptor in LPS-induced liver injury.

To examine the role of histamine H1 and H2 receptors in the regulation of lipopolysaccharide (LPS)-induced liver injury, a combination of D-galactosamine and LPS (GalN/LPS) was administered to histamine H1 receptor knockout (H1-R KO) and H2 receptor knockout (H2-R KO) mice. The numbers of necrotic and apoptotic hepatocytes in the liver, as well as the levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), were increased significantly by GalN/LPS treatment compared to the appropriate controls. Pretreatment with histamine ameliorated the GalN/LPS-induced necrotic and apoptotic changes in the hepatocytes and inhibited the elevation of serum AST and ALT levels. Histamine attenuated the GalN/LPS-induced increases in the levels of TNF-alpha, but augmented those of IL-10 both in the liver and serum. Histamine inhibited the GalN/LPS-induced caspase-3 activity in the liver. Furthermore, these effects of histamine were completely or partially attenuated in H2-R KO mice, but not in H1-R KO mice. Peritoneal macrophages from H2-R KO mice exhibited blunted changes in the effects of histamine on LPS-induced TNF-alpha and IL-10 production in vitro compared to the wild-type (WT) controls. In summary, the present findings suggest that the histamine H2-R-TNF-alpha and -IL-10 pathways play protective roles in endotoxin-induced hepatic injury.

Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice.

Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)-induced liver injury using KK-Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by D-galactosamine/LPS (GalN/LPS) in KK-Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS-induced liver injury was more pronounced in KK-Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS-induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS-induced increases in serum and hepatic tumor necrosis factor alpha (TNF-alpha) levels and increased peroxisome proliferator-activated receptor (PPAR) alpha messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK-Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS-induced TNF-alpha production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF-alpha-induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS-induced hepatic injury by inhibiting the synthesis and/or release of TNF-alpha of KK-Ay obese mice.

A case of lupus cystitis with a history of idiopathic thrombocytopenic purpura.

A 36-year-old Japanese woman who had been diagnosed as having systemic lupus erythematosus (SLE) at the age of 34 began to complain of severe bowel symptoms and developed severe hydroureteronephrosis. She had a history of idiopathic thrombocytopenic purpura. Biopsy specimens from her bladder showed interstitial cystitis. She was diagnosed as having lupus cystitis, and treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone and ureter catheterization. Her urinary and bowel symptoms were alleviated and the level of hydroureteronephrosis improved. We note that cystitis could be a primary manifestation of SLE. Patients not only with SLE but also with some autoimmune diseases require careful urological evaluation when they complain of severe bowel symptoms.

Churg-strauss syndrome with cholecystitis and renal involvement.

A patient with bronchial asthma developed cholecystitis. Laboratory investigations revealed marked eosinophilia (6,615/mm3), an elevated anti-neutrophil cytoplasmic antibody level and renal dysfunction (blood urea nitrogen 14 mg/dl, creatinine 1.4 mg/dl). Following cholecystectomy, histopathological examination revealed a marked inflammatory cell infiltrate composed mainly of eosinophils with evidence of invasion of the wall of the gall bladder and granuloma formation of arterioles. A diagnosis of Churg-Strauss syndrome was made and she was treated with 60 mg of prednisolone per day. A renal biopsy was performed one year later in view of persistent renal dysfunction. Pathological analysis revealed a pauci-immune glomerulonephritis with interstitial changes but no crescent formation.

[A case of primary Sjögren's syndrome with severe pulmonary hypertension and glomerular damage].

We report a case of 58 years old female with primary Sjögren's syndrome who accompanied pulmonary hypertension and glomerular damage. Renal biopsy revealed interstitial nephritis and glomerular damage. Pulmonary perfusion scintigram revealed diffusely decreased pulmonary perfusion, but the defect was not observed. Immunocomplex positive indicated that immune disorder would damage her lung and kidney. Proteinuria and pulmonary hypertension were improved by high dose of prednisolone and low dose of oral cyclophosphamide treatment. No previous reports had shown pulmonary hypertension and glomerular damage complicated with primary Sjögren's syndrome in same patients at same time. But some reports had suggested immune disorder had caused pulmonary hypertension or glomerulonephritis in patients of primary Sjögren's syndrome. Our patient showed immune disorder, and it might cause pulmonary hypertension and glomerular damage.