Takao Nagashima

Increased Levels of Interleukin 33 in Sera and Synovial Fluid from Patients with Active Rheumatoid Arthritis

Objective. To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33. Methods. Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1ß and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting. Results. Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS. Conclusion. IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

Reactivation of hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs

To examine the incidence of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving biological disease‐modifying antirheumatic drugs (DMARDs).

Systemic lupus erythematosus and Sjögren's syndrome induced in a case by interferon-α used for the treatment of hepatitis C

A 57-year-old Japanese woman developed skin eruption, pleuritis, pancytopenia, parotid gland swelling and glomerulonephritis after 7-month treatment with pegylated interferon-α and ribavirin for chronic hepatitis C. Disease-specific autoantibodies such as anti-SSA, anti-SSB, anti-Sm and anti-dsDNA antibodies became positive. The diagnosis of systemic lupus erythematosus and Sjögren’s syndrome was made and treatment with glucocorticoid pulse followed by oral glucocorticoid was started. It is highly probable that interferon-α-induced systemic lupus erythematosus and Sjögren’s syndrome in this case. Interferon-α might be important pathogenically in these diseases. Lupus (2010) 19, 753—755.

Destructive arthropathy associated with dermatomyositis sine myositis positive for anti-Jo-1 and anti-cyclic citrullinated peptide antibodies.

To the Editor: Polymyositis (PM) associated with anti-synthetase antibodies is often accompanied by arthritis, but it is usually mild and self-limiting1. Subluxing arthropathy associated with anti-Jo-1 antibody (anti-Jo-1)-positive PM or dermatomyositis (DM) has been described as a distinct subset of PM/DM2,3. It is characteristically a deforming, predominantly nonerosive arthropathy associated with subluxation of the interphalangeal (IP) joints, especially those of the thumbs. We encountered 2 patients who had severe, deforming, destructive arthropathy associated with DM sine myositis and who were positive for anti-Jo-1 and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Both patients fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA). ### Patient 1 In 1996, a 57-year-old Japanese woman was referred to our hospital with dyspnea on exertion. She had Gottron’s sign in her hands, elbows, and knees, but there was no weakness, arthralgia, or Raynaud’s phenomenon. Interstitial lung disease (ILD) was detected by chest radiography. Serum creatine kinase (CK) was normal, anti-Jo-1 was positive at 1:2, and rheumatoid factor (RF) and anti-SSA antibody were negative. She was … Address correspondence to Dr. Nagashima; E-mail: naga4ma{at}jichi.ac.jp

Protein-losing gastroenteropathy associated with primary Sjögren's syndrome: a characteristic oriental variant.

Protein-losing gastroenteropathy (PLGE) is a rare manifestation of primary Sjögren’s syndrome (SS). We report a case of a 41-year-old Japanese man, who is the first male patient, with PLGE associated with primary SS. Although serum anti-SSA and SSB antibodies were detected, he had no subjective sicca symptoms. He had multiple annular erythema: a characteristic skin manifestation of Asian SS patients. A diagnosis of PLGE was made from results of 99mTc-labelled albumin scintigraphy and a faecal alpha-1-antitrypsin clearance test. Intravenous administration of high-dose glucocorticoid was not effective, but pulse methylprednisolone therapy alleviated disease manifestations. As all cases of PLGE associated with primary SS have been reported from East Asia, this complication could be essentially limited to Asian patients.

Dermatomyositis associated with thyroid cancer: a paraneoplastic syndrome?

We have read the recent article by Fujita et al. [1] “Dermatomyositis associated with thyroid cancer” with great interest. They reported the removal of the coexisting thyroid cancer in a patient with corticosteroid resistant dermatomyositis (DM) resulted in improvement of DM. We have experienced two cases of DM associated with thyroid cancer, both of them responded to conventional immunosuppressive treatment without removal of thyroid cancer.

Antineutrophil cytoplasmic autoantibody specific for proteinase 3 in a patient with shunt nephritis induced by Gemella morbillorum.

A 17-year-old girl had been placed with ventriculoperitoneal, then ventriculoatrial shunts for congenital hydrocephalus since birth. The patient originally was diagnosed as having a lupus-like disease, but later turned out to have shunt nephritis, presenting with fever, proteinuria, pancytopenia, and hypocomplementemia. Antineutrophil cytoplasmic autoantibody specific for proteinase 3 (PR3-ANCA) was detected in her serum. The patient received oral prednisolone and repeated methylprednisolone pulses, with essentially no beneficial effects. A gram-positive coccus, Gemella morbillorum, was recovered from her blood as well as cerebrospinal fluid, and the culture of the shunt catheter established the diagnosis of shunt nephritis. Removal of the shunt catheter improved symptoms dramatically and decreased PR3-ANCA in serum to an undetectable level. Because steroids had no effects and the control of bacterial infection lowered PR3-ANCA levels, the antibody would have been induced by continuous infection with G morbillorum.

Unchanged serum viral load and liver function during tocilizumab treatment in a patient with rheumatoid arthritis and hepatitis C virus infection.

Treatment of rheumatoid arthritis (RA) with biological agents in patients who have viral hepatitis is problematic and difficult. So far, little is known about the safety of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, in RA patients with hepatitis B or C virus infection [1, 2]. Here, we report a patient with RA who was a hepatitis C virus (HCV) carrier, in whom there were no deleterious effects on liver function and viral load during treatment with TCZ. A 53-year-old man with an 8-year history of RA was referred to our hospital. He had been treated with prednisolone and various disease-modifying anti-rheumatic drugs (including methotrexate), but reported no response. He had a history of necrotizing fasciitis in his left arm, resulting in amputation 2 years earlier. Serum anti-HCV antibody had been detected 18 years ago, and he had been treated with intravenous glycyrrhizin and oral ursodeoxycholic acid. He also had severe interstitial pneumonia and diabetes mellitus. Both rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive at 1:5, 120, and 140 U/ml (normal \ 4.5 U/ml), respectively. Serum transaminases were normal. The HCV viral load was 6.2 log IU/ml. His disease activity score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR) was 3.87, while that based on C-reactive protein (DAS28-CRP) was 4.28. Abdominal ultrasonography demonstrated chronic liver damage with mild splenomegaly. No ascites or liver masses were detected, and his hepatic status was ChildPugh class A. He chose treatment with biological agents after receiving an explanation of the risks and benefits. Etanercept was started at a dose of 25 mg/week and increased to 50 mg/week 2 months later. There was no response, so etanercept was replaced with adalimumab (40 mg fortnightly), but there was also no improvement. Since two tumor necrosis factor (TNF) inhibitors were ineffective, TCZ (8 mg/kg) was tried. The serum HCV load before starting TCZ was 6.5 log IU/ml. Although DAS28ESR and DAS28-CRP decreased, clinical improvement was not observed. Instead, prednisolone had to be increased from 5 to 10 mg/day and intra-articular glucocorticoid therapy was required. His viral load and liver function were examined monthly during TCZ treatment. The viral load was between 6.2 and 6.9 log IU/ml, showing little change, while transaminases were normal or only slightly elevated. After 6 doses of TCZ, he was hospitalized for cellulitis of his left foot and TCZ was discontinued. The final viral load was 6.5 log IU/ml. He is now receiving abatacept, and the viral load and transaminases have been stable for 3 months. Serum IL-6 is elevated in patients with chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC) due to HCV infection compared with healthy controls [3, 4]. IL-6 is mainly produced by Kupffer cells and is involved in regeneration and malignant transformation of hepatocytes [5]. In an animal model, carcinogen-induced HCC is reduced in IL-6-deficient mice, suggesting that IL-6 plays an important role in hepatocarcinogenesis [6]. A high serum IL-6 level is a risk factor for hepatitis Bor C-related HCC [3, 7]. Thus, anti-IL-6 therapy could be beneficial for patients with chronic hepatitis. However, TCZ causes immunosuppression and could increase the viral load, although data are lacking. T. Nagashima (&) A. Maruyama Y. Kamata S. Minota Division of Rheumatology and Clinical Immunology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan e-mail: naga4ma@jichi.ac.jp

Prognostic indicators related to death in patients with Pneumocystis pneumonia associated with collagen vascular diseases

The objective of this study is to investigate the clinical markers of life-threatening Pneumocystis pneumonia (PCP) in patients with collagen vascular diseases (CVD). The patients who contracted Pneumocystis jeroveccii were retrospectively selected from our medical charts and conditions related to the patients’ death were reviewed. The findings indicated that lower levels of serum albumin and cholinesterase, increased alveolar–arterial oxygen gradient, intratracheal intubation, and necessity to treat in the intensive care unit were significantly related to deaths associated with PCP in CVD. A special attention should be paid to decreased serum albumin and cholinesterase as ominous predictors in PCP occurred in patients with CVD.

Kimura’s Disease Presenting as Steroid-Responsive Thromboangiitis Obliterans

A 60-year-old Japanese man presented with severe numbness in the fingers of both hands, which were cold and pale in appearance. He was found to have marked eosinophilia (leukocyte count 18 500 /μL with 58.3% eosinophils) and was admitted immediately to the nearby hospital. Treatment with intravenous methylprednisolone pulse (1 g for 3 days) was initiated, followed by oral prednisone 60 mg daily. Although his blood eosinophilia normalized rapidly, gangrene developed in his fingers (Figure 1). Bone marrow examination showed no blast cell proliferation. Tests for antinuclear and antiphospholipid antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, and cryoglobulins were all negative. Protein S and protein C were within the normal range. After prednisone was tapered gradually and discontinued, he was referred to our hospital with a diagnosis of …