Association of Baseline Serum Soluble Tumour Necrosis Factor Receptor Levels with the Response of Rheumatoid Arthritis to Janus Kinase Inhibitor Therapy.

Aim: The aim of this study was to investigate whether cytokines associated with tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 signalling could predict rheumatoid arthritis (RA) clinical remission (CR) with Janus kinase inhibitor (JAKinib) treatment using the Simplified Disease Activity Index (SDAI). Methods: Eighty-nine patients with RA treated with JAKinibs were enrolled, and their clinical data were collected retrospectively. CR was defined as an SDAI ≤ 3.3 after 6 months of treatment with JAKinib. The serum samples of 89 patients were analysed for IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (spg130), and soluble TNF receptor- (sTNFR-) I and sTNFR-II titres. Results: There were no significant differences in the baseline clinical parameters between the CR and non-CR groups. Serum levels of IL-6, sIL-6R, and sgp130 were not significantly different; whereas, the serum sTNFR-I and sTNFR-II levels were significantly lower in the CR group. Univariate and multivariate logistic regression analysis showed that the baseline log sTNFR II values (OR: 0.002; p = 0.034) were predictors of CR. Conclusions: Patients with RA can be stratified prior to JAKinib administration using serum sTNFR-I and sTNFR-II levels but not serum IL-6 axis cytokine levels (IL-6, sIL-6R, and sgp130).

Involvement of YKL-40-positive macrophages commonly identified in polymyositis and dermatomyositis in the pathogenesis of myositis: a retrospective study.

YKL-40 is implicated in inflammation and tissue repair, but no reports have investigated its involvement in myositis in polymyositis (PM) and dermatomyositis (DM). Therefore, we aimed to investigate the relationship between YKL-40 and PM/DM. We retrospectively enrolled 35 patients diagnosed with PM/DM along with 26 healthy controls (HCs). Both PM and DM were diagnosed according to Bohan and Peter's criteria. Serum YKL-40 levels were measured, age-corrected to YKL-40 percentile values, and compared to HCs. Patients with myositis without interstitial lung disease were also enrolled and compared to HCs. Immunofluorescence staining was performed to identify YKL-40-positive inflammatory cells in muscle biopsy samples from two patients each with PM and DM. Age-corrected serum YKL-40 levels were significantly higher in patients with PM/DM compared to HCs with and without lung disease; however, these levels decreased significantly after treatment. Immunohistochemical analysis showed infiltration of YKL-40-positive inflammatory cells into the intramuscular sheath and perimuscular membrane. Immunofluorescence staining showed CD68 expression in YKL-40-positive inflammatory cells, suggesting that these cells were macrophages. To the best of our knowledge, this is the first study to demonstrate that YKL-40-positive macrophages are present in PM and DM, indicating that YKL-40 may be involved in PM/DM.

Quantitative bone SPECT/CT for evaluating treatment response in patient with sternoclavicular arthritis.

We report here a case of sternoclavicular arthritis due to SAPHO syndrome in a 60-year-old female in which quantitative values determined using bone SPECT/CT were useful to evaluate response. After celecoxib and alendronate sodium hydrate therapy, the chief complaints were well relieved and post-treatment Tc-99m HMDP bone SPECT/CT examination showed decreased uptake. The maximum standardized uptake value (SUV), peak SUV, mean SUV, metabolic bone volume, and total bone uptake of the untreated lesion were 18, 16, 10, 17 mL, and 180, respectively, which were decreased to 8, 7, 5, 15 mL, and 75, respectively, after the treatment. In comparison with pre-treatment situation, those parameters were decreased by -56%, -56%, -50%, -12%, and -58%, respectively, following celecoxib and alendronate sodium hydrate therapy, likely reflecting treatment response. Quantitative bone SPECT/CT may be useful to evaluate joint inflammatory activity and treatment response in a patient with osteoartritis.

Serum B cell activating factor (BAFF) as a biomarker for induction of remission with rituximab in ANCA-associated vasculitis.

We examined whether serum B cell activating factor (BAFF) is useful for predicting the remission of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) following rituximab treatment. We used the Birmingham Vasculitis Activity Score (BVAS) 2008 version 3 for the evaluation of 27 patients with AAV 6 months after rituximab treatment. Those with BVAS = 0 achieved remission, whereas those with BVAS score > 0 did not achieve remission. We considered changes in serum BAFF before rituximab treatment, 1 month after treatment, and 6 months after treatment. In the remission group, the serum BAFF increased consistently. In the non-achieved group, serum BAFF was within the normal range. In addition, there was no statistically significant difference between the two groups in terms of serum BAFF before and 1 month after rituximab treatment. However, the serum BAFF level at 6 months after rituximab treatment was significantly higher in the remission group than in the non-achieved group. If serum BAFF does not increase after 6 months of rituximab in AAV, it may be assumed that there are residual B cells and plasma cells in the tissues. Enhanced treatment targeting B cells, including re-administration of rituximab or the addition of other immunosuppressive drugs, should be considered.

Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis.

Background: Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV. Methods: We enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed. Results: Serum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion. Conclusion: cfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.

A retrospective analysis of 7 cases of familial mediterranean fever.

BACKGROUND: Familial mediterranean fever (FMF) is a single inherited autoinflammatory disease characterized by periodic fever with relatively short duration of 1 to 3 days and sterile serositis. Although the prevalence rate is highest in the Mediterranean coastal area, a large number of cases have been reported recently by genetic analysis by identification of MEFV (Mediterranean fever) which is responsible gene in Japan too. In outpatient department of rheumatology, diagnosis and treatment of FMF is performed in cases where fever and abdominal pain attack are repeated for a short period of time. PATIENTS AND METHODS: We examined cases in which symptoms considered periodic seizures were repeated, excluding autoimmune diseases, infectious diseases, and malignant tumors. In both cases, genetic analysis is performed as auxiliary diagnosis. RESULTS: Seven cases satisfied the Tel-Hashomer criteria criteria and MEFV gene mutation was detected. Everyone was a female, and half had seizure symptoms at menstruation. Even though there is a difference in the amount of colchicine to be used, either one is effective. CONCLUSION: In cases of periodic symptoms or cases called periodic fever, exclusion diagnosis is carried out, there is a need to suspect FMF, determine the effect of colchicine, and perform genetic analysis.

[A case of anti-PL-7 antibody positive polymyositis with thrombotic microangiopathy].

  A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.

Reliability and clinical utility of Enzyme-linked immunosorbent assay for detection of anti-aminoacyl-tRNA synthetase antibody.

Anti-aminoacyl-tRNA synthetase (ARS) antibody is one of the myositis-specific autoantibodies to make a diagnosis of polymyositis (PM) and dermatomyositis (DM). Recently a new enzyme-linked immunosorbent assay (ELISA) kit of concurrently detected anti-ARS antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ and anti-KS) have become to measure in the clinical setting. To evaluate the reliability of this ELISA kit, we measured anti-ARS antibodies in 75 PM and DM patients using by this ELISA assay and compared them with the results by RNA immunoprecipitation assay. Between the measurements of anti-PL-7, anti-PL-12, anti-EJ and anti-KS autoantibodies by ELISA assay and RNA-IP assay, the concordance rate of reproducibility is 95.1% and the positive agreement rate is 90.9% and negative agreement rate is 96.0% and kappa statistic is 0.841. Between the measurements of existing anti-Jo-1 antibody ELISA kit and anti-ARS antibody ELISA kit, the concordance rate of reproducibility is 96.9%, the positive agreement rate is 100%, negative agreement rate is 96.1% and kappa statistic is 0.909. The lung involvement in patients with PM and DM patients are positive of anti-ARS antibodies and anti-melanoma differentiation associated gene5 (MDA5) antibody at a rate around 70%. Then most life-threatening ILD with anti-MDA5 positive clinically amyopathic dermatomyositis patients could be highly guessed when anti-ARS antibodies are negative.

A case of anti-aminoacyl tRNA synthetase antibody syndrome complicated by hemophagocytic syndrome.

A 48-year-old woman had suffered from a fever and general fatigue, and visited the other hospital for fever elevation in November 2013, at which time interstitial lung disease was revealed. In January 2014, she experienced an eruption in the hand and developed peripheral blood flow damage. Under a diagnosis of adult Still's disease, the patient was administered 0.5 mg of betamethasone as well as cyclosporin at 75 mg/day. In November 2014, general fatigue, fever, and headache were noted, while MRI revealed an enlarged hypophysis and laboratory findings were positive for the anti-pituitary cell antibody, thus a diagnosis of autoimmune hypophysitis was made. Although disease activity was low, she requested hospitalization and was admitted by the Division of Endocrinology and Metabolism at our hospital in May 2015, though only observed. Fever developed again, along with interstitial lung disease, Raynaud's phenomenon, and pain in the crural area again, and we considered the possibility of another disease. After stopping administration of betamethasone and cyclosporin, we made a diagnosis of anti-aminoacyl tRNA synthetase antibody syndrome, and administered methylprednisolone at 500 mg for 3 days as well as prednisolone at 35 mg/day following steroid pulse therapy. Although her condition soon improved, fever, muscle pain, and pancytopenia returned after 3 days. Bone marrow findings revealed the existence of hemophagocytosis, for which we again gave methylprednisolone at 500 mg for 3 days and cyclosporin at 125 mg/day. Thereafter, the patient recovered and was discharged from the hospital.

Marked efficacy of adalimumab for secondary gastrointestinal amyloidosis accompanied with ankylosing spondylitis.

A 39-year-old man with seronegative rheumatoid arthritis which was refractory to methotrexate and prednisolone therapy complained of epigastralgia, melena and diarrhea. Diffuse mucosal damage was observed on endoscopic examination, and histological findings of the gastric and colonal mucosa showed AA type amyloidosis. He was diagnosed with ankylosing spondylitis (AS) on the basis of the clinical feature such as the limitation in range of motion of lumber spine, and sacroiliitis on MR imaging. Although digestive symptom ameliorated by fasting and antibiotic therapy, laboratory findings continued to reveal an elevation of serum C-reactive protein (CRP) value and arthritis worsened. However, after the initiation of the treatment with adalimumab (ADA), not only his manifestation but also serum levels of CRP became normalized promptly. As far as we could evaluated, follow-up colonoscopic examination showed normal mucosal findings and histologic examination proved that amyloid protein disappeared. Secondary gastrointestinal amyloidosis is ralely associated with AS. Therefore standard therapy is not established. This case might indicate an efficacy of ADA for secondary gastrointestinal amyloidosis accompanied with AS.

[Hypereosinophilic syndrome accompanied with digital gangrene: efficacy of therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantaion].

A 62-year-old-man presented to our hospital with complaints of coldness, numbness, pain, weakness and cyanosis on the fingers and toes in March 2010. Laboratory findings revealed marked eosinophilia (46.6%; WBC 20600/µl), an elevation of serum creatine kinase, proteinuria and hematuria. He was diagnosed as hypereosinophilic syndrome (HES) without evidence to support a diagnosis of underlying diseases causing eosinophilia. After the initiation of corticosteroid therapy, peripheral eosinophil count was dramatically decreased, and both serum CK value and urinary findings became normalized. However, his symptoms persisted and digital necrotic changes developed. Angiography of the bilateral upper and lower extremities showed multiple arterial occlusions with poor collaterals. The digital gangrenes were unresponsive to peripheral circulation ameliorators and gradually progressed. In July 2010, autologous transplantation of bone marrow mononuclear cells was performed for achievement of therapeutic angiogenesis. His digital skin color was ameliorated by the angiogenic therapy in two weeks, and digital gangrenes did not progress after that. After amputation of his fingers and toe, cut surfaces healed with favorable epithelization, and the symptoms were subsequently eliminated. Moreover, during three years after the therapy, as well as the effect on the skin lesion, the significant improvement in peripheral circulation was observed. Therefore, we proposed that therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantation was a novel and effective treatment for intractable digital gangrene associated with HES.

Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-κB ligand (RANKL) expression in rheumatoid arthritis.

Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-κB ligand (RANKL) in RA synoviocytes and CD4(+) T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4(+) T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4(+) T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-α in MH7A cells and CD4(+) T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4(+) T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

[Marked efficacy of metronidazole for the intestinal pseudoobstruction associated with systemic sclerosis].

In May 2009, a 57-year-old woman who had rheumatoid arthritis since 9 years was admitted to our hospital for dyspnea due to interstitial pneumonia (IP). On admission, she exhibited proximal scleroderma, finger edema, Raynaud's phenomenon, digital pitting scars, ankyloglossia, and esophageal dysmotility. The patient was diagnosed as having systemic sclerosis (SSc), according to the American College of Rheumatology criteria. After initiation of high-dose corticosteroid therapy, gradual amelioration of IP was observed. However, the patient complained of abdominal fullness. Computed tomography and intestine series findings revealed significant dilatation of the small intestine due to intra-abdominal free air and pneumatosis cystoides intestinalis but no mechanical obstruction, leading to a diagnosis of SSc with pseudo-obstruction. The patient underwent decompression with a long intestinal tube, which led to improvement in her symptoms. Although erythromycin (EM) and some prokinetic agents were administered, abdominal involvement recurred several days after resumption of oral ingestion. Therefore, we changed the antibiotic from EM to metronidazole (750 mg/day). Her manifestations were promptly ameliorated by metronidazole therapy in 4 days and did not recur. Metronidazole is an antibiotic used to treat intra-abdominal anaerobic bacterial infections and is also commonly used in preoperative treatment for colorectal surgery. In conclusion, we report a case where SSc-associated pseudo-obstruction was successfully managed by metronidazole therapy.

[Tuberculous peritonitis during etanercept therapy for rheumatoid arthritis].

In August 2010, a 73-year-old woman with rheumatoid arthritis receiving etanercept (ETN) therapy for two years, developed high-fever and abdominal fullness. Though she had not been exposed to tuberculosis, isoniazid prophylaxis was administrated. Antibiotics were not effective. CT images revealed the massive ascites and peritonitis, and Ga scintigraphy demonstrated notable uptake in the peritoneum. Ascites analysis showed an elevated adenosine deaminase activity value (104.9 IU/l) without malignant cells. Moreover, PCR and culture for Mycobacterium tuberculosis were positive. Finally, a diagnosis of tuberculous peritonitis was established. After initiating a standard anti-tuberculosis regimen with four drugs, her clinical condition ameliorated and ascites promptly regressed. Although the tuberculous peritonitis during ETN therapy is rare, this report emphasized the importance of initial suspicion of tuberculosis in these patients with tumor necrosis factor inhibitors such as ETN.

[Cutaneous necrotizing vasculitis in a patient with Behcet's disease; mimicking polyarteritis nodosa].

A 25-year-old-man was referred with an approximately 1-year history of recurrent fever, tonsillitis, testicular pain and testicular swelling in June 2009. He also complained of visual disturbance, some erythema nodosum (EN) like lesions on his lower extremities and oral aphthous ulcerations for 5 months. Opthalmological consultation confirmed retinochoroiditis, and ultrasonography revealed epididymitis. A biopsy of the EN like lesion showed a necrotizing vasculitis of the small and medium-sized vessels with septal panniculitis in the subcutis. The laboratory findings revealed an elevation of CRP and positive HLA-B51. He was diagnosed with incomplete Behcet's disease according to the Japanese criteria (1987). After the initiation of the therapy with 10 mg/day of prednisolone, his symptoms promptly ameliorated. In our case, although epididymitis as well as the histopathological findings suggested polyarteritis nodosa (PN), a diagnosis of BD was established on the basis of other contemporaneous findings. Necrotizing vasculitis as a cutaneous manifestation in patients with BD has been rarely reported. However, BD and PN, including cutaneous PN, have rarely described in conjunction. Therefore, we propose that PN-like necrotizing vasculitis might be the subtype of BD.

Mizoribine protects against bleomycin-induced lung injury.

Bleomycin (BLM)-induced lung injury has become a model for studies of interstitial pneumonitis and pulmonary fibrosis. BLM induces lung injury in two phases: early inflammation characterized by infiltration of inflammatory cells into the lungs, followed by a late phase of fibrosis characterized by deposition of collagen. In this study, we examined the role of mizoribine (MZB) in the regulation of inflammatory tissue injury caused by BLM. We examined the role of MZB using a mouse model of BLM-induced lung injury. We demonstrated that mice subjected to instillation of BLM into the lungs had a significantly increased number of macrophages and lymphocytes in bronchoalveolar lavage fluid (BALF), but that those treated with MZB in the early phase showed a significant reduction in the total number of BALF macrophages and lymphocytes. However, MZB was unable to inhibit fibrosis in the late phase of BLM injury. Our findings suggest that MZB inhibits the proliferation of both lymphocytes and macrophages in the early phase of the BLM-induced acute inflammatory response, as well as its development and amplification, but does not inhibit fibrotic change in the late phase.

M-protein-positive chronic active Epstein-Barr virus infection: features mimicking HIV-1 infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a unique and fatal lymphoproliferative disease (LPD), which often shows high serum IgG and/or IgE. The significance of such immunoglobulin abnormalities in CAEBV has not been fully evaluated and discussed. In addition, such clinical features mimic HIV-1 infection. We report here a case of CAEBV with M-protein detected which may shed a new light on the pathogenesis of this disease.

[A case of Achilles tendon rupture in a patient of refractory Reiter's syndrome].

We herein report a case of spontaneous rupture of Achilles tendon in a 51-year-old man with refractory Reiter's syndrome. On the diagnosis in November, 2006, physical examinations and MR images showed a remarkable inflammation at the calcaneal insertion area of Achilles tendon. He required aggressive treatments with nonsteroidal anti-inflammatory drug (NSAID), oral prednisolone 30 mg daily and methotrexate (8 mg weekly) to control the disease. Two months later, the Achilles tendon ruptured at its insertion point. This ruptured lesion of Achilles tendon was an unusual site compared to previous reports. Histological findings in the ruptured lesion of Achilles tendon revealed the existence of granulomatous lesion consisted of severe infiltration of fibroblasts and vessels proliferation beside tendon. These findings suggest a prolonged inflammation. Although it is widely accepted that Reiter's syndrome is associated with enthesis, especially at the attachment of Achilles tendon to calcaneum, there have been only two reports of Achilles tendon rupture associated with Reiter's syndrome. The possible cause of the Achilles tendon rupture in this patient might be due to the weakened strength of the Achilles tendon by the prolonged and severe enthesis of Achilles tendon near the insertion lesion.

A case of granuloma in the occipital lobe of a patient with Wegener's granulomatosis.

We report a case of Wegener's granulomatosis (WG) with central nervous system (CNS) involvement in a woman who complained of bilateral visual disturbance. The intracranial necrotizing granulomatous lesion was confirmed by MR imaging and brain biopsy. After high-dose oral corticosteroid treatment, not only clinical manifestations but also laboratory tests improved. Moreover, the CNS lesion completely regressed. This suggests that high-dose corticosteroid alone might be effective in treating WG with CNS involvement.