HMG-CoA (3-hydroxy-3-methyglutaryl coenzyme A) reductase inhibitors (statins) reduce cardiovascular morbidity and mortality. Although statins work in part via lipid modulation, several findings of statins indicate they have broader properties, including alteration of inflammatory pathways. Ex-vivo activities of statins include suppression of adhesion molecule expression, MHC class II expression, and effects on reactive oxygen and nitrogen intermediate production. Statins also modify apoptosis in smooth muscle and endothelial cells leading to altered vascular function and neovascularization. These properties offer the potential to modify the states of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis with drugs that show minimal toxic effects in both the short and long term.

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  Hyperimmunoglobulin-E syndrome is one of the primary immunodeficiency with the manifestations of recurrent infections especially with Staphylococcus aureus, characteristic facies, hyperextensibility of joints, multiple bone fractures, scoliosis, and delayed shedding of the primary teeth. It is a multisystem disease of autosomal dominant inheritance. Recently, a new type of hyper-IgE syndrome with autosomal recessive inheritance was identified. Although Th1/Th2 imbalance has been suspected to be a cause of this diesease, it is not clarified yet.

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  Salmonella is one of the gram negative intracellular pathogens. The immune response to Salmonella includes innate immunity and adaptive immunity. The intestinal epithelium, neutrophil, macrophage, dendritic cell, NK cell, NK T cell and γδ T cell take important part in former process, and antigen specific T cell and B cell take part in the later process.
   Macrophages and dendritic cells increase in number early after Salmonella infection and produce variety of cytokines. Especially, IL-12, IL-15 and IL-18 play important roles in protection against Salmonella infection, proliferation of NK cell, NKT cell and γδ T cell, producing IFN-γ, in addition, IL-12 and IL-18 induce IFN-γ production by Th1 cells and adaptive immune response.

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  Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). β₂-glycoprotein I(β₂-GPI) and prothrombin are representative autoantigens, the former more extensively investigated. Anti-β₂-GPI antibodies are not only markers of APS, but also are considered to be pathogenic. Possible roles of anti-β₂-GPI antibodies are, 1) enhancement the binding of β₂-GPI to anionic phospholipid and inhibition of protein C activation/activated protein C, 2) to form anti-β₂-GPI antibody-β₂-GPI-oxidized LDL complex and to promote uptake by sub-endothelial macrophage, resulting in atherosclerosis, 3) to dimerize β₂-GPI on the surface of platelets and to activate platelets via apoE receptor 2 and subsequent signal transduction, 4) stimulation of monocytes via p38 MAP kinase pathway and induction of tissue factor production. In pregnancy morbidity, activation of complement cascade plays an important role. These findings may provide a novel target in the management of APS.

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  CD40 and CD154 belong to the tumor necrosis factor (TNF) receptor superfamily and the TNF superfamily, respectively. Evidence is accumulating that indicates the importance of this receptor-ligand pair in the immunopathogenesis of autoimmune diseases. The CD40-CD154 interaction influences antigen presentation, tolerance, autoantibody production and tissue damage, all of which are relevant to the development and perpetuation of autoimmune diseases. Among the collagen diseases, the CD40-CD154 interaction has been intensively investigated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In this article, both basic and clinical research suggesting the involvement of the CD40-CD154 interaction in SLE, RA, inflammatory myopathies, systemic sclerosis and antiphospholipid syndrome are reviewed. The results of clinical trials from CD40-CD154 blockade are also analyzed. CD40-CD154 blockade in animal models of autoimmune diseases has been reported to be a promising novel therapeutic approach and, thus, has attracted great attention from pharmaceutical companies. However, the development of CD40-CD154 blockers with both significant clinical efficacy and safety has not been successful and research advances in this field are eagerly awaited.

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  The association of malignancy with collagen diseases has been a focus of interest. Especially, relation between dermatomyositis and malignancy is well-recognized. I reviewed here about the coexistence of SSc and malignancy in literature. I would like to raise four points as characteristics of the relationship.
   ① Special attention should be paid to the patients who is late-onset, with advanced skin sclerosis (ex. Barnett III type) and male.
   ② There are three generalized mechanisms of the association. The first is the predisposition of the malignancy on the basis of organ fibrosis, such as pulmonary fibrosis and lung cancer. The second is the nature of paraneoplastic syndrome. Lastly, immunological derangement inherent to SSc might cause carcinogenesis.
   ③ It has been documented that the interval of the onsets of SSc and breast cancer is extremely short.
   ④ Longstanding reflux esophagitis and Barrett’s esophagus with SSc is suspected to predispose to esophageal carcinoma.

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  Purpose : To determine the prevalence of liver involvement in patients with primary Sjogren’s syndrome (SS) and to evaluate the association of this complication with other extra-glandular manifestations and serologic markers.
  Methods : We examined 155 Japanese patients (150 women and 5 men. mean age 66.6 years) who met the European Epidemiology Center Criteria for primary SS. Liver involvement was considered present when abnormal liver function tests (AST, ALT, ALP, GTP, or bilirubin) were detected more than three times.
  Results : 20 patients (13%) had liver involvement including 2% with clinically overt liver disease. The causes of liver involvement were primary biliary cirrhosis (PBC) 6, autoimmune hepatitis (AIH) 2, hepatitis C virus (HCV) infection 2, concurrence of AIH and HCV infection 1, fatty liver 1. In 8 patients, the cause remained unclear. Of 6 patients complicated with PBC, four patients had PBC-specific antimitochondrial antibodies (AMA). Liver dysfunction was transient in two patients. Hepatocelluar carcinoma developed in a patient whose liver involvement was due to AIH and HCV. Patients with liver involvement were more likely to have cutaneous and neurological manifestations, when compared to SS without liver involvement. A positive antinuclear antibody, rheumatoid factor, and anticentromere antibody were also associated with liver involvement. Other autoantibodies did not correlate with the prevalence of liver involvement.
  Conclusion : Although symptomatic liver involvement is rare in SS patients, asymptomatic liver involvement is common. Clinicians must be aware of the possibility of liver involvement so that it can be treated as soon as possible.

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  The rate of concomitance of systemic sclerosis and malignant neoplasm is not still ascertained. Therefore we reviewed 8,327 patients who were diagnosed with systemic sclerosis and received public financial aid from the Ministry of Health, Labour and Welfare of Japan in 1999. The concomitance rate was 3.1% of all patients, however, it was more frequent among men than among women (5.4% for men and 2.8% for women, respectively, P<0.01), and the mean age of patients with complicated malignant neoplasms was significantly higher than that of patients without malignancy (P<0.01). For comparison with the Japanese general population, O/E ratios (ratio of observed-to- expected malignant neoplasms) were calculated, and it was found that both men and women had significantly higher O/E ratios (O/E ratio 2.31, 95% confidence interval [CI] 1.68-2.94, P<0.001 for men and O/E ratio 1.64, 95% CI 1.41-1.86, P<0.001 for women). In addition we also assessed laboratory findings including autoantibodies and respiratory function tests for patients with malignant neoplasms by logistic regression analysis adjusted for sex and age. Decreased DLco (pulmonary CO diffusing capacity) appeared to be a risk factor for the concomitant malignant neoplasms among patients with systemic sclerosis (odds ratio 2.00 for DLco ≦70%, CI 1.06-3.74, P=0.032). These results may help to elucidate the etiology of systemic sclerosis.

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  A 40-year-old female noticed edema of the lower limbs in March 1995. Nephrotic syndrome due to membranous nephropathy was diagnosed and administration of high-dose corticosteroids resulted in incomplete remission. Progressively enlarging, red scaling skin lesions developed concomitantly from the scalp to the extremities. Pityriasis rubra pilaris (PRP) was diagnosed in 1996 in the Department of Dermatology at Sapporo Medical University hospital. Various treatments proved ineffective. Arthritis of the finger joints developed in July 1999, and proteinuria recurred in April 2000. She was admitted to our department in August 2000. Physical examination on admission revealed marked swelling of both distal interphalangeal (DIP) joints and the right fourth proximal interphalangeal (PIP) joint. Results of testing for antinuclear antibody, rheumatoid factor, and HLA-B27 were all negative. Radiography of the hands revealed destruction of the DIP and PIP joints where MRI indicated the presence of synovitis. Bone scintigraphy demonstrated accumulation in bilateral metatarso-phalangeal joints and the left sacroiliac joint. Arthritis associated with PRP was diagnosed, as both PRP and psoriasis represent keratinizing disorders of the skin and clinical features in the present case resembled those of psoriatic arthritis. Despite administration of high-dose corticosteroids, destruction of finger joints progressed rapidly. Administration of cyclosporine in April 2002 improved arthritic symptoms. Cases of PRP accompanied by arthritis need to be accumulated to allow analysis of the pathogenesis and clinical picture of this association.

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  In 1996 36-year-old man was admitted into our hospital because of polyarthralgia, skin eruptions followed by multiple cutaneous ulcers, dry cough and elevation of C-reactive protein level. The finding of skin biopsy from left elbow was vasculitis. Chest CT showed linear interstitial shadow at bilateral dorsalis lungs. Transbronchial lung biopsy (TBLB) revealed marked infiltration of inflammatory cells in the bronchial walls and peripheral alveoli. In addition, eosinophils were not in branchoalveolar lavage (BAL) fluid. Moreover, video-assisted thoracic surgery (VATS) revealed organizing fibroblastic polyp and bronchiolitis obliterans at terminal bronchiole. We diagnosed his pneumonia as bronchiolitis obliterans organizing pneumonia (BOOP). Administration of oral prednisolone (40 mg/day) was begun and he experienced diminished BOOP and other clinical manifestations. Three years later he developed dry cough, dyspnea and digital ulcers again. Arterial blood gas analysis revealed marked hypoxemia and laboratoly studies showed LDH (377 IU/ml) and CRP (8.27 mg/dl) levels were elevated. Chest CT pointed out an exacerbation of BOOP. Treatment with intravenous pulses methylprednisolone and oral prednisolone (60 mg/day) resulted in marked improvement of the clinical manifestations. We describe a rare case of vasculitis associated with BOOP.

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  A 73-year-old woman with a three-year history of allergic rhinitis and bronchial asthma was found to have Churg-Strauss syndrome combined with fever, eosinophilia, mononeuritis multiplex, and acute coronary syndrome. After the treatment with a methylprednisolone pulse therapy and a high dose of corticosteroids were initiated, eosinophilia normalized together with decline of fever, but acute superior mesenteric artery occlusion occurred, which improved with conservative therapy. Severe stenosis of bilateral carotid arteries was found, so immunosuppressive drugs were added. In general, Churg-Strauss syndrome is a disease with vasculitis affecting small arteries, arterioles, venules, or capillaries, and cases with arteritis in large and medium-sized arteries, such as this case are rare. This suggested that in cases of Churg-Strauss syndrome of the elderly patients, physicians must be careful about involvement of larger vessels.

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  The patient is a 56-year-old Japanese woman who suffered from breast cancer and ovarian cancer at intervals of 6 years, and was also complicated by two episodes of dermatomyositis, each of which occurred simultaneously with each of two cancers. When she was 51 years old, she developed dermatomyositis for the first time 6 months after the resection of breast cancer, whose histological type was tubular adenocarcinoma. The dermatomyositis remitted without oral corticosteroids in 2 months, and the remission had continued for 6 years. However, at the age of 56, dermatomyositis abruptly recurred with a pruritic generalized rash, Gottron’s papules and elevated serum CK levels. Examination for malignancy revealed an ovarian tumor, which was diagnosed as serous papillaly adenocarcinoma, and the surgery was performed. After the resection of the ovarian cancer, skin rash was improved dramatically and CK levels were normalized again without oral corticosteroids. Since there were no evidences of recurrence of the breast cancer, it was considered that each episode of dermatomyositis was associated with each of the cancers, respectively. We report this rare and interesting case to consider the etiology of cancer-associated myositis as a paraneoplastic syndrome, since the two cancers have different histological types.

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