Perihepatitis as an Initial Manifestation of Systemic Lupus Erythematosus.

A 25-year-old man presented with a fever and right upper quadrant abdominal pain. Computed tomography (CT) of the abdomen revealed diffuse perihepatic capsular enhancement, suggesting perihepatitis. Although the patient was a man, Fitz-Hugh-Curtis syndrome was suspected based on the CT findings. Treatment with several antibiotics was ineffective. Urinary tract infection was ruled out due to negative urinary bacterial screening and careful history taking. He was finally diagnosed with systemic lupus erythematous (malar rash, pleuritis, positive antinuclear antibody, and positive anti-ds-DNA antibody). Perihepatitis resolved quickly with high-dose prednisolone. Perihepatitis may be the first manifestation of SLE.

Essentiality of Nfatc1 short isoform in osteoclast differentiation and its self-regulation.

During osteoclast differentiation, the expression of the transcription factor nuclear factor of activated T cell 1 (Nfatc1) increases in an autoproliferative manner. Nfatc1 isoforms are of three sizes, and only the short isoform increases during osteoclast differentiation. Genetic ablation of the whole Nfatc1 gene demonstrated that it is essential for osteoclastogenesis; however, the specific role of the Nfatc1 short form (Nfatc1/αA) remains unknown. In this study, we engineered Nfatc1 short form-specific knockout mice and found that these mice died in utero by day 13.5. We developed a novel osteoclast culture system in which hematopoietic stem cells were cultured, proliferated, and then differentiated into osteoclasts in vitro. Using this system, we show that the Nfatc1/αA isoform is essential for osteoclastogenesis and is responsible for the expression of various osteoclast markers, the Nfatc1 short form itself, and Nfatc1 regulators.

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.

Transition from epoprostenol to selexipag in a patient with systemic sclerosis and pulmonary hypertension during the postoperative period of colon cancer surgery: A case report.

Introduction: Most pulmonary vasodilators are administered orally; however, in patients with pulmonary hypertension undergoing gastrointestinal surgery, a switch to parenteral drugs is needed. Parenteral pulmonary vasodilators carry a risk of infection and reduced quality of life owing to long-term central venous catheterization; therefore, it is preferable to switch them to oral vasodilators after surgery. Here, we present the case of a patient with systemic sclerosis complicated by pulmonary hypertension and colon cancer, for which treatment was successfully switched from epoprostenol to selexipag postoperatively. Case Description: A 59-year-old woman, who was diagnosed with mixed group I and III pulmonary hypertension and systemic sclerosis, was on oral triple pulmonary vasodilators for pulmonary hypertension and Raynaud's phenomenon. She was diagnosed as having colon cancer 3 months before admission. Despite the severe pulmonary condition and treatment with oral triple pulmonary vasodilators, colon cancer resection surgery was performed with the management for pulmonary hypertension through multidisciplinary treatments in collaboration with cardiology specialists. Medications for patients with pulmonary hypertension undergoing gastrointestinal surgery need to be switched from oral vasodilators to epoprostenol perioperatively. On postoperative day 19, 0.4 mg/day of selexipag was administered with epoprostenol. Subsequently, the epoprostenol dosage was gradually decreased, and selexipag was increased. On postoperative day 30, the dose of selexipag was increased to 1.2 mg/day and epoprostenol was discontinued. The patient was discharged on postoperative day 40. Conclusion: In our case, transition from epoprostenol to selexipag contributed to a more useful management strategy for systemic sclerosis and pulmonary hypertension in the postoperative period.

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.

Course of insight, depression and suicidality in inpatients with first-episode schizophrenia who received group psychoeducation.

AIM: We aimed to investigate whether gaining insight through psychoeducation for first-episode schizophrenia is associated with increased suicidality. METHODS: We conducted a secondary analysis of a prospective cohort study that included inpatients with first-episode schizophrenia who attended a group psychoeducation program during their admission. The group psychoeducation program consisted of four weekly sessions provided by a multidisciplinary team. The primary outcome was the correlation between changes in insight and suicidality. We also examined whether change in insight was associated with changes in hopelessness and depression. We measured insight using the Birchwood Insight Scale. Suicidality, hopelessness and depression were measured using the Calgary Depression Rating Scale for Schizophrenia. RESULTS: A total of 125 people participated in the educational program. The Spearman's correlation coefficient between changes in insight and suicidality was -0.14 (95% confidence interval, -0.31 to 0.04; p = .12). Similarly, gain in insight did not significantly correlate with change in depression (0.01, 95% confidence interval, -0.17 to 0.18; p = .93) and change in hopelessness (0.01, 95% confidence interval, -0.16 to 0.19; p = .88). CONCLUSIONS: We observed almost no association between gaining insight and suicidality after a group psychoeducation program in inpatients with first-episode schizophrenia.

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.

Dual effects of interleukin-10 on natural killer cells and monocytes and the implications for adult-onset Still's disease.

OBJECTIVES: We compared the serum levels of multiple cytokines in patients with adult-onset Still's disease (AOSD) and healthy controls to assess the effects of humoral factors on natural killer (NK) cells and monocytes. METHODS: We quantified the serum levels of 10 cytokines in the patients using bead-based multiplex immunoassays, along with interleukin (IL-)18 using ELISA. We then sorted NK cells and monocytes from the peripheral blood mononuclear cells (PBMCs) of healthy volunteers, cultured them in the presence or absence of cytokines that were detected in some or all of the serum samples from the AOSD patients and their combinations in vitro, and analysed the culture supernatant. RESULTS: IL-6 and IL-18 were the main cytokines increased in the serum of AOSD patients. When NK cells were cultured with the cytokines and IL-10, the combination of IL-10 and IL-18 substantially induced interferon (IFN-)γ. IL-6 had little effect on NK cells, probably because they barely expressed the IL-6 receptor and glycoprotein 130 (gp130). IFN-γ induced monocytes to produce IL-1ß, IL-6 and tumour necrosis factor (TNF-)α whereas IL-10 inhibited the induction of these proinflammatory cytokines. CONCLUSIONS: IL-10 evidently has dual effects on NK cells (stimulation) and on monocytes (inhibition). Better understanding the roles of the cytokine network would shed light on the pathogenesis of AOSD.

Characterization and Function of Tumor Necrosis Factor and Interleukin-6-Induced Osteoclasts in Rheumatoid Arthritis.

OBJECTIVE: We have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. METHODS: Peripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined. RESULTS: Peripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1ß, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. CONCLUSION: Our results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

Treatment of psoriatic arthritis complicated by systemic lupus erythematosus with the IL-17 blocker secukinumab and an analysis of the serum cytokine profile.

Psoriasis is a chronic disease of the skin that often affects the joints (psoriatic arthritis, PsA). Biologic agents such as TNF-α, IL-23 and IL-17 blockers have been proven to be quite effective against psoriasis and PsA, indicating the importance of those cytokines in the pathogenesis of the diseases. The importance of the IL-23/IL-17 axis has also been reported in systemic lupus erythematosus (SLE), but the safety and effectiveness of IL-17 blockers in SLE remain largely unknown. We encountered a patient with PsA and SLE. We treated him with an IL-17 blocker, secukinumab, and quantified the serum levels of various cytokines before and after the initiation of secukinumab therapy. As expected, the treatment was effective against the symptoms of PsA. No serious adverse events were observed in terms of SLE. Interestingly, serum IL-6 was substantially decreased after the initiation of therapy, whereas serum IL-17 was under the detection limit. These data indicate that IL-17 is produced locally, upstream of IL-6 production.

Risk factors correlated with immunosuppressant discontinuation in antineutrophil cytoplasmic antibody-associated vasculitis patients.

AIM: The use of an immunosuppressant is recommended as a treatment for remission induction in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the immunosuppressant is sometimes discontinued due to an adverse event. We sought to identify the cause and risk factors for immunosuppressant discontinuation in patients with AAV receiving remission induction treatment. METHODS: We retrospectively analyzed the cases of AAV patients treated in 2005-2016 with immunosuppressants to induce remission. We defined "discontinuation" as stopping, switching, or delaying immunosuppressant administration due to adverse events. We performed a multivariate analysis to identify risk factors for immunosuppressant discontinuation. RESULTS: We identified 50 patients treated with an immunosuppressant for remission induction: cyclophosphamide was used in 45 patients (90%), methotrexate in 4 (8%), and cyclosporine A in 1 patient (2%). Among them, 26 patients (52%) underwent discontinuation of the immunosuppressant. Infection and myelosuppression were the major causes of discontinuation. Multivariate Cox proportional hazards regression analysis revealed that a cumulative dose of prednisolone ≥ 2000 mg (hazard ratio [HR] =2.18, 95% confidence interval [CI] =1.37-3.70, P < .001), performance status of 3-4 (HR = 1.80, 95% CI = 1.07-3.03, P = .027), and oral cyclophosphamide (HR = 1.81, 95% CI = 1.11-2.97, P = .018) were independent risk factors correlated with immunosuppressant discontinuation. CONCLUSION: Physicians should be aware of risk factors predicting immunosuppressant discontinuation when treating AAV patients with an immunosuppressant.

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.

A Non-smoking Woman with Anti-phospholipid Antibodies Proved to Have Thromboangiitis Obliterans.

A 48-year-old woman with severe pain and numbness of her right leg and foot was admitted to our hospital. She had never smoked and had little exposure to passive smoking. Initially, polyarteritis nodosa with anti-phospholipid antibodies was considered. Combination therapy with methylprednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, vasodilators, antiplatelet agents, and anticoagulants was not effective. Vasculopathy was progressive, and she presented with gangrene of the toes. She required amputation of her right leg. The pathological findings of the amputated leg revealed thromboangiitis obliterans (TAO). TAO should be considered even in non-smoking women. Non-response to immunosuppressant and anticoagulant therapies may be a clue to the diagnosis of TAO.

Change in smoking cessation stage over 1 year in patients with schizophrenia: a follow up study in Japan.

BACKGROUND: We performed a follow up study about willingness and behaviors to quit smoking among smokers with schizophrenia in Japan. METHODS: Participants were outpatients with schizophrenia aged 20-69 years who had been visiting the hospital for ≥1 year as of April 1, 2016, and had visited the hospital more than once in the previous 6 months. A baseline survey on smoking behaviors including current smoking status and smoking cessation stage, was administered in 420 participants that were randomly extracted from a patient pool (n = 680) in 2016, and a follow-up survey was administered in 2017. We calculated the distribution and change in smoking cessation stage, number of smokers and nonsmokers after 1 year, and quitting rate from a naturalistic 1-year smoking-cessation follow up. RESULTS: The number of baseline respondents was 350; 113 current smokers and 68 former smokers. Among the 113 current smokers, 104 (92.0%) were followed for 1 year, 79 (70.0%) were interested in smoking cessation, and only 7 had received smoking cessation treatments at baseline. Among the tracked 104 participants, only 6 (5.8%) stopped smoking after 1 year. Among the 25 participants who had intentions to quit smoking within 6 months at baseline, 6 (24.0%) maintained their intention to quit smoking for 1 year, and 16 (64.0%) did not maintain their intention to quit smoking. CONCLUSIONS: Our findings showed that many smokers with schizophrenia were interested in quitting smoking, but few patients received treatment and actually quit smoking. Timely intervention, including the option to receive smoking cessation treatment, is necessary for those patients with schizophrenia who smoke. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000023874, registered on August 31, 2016).

Osteomyelitis due to methicillin-resistant Staphylococcus aureus successfully treated by an oral combination of minocycline and trimethoprim-sulfamethoxazole.

Most of the anti-methicillin-resistant Staphylococcus aureus drugs available in Japan are administered intravenously, except for linezolid, which can also be administered orally. Here, we report a lupus patient with methicillin-resistant S. aureus-induced osteomyelitis. Linezolid had to be stopped due to severe anemia. In an effort to treat her on an outpatient basis, we planned to use a combination of minocycline and trimethoprim-sulfamethoxazole that exhibited in vitro sensitivity against the methicillin-resistant S. aureus detected, and rifampicin is used against methicillin-resistant S. aureus in certain cases. The use of rifampicin increased the level of C-reactive protein even though the prednisolone dose used was doubled, so we gave up using it. The combined application of oral minocycline and trimethoprim-sulfamethoxazole, however, controlled the inflammation, and the patient was able to be discharged. Fourteen months later, we discontinued the administration of both drugs and there has been no relapse more than a year. This combination of antibiotics may be useful, especially when patients want to be treated on an outpatient basis.

Predictors of remission during acute treatment of first-episode schizophrenia patients involuntarily hospitalized and treated with algorithm-based pharmacotherapy: Secondary analysis of an observational study.

AIM: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy. METHODS: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge. RESULTS: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge. CONCLUSIONS: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted.

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study.

RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

Algorithm-based pharmacotherapy for first-episode schizophrenia involuntarily hospitalized: A retrospective analysis of real-world practice.

BACKGROUND: Little is known about the clinical outcomes of severely ill patients with first-episode schizophrenia spectrum disorders (FES) who are considered to lack the capacity to consent to clinical trials. We investigated the feasibility of an algorithm-based pharmacotherapy (ABP) and clinical outcomes of patients with FES involuntarily hospitalized and treated with ABP. METHODS: We conducted a retrospective chart review of 160 patients admitted involuntarily between October 2012 and October 2015. Our algorithm aimed to delay olanzapine, standardize medications and suggest initiation of clozapine after failure (non-response or intolerability) of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at optimal dosage was 4 weeks or more. RESULTS: The physician adherence rate to ABP was 95%. Response and remission rates were 76.0% and 48.6% in the first adequate antipsychotic trial (Phase I, n = 146), 62.5% and 25.0% in the second adequate antipsychotic trial (Phase II, n = 32), and 16.7% and 0% in the third adequate antipsychotic trial (Phase III, n = 6). Response and remission rates in the clozapine trial (n = 9) increased to nearly the level of Phase I (66.7% and 44.4%). The treatment-resistance rate was 8.4% to 10.3%. CONCLUSIONS: These findings suggested the validity of ABP and initiation of clozapine for treatment-resistant psychotic symptoms for even severely ill involuntarily hospitalized patients with FES.

Changes in the pattern of cytokine production from peripheral blood mononuclear cells in patients with rheumatoid arthritis treated with infliximab and their relation to plasma arginase activity.

AIM: The aim of this study was to quantify the production of T-cell cytokines from the peripheral blood mononuclear cells (PBMCs) of RA patients before and after treatment with anti-tumor necrosis factor (TNF)-α infliximab (IFX). METHOD: We stimulated the PBMCs of RA patients (n = 24) in vitro and quantified the cytokines in the culture supernatant using enzyme-linked immunosorbent assay. RESULTS: Unexpectedly, the cytokines tested, interferon (IFN)-γ, interleukin (IL)-4 and IL-17, were all found to have increased, rather than decreased, after the treatment. When the patients were divided into two groups according to the plasma activity of arginase, which is implicated in the immune-suppressive function of myeloid-derived suppressor cells, the substantial increase in the cytokine production ex vivo was only detected in the group in which the arginase activity was decreased after the treatment with IFX. In fact, although the ex vivo production of IL-21 increased along with the other cytokines, the plasma concentration of IL-21 decreased significantly after IFX treatment. CONCLUSION: It is important to exercise caution in interpreting ex vivo cytokine production data, in that they can be negatively influenced by the immune-suppressive mechanisms that prevent excessive inflammation. Thus, to analyze the T-cell response accurately, T-cell markers that are detectable in the serum or plasma need to be discovered. The concentrations of IFN-γ, IL-4 and IL-17 were all below detection limits, but that of IL-21 was detectable in the plasma and inversely correlated with the production of IL-21 ex vivo. This may indicate the involvement of Th17 response in the pathogenesis of RA.