Recent advances have improved our understanding of the pathogenesis of rheumatoid arthritis (RA), and the development of new therapeutics, including biological agents, have thus made it possible to strive for remission as a primary goal. Biological agents targeting a specific molecule have powerful functional capabilities, and the introduction of biological therapies has brought about revolutionary progress in RA management, culminating in a paradigm shift. There is clear evidence that a delay in treatment initiation and poor control of disease activity are associated with joint damage progression, so treatment should be started immediately after the diagnosis of RA and adapted according to disease activity as assessed by validated composite measures. In this review, we will summarize the changes in the classification and remission criteria and describe the clinical efficacies of biological agents in RA. We also discuss new promising therapies and propose future perspectives in the rheumatology field.

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Objective Although the serum C-reactive protein (CRP) level may, to some extent, predict the disease activity in patients with Crohn's disease (CD), it is not always elevated during periods of disease activity. This study aimed to identify factors predicting the presence of active intestinal lesions in CD patients without an elevated CRP level.
Methods CD patients in whom the presence or absence of active intestinal lesions was evaluated using endoscopic and/or radiologic modalities were divided into two groups based on a negative (<3 mg/L) or positive (≥3 mg/L) CRP level. The correlations between the presence of active intestinal lesions and various clinical variables, including the Crohn's Disease Activity Index (CDAI), leukocyte and platelet counts and hemoglobin, serum albumin and CRP levels, were determined in the CRP-negative patients.
Results Of the 128 patients examined, 70 had a negative CRP status, approximately half of whom had active intestinal lesions. The multivariate analysis revealed a CDAI of >100 and platelet count of >33×10⁴ /μL to be significant predictive factors for the presence of active lesions in the CRP-negative patients [CDAI >100, odds ratio (OR) =5.55; 95% confidence interval (CI), 1.80-18.74, platelet count >33×10⁴ /μL, OR =5.94; 95% CI, 1.34-28.87]. The sensitivity of fulfillment of either criterion for the presence of active intestinal lesions was 83%, while the specificity of fulfillment of both criteria was 94%.
Conclusion A relatively low CDAI and platelet count were identified as predictive markers of the presence of active intestinal lesions in CRP-negative CD patients. These results suggest that symptoms and laboratory data should be evaluated very carefully in such patients.

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Objective Beraprost was developed as the first oral prostacyclin analog to treat patients with pulmonary arterial hypertension (PAH). Although this drug demonstrates improvements in the patient's exercise capacity and symptoms, it carries a weak recommendation in the PAH evidence-based treatment algorithm due to a lack of durability of effects. However, this therapy remains a major treatment method in Japan due to its availability and inexpensive cost. The purpose of this study was to elucidate whether this drug exhibits durable effects on sustained overall survival.
Methods A comparison of survival benefits was completed among patients undergoing treatment with beraprost (n=35) or conventional therapy (n=44). In addition, the estimated survival calculated using the equation developed by the National Institutes of Health Registry was used for the analysis.
Results Although no significant differences were observed between the two groups using the Kaplan-Meier survival curve, a statistical difference was observed between the patients receiving high-dose beraprost therapy (>120 μg) and those receiving conventional therapy (5- and 10-year survival: 71.1% and 49.4% vs. 37.7% and 21.2%, respectively; p=0.0466). Moreover, the cumulative survival rates in the patients receiving beraprost were slightly better than the estimated survival rates. In the PAH patients with connective tissue diseases, a tendency towards better survival outcomes was observed in the group treated with beraprost.
Conclusion This study suggests the survival benefits of high-dose beraprost therapy for patients with PAH. The retrospective nature of this study, however, makes it difficult to conclude definitively that beraprost exerts significant beneficial effects on survival.

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Objective Direct hemoperfusion with polymyxin B-immobilized fiber columns (PMX-DHP) has been used for the treatment of septic shock. It was recently suggested that PMX-DHP may also be effective in acute exacerbations of idiopathic pulmonary fibrosis (IPF). However, all previous reports are case series without controls. The aim of the study was to determine the effects of PMX-DHP on the prognosis of the patients with rapidly progressive interstitial lung diseases (ILDs) in a case-control setting.
Methods We herein retrospectively examined the clinical records of consecutive patients with acute exacerbation of IPF or rapidly progressive ILDs treated in our institute. We excluded those who had been treated with steroid pulse therapy for lung diseases, including those who had been taking more than 15 mg of oral prednisolone daily, or had undergone an operation within one month before the onset of acute respiratory failure. We compared the results of the laboratory tests and survivals between patients treated with and without PMX-DHP.
Results Twenty-six patients were enrolled in the study. Among them, 13 patients were treated with PMX-DHP in addition to immunosuppressive therapy, including steroid pulse therapy. The mean survival time of patients treated with PMX-DHP tended to be longer than patients not treated with PXM-DHP (p=0.067). Six patients who underwent PMX-DHP on the first day of steroid pulse therapy had significantly longer survival times than those who were treated with standard medication alone (p<0.01).
Conclusion These results suggest that PMX-DHP performed on the first day of steroid pulse therapy may improve the prognosis of patients with rapidly progressive ILDs.

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Objective No clinically effective treatment for promoting peripheral axonal regeneration has yet been established. Several experimental studies in vitro and in vivo have shown that a high dose of methylcobalamin (MeCbl), an analogue of vitamin B12, promotes axonal growth in peripheral nerve injury. We herein assessed the safety and efficacy of an ultra-high dose MeCbl treatment for patients with peripheral neuropathy and chronic axonal degeneration.
Methods Fourteen patients with immune-mediated or hereditary neuropathy in the chronic progressive or stable phase were enrolled. MeCbl, 25 mg/day for 10 days followed by monthly 25 mg for 5 months, was intravenously administered. The patients were evaluated before and 1 year following treatment. The primary endpoints were safety and improvement in the Medical Research Council (MRC) sum score in at least two muscles of the 20 muscles. This trial is registered with the University Hospital Medical Information Network (UMIN) Center in Japan under the ID: UMIN000009359.
Results There were no adverse effects in twelve of the patients, whereas treatment was discontinued in two patients who had seborrheic dermatitis at 3 months and respiratory tract infection at 2 months, respectively. Therefore, twelve patients were evaluated for the primary outcomes; the MRC sum score was improved in seven of the patients and unchanged or worsened in the remaining five patients.
Conclusion Intravenous ultra-high dose MeCbl treatment is a safe and potentially efficacious therapy for patients with peripheral neuropathy and chronic axonal degeneration.

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Objective The recurrence rate after acute cystitis treatment failure with inappropriate antimicrobials remains unclear. The goal of this study was to explore the relationship between cystitis recurrence and nonadherence of antimicrobial prescriptions to national guidelines using a nationwide population-based data set.
Methods This was a retrospective longitudinal observational cohort study that was conducted using the clinical records of the National Health Insurance Research Database in Taiwan from 2006-2007. After excluding patients younger than 18 years of age, with concurrent infections, urinary tract anomaly, and no antimicrobial treatment, the remaining study population included 36,395 patients with acute cystitis. We evaluated the hazard ratio (HR) of cystitis recurrence within 28 days between the adherence and nonadherence groups using Cox proportional hazard regression analysis.
Results Adherence to antimicrobial prescription guidelines was the factor that most strongly influenced acute cystitis recurrence, with a HR of 0.91 (95% confidence interval 0.87-0.95) after adjusting for all variables. The incidence rate of acute cystitis in patients receiving antimicrobials adherent to national guidelines was 59.78 per 10,000 person-days. The results of the likelihood ratio test indicated that age, sex, and guideline nonadherence were significant risk factors for recurrent cystitis. The percentage of first-generation cephalosporin prescription was 31.61%, making it the most frequently prescribed guideline-recommended drug.
Conclusion Acute cystitis patients with or without multiple chronic comorbidities should be treated with antimicrobials that adhere to recommended guidelines to attain a better therapeutic outcome.

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Objective The clinical features of bacteremia due to Campylobacter jejuni (C. jejuni) have yet to be fully elucidated.
Methods and Results The cases of C. jejuni bacteremia were retrospectively reviewed during a twelve-year period in a single institute. C. jejuni was identified in 7 patients through blood cultures, and disease onset occurred between June and October. Except for 2 previously healthy individuals, 5 patients had underlying diseases (chronic liver diseases, n=3; hematological malignancies, n=2). All patients were febrile, but 2 patients did not present with gastrointestinal symptoms. C. jejuni isolates were susceptible to gentamicin and macrolides, but about half of them were resistant to fluoroquinolones. Disease outcomes were favorable, and no deaths related to C. jejuni bacteremia were observed.
Conclusion These results suggest that C. jejuni bacteremia could occur primarily or secondarily to gastroenteritis with a seasonal peak and that prognosis would be favorable regardless of the underlying diseases.

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An esophageal hamartoma is a rare, benign germ-cell condition. Most hamartomas are intraluminal tumors located in the upper third of the esophagus. We herein report an unusual case of a pedunculated hamartoma that involved the lower third of the esophagus that was diagnosed incidentally during investigations for epigastric pain. The features noted on endoscopy, endoscopic ultrasound/Doppler endoscopic ultrasound and computed tomography of the chest are also presented.

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Primary cardiac angiosarcoma is a rare and highly malignant condition. Besides performing complete surgical excision, it remains controversial as to whether survival can be improved with additional treatment. We herein describe a 30-year-old man with a right atrial angiosarcoma. He underwent two operations for the resection of the primary lesion, and the patient's metastatic lesions involved an intestinal segment. With chemotherapy, radiotherapy, and molecular targeted therapy, he survived for 33 months. The literature describing adjuvant therapy for cardiac angiosarcoma, which is mostly case reports, is also reviewed. In conclusion, the limited evidence suggests that multimodality treatment for cardiac angiosarcoma is a beacon of hope to improve the survival of such patients.

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Although hirsutism is classically part of the clinical presentation of polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia and Cushing's syndrome (CS), CS associated with underlying late-onset congenital adrenal hyperplasia (LCAH) in an adult has not been previously reported. We herein present the case of a 25-year-old woman who was followed for PCOS for seven years. After undergoing detailed tests described within the text, she received the diagnosis of LCAH and was found to have point mutations. Interestingly, she later had diagnosis of endogenous CS that regressed folowing excision of an adrenal adenoma found on MRI. The present patient thus exhibited the coexistence of two paradoxical endocrine pathologies.

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Hypopituitarism often develops insidiously, and undiagnosed hypopituitarism can influence the glycemic profile of patients with type 1 diabetes. We herein report the case of a 49-year-old man with type 1 diabetes and Hashimoto's thyroiditis who experienced an unexplained improvement in his glycemic level and recurrent severe hypoglycemia, despite a reduction in the dose of insulin. Based on the patient's endocrinological findings, he was diagnosed with hypopituitarism possibly due to lymphocytic hypophysitis, as supported by positive results for human leukocyte antigen A24 and Cw3. Following the administration of hydrocortisone replacement therapy, his insulin requirement increased to a premorbid level, and the severe hypoglycemia resolved.

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Pituitary metastasis is an uncommon first presentation of systemic malignancy. The most common presenting symptom of pituitary metastasis is diabetes insipidus reflecting involvement of the stalk and/or posterior pituitary. We herein present a unique case of the coexistence of both a functioning pituitary adenoma (prolactinoma) and pituitary metastasis of advanced colorectal cancer with pituitary apoplexy as the first manifestation of underlying malignancy. The present case emphasizes the need to consider pituitary metastasis as a differential diagnosis in patients presenting with pituitary lesions and be aware that tumor-to-tumor metastasis can occur unexpectedly in those with pituitary metastases.

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The craniofacial skeleton represents a peculiar target of hyperparathyroidism in patients with end-stage renal disease who exhibit a dramatic pattern of uremic leontiasis ossea. Scant information regarding this condition is available in the renal literature, as the extreme and typical manifestations of leontiasis ossea have been described in only a small series of patients. We herein report a case of significant amelioration of massive modification of the facial appearance of a 30-year-old uremic Chinese woman with severe skeletal deformities who underwent total parathyroidectomy with a forearm autograft concurrently with effective drug treatment. This report may shed light on how to better understand and treat this metabolic derangement.

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Malignant pleural mesothelioma (MPM) is an uncommon tumor derived from mesothelial lining cells. MPM has been described as an insidious neoplasm because of its long latency period. The tumor is typically found in patients several decades after asbestos exposure. We herein describe a 26-year-old patient with MPM who presented with pleural effusion. The patient had not been exposed to asbestos or erionite. There are few case reports of non-asbestos-related MPM in young patients. We report this case to remind physicians to consider MPM in the differential diagnosis of pleural effusion in young patients without exposure to asbestos or erionitis.

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A 58-year-old man presented with right-sided chest pain. Radiography and computed tomography showed a pleural effusion in the right chest and a mass in the right hilum. Thoracentesis showed a hemothorax. The carbohydrate antigen (CA) 19-9 level in the pleural effusion was very high, requiring differentiation from malignancy. Positron emission tomography showed no significant fluorodeoxy glucose (FDG) accumulation. Magnetic resonance imaging revealed a cystic lesion. The tumor was resected for both a diagnosis and treatment. A pathological examination demonstrated a bronchogenic cyst. An immunohistochemical study suggested that the cyst was the source of the hemothorax and the high CA19-9 level.

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Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.

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A 52-year-old woman with a high serum alkaline phosphatase (ALP) level underwent a liver biopsy, which showed diffuse heavy deposition of Aκ amyloid, and was diagnosed as having immunoglobulin light chain (AL) amyloidosis. Although she received high-dose melphalan with stem cell transplantation and achieved a hematologic complete response (CR), her ALP level began to increase one year after treatment. Further examinations revealed that she was still in a CR state with dominant bone-type ALP, and re-biopsied liver specimens demonstrated marked regression of amyliod deposition, providing important evidence that the turnover of hepatic amyloid proteins can actually occur more rapidly than previously thought.

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We herein report that the clinical, laboratory, and radiographic features and positron emission tomography (PET) imaging may provide valuable clues to the pathogenesis of cerebral amyloid angiopathy (CAA)-associated encephalopathy, which currently remains unclear. We herein describe two cases of encephalopathy with CAA, with an emphasis on PET imaging with ¹¹C-Pittsburgh compound B (¹¹C-PiB) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). One case of Alzheimer's disease for which a brain biopsy was performed showed CAA-related inflammation. Another case that had developed sudden sensory aphasia presented with posterior reversible encephalopathy syndrome-like vasogenic edema in the left temporal region with ¹¹C-PiB uptake and microhemorrhages. ¹¹C-PiB and ¹⁸F-FDG PET are useful for detecting CAA-associated encephalopathy, including atypical CAA cases.

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We herein describe a case of Wuchereria bancrofti infection in a previously healthy 37-year-old Nepalese man. The patient presented with a history of milky urine with subsequent acute urinary retention lasting for a few days. The presence of microfilariae was confirmed on both peripheral blood and urine smears obtained at midnight. He was conservatively treated with diethylcarbamazine combined with doxycycline. Filariasis was previously endemic in southern parts of Japan, although it has been eradicated. Clinicians should remember filariasis as a potential etiology of urinary retention, especially in cases that may be associated with imported infectious disease.

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Diagnosing primary cerebral nocardiosis is difficult. This case report describes a 79-year-old immunocompetent Japanese woman with a primary brain abscess caused by Nocardia otitidiscaviarum (IFM 11321) and reviews the findings of 11 previous patients with N. otitidiscaviarum-induced brain abscesses. Four patients survived, including ours. Beta-lactams were not effective in our patient, and the diagnosis required a pathologic analysis of the surgical specimen. Sulfamethoxazole/trimethoprim (ST) was administered to the patient. On antibiotic susceptibility testing, N. otitidiscaviarum (IFM11321) was found to be resistant to amoxicillin-clavulanic acid, ceftriaxone, cefotaxime, cefepime, imipenem and clarithromycin, but sensitive to amikacin, gentamicin, ST and linezolid. Antimicrobial susceptibility patterns differ among Nocardia species, making species identification important for treatment. Patients with suspected Nocardia infection should therefore be treated empirically with ST and/or amikacin and considered for surgical management.

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Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by periodic fever and serosal inflammation. FMF is mostly reported in the Mediterranean region and is considered to be rare in Japan with estimated 292 cases. We treated three unrelated FMF patients in one year in a city with 144,000 residents. Two of the three patients were over 70 years old. FMF may therefore be underdiagnosed in Japan.

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