Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.

A case of TAFRO syndrome maintained in remission for 5 years after discontinuation of tocilizumab.

TAFRO syndrome is a subtype of idiopathic multicentric Castleman's disease (iMCD) that is characterised by thrombocytopenia, generalised oedema, fever, bone marrow fibrosis, renal failure, and organ enlargement and has a poor prognosis. The prognosis of TAFRO syndrome is worse than that of iMCD-not otherwise specified, with a high mortality rate. There are only a few long-term follow-up reports after remission of TAFRO syndrome with tocilizumab (TCZ) treatment in a patient in whom all drugs were discontinued after attaining sustained remission. Here, we report a case in which interleukin-6 negativity was confirmed and remission was maintained without relapse for 5 years after all drug treatments, including TCZ, were discontinued.

A Missense Mutation of the Plasminogen Gene in a Japanese Family with Hereditary Angioedema with Normal C1 Inhibitor: Third Family Survey in Asia.

Hereditary angioedema (HAE) is a life-threatening disease associated with recurrent episodes of subcutaneous and mucosal swelling, painful abdominal cramping, and asphyxiation. HAE has long been thought to be caused by genetic defects of C1 inhibitors (C1-INH). Recently, HAE with a normal C1 inhibitor expression (HAEnCI) was reported, and the missense mutation p.Lys330Glu (K330E) in exon 9 of the plasminogen (PLG) gene was shown to be responsible for a subset of HAEnCI. HAE with the K330E mutation in the PLG gene-PLG (HAE-PLG) has been reported in only two Japanese families in Asia. We herein report a third family with HAE-PLG in Japan.

Primary Cutaneous Gamma-Delta T-Cell Lymphoma Initially Diagnosed as Subcutaneous Panniculitis-like T-Cell Lymphoma with Dermatomyositis.

Primary cutaneous gamma-delta T-cell lymphoma (CGD-TCL) is a rare cutaneous lymphoma. Panniculitis-like T-cell lymphoma (SPTCL) has a better prognosis than CGD-TCL. SPTCL is sometimes associated with autoimmune disease. A 64-year-old Japanese female with a history of dermatomyositis presented with subcutaneous nodules on the upper extremities and exacerbated dermatomyositis. A skin biopsy showed lobular panniculitis, a vacuolar interface change, and a dermal mucin deposit. Fat cells rimmed by neoplastic cells, fat necrosis, and karyorrhexis were observed. The atypical lymphoid cells showed CD3+, CD4-, CD8+, granzyme B+, CD20-, and CD56-. Polymerase chain reaction analysis demonstrated a T-cell receptor rearrangement. The patient was initially diagnosed with SPTCL, so the dose of prednisone was raised from 7.5 to 50 mg daily (1 mg/kg). After one month, erythematous nodules regressed, and muscle symptoms improved. Subsequently, prednisone was tapered, and cyclosporin A was added. After one year, the patient remained symptom-free and continued taking 7.5 mg prednisone and 100 mg cyclosporin A daily. Afterward, we immunostained skin samples with antibodies against TCR-ß and δ and found positive TCR-δ and negative TCR-ß. Therefore, we corrected the diagnosis to CGD-TCL, although the clinical course and the presence of dermatomyositis were reminiscent of SPTCL.

Impact of diabetes and Krebs von den Lungen-6 on coronavirus disease 2019 severity: A single-center study from Japan.

AIMS/INTRODUCTION: Diabetes mellitus is reported as a risk factor for increased coronavirus disease 2019 (COVID-19) severity and mortality, but there have been few reports from Japan. Associations between diabetes mellitus and COVID-19 severity and mortality were investigated in a single Japanese hospital. MATERIALS AND METHODS: Patients aged ≥20 years admitted to Osaka City General Hospital for COVID-19 treatment between April 2020 and March 2021 were included in this retrospective, observational study. Multivariable logistic regression analysis was carried out to examine whether diabetes mellitus contributes to COVID-19-related death and severity. RESULTS: Of the 262 patients included, 108 (41.2%) required invasive ventilation, and 34 (13.0%) died in hospital. The diabetes group (n = 92) was significantly older, more obese, had longer hospital stays, more severe illness and higher mortality than the non-diabetes group (n = 170). On multivariable logistic regression analysis, age (odds ratio [OR] 1.054, 95% confidence interval [CI] 1.023-1.086), body mass index (OR 1.111, 95% CI 1.028-1.201), history of diabetes mellitus (OR 2.429, 95% CI 1.152-5.123), neutrophil count (OR 1.222, 95% CI 1.077-1.385), C-reactive protein (OR 1.096, 95% CI 1.030-1.166) and Krebs von den Lungen-6 (OR 1.002, 95% CI 1.000-1.003) were predictors for COVID-19 severity (R2 = 0.468). Meanwhile, age (OR 1.104, 95% CI 1.037-1.175) and Krebs von den Lungen-6 (OR 1.003, 95% CI 1.001-1.005) were predictors for COVID-19-related death (R2 = 0.475). CONCLUSIONS: Diabetes mellitus was a definite risk factor for COVID-19 severity in a single Japanese hospital treating moderately-to-severely ill patients.

Recent Outpatient Services in General Internal Medicine: 6.4% of Symptomatic Patients Were Post-Acute COVID-19.

PURPOSE: It is important to understand how COVID-19 is affecting general outpatient services, since hospitals see a wide variety of patients. This study aimed to evaluate the incidence and clinical picture of COVID-19 in general outpatient services. Currently, the diagnosis of COVID-19 depends strongly on the results of polymerase chain reaction (PCR) assays. However, since the sensitivity of PCR tests for SARS-CoV-2 is not high enough to assure confidence. On the other hand, the SARS-CoV-2 antibody (Ab) test is highly sensitive after 2 weeks of symptom onset, and might complement the PCR test. Therefore, we measured Ab in addition to PCR to obtain a more accurate clinical profile of COVID-19, which might be helpful in building future practice strategies. PATIENTS: The study patients were those who visited our department for the first time between November 2020 and March 2021 and fulfilled the enrolment criteria. METHODS: All patients underwent total SARS-CoV-2 Ab testing, and PCR tests were performed in only some of them; patients were classified according to the performance of PCR tests for comparisons. RESULTS: Ninety-four patients who underwent Ab testing during the study period were eligible for study enrolment, and the PCR test was performed in 40 of them. Only one patient was diagnosed with acute stage COVID-19 based on a positive PCR test. Antibodies were positive in six (6.4%) of the 94 patients. Five of the six Ab-positive patients were negative for PCR, and the test was not performed in the sixth patient. All the six patients had prior symptoms suggestive of infection, and respiratory symptoms were more noticeable than fever. The Ab positivity rate was significantly higher than published data. CONCLUSION: COVID-19 is not rare in general outpatient services and can be missed based on PCR tests alone. The diagnosis should be made from a comprehensive perspective.

Patient's age and D-dimer levels predict the prognosis in patients with TAFRO syndrome.

OBJECTIVES: To identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. METHODS: Data of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan-Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox proportional hazards model. RESULTS: We extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥60 years and D-dimer ≥18 µg/dL remained significant predictors of poor overall survival in the multivariable Cox proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS). CONCLUSION: Patients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies.

Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases, One with Takayasu Arteritis and the Other with Relapsing Polychondritis.

Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC.

Acute Urinary Retention Induced by Chemical Meningitis Which Occurred Due to a Ruptured Dermoid Cyst.

Meningitis retention syndrome (MRS), a rare complication of aseptic meningitis, can present with acute urinary retention. The rupture of a dermoid cyst, which is a benign intracranial tumor, can sometimes induce chemical meningitis. We herein present a case of chemical meningitis and acute urinary retention that was induced by the rupture of a dermoid cyst. The patient experienced urinary retention for approximately 60 days, and then made a complete recovery thereafter. This is the first reported case of acute urinary retention due to the rupture of a dermoid cyst.

Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA.

Familial Mediterranean fever (FMF) can be classified into typical and incomplete/atypical types. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome-like symptoms have been found in atypical type carrying P369S-R408Q mutations in the responsible gene MEFV. A 28-year-old female with recurrent fever and her young sisters and mother, all of whom had tonsillectomy for tonsillitis, carried heterozygous alterations involving E148Q/P369S/R408Q. A diagnosis of atypical FMF, MEFV exon3 variants with PFAPA syndrome-like symptoms, was made.

Macro TSH in patients with subclinical hypothyroidism.

OBJECTIVE: TSH is a sensitive indicator of thyroid function. In subclinical hypothyroidism, however, serum TSH concentrations are elevated despite normal thyroid hormone levels, and macro TSH is one of the causes. This study aimed to clarify the prevalence and nature of macro TSH in patients with subclinical hypothyroidism. DESIGN: We conducted a 2-year cross-sectional observational study. PATIENTS: We included 681 patients with subclinical hypothyroidism and 38 patients with overt hypothyroidism (controls). MEASUREMENTS: Macro TSH was screened by polyethylene glycol (PEG) method and analysed by gel filtration chromatography and bioassays. RESULTS: Among 681 serum samples, 117 exhibited PEG-precipitable TSH ratios greater than 75% (mean + 1·5 SD in controls) and were subjected to gel filtration chromatography. TSH was eluted at a position greater than 100 kDa in 11 patients with subclinical hypothyroidism (1·62%); these patients were diagnosed with macro TSH. The nature of macro TSH included eight anti-TSH autoantibodies of IgG class, two non-IgG-associated and one human anti-mouse antibody (HAMA). Macro TSH showed low bioactivity. CONCLUSIONS: Macro TSH was heterogeneous, but it is mostly comprised of TSH and anti-TSH autoantibodies. When PEG-precipitable TSH exceeds 90% in serum samples with TSH above 10 mU/l, clinicians should strongly suspect the presence of macro TSH and confirm it by gel chromatography. Because macro TSH exhibited low bioactivity, thyroid hormone replacement therapy may not be required in patients with subclinical hypothyroidism due to macro TSH except for those with high serum free TSH levels.

Sitagliptin reduces the urine albumin-to-creatinine ratio in type 2 diabetes through decreasing both blood pressure and estimated glomerular filtration rate.

BACKGROUND: We investigated the change in the urine albumin-to-creatinine ratio (ACR) to examine the effect of sitagliptin on diabetic nephropathy. METHODS: Sitagliptin at a dose of 50 mg was administered to 247 outpatients with type 2 diabetes. Data were collected on the patients' laboratory results (including the ACR), blood pressure, and body weight. Clinical data were compared before and after 3 months' administration of sitagliptin. RESULTS: The ACR changed from 150.0 ± 538.6 mg/gCre to 148.3 ± 764.6 mg/gCre over 3 months. In the patients with micro- and macro-albuminuria, the ACR after 3 months significantly decreased compared with the baseline (P = 0.04 and P = 0.02, respectively). The subjects whose ACR decreased experienced significantly larger decreases over the 3-month period in blood pressure and estimated glomerular filtration rate (eGFR) than the other subjects. There was no significant correlation between change in ACR (ΔACR) and change in hemoglobin A1c (ΔHbA1c) during 3 months (r = 0.04, P = 0.59), but there was a significant correlation between change in ΔACR and change in systolic blood pressure (r = 0.16, P = 0.03). Multiple regression analysis revealed that the significant predictors for ΔACR were change in systolic blood pressure (ß = 0.21, P = 0.016) and change in eGFR (ß = 0.20, P = 0.024) over 3 months (r = 0.35, P = 0.04). CONCLUSIONS: Sitagliptin reduces the ACR through decreasing both blood pressure and eGFR, with no correlation with a decrease in HbA1c over a 3-month period. These results may reflect the direct action of sitagliptin on the kidneys.

Campylobacter fetus bacteremia with purulent pleurisy in a young adult with primary hypogammaglobulinemia.

A 24-year-old man presented with fever and pleural effusion predominantly containing lymphocytes. Cultures of the pleural effusion and blood revealed Campylobacter fetus, and laboratory studies showed a low serum level of immunoglobulin. The patient was diagnosed with C. fetus pleuritis, bacteremia and primary hypogammaglobulinemia, and subsequent treatment with meropenem and immunoglobulin improved his condition. Although the underlying cause of the primary hypogammaglobulinemia remains unclear, the patient's status improved under immunoglobulin replacement therapy. C. fetus pleuritis is a rare infectious disease usually observed in immunocompromised hosts. We herein describe the first report of C. fetus pleuritis in a young adult with primary hypogammaglobulinemia.

A case of chronic active Epstein-Barr virus infection mimicking adult-onset Still's disease.

An 83-year-old man was diagnosed with adult-onset Still's disease (AOSD) based on clinical and laboratory findings. However, glucocorticoid had little effect. Epstein-Barr virus (EBV)-DNA was detected in peripheral blood, and autopsy findings confirmed a diagnosis of chronic active EBV infection (CAEBV). CAEBV mimics AOSD, and the presence of articular involvement and leukocytosis does not exclude the possibility of CAEBV. CAEBV should be included in the differential diagnosis of AOSD, and measurement of EBV-DNA is essential.

Pulmonary and gastric metastatic calcification due to milk-alkali syndrome: a case report.

The incidence of metastatic calcification is influenced by high serum calcium and phosphate concentrations and local physicochemical conditions, such as pH. A high pH accelerates tissue calcification. Patients with milk-alkali syndrome typically present with renal failure, hypercalcemia, and metabolic alkalosis, which are caused by the ingestion of calcium and absorbable alkali. Among patients with impairment of renal function, milk-alkali syndrome is a major cause of hypercalcemia. Long-term use of furosemide will lead to hypokalemia, metabolic alkalosis, and eventually renal failure (i.e., pseudo-Bartter syndrome). Even if the level of calcium ingestion is relatively low, the renal failure caused by long-term furosemide use can readily lead to milk-alkali syndrome. We describe a case of a 45-year-old woman who was admitted with cough and dyspnea and presented with pulmonary and gastric metastatic calcification. She had been taking alfacalcidol and oral alkaline medications such as sodium bicarbonate and calcium carbonate as well as oral furosemide for a long time. The patient was found to have hypercalcemia, chronic renal failure, and metabolic alkalosis, so milk-alkali syndrome was diagnosed. Saline was administered and oral medications were discontinued. Serum creatinine levels subsequently decreased, but pulmonary metastatic calcification was not diminished. In this case, the milk-alkali syndrome that caused the severe metastatic calcification was exacerbated by multiple factors, including oral alkaline medications such as sodium bicarbonate and calcium carbonate. In addition, metabolic alkalosis and renal failure were affected by long-term furosemide use (i.e., pseudo-Bartter syndrome).

Granulomatous mastitis complicated by arthralgia and erythema nodosum successfully treated with prednisolone and methotrexate.

A 23-year-old woman was admitted with complaints of swelling and pain in the left breast, fever, polyarthralgia and erythema nodosum. A fine-needle biopsy of the mass in the left breast revealed non-caseous granulomatous lobulitis. A diagnosis of granulomatous mastitis was thus made. The administration of prednisolone 40 mg/day resulted in the resolution of the patient's symptoms, and the breast mass thereafter decreased in size. The mass relapsed during the subsequent prednisolone taper. Additional therapy with methotrexate resulted in complete remission. Granulomatous mastitis should therefore be included in the differential diagnosis of polyarthralgia.