Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

Efficacy and safety of 5-aminolevulinic acid in adult-onset Still's disease: A preclinical study in mice and a pilot study in humans.

The study aimed to investigate the therapeutic effects of 5-aminolevulinic acid/sodium ferrous citrate (5-ALA/SFC) on adult-onset Still's disease (AOSD), specifically focusing on arthritis and macrophage activation syndrome (MAS). We used mouse models to assess the impact of 5-ALA/SFC on collagen-induced arthritis (CIA) and MAS induced by synthetic oligonucleotides containing CpG motifs (CpG-S-ODN). Additionally, we conducted a pilot study with AOSD patients receiving prednisolone (PSL) treatment and 5-ALA/SFC administration to evaluate its efficacy and safety. The 5-ALA/SFC group exhibited significantly lower joint scores in CIA mice. In CpG-S-ODN-treated mice, 5-ALA/SFC administration led to reduced hemophagocytosis and splenomegaly. The anti-inflammatory properties of 5-ALA/SFC were attributed to the suppression of CCL4 and CXCL10 production in monocytes and the induction of M2 macrophages. AOSD patients treated with 5-ALA/SFC demonstrated successful PSL tapering without adverse events. Collectively, the administration of 5-ALA/SFC showed promising potential in ameliorating arthritis and MAS in AOSD patients.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Prediction of radiographic progression during a treat-to-target strategy by the sequential application of MRI-proven bone marrow oedema and power-Doppler grade ≥2 articular synovitis in rheumatoid arthritis: Retrospective observational study.

OBJECTIVES: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). METHODS: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. RESULTS: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. CONCLUSION: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA.

Abnormalities of T cells in systemic lupus erythematosus: new insights in pathogenesis and therapeutic strategies.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and sustained production of autoantibodies. Multiple and profound T cell abnormalities in SLE are intertwined with disease expression. Both numerical and functional disturbances have been reported in main CD4+ T helper cell subsets including Th1, Th2, Th17, regulatory, and follicular helper cells. SLE CD4+ T cells are known to provide help to B cells, produce excessive IL-17 but insufficient IL-2, and infiltrate tissues. In the absence of sufficient amounts of IL-2, regulatory T cells, do not function properly to constrain inflammation. A complicated series of early signaling defects and aberrant activation of kinases and phosphatases result in complex cell phenotypes by altering the metabolic profile and the epigenetic landscape. All main metabolic pathways including glycolysis, glutaminolysis and oxidative phosphorylation are altered in T cells from lupus prone mice and patients with SLE. SLE CD8+ cytotoxic T cells display reduced cytolytic activity which accounts for higher rates of infection and the sustenance of autoimmunity. Further, CD8+ T cells in the context of rheumatic diseases lose the expression of CD8, acquire IL-17+CD4-CD8- double negative T (DNT) cell phenotype and infiltrate tissues. Herein we present an update on these T cell abnormalities along with underlying mechanisms and discuss how these advances can be exploited therapeutically. Novel strategies to correct these aberrations in T cells show promise for SLE treatment.

Efficacy and safety of canakinumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: A single-centre observational study.

OBJECTIVES: To evaluate the efficacy and safety of canakinumab in Japanese patients with colchicine-resistant or colchicine-intolerant familial Mediterranean fever (FMF) in a real-world clinical setting. METHODS: We reviewed 13 Japanese FMF patients to whom canakinumab was introduced during the period of October 2017 to December 2020. All patients were diagnosed as FMF according to Tel-Hashomer criteria. We performed genetic analyses for Mediterranean fever or MEFV by targeted next-generation sequencing. Efficacy was assessed by attack frequency and the percentage of patients who achieved attack improvement at 24 weeks. Safety was assessed by adverse events observed during canakinumab treatment. RESULTS: The median duration and follow-up of canakinumab treatment were 13 and 16 months, respectively. The median attack frequency was 0.50 [0.30-1.00] at 24 weeks, which was a significant decrease from 2.00 [0.85-2.88] at the time of induction (p = .019). There were three patients (23%) with complete resolution of attacks at 24 weeks. No serious adverse events were observed. However, one patient had small intestinal ulceration which led to the discontinuation of canakinumab. CONCLUSIONS: Although the number of cases is small, this study suggests that canakinumab is efficacious and safe for use in Japanese patients with colchicine-resistant or colchicine-intolerant FMF in a real-world clinical setting in Japan.

Systemic lupus erythematosus overlapping dermatomyositis owing to a heterozygous TREX1 Asp130Asn missense mutation.

The 3' repair exonuclease 1 (TREX1) gene encodes a nuclear protein with 3' exonuclease activity, and the mutations have been associated with autoimmune diseases. Herein, we performed genetic analysis for the TREX1 gene in 55 patients with systemic lupus erythematosus (SLE). We identified one SLE patient with overlapping dermatomyositis having a heterozygous p.Asp130Asn mutation in the TREX1 gene. The patient had a high level of serum interferon (IFN)-α compared with that in healthy controls and other patients with SLE. In addition, the patient expressed elevated IFN signature genes compared with healthy controls. Our molecular dynamics simulation of the TREX1 protein in a complex with double-stranded DNA revealed that the D130N mutant causes significant changes in the active site's interaction network. One of our cases exhibited a heterozygous TREX1 p.Asp130Asn mutation that contributed to the type I IFN pathway, which may lead to the development of a severe SLE phenotype.

Mediterranean fever gene variants modify clinical phenotypes of idiopathic multi-centric Castleman disease.

Four cases of idiopathic multi-centric Castleman disease (iMCD) reportedly have variants in hereditary autoinflammatory disease-related genes; however, the frequency and role of these variants in iMCD is still unknown. We therefore investigated such gene variants among patients with iMCD and aimed to reveal the relationship between iMCD and autoinflammatory disease-related genes. We reviewed 14 Japanese iMCD patients who were recruited between January 2015 and September 2019. All patients met both the Japanese tentative diagnostic criteria for Castleman disease and the international consensus diagnostic criteria for iMCD. We performed genetic analyses for 31 autoinflammatory disease-related genes by targeted next-generation sequencing. The MEFV gene variants were observed in 10 of 14 patients with iMCD. Although iMCD had a high percentage of exons 2 or 3 variants of MEFV, comparison of data from healthy Japanese subjects indicated that there was no significant difference in the percentage between healthy Japanese subjects and patients with iMCD. Variants of uncertain significance (VUS) in the TNFRSF1A and CECR1 genes were observed in two of the patients, respectively. We divided patients into two groups-those with MEFV variants (excluding E148Q variants) and those without MEFV variants-and compared the clinical characteristics between these two groups. Patients with MEFV variants, excluding E148Q variants, exhibited a significantly higher likelihood of fever and significantly lower levels of hemoglobin than those lacking MEFV variants. Our results indicated that patients with iMCD tended to have a high frequency of MEFV gene variants and the presence of such variants can affect iMCD clinical phenotypes.

Idiopathic multicentric Castleman disease with novel heterozygous Ile729Met mutation in exon 10 of familial Mediterranean fever gene.

OBJECTIVE: While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene. METHODS: We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin. RESULTS: In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease-related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines. CONCLUSION: The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling.

Comparison of the quantitative measurement of 18F-FDG PET/CT and histopathological findings in IgG4-related disease.

OBJECTIVES: To investigate the utility of 18F-FDG PET/CT in the diagnostic procedure of IgG4-related disease (IgG4-RD), we analysed the association between quantitative method of 18F-FDG PET/CT and histological findings. METHODS: Twenty-one patients with IgG4-RD in whom 18F-FDG PET/CT was performed at the time of diagnosis were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardised uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference. RESULTS: The mean age at diagnosis was 64.6±11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue (4.98 and 3.54, respectively p<0.05). The values of SUVmean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively p<0.05). To establish a cut-off value of SUVmean to determine which of multiple lesions should be biopsied, a ROC curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver=1.66 as a cut-off value. CONCLUSIONS: Our present study suggested that quantitative analysis of 18F-FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.

Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan.

BACKGROUND: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. METHODS: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. RESULTS: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status. CONCLUSION: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept. TRIAL REGISTRATION: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.

Methotrexate Alters the Expression of microRNA in Fibroblast-like Synovial Cells in Rheumatoid Arthritis.

We aimed to investigate the effect of methotrexate (MTX) on microRNA modulation in rheumatoid arthritis fibroblast-like synovial cells (RA-FLS). RA-FLS were treated with MTX for 48 h. We then performed miRNA array analysis to investigate differentially expressed miRNAs. Transfection with miR-877-3p precursor and inhibitor were used to investigate the functional role of miR-877-3p in RA-FLS. Gene ontology analysis was used to investigate the cellular processes involving miR-877-3p. The production of cytokines/chemokines was screened by multiplex cytokine/chemokine bead assay and confirmed by ELISA and quantitative real-time PCR. The migratory and proliferative activities of RA-FLS were analyzed by wound healing assay and MKI-67 expression. MTX treatment altered the expression of 13 miRNAs (seven were upregulated and six were downregulated). Among them, quantitative real-time PCR confirmed that miR-877-3p was upregulated in response to MTX (1.79 ± 0.46-fold, p < 0.05). The possible target genes of miR-877-3p in RA-FLS revealed by the microarray analysis were correlated with biological processes. The overexpression of miR-877-3p decreased the production of GM-CSF and CCL3, and the overexpression of miR-877-3p inhibited migratory and proliferative activity. MTX altered the miR-877-3p expression on RA-FLS, and this alteration of miR-877-3p attenuated the abundant production of cytokines/chemokines and proliferative property of RA-FLS.

Contributing factors of clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis patients with tightly controlled disease activity in clinical practice: a retrospective study.

OBJECTIVES: To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the 'treat-to-target' strategy in clinical practice. METHODS: We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients' symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients' clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis. RESULTS: Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient's/evaluator's global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy. CONCLUSION: The value of the expected poor-prognosis factors may be diminished by intensive therapy within the 'windows of opportunity'.

Effectiveness and safety of non-tumor necrosis factor inhibitor therapy for anti-human T-cell leukemia virus type 1 antibody-positive rheumatoid arthritis.

OBJECTIVES: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. METHODS: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. RESULTS: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. CONCLUSION: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

The possession of exon 2 or exon 3 variants in the MEFV gene promotes inflammasome activation in Japanese patients with familial Mediterranean fever with a heterozygous exon 10 mutation.

OBJECTIVES: The modification and pathogenesis of MEFV exon 2 or 3 variants in familial Mediterranean fever (FMF) remains unclear. We compared the clinical and laboratory characteristics between the coexistence and noncoexistence of MEFV exon 2 or 3 variants in patients with FMF that had a heterozygous MEFV exon 10 mutation. METHODS: We excluded patients with FMF that had two MEFV exon 10 mutations in one or more alleles and/or MEFV mutations in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygous MEFV exon 10 mutation, and they were divided into the groups with and without MEFV exon 2 or 3 variants of 97 and 34, respectively. RESULTS: All patients with MEFV exon 2 variants had either E148Q and/or L110P variants, none of patients had exon 3 variants. In the univariate analysis, the group with variants had significantly earlier onset, a higher percentage of thoracic pain with febrile attacks, a higher frequency of attack, and a higher IL-18 level at remission compared to the group without variants (all, p<0.05). Importantly, multivariate analyses showed that the coexistence of MEFV exon 2 variants was independently and significantly associated with earlier onset of FMF and thoracic pain (both, p<0.05). CONCLUSIONS: Our results suggested that coexistence of MEFV exon 2 variants have additional effects on manifestations of FMF with MEFV exon 10 mutations. Our findings highlighted the modifications and pathogenesis of such MEFV variants in FMF.

Next-generation sequencing of the whole MEFV gene in Japanese patients with familial Mediterranean fever: a case-control association study.

OBJECTIVES: We aimed to identify the whole nucleotide sequence of the Mediterranean fever (MEFV) gene in familial Mediterranean fever (FMF) and reveal novel single nucleotide variants (SNVs) associated with the susceptibility of FMF. METHODS: SeqCap capturing technique followed by Illumina next-generation sequencing have been used to assess two hundred SNVs in the whole region of MEFV in 266 Japanese patients with FMF and 288 ethnically matched controls. We performed an association analysis using these SNVs to identify genetic variants that predispose to FMF. RESULTS: We identified the two most significant SNVs [rs28940578; M694I in exon 10, odds ratio (OR) = 153, p=2.47×10-21 and rs3743930; E148Q in exon 2, OR = 1.65, p<0.0005]. Stratified analysis identified rs28940578 as a risk allele in typical FMF. Haplotype AG, defined by rs401298 and rs28940578, was the most significant and prevalent among patients with typical FMF compared with controls (22.4% vs. 0%, respectively; OR = 137, p=1.44×10-31). Haplotype GTC, defined by rs11466018, rs224231, and rs401877, was the most significant among patients with typical FMF without the rs28940578 mutation compared with controls (15.9% vs. 6%, respectively; OR = 12.4, p=0.004). CONCLUSIONS: rs28940578 is associated with the highest risk in typical FMF cases. This is consistent with results from previous studies in Japan. We found a novel MEFV gene haplotype that confers susceptibility of FMF among typical FMF without the rs28940578 mutation. There were no relevant SNVs identified in MEFV among the atypical FMF group.

Diagnostic efficacy of ultrasound detection of enthesitis in peripheral spondyloarthritis.

Objective: We investigated the diagnostic efficacy of power Doppler ultrasound (PDUS) to detect enthesitis in Japanese patients with peripheral spondyloarthritis (SpA).Methods: This was a single-center cohort study of patients with peripheral symptoms suggestive of SpA. Articular synovia, tendons, and entheses were assessed by PDUS at baseline. Clinical, laboratory, and radiologic findings and classification criteria for SpA were also evaluated.Results: 136 patients were consecutively evaluated. A definite diagnosis was obtained in 111 patients, including 72 with SpA and 39 non-SpA. Among the patients with SpA, PDUS demonstrated articular synovitis in 40 of the 72 patients (56%), tenosynovitis or peritendinitis in 48 (67%), and enthesitis in 63 (88%). Considering PDUS alone, enthesitis in at least one site was the most useful means of differentiating SpA from non-SpA (sensitivity 87.5%; specificity 82.1%; accuracy 85.6%; positive likelihood ratio 4.88). Combining that finding along with fulfillment of Amor, European Spondyloarthropathy Study Group, or Assessment of SpondyloArthritis international Society criteria for peripheral SpA increased the specificity of the diagnosis (92.5%, 92.3%, and 97.4%, respectively).Conclusion: PDUS enthesitis is useful for the diagnosis of SpA with peripheral symptoms. Combining PDUS enthesitis with established SpA classification criteria is beneficial in diagnosing peripheral SpA.

Denosumab is effective toward glucocorticoid-induced osteoporosis patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drugs.

We examined the efficacy and safety of denosumab as treatment for glucocorticoid-induced osteoporosis (GIOP) patients complicated with rheumatic diseases, by measuring patients' lumber bone mineral density (BMD) and bone turnover markers. A total of 66 consecutive patients for whom denosumab was initiated between July 2013 and August 2016 were enrolled and evaluated for 12 months. All of the patients were treated with glucocorticoids for underlying rheumatic diseases. The clinical assessment included measurements of the BMD of the lumbar spine (L2-L4) by a dual-energy X-ray absorptiometry technique and the bone turnover markers N-terminal telopeptide of type 1 collagen (NTX) in urine, serum intact procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatase (BAP) at baseline, 6 months and 12 months after the start of denosumab treatment. Adverse events (AEs) until 12 months were also analyzed. The mean percentage changes in BMD from baseline to 6 and 12 months were significant (2.85% increase, p < 0.0001 and 4.40% increase, p < 0.0001, respectively) regardless of the prior anti-osteoporotic drugs treatment (16 no transition from anti-osteoporotic drugs, 27 transition from bisphosphonate, 23 transition from teriparatide). The decreases in NTX, P1NP and BAP at 6 and 12 months were also significant. No serious AEs were noted. A multivariable logistic analysis showed that the prednisolone dose at baseline was associated with the clinical response to denosumab. In a real-world setting, denosumab was effective and safe for treating GIOP patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drug treatment.