Yasuyuki Kamata

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.

A case of rheumatoid arthritis with protein losing enteropathy induced by multiple diaphragmatic strictures of the small intestine: successful treatment by bougieing under double-balloon enteroscopy

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most favoured for the treatment of rheumatoid arthritis (RA) but they sometimes induce inflammation and ulceration of the gastrointestinal tract.1 Approximately 75% of patients receiving long term NSAIDs develop inflammation in the small intestine that in rare cases results in protein losing enteropathy.2,3 Furthermore, NSAIDs can bring about diaphragmatic strictures in the small intestine as a consequence of ulcer healing. We report here a patient with RA who had multiple diaphragmatic strictures in the small intestine and subsequent protein losing enteropathy, probably due to long term non-steroidal anti-inflammatory drugs use. Her intestinal stricture and protein losing enteropathy, however, were successfully corrected by bougieing under double balloon enteroscopy without resort to surgical resection. A 57 year old …

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.

Successful treatment of massive intractable pericardial effusion in a patient with systemic lupus erythematosus with tocilizumab.

A 51-year-old Japanese woman developed systemic lupus erythematosus (SLE) in 1995. In August 2005, she had massive pericardial effusion due to lupus pericarditis, which was compromising her circulation. Methylprednisolone pulse, intravenous cyclophosphamide pulse and pericardiocentesis were all ineffective. The pericardium was cut surgically to create a passage to drain the liquid into the pleural cavity. The procedure was temporarily effective; however, massive liquid accumulated in the pleural cavity within 1 year. Oral tacrolimus and topical betamethasone injection were ineffective. Since the interleukin-6 (IL-6) level in the effusion was markedly increased (1160 pg/ml), tocilizumab was administered intravenously at a dose of 8 mg/kg every 4 weeks. The effect was astonishing and only a residual amount of pericardial effusion remained. Prednisolone was tapered successfully from 15 to 5 mg daily. Tocilizumab is a treatment of choice when we confront an intractable serositis with massive effusion in SLE, if the IL-6 level is high.

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.

Urinary β2-microglobulin as a sensitive marker for haemophagocytic syndrome associated with collagen vascular diseases

activation, as well as the release of MMPs. ET-1 may lead to NFB stimulation and may subsequently stimulate the production of pro-inflammatory cytokines like IL-6, IL-8 and TNF[10]. The use of an oral ET dual receptor antagonist in our patient led to a rapid remission of ischaemia. This fast and sustained response had probably been achieved by potent vasodilatation. The reversal of the obstructive vasculitis documented by MRA might also at least partially be related to bosentan. The blockade of ET might have caused a down-regulation of pro-inflammatory cytokines and cells by a mechanism mentioned earlier. Corticosteroids were already terminated 4 weeks after the start of the bosentan therapy. Now, 9 months later, there is no evidence of reoccurrence of vasculitis. Bosentan might, therefore, be responsible for sustained remission. This could be interpreted as further piece of evidence of its anti-inflammatory potential in this case. In conclusion, we think that bosentan, in this individual patient, exhibited compelling vasodilatatory and anti-inflammatory effects leading to a rapid and sustained clinical improvement of the ischaemia, probably achieved by antagonization of endothelin. Bosentan might, for this reason, be regarded as therapeutic alternative in ischaemic complications caused by vasculitic syndromes resistant to standard treatment regimes.

Abrupt development of sarcoidosis with a prodromal increase in plasma osteopontin in a patient with rheumatoid arthritis during treatment with etanercept.

To the Editor: Biologic disease-modifying antirheumatic drugs (DMARD) targeting tumor necrosis factor-α (TNF-α) are very efficacious and the number of patients with rheumatoid arthritis (RA) treated with these drugs is increasing rapidly. Because granulomatous diseases as typified by sarcoidosis are considered to develop in the Th1 cytokine milieu dominated by interferon-γ (IFN-γ) and TNF-α, anti-TNF-α agents have been used for treatment of sarcoidosis. Reports show that infliximab is effective, while etanercept is not, in the treatment of sarcoidosis1,2. In contrast, anti-TNF-α agents may have induced sarcoidosis in patients with RA and spondyloarthropathy3–6. The patient we describe had acute onset of sarcoidosis in several organs simultaneously after a long period of remission of RA while receiving etanercept. Based on serum and plasma levels of laboratory indicators related to sarcoidosis, the condition might have developed as quickly as within 1 or 2 months. A 52-year-old Japanese woman was diagnosed with RA in 1980 and had been treated with several DMARD such as injectable gold salt, sulfasalazine, actarit, methotrexate, and mizoribine with no appreciable effects. Leflunomide was started in … Address correspondence to Dr. S. Takatori, Division of Rheumatology and Clinical Immunology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-shi, Tochigi 329-0498, Japan. E-mail: stori{at}jichi.ac.jp

Low level of seroconversion after a novel influenza A/H1N1/2009 vaccination in Japanese patients with rheumatoid arthritis in the 2009 season

We examined change in the antibody titre against pandemic influenza A/H1N1/2009 before and after vaccination in Japanese patients with rheumatoid arthritis. This observational study was conducted with the participation of five hospitals in Japan. A total of 89 patients with rheumatoid arthritis were included in this study. The seroprotection and seroresponse rates to vaccination with the pandemic influenza A/H1N1/2009 vaccine were analysed. The seroprotection rates prior to the vaccination were 5.6% in the Japanese patients with rheumatoid arthritis. The seroprotection rates after subcutaneous vaccination were 55.1%. The seroresponse rate after subcutaneous vaccination was 50.6% in the patients with rheumatoid arthritis. Both the seroprotection and seroresponse rates obtained after the vaccination with the pandemic influenza A/H1N1/2009 vaccine were low in Japanese patients with rheumatoid arthritis. We should realise that a vaccination against this newly emerged influenza virus may protect only half of the Japanese patients with rheumatoid arthritis in a real world.

Repeated local implantation of autologous peripheral blood mononuclear cells for the treatment of ischaemic digits in patients with connective tissue diseases

OBJECTIVES Blood flow in fingers and toes is often impaired in patients with CTDs, mandating amputation in some. Our previous study showed that a single implantation of autologous bone marrow cells is as effective as peripheral blood mononuclear cells (MNCs) to restore impaired blood flow, although neither has long-lasting efficacy. In this study, autologous peripheral blood MNCs were implanted repeatedly to evaluate a better efficacy. METHODS Three patients with SSc, two with microscopic polyangiitis and one with MCTD were enrolled. All patients had severe RP, ulcers and/or necrosis in the extremities. MNCs were obtained from 400 to 1600 ml of peripheral blood and implanted into 20-80 different sites in the palms and/or soles. This procedure was repeated every 3 months up to 1 year. Humoral factors were measured by ELISAs. RESULTS Visual analogue scale scores for pain, coldness and subjective satisfaction were improved after implantation in all patients. Pre-treatment ulcers in five patients were cured after repeated implantations. Angiography showed increased vasculature compared with baseline. Serum levels of VEGF increased after implantation, whereas levels of IL-1β, fibroblast growth factor and endostatin had variable results. None of the patients had any adverse reactions during a follow-up period of up to 3 years. CONCLUSIONS Repeated implantation of peripheral blood MNCs was effective and safe for the treatment of recalcitrant ulcers developing in ischaemic digits and toes in patients with CTD.