Clinical Characteristics and Corticosteroid Responses of Acoustic Neuroma Treated as Idiopathic Sudden Sensorineural Hearing Loss.

BACKGROUND: Few investigations have been conducted on the clinical characteristics of the differential diagnosis of acoustic neuroma with acute sensorineural hearing loss and idiopathic sudden sensorineural hearing loss. The aim of the study was to investigate the clinical characteristics of the differential diagnoses between acoustic neuroma and idiopathic sudden sensorineural hearing loss. METHODS: The medical records of patients with acute sensorineural hearing loss (142 ears), including acoustic neuroma (19 ears) and idiopathic sudden sensorineural hearing loss (123 ears), who underwent audiometric and hematologic examinations and received systemic corticosteroid treatment, were retrospectively reviewed. RESULTS: Hematological examination revealed that the erythrocyte sedimentation rate and fibrinogen values were significantly higher in the idiopathic sudden sensorineural hearing loss group compared to the acoustic neuroma group. Although all patients received corticosteroid treatment, hearing thresholds at the initial examination and 3 months after corticosteroid treatment were significantly higher in the idiopathic sudden sensorineural hearing loss group compared to the acoustic neuroma group at all frequencies. However, hearing recovery was worse in the acoustic neuroma group compared to the idiopathic sudden sensorineural hearing loss group. Furthermore, speech discrimination and short increment sensitivity index tests were not significantly different between the acoustic neuroma and idiopathic sudden sensorineural hearing loss groups. CONCLUSION: This is the first study to reveal that speech discrimination and short increment sensitivity index tests are not useful for the differential diagnoses between acoustic neuroma and idiopathic sudden sensorineural hearing loss, whereas erythrocyte sedimentation rate and fibrinogen, blood biomarkers of inflammation and blood viscosity, would be considered valuable. Furthermore, acoustic neuroma should be considered in cases where acute sensorineural hearing loss did not recover after corticosteroid treatment, although the initial hearing loss was mild.

Long-term outcomes of stapes surgery.

OBJECTIVE: Hearing improvement following stapes surgery is generally good; however, we sometimes encounter patients where hearing loss gradually progresses over the long term. In this study, we investigated the causes of hearing loss in these cases. METHODS: A total of 30 ears from 23 patients, who underwent stapes surgery at Kitasato University Hospital from 2001 to 2021 and were followed up for ≥5 years, were included in the study. Changes in air conduction (AC) and bone conduction (BC) thresholds were measured, and hearing evaluation was performed by calculating the air-bone gap (ABG) at the mean of 4 frequencies. Cases with a postoperative ABG of ≤10 dB at 6 months after surgery were classified into the following groups according to their hearing changes at 5 years after surgery: Group A (no ABG increase of ≥10 dB and no AC threshold increase of ≥10 dB) and Group B (an ABG increase of ≥10 dB and an AC threshold increase of ≥10 dB). In groups A and B, we examined factors affecting long-term postoperative results. In addition, the patients who underwent reoperation were examined. RESULTS: The AC thresholds 6 months and 5 years after surgery decreased significantly compared with those before surgery (p  <  0.01); however, the BC thresholds 6 months and 5 years after surgery did not vary significantly from those before surgery (p  >  0.05). Group A included 16 ears from 13 patients (53.3%), and Group B included 3 ears from 3 patients (10.0%). There were no significant differences in age, sex, surgical method, piston type, piston length, presence of incudostapedial joint subluxation, computed tomography findings, and preoperative ABGs between groups A and B (p  >  0.05). A total of 6 reoperations were performed in 3 ears from 3 patients, and there were 5 operations with the platinotomy hole to be closed by bone regrowth and 3 operations with the narrowed long process of the incus. CONCLUSION: In 10.0% of the patients who underwent stapes surgery, the ABG improved 6 months after surgery; however, the AC threshold and ABG increased 5 years after surgery. Our findings suggested that piston displacement and the platinotomy hole to be closed by bone regrowth are possible causes of hearing loss in cases where hearing loss progresses in the long term after stapes surgery.

Retrofacial Approach for Cochlear Implantation in Chronic Otitis Media: A Case Report.

Cochlear implantation is anatomically more difficult in postoperative ears than in normal ears due to chronic otitis media. In cochlear implantation after canal wall down mastoidectomy, the electrodes must be protected. We report a case of cochlear implantation with partial mastoid obliteration using a retrofacial approach in an 81-year-old woman. Bilateral tympanoplasty was performed for bilateral chronic otitis media, but no improvement in hearing was observed. Hearing aids were used, but their effect was insufficient and cochlear implantation was needed. Since the patient was an older adult with diabetes, it was necessary to avoid the risk of wound infection associated with fat harvesting from the abdomen, which is necessary for overclosure of the external ear. Therefore, we chose to perform partial mastoid obliteration using a retrofacial approach to ensure the prevention of electrode exposure. One year after surgery, the electrode had not been exposed or infected. The ear canal was preserved, and the eardrum could be observed. Although long-term follow-up is required, this approach may be useful for cochlear implantation in patients with chronic otitis media after canal wall down mastoidectomy.

Long-term administration of vitamin B12 and adenosine triphosphate for idiopathic sudden sensorineural hearing loss: a retrospective study.

BACKGROUND: In idiopathic sudden sensorineural hearing loss (ISSNHL), the relationship between the administration duration of vitamin B12 (vit B12) with adenosine triphosphate (ATP) and their therapeutic effect is not fully understood. OBJECTIVE: To investigate the therapeutic effect of long-term 16 (≥weeks) administration of vit B12 with ATP on the prognosis of ISSNHL patients and compare it with those of short-term (<8 weeks) and middle-term (≥8 weeks, <16 weeks) administration. METHODS: We retrospectively reviewed the medical records of 117 patients with ISSNHL treated between 2015 and 2018. RESULTS: The overall recovery rate was 32.5%. Initial higher hearing threshold and initial higher grade of hearing loss (HL) were associated with a poor prognosis. However, the administration duration of vit B12 and ATP did not influence the overall hearing improvement. With regard to the time course of hearing recovery, there was no significant difference in hearing recovery among the long-, middle-, and short-term administration groups until 16 weeks after treatment. However, at 16-24 weeks after initial treatment, the short-term administration group exhibited significantly lower hearing recovery than did the long-term administration groups. CONCLUSIONS: The administration duration of vit B12 and ATP did not influence the overall hearing prognosis in ISSNHL, but long-term administration of vit B12 and ATP helped prevent the progression of HL after ISSNHL. Our results suggest that long-term administration of vit B12 and ATP is not necessarily required to treat ISSNHL patients, except for slowly progressing HL in the affected ears.

First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

OBJECTIVE: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort. METHODS: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees. RESULTS: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%). CONCLUSIONS: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.

Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis.

Objective: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM). Methods: In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed. Results: Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3-48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5-11.4) nmol/L at 6 months after treatment introduction. Conclusions: Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.

Fever of unknown origin following parathyroidectomy prior to onset of typical polymyalgia rheumatica symptoms: a case report.

Polymyalgia rheumatica (PMR) is a disease commonly seen in elderly individuals, however, the etiology has not been reported. Typical clinical features include bilateral shoulder pain and morning stiffness, while serologic autoantibody test findings are negative. Approximately 40%-50% of affected patients present with low-grade fever, fatigue, and appetite loss, which we often experience in the field of general medicine, and thus, the condition should not be given low priority. However, knowledge regarding such constitutional manifestations is also limited. We encountered an elderly woman with a fever of unknown origin that developed following a parathyroidectomy for a single parathyroid adenoma, after which severe shoulder pain and morning stiffness emerged, leading to a diagnosis of PMR. The fever developed several days prior to appearance of severe pain, which is an uncommon presentation in PMR cases. Our patient had low-grade inflammation without pyrexia prior to the surgery, which might have been an important reason for the accelerated immoderate immune activation leading to PMR induced by surgery in this case. Furthermore, she was infected with the influenza A virus 3 weeks before coming to us. Some reports have suggested a relationship between the influenza virus or vaccine and PMR. It is difficult to conclude regarding the definite trigger in our patient, though the details of this case should be helpful for a better understanding of the disease.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

A retrospective analysis of 7 cases of familial mediterranean fever.

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

Relationships among drinking and smoking habits, history of diseases, body mass index and idiopathic sudden sensorineural hearing loss in Japanese patients.

OBJECTIVES: To present the cardiovascular risk factors in idiopathic sudden sensorineural hearing loss (SSNHL) patients enrolled in a nationwide epidemiological survey of hearing disorders in Japan. MATERIALS AND METHODS: We compiled the cardiovascular risk factors in 3073 idiopathic SSNHL subjects (1621 men and 1452 women) and compared their proportions with controls as part of the National Health and Nutrition Survey in Japan, 2014. The cardiovascular risk factors consisted of drinking and smoking habits, a history of five conditions related to cardiovascular disease and body mass index. RESULTS: The proportion of current smokers was significantly higher among men aged 50-59, 60-69 and 70+ and among women aged 30-39, 40-49 and 60-69. The proportion of patients with a history of diabetes mellitus was significantly higher among men aged 50-59, 60-69 and 70+, but not in women. In addition, male and female SSNHL subjects aged 60-69 showed lower proportions of current drinking; and female SSNHL subjects aged 60-69 showed higher proportions of overweight (BMI ≥25 kg/m2). CONCLUSIONS: The present cross-sectional study revealed showed significantly higher proportions of current smokers among both men and women as well as those with a history of diabetes mellitus among men across many age groups in patients with idiopathic SSNHL compared with the controls.

The clinical features and prognosis of mumps-associated hearing loss: a retrospective, multi-institutional investigation in Japan.

CONCLUSIONS: The majority of hearing loss due to mumps presents as unilateral profound sensorineural hearing loss, which is refractory to treatment. In rare cases of bilateral total deafness, cochlear implants were beneficial for speech perception. Vaccination against mumps is recommended to prevent mumps-associated hearing loss. OBJECTIVE: The objective of this study is to investigate the clinical characteristics of hearing loss due to mumps and to evaluate hearing outcomes. SUBJECTS AND METHODS: The clinical parameters were analyzed under a retrospective multi-institutional study design in patients diagnosed with hearing loss due to mumps at the Otolaryngology departments of 19 hospitals between 1987 and 2016. RESULTS: Sixty-seven patients with hearing loss due to mumps were enrolled. The study population consisted of 35 males and 32 females, ranging in age from 1 to 54, with a median age of 9.5 years. Sixty-three patients presented with unilateral, and 4 with bilateral hearing loss. Profound hearing loss was observed in 65 ears. Only one ear with severe hearing loss showed complete recovery. Four patients with bilateral hearing loss received cochlear implant surgery. Most of the patients with hearing loss due to mumps had no history of vaccination.

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

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

A comparative proteomics study of a synovial cell line stimulated with TNF-α.

To elucidate the pathogenesis of rheumatoid arthritis (RA), we used proteomic analysis to determine the protein profile in a synovial cell line, MH7A, established from patients with RA. Proteins were extracted from MH7A cells that were or were not stimulated with tumor necrosis factor-α (TNF-α), and then analyzed on a liquid chromatography/mass spectrometry system equipped with a unique long monolithic silica capillary. On the basis of the results of this proteomic analysis, we identified 2650 proteins from untreated MH7A cells and 2688 proteins from MH7A cells stimulated with TNF-α. Next, we selected 269 differentially produced proteins that were detected only under TNF-α stimulation, and classified these proteins by performing gene ontology analysis by using DAVID as a functional annotation tool. In TNF-α-stimulated MH7A cells, we observed substantial production of plasminogen-activator inhibitor 2 and apoptosis-regulating proteins such as BH3-interacting domain death agonist, autophagy protein 5, apolipoprotein E, and caspase-3. These results indicate that the upregulation of plasminogen-activator inhibitor 2 and apoptosis-regulating proteins in synovial cells in response to TNF-α stimulation might represent a predominant factor that contributes to the pathogenesis of RA.

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

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

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

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

A case of atypical teratoid/rhabdoid tumor in the internal auditory canal.

OBJECTIVE: The case of a thirteen-year-old woman showing an atypical teratoid/rhabdoid tumor (AT/RT) primarily occurred in the internal auditory canal was presented. RESULTS: There was a delay in diagnosing AT/RT because of the first histological diagnosis of benign neurofibroma. If we had changed the surgical approach to one which was middle cranial fossa-based or translabyrinthine in the second or third operation, we might have reached an earlier final diagnosis. Although we faced a dilemma about whether to sacrifice facial nerve function for dissection of the tumor, we should have considered the possibility of malignancy at an earlier stage. CONCLUSION: This is a case report of AT/RT in the internal auditory canal presenting with progressive hearing loss as the initial symptom. Although no previous reports of AT/RT primarily occurring in the internal auditory canal are existent, this rare form of the disease should be considered in future evaluations as a differential diagnosis for internal auditory canal tumor.

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

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

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

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

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study.

OBJECTIVES: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. METHODS: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. RESULTS: A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. CONCLUSIONS: TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.

Inhibitory effects of H-Ras/Raf-1-binding affibody molecules on synovial cell function.

Affibody molecules specific for H-Ras and Raf-1 were evaluated for their ability to inhibit synovial cell function. Affibody molecules targeting H-Ras (Zras122, Zras220, and Zras521) or Raf-1 (Zraf322) were introduced into the MH7A synovial cell line using two delivery methods: transfection with plasmids encoding the affibody molecules or direct introduction of affibody protein using a cell-penetrating peptide reagent. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) production by MH7A cells were analyzed by enzyme-linked immunosorbent assay after stimulation with tumor necrosis factor-alpha (TNF-α). Cell proliferation was also analyzed. Phosphorylation of extracellular signal-regulated kinase (ERK) was analyzed by western blot. All affibody molecules could inhibit IL-6 and PGE2 production in TNF-α-stimulated MH7A cells. The inhibitory effect was stronger when affibody molecules were delivered as proteins via a cell-penetrating peptide reagent than when plasmid-DNA encoding the affibody moelcules was transfected into the cells. Plasmid-expressed Zras220 inhibited phosphorylation of ERK in TNF-α-stimulated MH7A cells. Protein-introduced Zraf322 inhibited the production of IL-6 and PGE2 and inhibited cell proliferation in MH7A cells. These findings suggest that affibody molecules specific for H-Ras and Raf-1 can affect intracellular signal transduction through the MAP kinase pathway to inhibit cell proliferation and production of inflammatory mediators by synovial cells.