Potential role of type I interferon/IP-10 axis in the pathogenesis of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. METHODS: We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. RESULTS: The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. CONCLUSIONS: IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

Immune Reconstitution Inflammatory Syndrome Associated with Pneumocystis jirovecii Pneumonia and Cytomegalovirus Colitis in a Patient with Rheumatoid Arthritis.

A 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum ß-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.

Epstein-Barr virus encephalitis in a patient with rheumatoid arthritis.

A 53-year-old woman with a 6-year history of rheumatoid arthritis (RA) presented with pharyngeal pain, fever, and altered mental status. The patient had been treated with methotrexate (MTX) 12 mg/week, baricitinib 4 mg/day, and tacrolimus 2 mg/day. Magnetic resonance imaging of the brain revealed diffuse high-intensity lesions in the cerebral white matter, basal ganglia, brainstem, and right cerebellar hemisphere. She was diagnosed with Epstein-Barr virus (EBV) encephalitis due to elevated levels of EBV-DNA in the cerebrospinal fluid and serum. Although MTX-associated lymphoproliferative disorders are well-known complications in patients with RA, EBV encephalitis requires careful attention for such patients undergoing treatment with multiple potent immunosuppressants.

Salmonella enterica Subspecies arizonae Detected from Bilateral Pleural Fluid in a Patient with Systemic Lupus Erythematosus and Malignant Lymphoma.

A 72-year-old woman was admitted to our hospital with bilateral pleural effusions. She had a 31-year history of systemic lupus erythematosus and had been treated with prednisolone and azathioprine. Pleural fluid culture revealed Salmonella enterica subsp. arizonae infection. This pathogen rarely infects humans but is commonly found in the gut flora of reptiles, especially snakes. Our patient had not come in contact with reptiles. Despite antibiotic therapies and negative pleural cultures, the pleural effusion persisted. Colon cancer was detected concomitantly, and she finally died. The autopsy revealed that the pleuritis was due to underlying diffuse large B cell lymphoma.

Status quo of osteoporosis treatment in Japan disclosed by the National Database of Health Insurance Claims and Specific Health Checkups: too late in treatment initiation and too few in treated patients?

For the first time ever, the details of osteoporotic treatment were unveiled through the big data published by the government of Japan. The number of patients being treated is low and treatment start is late, especially in men. Our data are useful for education to not only patients but also doctors. PURPOSE: To analyze the current status and trend of osteoporosis treatment in Japan by analyzing the data on main drugs for osteoporosis disclosed in the National Database open data. METHODS: We used the National Database open data released by the Ministry of Health, Labour and Welfare in September 2018. Data on bisphosphonates, denosumab, and teriparatide were extracted to calculate the number of patients treated with these drugs based on the number of prescriptions filed. Using these prescription numbers, the proportion of patients treated with bisphosphonates, denosumab, or teriparatide among osteoporosis patients was calculated. Further, the data on the incidence of hip fractures were employed to validate the appropriateness of the timing of treatment initiation to osteoporosis patients in Japan. RESULTS: The number of patients in men administered bisphosphonates, denosumab, or teriparatide was about one tenth of that in women. The proportion of osteoporosis patients in men treated with bisphosphonates, denosumab, or teriparatide was highest in age group over 80 years at 19.4%. The proportion of osteoporosis patients in women treated with bisphosphonates, denosumab, or teriparatide was highest in age group 70-79 years at 23.7%. The incidence of hip fractures increases sharply over 80 years of age in both genders. CONCLUSION: Our findings suggested that osteoporosis treatment should be initiated in younger age, especially in men, in order to avoid osteoporotic fractures in Japan.

Liver dysfunction in anti-melanoma differentiation-associated gene 5 antibody-positive patients with dermatomyositis.

The objective was to investigate the clinical and histological features of liver dysfunction in patients with polymyositis (PM) or dermatomyositis (DM).A total of 115 patients (38 with PM and 77 with DM), who were admitted to our hospital between 2001 and 2012, were retrospectively reviewed. Liver dysfunction was defined as an alanine transaminase (ALT) level ≥ 60 U/l and a disproportionate ALT elevation relative to the creatine kinase level. The histological findings from liver biopsies were also assessed.The frequencies of liver dysfunction were 3% and 17% in the patients with PM and DM, respectively. Liver dysfunction was not observed in the patients who had malignancies. Among the patients with DM with no malignancies (n = 50), 20% had liver dysfunction, and all of the patients with liver dysfunction were positive for the anti-melanoma differentiation-associated gene 5 (MDA5) antibody. Compared with those in the patients who did not have liver dysfunction, the ALT, alkaline phosphatase, γ-glutamyl transferase, and KL-6 levels were significantly elevated in the patients who had liver dysfunction. Six patients, comprising four with DM and two with PM, underwent liver biopsies, and the common histological findings associated with DM were steatosis, hepatocyte ballooning, increases in the pigmented macrophage numbers, and glycogenated nuclei. Hemophagocytosis was detected in two of three patients with DM who underwent liver biopsies and bone marrow aspirations. In conclusion, Liver dysfunction might be an extramuscular manifestation in patients with DM who are anti-MDA5 antibody-positive. Steatosis and hepatocyte ballooning could be common histological features.

Wide difference in biologics usage and expenditure for the treatment of patients with rheumatoid arthritis in each prefecture in Japan analyzed using "National Database of Health Insurance Claims and Specific Health Checkups of Japan".

To analyze the biologics usage and expenditure for the treatment of patients with rheumatoid arthritis (RA) in each prefecture throughout Japan using the national open database, the Ministry of Health, Labour and Welfare of Japan disclosed; in Oct 2016, the data of the top 30 most-frequently prescribed drugs during a 1-year period from April 2014 to March 2015 in each prefecture in Japan, along with the patients' age and sex. Seldom-used drugs were excluded. We picked up only biologics for the present study. The total expenditure on biologics used in each prefecture was correlated with the population thereof. However, there was a big difference, up to ~ twofold, in the average expenditure used for an RA patient: highest in Toyama and lowest in Wakayama. There was also a big difference, ~ 4.5-fold, in the number of rheumatologists/1000 RA patients, highest in Kyoto and lowest in Aomori. The average expenditure used for an RA patient was correlated with the number of rheumatologists in the western part of Japan. Etanercept seemed to be used most frequently to Japanese RA patients followed closely by infliximab. Abatacept was used more frequently to the elderly than other biologics. There was a big difference in the number of rheumatologists and expenditure on biologics for the treatment of an RA patient among prefectures in fiscal 2014. Factors that brought this unevenness need to be scrutinized for universal implementation of good RA care throughout Japan, where there are uniform health insurance system and free access to rheumatologists.

Case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon with a novel mutation in the SLC29A3 gene.

We describe a case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon. A 48-year-old man with parents of a consanguineous marriage, first appeared with decreased urine output, skin sclerosis on his inner thighs and short stature (142 cm, 47 kg). The patient had suffered from hearing loss since the age of 1 year, and his secondary sexual characteristics had not developed. Computed tomography showed periaortic fibrosis, bilateral ureteral stenosis, hydronephrosis and sclerosis of the germinal cords. A biopsy from the retroperitoneal mass revealed remarkable fibrosis with chronic inflammatory cells. Biopsies from the skin lesion showed thick collagen bundles through the dermis and lymphohistiocytic infiltration with numerous plasma cells. Serum inflammatory markers, such as C-reactive protein, vascular endothelial factor, transforming growth factor-ß and soluble interleukin-2 receptor, were elevated. Prednisolone was effective in treating skin lesions and in lowering serum inflammatory markers. After a long period of follow up, genomic DNA of the patient was obtained, and we identified a homozygous mutation in exon 5, c.625G>A, which caused transition of glycine to arginine, p.Gly208Arg, in the patient, but not in DNA samples from another 50 healthy individuals. This is the first case of H syndrome with Raynaud's phenomenon and retroperitoneal fibrosis, and the first Japanese case of H syndrome reported in the English published work with a novel mutation in the SLC29A3 gene.

Effects of phosphodiesterase type 5 inhibitors on Raynaud's phenomenon.

Raynaud's phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 °C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 °C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs.

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.

Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1ß signaling and a poor clinical response.

Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1ß. IL-1ß increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1ß might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.

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.