Fragility Fracture Network-Japan: The challenge of establishment of a national hip fracture database and successful achievement of nationwide health system change for hip fracture care in Japan.

BACKGROUND: In April 2022, a new reimbursement scheme for hip fracture was implemented by the Japanese health ministry. Japan is one of the world's most aged societies, facing a significant, rapidly growing burden of osteoporosis and fragility fractures. The incidence of hip fractures is projected to increase from 240,000 in 2020 to 320,000 by 2040. In 2015, Fragility Fracture Network-Japan (FFN-Japan) was formally established as a nonprofit organization in order to create the optimal fragility fracture care system in Japan. METHODS: FFN-Japan launched the Japan National Hip Fracture Database (JNHFD) in 2017, initially with only eight participating hospitals across Japan. The number of patients enrolled from May 2017 to the end of 2020 in the JNHFD from the 16 hospitals registered the patients during this period with amounting to 4271 patients in total. FFN-Japan invited officials from the Ministry of Health, Labor and Welfare (MHLW) to participate in round table meetings to discuss the data collected in the JNHFD and to consider opportunities for nationwide improvement in hip fracture care. RESULTS: The proportion of patients who underwent surgery within 36 h of arrival at hospital was 48.1% in 2018, 58.6% in 2019, and 44.9% in 2020 indicating the delay of surgery. Regarding secondary fracture prevention, initiation of osteoporosis treatment during the in-patients was 60.2% in 2018, 54.0% in 2019, and 64.5% in 2020 indicating the inadequate post fracture care. In April 2022, the Central Social Insurance Medical Council of the Japanese MHLW announced a new reimbursement scheme for hip fracture care including two key components: Early surgery (within 48 h from injury) and Secondary fracture prevention immediately after fracture. DISCUSSION: The new reimbursement scheme of hip fracture care in Japan will catalyze and underpin major improvements on acute multidisciplinary care and post-fracture care with secondary fracture prevention. FFN-Japan played a key role on these policy changes to the health system by means the close collaboration and ongoing communication with the government. CONCLUSION: Within five years of establishment of the JNHFD, FFN-Japan in collaboration with visionary leaders from the Japanese government have successfully achieved a major reform of the Japanese health system's reimbursement of hip fracture care. This reform has laid the foundation for transformation of management of this debilitating and life-threatening injury that currently afflicts almost a quarter of a million older Japanese citizens each year.

Clinical features of patients with connective tissue disease with anti-human upstream binding factor antibodies: A single-center retrospective study.

Anti-human upstream-binding factor (anti-hUBF) antibodies have been reported predominantly in patients with connective tissue diseases (CTDs); these have also been reported in patients without CTDs such as hepatocellular carcinoma. Because of the low frequency of expression and few case reports, there is no consensus on the clinical significance of these antibodies. Thus, we aimed to examine the clinical features of patients with anti-hUBF antibodies and analyzed 1042 patients with clinically suspected CTDs. The presence of anti-hUBF antibodies was screened using immunoprecipitation assays. Of the 1042 patients, 19 (1.82%) tested positive for anti-hUBF antibodies; among them, 10 (56%) were diagnosed with undifferentiated CTD (UCTD), six with systemic sclerosis (SSc) and three with other diseases. Five of the 10 patients with UCTD were referred to our hospital with suspected SSc. None of the five patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria, but three scored seven points, a relatively high score. Six anti-hUBF-positive patients with SSc had a significantly lower modified Rodnan skin score (mRSS) than that of anti-hUBF-negative patients with SSc (2 [0-2] vs 7 [0-49], p < 0.01). Compared with anti-topoisomerase I-positive patients, anti-hUBF-positive patients had a significantly lower mRSS (2 [0-2] vs 13 [0-42], p < 0.01) and lower incidence of scleroderma renal crisis (0 of 6 vs 8 of 184, p < 0.01). Compared with anti-centromere-positive patients, anti-hUBF-positive patients had a higher incidence of interstitial lung disease (ILD), but the difference was not statistically significant (4 of 6 vs 19 of 239). In conclusion, anti-hUBF antibodies were predominantly detected in patients with CTDs and UCTD. In patients with CTDs, SSc exhibited a high ratio, displaying a lower mRSS and higher incidence of ILD. In patients with UCTD, careful follow-up is recommended as they may develop CTDs in the future.

De novo normotensive scleroderma renal crisis six years after living-donor renal transplantation in a patient with overlapping systemic sclerosis/systemic lupus erythematosus syndrome: a case report.

BACKGROUND: Scleroderma renal crisis (SRC) is a critical kidney involvement of systemic sclerosis (SSc), often resulting in end-stage renal disease. Although the recurrence of SRC in the allograft has been reported, the development of de novo SRC after kidney transplantation has not been reported. Furthermore, normotensive SRC, which rarely occurs, makes prompt diagnosis more challenging. This fact should be recognized widely among nephrologists. CASE PRESENTATION: We report a 37-year-old Japanese man with overlapping SSc/systemic lupus erythematous syndrome who developed normotensive SRC in the transplanted kidney shortly after glucocorticoid escalation. Six years prior to admission, he underwent an ABO-compatible living donor kidney transplantation because of lupus nephritis. He was admitted to our hospital for gradually worsening kidney dysfunction. A kidney biopsy showed idiopathic granulomatous interstitial nephritis and high-dose prednisolone was prescribed. Although renal function improved tentatively, it deteriorated again a week later. A secondary kidney biopsy revealed acute thrombotic microangiopathy, leading to the diagnosis of normotensive SRC because all other causes were excluded, and blood pressure was within normal range. Adding an angiotensin-converting enzyme inhibitor and tapering glucocorticoid slowed the speed of deterioration of his kidney function, but he finally required hemodialysis induction. CONCLUSIONS: SRC can newly develop even in the transplanted kidney, especially when high-dose glucocorticoid is administered. Normotensive SRC makes the diagnosis challenging, so nephrologists should carefully monitor patients with SSc and transplanted kidneys to treat SRC promptly.

An autopsy case of anti-MDA5 antibody-positive amyopathic dermatomyositis with an initial manifestation of panniculitis on the left upper arm.

A 53-year-old man was presented with refractory panniculitis on the left upper arm that had persisted for 10 months. The patient was diagnosed with lupus profundus, wherein oral glucocorticoid therapy was initiated. Four months prior, ulceration was observed in the same area. Dapson was administered instead, scarring the ulcer but enlarging the panniculitis. Five weeks earlier, he developed a fever, productive cough, and dyspnoea. Three weeks earlier, a skin rash was observed on the forehead, left auricle posterior to the neck, and extensor aspect of the left elbow. Chest computed tomography showed pneumonia in the right lung, after which the patient's dyspnoea worsened. The patient was admitted and diagnosed with anti-MDA5 antibody-positive amyopathic dermatomyositis (ADM) based on skin findings, hyperferritinaemia, and rapidly progressive diffuse lung shadows. Glucocorticoid pulse therapy, intravenous cyclophosphamide, and tacrolimus were initiated, and later, plasma exchange therapy was combined. However, his condition worsened and required management with extracorporeal membrane oxygenation. The patient expired on day 28 after hospitalisation. An autopsy revealed hyalinising to fibrotic stages of diffuse alveolar damage. Strong expression of myxovirus resistance protein A was observed in three skin biopsy specimens from the time of initial onset, consistent with ADM. Anti-MDA5 antibody-positive ADM not only manifests typical cutaneous symptoms, but also rarely occurs with localised panniculitis, such as in the present case. In patients with panniculitis of unknown aetiology, the possibility of initial symptoms of ADM should be included in the differential diagnosis.

Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide.

Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft-versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance.

Longitudinal changes in nailfold videocapillaroscopy findings differ by myositis-specific autoantibody in idiopathic inflammatory myopathy.

OBJECTIVE: To assess the longitudinal changes in nailfold videocapillaroscopy (NVC) in patients expressing myositis-specific autoantibodies [anti-aminoacyl-tRNA synthetase (ARS), anti-transcriptional intermediary factor 1 (TIF1), and anti-melanoma differentiation-associated gene 5 (MDA5)]. METHODS: This study was performed retrospectively, at a single site, on an observational cohort. Seventy-one idiopathic inflammatory myopathy patients were included (25 patients expressed anti-MDA5 Abs, 24 patients expressed anti-TIF1 Abs, and 22 patients expressed anti-ARS Abs). NVC findings included giant, enlarged, and reduced capillaries, haemorrhages, capillary ramification, disorganization of the vascular array, and capillary loss. NVC findings were compared from baseline to after disease activity stabilization. RESULTS: The frequency of enlarged capillaries at baseline was different among the three groups, and was significantly higher in patients with anti-TIF1 Abs compared with those with anti-ARS Abs (88% vs 55%, P < 0.05). Reduced capillaries were significantly increased in patients with anti-TIF1 Abs compared with those with anti-MDA5 (96% vs 44%, P < 0.0001) or anti-ARS Abs (96% vs 50%, P < 0.0005). Both enlarged and reduced capillaries improved after stabilization in patients with anti-MDA5 Abs (P < 0.0001 and P < 0.05, respectively). These improvements were not observed in patients expressing anti-TIF1 and anti-ARS Abs. However, a significant reduction in haemorrhages was observed in all three groups (P < 0.0001 for each group). CONCLUSIONS: The results of this study demonstrate that longitudinal changes in NVC findings may vary depending on myositis-specific Ab expression. Therefore, it is crucial to assess individual NVC findings separately, as each finding may impact disease activity in a different manner.

Fragility Fracture Systems: International Perspectives - Asia & Australia.

Background: The incidence and burden of fragility fractures have reached the level where comprehensive systematic care is warranted to optimize the care of these patients. Hip fractures are the most frequently lethal and independence level changing fragility fractures, responsible for 30-day mortality comparable to high-energy trauma patients with injury severity scores over 12. It is a reasonable expectation that countries have a hip fracture treating system of care in place for this high-risk population. This review explores the systems of care from the Asia-Pacific Perspective. Methods: From the International Orthopaedic Trauma Association's member societies, nations from the Asia-Pacific Region were requested to contribute with an overview of their fragility fracture management systems. The content or the review was standardized by a template of headings, which each country endeavored to cover. Results: Australia, Japan, and South Korea contributed voluntarily from the 5 member countries of the region. Each country has made considerable efforts and achievements with diverse approaches to standardize and improve the care of fragility fractures, particularly hip fractures. Beyond the individual nations' efforts there is also an existing Asia-Pacific Collaborative. The data collection and in some counties the existence of a registry is promising; funding and recognition of the problem among competing health care budget priorities are common. Conclusions: Our review covers some of the countries with strongest economy and highest health care standards. The lack of a universal robust system for hip fracture care is apparent. The data collection from registry initiations is expected to drive system development further in these countries and hopefully fast track the development in other countries within the most populous geographical region of the Earth.

Transcutaneous CO2 Pressure Monitoring Increases Salvage Rates after Free Tissue Transplantation for Extremity Reconstruction.

Although free tissue transplantation (FTT) is an essential technique in extremity functional reconstruction, postoperative blood flow disturbance is one of the critical complications leading to transplanted tissue necrosis. Early detection of this complication may prevent tissue failure by prompt improvement of blood flow. The aim of this study was to determine whether transcutaneous carbon dioxide pressure (TcPCO2) monitoring increases the salvage rates after FTT. Methods: We retrospectively reviewed 75 consecutive patients who underwent FTT for extremity reconstruction with TcPCO2 monitoring postoperatively between December 2016 and September 2021. Results: Extremity reconstruction was performed in 53 cases due to trauma, 20 cases due to infection, and two cases due to tumor resection for tissue defects. The overall success rate of the FTT was 98.7%, with 13 complications. Of the 11 patients who underwent reoperation, nine had thrombosis and two had vascular strangulation. However, when reoperation was decided, none of the reoperation cases still exhibited any deterioration in the Doppler or clinical assessment. All reoperated cases were salvaged. Of the two patients who did not undergo reoperation, one had failed flaps and one had partial skin necrosis. With a TcPCO2 cutoff value of 70 mm Hg, the sensitivity and specificity for detecting complications due to impaired blood flow were 100% and 93.5%, respectively. Conclusions: TcPCO2 monitoring was performed after FTT for extremity reconstruction, and all cases of reoperation were salvaged. TcPCO2 monitoring can detect impaired postoperative blood flow critically earlier than clinical assessments and may increase salvage rates of transplanted tissue.

Cytokine-producing B-cell balance associates with skin fibrosis in patients with systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. Over 90% of patients with SSc are positive for autoantibodies. In addition, the serum levels of B-cell activating factor, a potent B-cell stimulator, are correlated with SSc severity and activity. Thus, B cells play an important role in SSc pathogenesis. However, two opposing B-cell subsets exist: effector B cells (Beff) and regulatory B cells (Breg). Interleukin (IL)-6-producing Beff have been shown to promote scleroderma in a mouse model, whereas IL-10-producing Breg inhibit scleroderma development. In the present study, we investigated the clinical association of effector and regulatory B cells in patients with SSc. The blood levels of IL-6-producing Beff and IL-10-producing Breg were measured in 30 patients with SSc and 21 healthy subjects by flow cytometry. The frequency of IL-6-producing Beff in the blood was significantly (p < 0.0001) elevated in patients with SSc (median, 56.2%; range, 35.3-81.3%) compared with that in healthy controls (median, 41.3%; range, 21.0-61.3%). In contrast, the frequency of IL-10-producing Breg in the blood was significantly (p < 0.05) decreased in patients with SSc (median, 1.4%; range, 0.5-2.8%) compared with that in healthy controls (median, 2.0%; range, 1.1-3.8%). The Beff/Breg ratio was significantly increased in patients with SSc. In addition, the Beff/Breg ratio was positively correlated with the skin score and extent of interstitial lung disease. These results suggest that dysregulation of effector and regulatory B-cell balance contributes to SSc pathogenesis.

Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress.

SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-ß (Aß), and overexpression of SIRT3ct suppressed the toxic function of Aß in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.

Distal tibial oblique osteotomy for reconstruction of ankle joint congruity and stability.

Teramoto distal tibial oblique osteotomy (DTOO) is a joint-preserving surgery for ankle osteoarthritis (AOA). However, there are few articles on the radiological assessment of DTOO. The purpose of this study was to report the clinical outcomes and radiological evaluations of weight-bearing radiographs before and after DTOO. We retrospectively reviewed 52 patients who underwent DTOO between 2007 and 2018. We recorded the Tanaka-Takakura classification, fixation methods, Japanese Society for Surgery of the Foot Ankle/Hindfoot Scale (JSSF scale), and complications. The tibial articular surface angle (TAS), medial malleolar angle (MMA), tibial lateral surface angle (TLS), talar tilt angle (TTA), and tibiotalar surface angle (TTS) were evaluated using weight-bearing ankle radiographs. The median patient age was 66 years, and the mean follow-up duration was 46 ± 23 months. Two stage 2, 9 stage 3a, 30 stage 3b, and 11 stage 4 according to the Tanaka-Takakura classification were performed using DTOO. The JSSF scale improved significantly from 39.9 ± 13.8 before surgery to 87.2 ± 7.5 after surgery. Seven cases were fixed using a locking plate, and 45 cases were fixed using a circular external fixator. The TAS, MMA, TLS, TTA, and TTS significantly changed before and after DTOO. Radiological evaluation indicated that DTOO influences talar behavior during weight-bearing, and improves the clinical outcomes of AOA.

Tibial condylar valgus osteotomy (TCVO): Surgical technique and clinical results for knee osteoarthritis with varus deformity.

Tibial condylar valgus osteotomy (TCVO) is an intra-articular proximal tibial osteotomy developed in 1989 and has since been used for the treatment of knee osteoarthritis (OA) associated with genu varum. This article describes the surgical technique and clinical results of TCVO. TCVO can be used for all grades of varus knee OA in patients of any age. he preoperative range of movement should be at least 90°. Preoperative screening showed varus-valgus instability due to an intra-articular deformity of the proximal tibia. Using intraoperative image intensification, a sagittally oriented "L"-shaped osteotomy is made from the medial to the tibial tuberosity to the center of the tibial plateau between the medial and lateral tibial spines. The separation of the osteotomy using the lamina spreader is gradually increased using an image intensifier guidance until the articular surface of the lateral tibial plateau comes in contact with the articular surface of the lateral femoral condyle. Adequate correction is indicated by parallelism of the lateral tibial plateau and a line tangential to the distal convexity of the lateral femoral condyle on an anteroposterior (AP) image and the elimination of the valgus instability with the knee in extended position. A "T"-plate (locking or non-locking plate or circular external fixator) is used to fix the osteotomy in the corrected position. Synthetic or autologous bone grafts can be used. We used the Japanese Orthopaedic Association score to evaluate the patient's function and also measured the %MAD, medial plateau opening angle, medial plateau angle, and lateral plateau opening angle on an AP view of the long length roentgenogram of the lower limb (standing position). The JOA score, radiologically measured values, and instability of the knee joint remarkably improved.

Radiological assessments and clinical results of intra-articular osteotomy for traumatic osteoarthritis of the ankle.

INTRODUCTION: Traumatic osteoarthritis of the ankle joint caused after malleolar fractures of the ankle and tibial plafond fractures are frequently observed in comparatively young and highly active patients. Since the ankle movement in these patients is in general, comparatively favorable, orthopedists may sometimes have difficulty in deciding on a treatment policy. In our department, when treating traumatic osteoarthritis patients having a movable range within their ankle joints, we proactively applied distal tibial oblique osteotomy (DTOO) developed by Dr. Teramoto in 1994 or intra-articular osteotomy developed based on DTOO concepts such as distal tibial intra-articular osteotomy (DTIO) and distal fibular oblique osteotomy (DFOO).The objectives of the current study are to radiologically assess the ankle joint after intra-articular osteotomy for traumatic ankle osteoarthritis and evaluate the change in configuration of the ankle joint. This study summarizes the clinical results of intra-articular osteotomy obtained through the above-mentioned study. PATIENTS AND METHODS: The subjects of this study were 20 patients diagnosed with traumatic osteoarthritis who were surgically treated for a total of 20 ankles. All patients underwent treatment with intra-articular osteotomy and were evaluated retrospectively for the following parameters: surgical procedure, fixation devices, clinical results based on the Japanese Society for Surgery of the Foot ankle/hindfoot scale (hereafter, JSSF scale) and post-operative adverse events. They were also assessed radiologically with pre- and post-operative anterior-posterior (AP) and lateral weight-bearing ankle radiographs. RESULTS: The 20 patients consisted of 12 males and 8 females. The median age at surgery was 49 years old (range 14 - 87 years old) and the average follow-up period was 42 months (range 19 to 121 months). DTOO was applied to 10 cases, DFOO to 2 cases, DTOO and DFOO to 2 cases, medial-distal tibial intra-articular osteotomy (M-DTIO) and DFOO to 1 case, lateral-distal tibial intra-articular osteotomy (L-DTIO) and DFOO to 3 cases, M-DTIO followed by DTOO and DFOO to 1 case, and DTOO followed by low tibial osteotomy (LTO) to 1 case. Fixation devices utilized included circular external fixator for 15 cases, locking compression plate (LCP) to 3 cases, LCP and Kirschner-wire (K-wire) to 1 case, and screw and K-wire to 1 case. Radiological assessment revealed significant changes in the following parameters after surgery: tibial ankle surface angle (TAS, P= 0.0203), tibiotalar surface angle (TTS, P= 0.0021), medial malleolar angle (MMA, P= 0.0217), empirical axis (EA, P= 0.0019), fibular angle (FA, P= 0.0002), talar tilt angle (TTA, P= 0.0374), and tibial lateral surface angle (TLS, P= 0.0279). The JSSF scale also improved significantly after surgery (pre-operative JSSF scale: 51.1±11.0, post-operative JSSF scale: 89.2±8.2), p=0.0001. CONCLUSION: Intra-articular osteotomy may change the radiological configuration of the ankle in a weight-bearing state. The present study showed very good short-term clinical results. Intra-articular osteotomy can prove a viable surgical option applicable for treatment of patients with traumatic ankle osteoarthritis having a reasonable range of motion within their ankle joints.

Chipping corrective osteotomy for reconstruction of malunion with angular deformity of the lower extremity: Technical tips and preliminary clinical results.

INTRODUCTION: Significant functional disturbance, deformity, and malalignment may occasionally develop after healing of a fracture, especially one involving the lower extremities. This study sought to provide preliminary evidence of the effectiveness of chipping corrective osteotomy (CCO), which does not require autologous bone grafting, for treating malunion with lower extremity angular deformity. METHODS: We retrospectively reviewed clinical and radiologic results of 6 male patients (median age 48.5 years) treated with CCO for femoral and tibial malunion (4 femurs, 4 tibias) with angular deformity in the coronal plane. In performing CCO, we applied a temporary external fixator to correct the deformity; definitive fixation was performed using a locking plate. Time to consolidation after the surgery was recorded. The Mikulicz line was evaluated before surgery and at final follow-up in each patient to confirm a change in alignment of the affected lower extremity. We measured the score taken as the ratio of the distance between the medial tibial joint surface and the Mikulicz line to the width of the tibial plateau. RESULTS: Median follow-up duration was 34 months. Bone healing was achieved by a median of 3.5 months postoperatively. Correction of the mechanical axis in the affected lower extremity was achieved in all 6 patients. Median score by the length from the tibial medial joint surface to the Mikulicz line to the tibial plateau width was 7.7% preoperatively and 25.7% at final follow-up. DISCUSSION: These preliminary findings suggest that CCO is potentially useful for treating malunion with lower extremity angular deformity. CONCLUSION: Further evaluation in a larger series is needed to clarify the usefulness of CCO in correction of angular malunion.

Sporadic Amyotrophic Lateral Sclerosis Due to a FUS P525L Mutation with Asymmetric Muscle Weakness and Anti-ganglioside Antibodies.

Amyotrophic lateral sclerosis (ALS) due to a fused in sarcoma (FUS) P525L mutation is characterized by a rapidly progressive course. Multifocal motor neuropathy (MMN) may resemble ALS in early stage and is associated with anti-ganglioside antibodies. A 38-year-old woman was admitted to our hospital because of progressive muscle weakness in the right limbs. She had mild mental retardation and minor deformities. Initially, we suspected MMN given the asymmetric muscle weakness and detection of anti-ganglioside antibodies. However, physical and electrophysiological tests did not support MMN, instead suggesting ALS. We confirmed a heterozygous P525L mutation and finally diagnosed this case as ALS due to an FUS mutation.

Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma.

BACKGROUND: Janus kinase (JAK)-signal transducer and activator of transcription (STAT) was hyperactivated in biopsies from patients with systemic sclerosis (SSc) and in several autoimmune disease models. Tofacitinib, a pan-JAK inhibitor, blocks the downstream signaling of multiple cytokines and has exhibited therapeutic efficacy in various autoimmune diseases, although its immunomodulating property in scleroderma is unclear. OBJECTIVE: To evaluate the effect of tofacitinib on the modulation of cytokine-producing T and B cells, and proinflammatory cells in a mouse model of SSc. METHODS: Bleomycin (BLM)-induced SSc was generated by intradermal injection of BLM or PBS for control. Mice received intraperitoneal tofacitinib (20 mg/kg) or vehicle 3 times per week from day 0-28. Mice were sacrificed at day 28 after the last BLM/PBS injection. RESULTS: Tofacitinib administration significantly alleviated fibrosis of the skin and lungs in scleroderma mouse model. Furthermore, tofacitinib suppressed adaptive and innate immune responses by reducing splenocytes, total lymphocytes, CD4+ T helper cells (especially Th2 and Th17 subtypes), IL-6-producing effector B cells, PDCA-1+ dendritic cells in the spleen, and infiltration of F4/80+, CD206+ and CD163+ macrophages in the skin and lungs. Conversely, tofacitinib increased the proportions of splenic regulatory T and B cells. The mRNA expression of extracellular matrix proteins and fibrogenic cytokines was downregulated by tofacitinib in both the skin and lungs. CONCLUSION: These observations suggest JAK inhibition as a therapeutic approach for the treatment of inflammatory and fibrotic diseases, and highlight the potential of tofacitinib as a promising candidate for treating patients with scleroderma.

Suppression of IL-23-mediated psoriasis-like inflammation by regulatory B cells.

Psoriasis is an inflammatory cutaneous disease mediated by T-cell dependent immune responses; however, B cells are also considered to play an important role its development. Regulatory B cells (Bregs) regulate immune responses negatively through interleukin-10 (IL-10) production. This study aimed to investigate the role of Bregs in IL-23-mediated psoriasis-like inflammation in mice. Psoriasis-like inflammation was induced in B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, in which Bregs were significantly expanded, and in their controls, by intradermal injection of 20 µL phosphate-buffered saline (PBS) containing 0.5 µg rmIL-23 into one ear, every other day for 16 days. IL-23-mediated psoriasis-like inflammation was suppressed in B cell-specific PTEN-deficient mice along with decreased ear thickness and epidermal thickness on day 15. Moreover, adoptive transfer of B1 B cells suppressed IL-23-mediated psoriasis-like inflammation. rmIL-23-injected B cell-specific PTEN-deficient mice showed expanded regulatory T cells (Tregs) in the spleen and draining lymph nodes along with increased Bregs. Further, T helper (Th) 17 differentiation in the rmIL-23-injected ear was suppressed in B cell-specific PTEN-deficient mice. Overall, these results indicate that increased Bregs suppress IL-23-mediated psoriasis-like inflammation through Treg expansion and inhibition of Th17 differentiation. Thus, targeting Bregs may be a feasible treatment strategy for psoriasis.

Long-term changes in nail fold capillary abnormalities and serum fibroblast growth factor 23 levels in dermatomyositis patients with anti-melanoma differentiating antigen 5 antibody.

Nail fold videocapillaroscopy (NVC) abnormalities are a characteristic finding of microangiopathy in dermatomyositis (DM). The aim of the present study was to examine long-term changes in NVC abnormalities and serum fibroblast growth factor 23 (FGF23) and vascular endothelial growth factor (VEGF) levels in DM patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab). Serum levels of FGF23 and VEGF were measured by enzyme-linked immunosorbent assay. NVC abnormalities were evaluated by capillaroscopy in 11 DM patients with anti-MDA5 Ab at baseline and after treatment. NVC abnormalities included irregularly enlarged capillaries, reduced capillaries, hemorrhages, capillary ramifications, disorganization of the vascular array, loss of capillaries and giant capillaries. Serum FGF23 levels were significantly decreased in patients with anti-MDA5 Ab (0.3 ± 0.3 pmol/L) compared with healthy controls (1.0 ± 0.6 pmol/L, P < 0.01). Serum FGF23 levels significantly increased after treatment (0.3 ± 0.3 vs 1.0 ± 0.7 pmol/L, P < 0.005), but serum VEGF levels were comparable between at baseline and after treatment. At baseline, irregularly enlarged capillaries were observed in 10 of 11 patients, but after treatment, they were significantly reduced in only two (91% vs 18%, P < 0.001). Hemorrhages were observed in all 11 patients at baseline, but disappeared in all after treatment (100% vs 0%, P < 0.001). These results suggest that NVC abnormalities are reversible by treatment and that serum FGF23 levels reflect the degree of microvascular damage in DM patients with anti-MDA5 Ab.

A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor.

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.