Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome.

OBJECTIVES: To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance. METHODS: We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases, and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The Presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electric medical records. RESULTS: PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs. CONCLUSION: Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement.

The Role of TLR7 and TLR9 in the Pathogenesis of Systemic Sclerosis.

The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.

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.

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.

SIRT1 decelerates morphological processing of oligodendrocyte cell lines and regulates the expression of cytoskeleton-related oligodendrocyte proteins.

SIRT1 is involved in the regulation of a variety of biological processes such as metabolism, stress response, autophagy and differentiation. Although progenitor cells of oligodendrocytes (OPCs) express high level of SIRT1, its function on differentiation is unknown. Because we have shown that SIRT1 plays a pivotal role in differentiation of neural precursor cells, we hypothesized that SIRT1 may also participate in the differentiation of oligodendrocytes (OLGs). We examined whether SIRT1 was expressed in two human oligodendrocyte cell lines: KG-1-C and MO 3.13 OLG. Transfection of cell lines with SIRT1-siRNA and SIRT2-siRNA promoted the extension of cellular processes. SIRT1-siRNA and SIRT2-siRNA increased acetyl-α-tubulin level, conversely, over expression of SIRTs resulted in decreased the ratio of acetyl-α-tubulin to α-tubulin. We also found knockdown of SIRT1 and SIRT2 induced overexpression of ßIV-tubulin and tubulin polymerization promoting protein (TPPP) (OLG-specific cytoskeleton-related molecules) that distributed widely in cell bodies. Taken together, SIRT1 may play a role in oligodenroglial differentiation and myelinogenesis.

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis.

OBJECTIVE: Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc. METHODS: Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR. RESULTS: Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score <10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers. CONCLUSION: Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc.

Availability of EuroQol-5-Dimensions-5-Level (EQ-5D-5L) as health-related QOL assessment for Japanese systemic sclerosis patients.

Objective: To assess the functional disability in Japanese patients with systemic sclerosis (SSc) using the EuroQol-5-Domain-5-Level health questionnaire (EQ-5D-5L), which was developed in Europe to demonstrate the cost utility of treatments for non-specific diseases.Methods: The EQ-5D-5L and Disability Index of the Health Assessment Questionnaire (HAQ-DI), which is a questionnaire for the quality of life for rheumatic diseases, were completed by 109 Japanese patients with SSc, and the clinical findings and laboratory data were collected at the same time.Results: There was a correlation between the EQ-5D-5L score and HAQ-DI score. The EQ-5D-5L index score was affected by the % of predicted vital capacity (%VC), pulmonary arterial hypertension, and renal crisis. The %VC and renal crisis were also indicated as factors reducing the quality of life in the HAQ-DI. There was no difference in the EQ-5D-5L score between the SSc subtypes or among autoantibodies.Conclusion: Our single-center study demonstrated the EQ-5D-5L to be a valuable assessment tool for functional disability in Japanese SSc patients, similarly to the disease specific HAQ-DI.

Human leukocyte antigen in Japanese patients with idiopathic inflammatory myopathy.

Objective: The human leukocyte antigen (HLA) is the strongest genetic risk factor for idiopathic inflammatory myopathy (IIM), and different HLA alleles have been reported to be associated with IIM susceptibility among different ethnic groups. In this study, we have investigated HLA alleles associated with IIM in Japanese patients.Methods: Genotyping of HLA-DRB1 and DPB1 were performed in 252 Japanese IIM patients (166 dermatomyositis [DM] and 86 polymyositis [PM] patients) and the association was analyzed with comparison to controls (n = 1026 for DRB1 and n = 413 for DPB1).Results: DRB1*08:03 was associated with IIM (p = 1.60 × 10-5, pc = .0005, odds ratio [OR] 2.11, 95% confidence interval [CI] 1.52-2.92) and DM (p = .0004, pc = .0128, OR 2.06, 95%CI 1.40-3.02). DPB1*05:01 was also associated with IIM (p = .0001, pc = .0021, OR 1.96, 95%CI 1.38-2.77) and DM (p = .0005, pc = .0075, OR 2.05, 95%CI 1.37-3.08). DRB1*09:01 (p = .0012, pc = .0368, OR 0.35, 95% CI 0.18-0.69) and DPB1*04:01(p = .0004, pc = .0057, OR 0.05, 95% CI 0.00-0.85) were protectively associated with PM. Two locus analyses suggested that DRB1*09:01 and DPB1*04:01 were independently associated with PM.Conclusion: Protective associations of HLA were detected in Japanese PM patients.

Increased expression levels of FcγRIIB on naïve and double-negative memory B cells in patients with systemic sclerosis.

OBJECTIVES: In systemic sclerosis (SSc), B cell hyperactivation and abnormality are considered to play an important role in the disease pathophysiology. We aimed to clarify if the abnormal activation of B cells involves inhibitory FcγRIIB on B cells in SSc patients. METHODS: Blood samples were collected from 76 SSc patients (38 limited cutaneous SSc and 38 diffuse cutaneous SSc) and 59 healthy controls. We evaluated the expression levels of FcγRIIB on different B cell subsets. B cells were classified into five subsets based on their surface phenotype as measured by flow cytometry: naïve B cells (CD19+IgD+CD27-), pre-switched memory B cells (CD19+IgD+CD27+), double-negative (DN) memory B cells (CD19+IgD-CD27-), switched memory B cells (CD19+IgD-CD27mid), and plasmablasts (CD19+IgD-CD27high). The expression levels of the activation markers CD80, CD86, and CD95 were also examined. RESULTS: The expression levels of FcγRIIB on SSc naïve and DN memory B cells were significantly increased compared to healthy controls (p<0.05 and p<0.001, respectively). CD80, CD86, and CD95 expression levels were significantly higher in all five B cell subsets, except for CD80 in switched memory B cells and plasmablasts. Increased FcγRIIB expression levels on DN memory B cells were associated with disease activity as assessed by the European Scleroderma Study Group Activity Index, presence of interstitial lung disease (ILD), and reduced lung function. Intravenous cyclophosphamide pulse therapy decreased FcγRIIB expression levels on memory B cell subsets. CONCLUSIONS: SSc B cells may exhibit compensatory elevation in the expression levels of FcγRIIB in order to suppress the abnormal activation of B cells. In addition, FcγRIIB expression levels may serve as a marker of severe complications, such as ILD, in SSc.

Long-term follow-up of finger passive range of motion in Japanese systemic sclerosis patients treated with self-administered stretching.

OBJECTIVE: Severe skin sclerosis in patients with systemic sclerosis (SSc) can result in a loss of hand function. The aim of this study is to examine the long-term changes of finger passive range of motion (ROM) in Japanese SSc patients treated with self-administered stretching. METHODS: This is a single-center, retrospective, observational cohort study. Forty-three Japanese patients with SSc were given instructions on self-administered stretching. ROM was assessed using a goniometer on their first visit and after 1 year, 3 years, 5 years and 9 years. Hand function was assessed by the Health Assessment Questionnaire disability index (HAQ-DI) at their first visit and after 9 years. RESULTS: Total passive ROM significantly improved in each finger after 3 years of finger stretching. Most patients (37 of 43 patients, 86%) improved or maintained total passive ROM and hand function within 9 years after their first visit. However, significant improvement of total passive ROM was lost in 6 of 43 SSc patients (14%) 9 years after their first visit. The HAQ-DI also was increased in these six patients. Multivariable analyses revealed that re-elevation of modified Rodnan total skin thickness score during the clinical course (OR = 5.260e + 7, 95% CI 1.52e + 150-uncalculated p = .0096) was the independent factor associated with deterioration of total passive ROM at 9 years. CONCLUSION: Patients with progressive skin sclerosis during the clinical course need multimodality therapy to maintain finger joint motion, since the effect of self-administered stretching is limited in these patients.

Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.

Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702-treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4+ T cells, CD8+ T cells, and CD11b+ cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblasts in vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc.

Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.

B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

Autoantibody to scaffold attachment factor B (SAFB): A novel connective tissue disease-related autoantibody associated with interstitial lung disease.

OBJECTIVE: To identify and characterize a novel connective tissue disease (CTD)-related autoantibody (autoAb) directed against scaffold attachment factor B (SAFB). METHODS: AutoAb specificity was analyzed using RNA and protein-immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. RESULTS: By immunoprecipitation assay, 10 sera reacted with a protein with a molecular weight of approximately 160 kDa. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that the Ab specifically recognized SAFB. Anti-SAFB Abs were detected in 2 of 646 patients with systemic sclerosis (SSc) (0.3%), 1 of 1570 patients with polymyositis/dermatomyositis (0.06%), 4 of 270 patients with interstitial lung disease (ILD) (1.5%), 1 of 43 patients with overlap syndrome (2.3%) and 2 patients with other diseases including primary Raynaud's disease and eosinophilic pneumonia. Five patients with anti-SAFB Abs had Raynaud's phenomenon and 3 had nail fold punctate hemorrhage. Of note, 8 of the 10 patients (80%) suffered from ILD. None of the patients with anti-SAFB Abs had pulmonary arterial hypertension, heart disease, or renal involvement. CONCLUSIONS: Anti-SAFB Ab is a novel CTD-related autoAb possibly associated with ILD.

A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation.

BACKGROUND: IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5+ B1 B cells, CD1dhiCD21+CD23- marginal zone (MZ) B cells, and CD1dhiCD21+CD23+ T2-MZ precursor B cells but do not exclusively belong to either subset. OBJECTIVE: In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. METHOD: We performed microarray analysis comparing IL-10+ and IL-10- B cells. B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in B cells, were examined. RESULTS: Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro. B10 cell numbers were significantly increased in B cell-specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. CONCLUSION: A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells.

Curtain osteophytes are one of the risk factors for the poor outcome of rotational acetabular osteotomy.

PURPOSE: Rotational acetabular osteotomy (RAO) is one of the surgical procedures for painful dysplastic hips. Although several risk factors for poor outcome of RAO have been reported, the presence of a curtain osteophyte in the acetabulum has not been evaluated as a possible risk factor. This study aimed to analyze the risk factors affecting the outcome of RAO and to clarify whether curtain osteophytes are one of the risk factors. METHODS: We retrospectively analyzed 87 hips in 78 patients with a mean age of 36 (range, 13-54) years. The mean follow-up period was 8.3 (range, 2.1-19.5) years. The radiographic severity of osteoarthritis was classified into four stages: pre-arthrosis, initial stage, advanced stage, and terminal stage. The Japanese Orthopaedic Association (JOA) hip score was used for clinical evaluation. Poor outcome was defined as a hip with a JOA score < 80 points or terminal-stage osteoarthritis at final follow-up. Several factors were evaluated by logistic regression analysis. RESULTS: At final follow-up, ten hips had a JOA score < 80 and nine hips had progressed to terminal-stage osteoarthritis. Since five hips had a JOA score < 80 as well as terminal-stage osteoarthritis, a total of 14 hips were determined to have poor outcome. An additional ten years of age at surgery, pre-operative minimal joint space < 2 mm, presence of a curtain osteophyte, and fair/poor congruency in abduction were identified as significant risk factors for poor outcome of RAO. CONCLUSIONS: Hips with curtain osteophyte should be evaluated carefully before RAO.

Chipping and lengthening over nailing technique for femoral shaft nonunion with shortening.

PURPOSE: Chipping and lengthening over nailing (CLON) technique was developed to treat femoral shaft nonunion with shortening more than 10 mm. The purpose of the current retrospective case series was to clarify the effectiveness of the CLON technique on the femoral shaft nonunion following intramedullary nailing. METHODS: Clinical and radiological outcomes in the patients receiving operative treatment for femoral shaft nonunion between August 2012 and December 2016 were retrospectively reviewed using the Refractory Fracture Data Registry at the authors' institution. The CLON technique was indicated for patients with the femoral shaft nonunion with shortening more than 10 mm. RESULTS: Five patients with median follow-up of 32 months (range, 14 to 50 months) were included in this study. All patients achieved bone union at the median of 8 months after the CLON technique. The median limb length discrepancy was 2.0 mm at the most recent follow-up. CONCLUSIONS: The present study demonstrated that the CLON technique for femoral shaft nonunion may be the first choice as operative treatment for femoral shaft nonunion with shortening more than 10 mm.

Classification of Japanese patients with mild/early systemic sclerosis (SSc) by the 2013 ACR/EULAR classification criteria for SSc.

OBJECTIVE: To classify Japanese patients with mild/early systemic sclerosis (SSc) by the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria (new 2013 criteria). METHODS: We assessed 120 patients who visited Kanazawa University Hospital suspected of SSc and who did not meet the 1980 ACR preliminary classification criteria for SSc. We clinically diagnosed 16 patients with primary Raynaud's disease and 104 with mild/early SSc prior to being assessed by the new 2013 criteria. RESULTS: None of the 16 patients with primary Raynaud's disease met the new 2013 criteria. On the other hand, 94 out of the 104 patients (90.3%) with mild/early SSc by our clinical diagnosis met the new 2013 criteria. Among the 94 SSc patients, sclerodactyly was detected in 58 (62%), puffy fingers in 62 (66%), abnormal nailfold capillaries in 89 (95%), Raynaud's phenomenon in 93 (99%), and SSc-related autoantibodies (Abs) in 85 (90%). The median (range) score of these 94 patients was 12 (9-14). Ten mild/early SSc patients who did not meet the new 2013 criteria had the following clinical features: puffy fingers in 1 (10%), abnormal nailfold capillaries in 8 (80%), Raynaud's phenomenon in 9 (90%), and SSc-related autoAbs in 8 (80%). The median (range) score of these 10 patients was 7 (5-8). CONCLUSION: The new 2013 criteria can classify most mild/early Japanese SSc patients, which may contribute to early treatment interventions.