Treatment with low-dose nintedanib and tacrolimus in patients with progressive fibrosing interstitial lung diseases with anti-ARS antibody-positive dermatomyositis.

Nintedanib has been demonstrated to inhibit the rate of forced vital capacity decline in patients with progressive fibrosing interstitial lung diseases (PF-ILD) at a dose of 200 or 300 mg/day in the INBUILD trial. Although concomitant use of nintedanib with P-glycoprotein inhibitors reportedly increases the plasma concentrations of the former, tacrolimus, a P-glycoprotein inhibitor, is often used to treat connective tissue diseases-related interstitial lung diseases. The optimal dose of nintedanib in combination with tacrolimus for the treatment of PF-ILD with connective tissue disease is unknown. We herein present two patients with PF-ILD with anti-aminoacyl-tRNA synthetase antibody-positive dermatomyositis who were successfully treated with low-dose nintedanib (<200 mg/day) in combination with tacrolimus.

Human granulocytic anaplasmosis with rash and rhabdomyolysis: A case report.

Human granulocytic anaplasmosis (HGA) is a tick-borne infection caused by Anaplasma phagocytophilum. Only seven cases of HGA have been reported in Japan to date. We report the case of a 61-year-old female farmer who developed HGA with rash and rhabdomyolysis. The patient had fever and erythema covering the entire body, including the palms. An induration with an eschar was observed on the right leg, indicating that the patient had been bitten by a tick. Elevated serum creatinine and creatinine kinase levels and hematuria indicated rhabdomyolysis. We suspected Japanese spotted fever, a tick-borne illness caused by Rickettsia Japonica, and administered minocycline and ciprofloxacin for a week. Transient neutropenia and thrombocytopenia were observed, but the symptoms improved. Polymerase chain reaction (PCR) and antibody tests for R. japonica and Orientia tsutsugamushi, which causes scrub typhus, were both negative. The PCR test for severe fever with thrombocytopenia syndrome virus was also negative. Antibodies against A. phagocytophilum-related proteins were detected by western blotting, indicating seroconversion of IgG with paired serum samples, and the patient was diagnosed with HGA. HGA should be suspected in acute febrile patients with a history of outdoor activity and cytopenia, with or without a rash. A testing system and the accumulation of cases in Japan are necessary for the early diagnosis and appropriate treatment of HGA.

Differences in muscle magnetic resonance imaging findings between anti-signal recognition particle antibody-positive myopathy and anti-aminoacyl-tRNA synthetase antibody-positive myositis.

OBJECTIVES: To compare the findings of muscle magnetic resonance imaging (MRI) between anti-signal recognition particle antibody-positive myopathy (anti-SRP myopathy) and anti-aminoacyl-tRNA synthetase antibody-positive myositis (anti-ARS myositis). METHODS: Of the patients newly diagnosed with polymyositis (PM)/dermatomyositis (DM) and immune-mediated necrotising myopathy (IMNM) admitted to our Department between April 2012 and December 2021, those who met the eligibility criteria of positive for anti-SRP or anti-ARS antibodies and thigh MRI at the time of diagnosis were included. We compared the lesion sites and MRI findings of the thigh muscles that were classified into oedema, fascial oedema, fatty replacement, and muscle atrophy between the three groups of anti-SRP myopathy, anti-Jo-1 antibody-positive myositis, and non-Jo-1 antibody-positive myositis. RESULTS: Of the 98 PM/DM and IMNM patients, five anti-SRP myopathy patients and 11 anti-Jo-1-positive and 22 non-Jo-1 antibody-positive patients with myositis were included. The SRP group showed significantly higher blood levels of myogenic enzymes such as serum creatinine kinase (CK) than the other groups (p=0.01). In thigh MRI findings, despite oedema in most cases in anti-SRP and anti-ARS groups, fascial oedema was identified only in the ARS group, frequently in Jo-1 positive patients in particular. Moreover, gluteus maximus muscle lesions occurred more frequently in the SRP group than in the ARS group (p=0.008). CONCLUSIONS: A comparison of thigh MRI between anti-SRP myopathy and anti-ARS myositis showed different findings and lesion sites reflecting the different pathophysiology that may contribute to their diagnosis.

Coronavirus disease 2019 in a patient with pulmonary fibrosis and emphysema: An autopsy report.

Various diseases (e.g., hypertension and diabetes) are risk factors for the exacerbation of coronavirus 2019 (COVID-19). Patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) tend to develop severe COVID-19. Patients with severe COVID-19 present with acute respiratory distress syndrome (ARDS), and many COVID-19-related ARDS survivors eventually develop fibrosis. However, the appropriate management of patients with COVID-19 and ILD and post-COVID-19 ILD remains unclear. Thus, a better understanding of the pathology that exacerbates COVID-19 in patients with ILD is needed. We report the autopsy results of a patient with COVID-19 and combined pulmonary fibrosis and emphysema, whose lung organization and fibrosis progressed after the acute phase of infection. Histopathological findings suggest that fatal pulmonary fibrosis persists after the negative conversion of SARS-CoV-2. Elucidating the cause of death by autopsy may help determine therapeutic strategies in patients with COVID-19 and ILD. Vaccination and early administration of anti-inflammatory drugs or antifibrotic agents may be crucial for preventing disease progression and fatal lung fibrosis. This report aims to clarify the histopathological features of COVID-19 in patients with ILD via autopsy and discuss treatment strategies.

HAS-Flow May Be an Adequate Method for Evaluating Human T-Cell Leukemia Virus Type 1 Infected Cells in Human T-Cell Leukemia Virus Type 1-Positive Rheumatoid Arthritis Patients Receiving Antirheumatic Therapies: A Retrospective Cross-Sectional Observation Study.

The study aims to assess the usefulness of human T-cell leukemia virus type 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow) as a monitoring method for adult T-cell leukemia (ATL) development in HTLV-1-positive patients with rheumatoid arthritis (RA) under treatment with antirheumatic therapies. A total of 13 HTLV-1-negative and 57 HTLV-1-positive RA patients participated in this study, which was used to collect clinical and laboratory data, including HAS-Flow and HTLV-1 proviral load (PVL), which were then compared between the two groups. CADM1 expression on CD4+ cells in peripheral blood (PB) was used to identify HTLV-1-infected cells. The population of CADM1+ CD4+ cells was significantly higher in HTLV-1-positive RA patients compared to HTLV-1-negative RA patients. The population of CADM1+ CD4+ cells was correlated with HTLV-1 PVL values. There were no antirheumatic therapies affecting both the expression of CADM1 on CD4+ cells and PVLs. Six HTLV-1-positive RA patients who indicated both high HTLV-1 PVL and a predominant pattern of CADM1+ CD7neg CD4+ cells in HAS-Flow can be classified as high-risk for ATL progression. HAS-Flow could be a useful method for monitoring high-risk HTLV-1-positive RA patients who are at risk of developing ATL during antirheumatic therapies.

Neuropsychiatric Systemic Lupus Erythematosus with Cerebral Vasculitis and Lupus Nephritis Successfully Treated with High-dose Glucocorticoids and Mycophenolate Mofetil.

Neuropsychiatric systemic lupus erythematosus (NPSLE) with cerebral vasculitis is rare, and its prognosis is unfavorable. High-dose glucocorticoids and cyclophosphamide are widely used for the treatment of NPSLE, but cyclophosphamide has a risk of cervical intraepithelial neoplasia and ovarian insufficiency, which may discourage its use in young women. We experienced a case of NPSLE with cerebral vasculitis and lupus nephritis that responded successfully to glucocorticoids and mycophenolate mofetil (MMF). MMF might be a treatment option for NPSLE without concern for reproductive toxicity. However, there are only a few reports on the efficacy of MMF in NPSLE, and further investigations are needed.

High incidence of serious infections requiring hospitalisation in human T-cell leukaemia virus type 1-positive rheumatoid arthritis: A case-controlled observational study.

OBJECTIVES: We aimed to assess the clinical features of human T-cell leukaemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. Furthermore, we investigated the impact of HTLV-1 infection on incidences of serious infections requiring hospitalisation (SIH) and malignancies. METHODS: A total of 150 sex- and age-matched HTLV-1-negative and 50 HTLV-1-positive RA patients were enrolled from the HTLV-1 RA Miyazaki Cohort Study. Clinical and laboratory data were collected from this cohort database. The incidence rate (IR) for SIH and malignancies from 2015 to 2020 was analysed. RESULTS: The median age and female ratio in the study population were 70 years old and 80%, respectively. Although no differences were found in inflammatory marker values between the two groups, the patient global assessment and Health Assessment Questionnaire scores were higher in HTLV-1-positive RA patients. In HTLV-1-negative RA patients, the IR for SIH was 6.37/100 person-years (PY) and 1.32/100 PY for malignancies. In HTLV-1-positive RA patients, SIH occurred in 11.1/100 PY and malignancies in 2.46/100 PY. The crude IR ratio comparing SIH between two groups was 1.74 (95% confidence interval, 1.04-2.84), which was a significant increase. CONCLUSIONS: HTLV-1-positive RA patients may worsen RA symptoms. HTLV-1 may be a risk factor for SIH.

Severe Fever with Thrombocytopenia Syndrome Accompanied by Invasive Pulmonary Aspergillosis: An Autopsy Case.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease in China, Korea, and Japan caused by the SFTS virus (SFTSV). SFTS has a high mortality rate due to multiorgan failure. Recently, there are several reports on SFTS patients with mycosis. Here, we report a middle-aged Japanese SFTS patient with invasive pulmonary aspergillosis (IPA) revealed by an autopsy. A 61-year-old man with hypertension working in forestry was bitten by a tick and developed fever, diarrhea, and anorexia in 2 days. On day 4, consciousness disorder was appearing, and the patient was transferred to the University of Miyazaki Hospital. A blood test showed leukocytopenia, thrombocytopenia, as well as elevated levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase. The SFTSV gene was detected in serum using a reverse-transcription polymerase chain reaction. On day 5, respiratory failure appeared and progressed rapidly, and on day 7, the patient died. An autopsy was performed that revealed hemophagocytosis in the bone marrow and bleeding of several organs. IPA was observed in lung specimens. SFTSV infection may be a risk factor for developing IPA. Early diagnosis and treatment of IPA may be important in patients with SFTS.

Detection of anti-SFTSV nuclear protein antibody in the acute phase sera of patients using double-antigen ELISA and immunochromatography.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening febrile illness that is caused by the SFTS virus (SFTSV). The diagnosis of SFTS is usually performed by detecting viral RNA. However, it has been reported that viral RNA is no longer detectable at 6-12 days after the onset of disease. In the current study, we have constructed a plasmid to express the recombinant nuclear protein (NP) based on the Japanese strain of SFTSV (J1). We developed a double-antigen enzyme-linked immunosorbent assay (ELISA) and immunochromatography (IC) assay using recombinant NP to detect antibody against SFTSV-NP. When we tested time-sequential samples from four patients with SFTS, antibody to SFTSV-NP were detectable not only during the recovery phase (days 10-622) but also during the acute phase (days 4-7) of the disease using both of a double-antigen ELISA and IC assay. SFTSV-RNA was detected until 8-11 days after onset, thus suggesting the coexistence of the virus and antibody during the acute phase of SFTS. These data suggest that assays for detecting antibody against SFTS-NP described in the current study may be applicable not only for the epidemiological studies but also for the diagnosis of SFTS.

Human T-cell leukemia virus type 1 may invalidate T-SPOT.TB assay results in rheumatoid arthritis patients: A retrospective case-control observational study.

BACKGROUND: CD4-positive T cells are the main target of human T-cell leukemia virus type 1 (HTLV-1). Interferon-γ release assays rely on the fact that T-lymphocytes release this cytokine when exposed to tuberculosis-specific antigens and are useful in testing for latent tuberculosis infection before initiating biologic therapy, such as anti-tumor necrosis factor agents. However, the reliability of interferon-γ release assays in detecting tuberculosis infection among HTLV-1-positive patients with rheumatoid arthritis (RA) remains unclear. The present study aimed to evaluate the use of the T-SPOT.TB assay in HTLV-1-positive RA patients. METHODS: Overall, 29 HTLV-1-positive RA patients and 87 age- and sex-matched HTLV-1-negative RA patients (controls) were included from the HTLV-1 RA Miyazaki Cohort Study. Results of the T-SPOT.TB assay for latent tuberculosis infection screening were collected from medical records of patients. RESULTS: Approximately 55% of the HTLV-1-positive RA patients showed invalid T-SPOT.TB assay results (odds ratio: 108, 95% confidence interval: 13.1-890, p < 0.0001) owing to a spot count of >10 in the negative controls. HTLV-1 proviral load values were significantly higher in patients with invalid results compared with those without invalid results (p = 0.003). CONCLUSION: HTLV-1 infection affects T-SPOT.TB assay results in RA patients. Assay results in HTLV-1 endemic regions should be interpreted with caution when screening for latent tuberculosis infection before initiation of biologic therapy.

Effective Treatment with Tocilizumab in a Rheumatoid Arthritis Patient Complicated with Human T-cell Leukemia Virus Type 1-associated Myelopathy.

A 61-year-old woman with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and interstitial pneumonia (IP) was admitted to our hospital. She complained of sicca symptoms, polyarthralgia, and swollen joints. She was diagnosed with rheumatoid arthritis (RA) and Sjögren's syndrome. Methotrexate and anti-tumor necrosis factor therapy were not utilized because of the inclusion of severe respiratory disorders among the complications and the neurological symptoms of HAM/TSP. Tocilizumab monotherapy improved the RA disease activity without exacerbating HAM/TSP. The present case suggests that tocilizumab might be a suitable treatment option in patients with RA and HAM/TSP.

The time-sequential changes of risk factors for adult T-cell leukemia development in human T-cell leukemia virus-positive patients with rheumatoid arthritis: a retrospective cohort study.

Objective: This study aimed to investigate the time-sequential changes of risk factors for adult T-cell leukemia (ATL) development in human T-cell leukemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. Methods: HTLV-1 infection was screened using particle agglutination assay and confirmed via western blotting in 365 RA patients. Twenty-three HTLV-1-positive RA patients were included in the study cohort. Blood samples were obtained from these patients at each observation time point. The values of HTLV-1 proviral load (PVL) and serum soluble IL-2 receptor (sIL2-R), which are risk factors for ATL development, were measured using real-time PCR and enzyme immunoassay, respectively. Results: The study cohort comprised 79 person-years. The median HTLV-1 PVL and sIL2-R values of the HTLV-1-positive RA patients were 0.44 copies per 100 white blood cells (WBCs) and 406 U/mL, respectively. Three HTLV-1-positive RA patients showed a high PVL value. No remarkable changes were observed in the PVL and sIL2-R values during the observation period. However, one elderly HTLV-1-positive RA patient who had a high PVL value developed ATL during treatment with methotrexate and infliximab. Conclusion: A thorough clinical assessment of the risk factors for ATL development may be necessary in daily clinical practice for RA patients in HTLV-1-endemic areas in Japan.

Infliximab as an alternative therapy for refractory adult onset Kawasaki disease: A case report.

RATIONALE: Kawasaki disease (KD) is an acute febrile illness predominantly affecting children less than 5 years of age and characterized by systemic inflammation in all medium-sized arteries. Adult-onset KD (AKD) is rare with only 105 case reports published. Recently, the efficacy of infliximab (IFX) for patients with refractory KD has been demonstrated. PATIENT CONCERNS: A previously healthy 24-year-old man was admitted because of a persistent fever, and elevated serum level of AST, ALT, LDH, and CRP. DIAGNOSIS: The patients met the diagnostic criteria for KD based on the findings of persistent fever, polymorphous exanthema, unilateral cervical lymphadenopathy, non-purulent palpebral conjunctivitis and membranous desquamation. Echocardiogram revealed the dilatation at the proximal sites of the right coronary artery (7.9 mm) and left anterior descending artery (5 mm). The patient was treated with high-dose intravenous immunoglobulin (1 g/kg/day for 2 days) and ASA (100 mg daily). However, his fever and arthralgia persisted. INTERVENTIONS: He was administered single 5 mg/kg doses of IFX. OUTCOMES: He became afebrile the next day and his arthralgia improved. LESSONS: We report the first case of administration of IFX in a patient with AKD refractory to intravenous immunoglobulin (IVIG), and successful reduction of systemic inflammation. However, the effectiveness of IFX in the regression of coronary artery aneurysm remains to be determined.

Sudden Respiratory Failure due to Tracheobronchomalacia by Relapsing Polychondritis, Successfully Rescued by Multiple Metallic Stenting and Tracheostomy.

Relapsing polychondritis (RP) is a rare systemic autoimmune disease that affects cartilaginous structures. RP causes tracheobronchomalacia (TBM) by affecting the bronchial cartilage. TBM is a fatal condition characterized by excessive weakening of the walls of the trachea and bronchi. We herein report a case of a 73-year-old man who experienced sudden respiratory failure due to TBM caused by RP. Immunosuppressive treatment did not improve his respiratory failure. Multiple metallic stentings dramatically improved his severe airway symptoms. When the airway condition becomes lethal in RP patients, then metallic stenting can be a useful treatment option.

Possible Case of Novel Spotted Fever Group Rickettsiosis in Traveler Returning to Japan from India.

A 60-year-old woman experienced fever, headache, rash, and altered vision after returning to Japan from India. Testing detected elevated antibody titers to spotted fever group rickettsia; PCR on blood yielded positive results for the rickettsial outer membrane protein A gene. We isolated a unique rickettsial agent and performed a full-genome analysis.

Severe fever with thrombocytopenia syndrome with myocardial dysfunction and encephalopathy: A case report.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Korea and Japan caused by a novel bunyavirus, SFTS virus (SFTSV). Although central nervous system manifestations are common in SFTS patients, the pathogenesis has not been elucidated; and there are few reports of myocardial dysfunction. Here we report an elderly Japanese patient with reversible myocardial dysfunction and encephalopathy. A previously healthy 65-year-old male engaged in forestry got a tick bite and developed fever and fatigue in 3 days. Three days after onset, he presented to a local hospital where the diagnosis of SFTS with hemophagocytotic syndrome was made. The blood test showed leukopenia and thrombocytopenia as well as elevated levels of alanine aminotransferase and aspartate aminotransferase. Marked hemophagocytosis was found on bone marrow smear. Peripheral blood was positive for SFTSV gene by reverse-transcription polymerase chain reaction. On day 7, the patient was transferred to our hospital. We observed disturbance of consciousness, Kernig sign and myoclonus to face and limbs. Decreased blood flow of whole cerebral cortex was detected by single photon emission computed tomography (SPECT). Chest X-ray revealed cardiomegaly and electrocardiography (ECG) showed abnormal T waves. These data suggested acute encephalopathy and myocardial dysfunction. We treated him with corticosteroid and blood transfusion, which resulted in the complete recovery of the above abnormal symptoms and laboratory data including the findings in SPECT and ECG in about a month. This case demonstrated transient myocardial dysfunction and encephalopathy can occur in addition to typical clinical manifestation of SFTS.

Crystalglobulinemia with fulminant course with cylinder-like bodies on peripheral blood smear.

A 63-year-old woman presented to our hospital with fever, purpura and pain in both legs and died 4 days after admission. Her blood smear and skin biopsy showed cylinder-like bodies (20×120 µm). She was diagnosed to have monoclonal gammopathy (IgG, lambda type). An autopsy revealed cylinder-like bodies in the vasculature of various organs. We noted a proliferation of atypical plasma cells in her bone marrow, suggesting pre-existing myeloma. Crystalglobulinemia is a rare manifestation of hypergammaglobulinemia that can cause multiple embolisms of the small vessels, and this resulted in the patient's fulminant course. The identification of cylinder-like bodies in the peripheral blood may help in reaching a diagnosis in such cases.

Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature.

Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media.