Denosumab use reduces risk of rheumatoid arthritis in patients with osteoporosis.

OBJECTIVES: To investigate the protective effect of osteoporosis medications on the risk of developing rheumatoid arthritis (RA) in patients with osteoporosis. METHODS: We conducted a retrospective cohort study from 1 January, 2011 to 31 March, 2023. There was a total of 971901 patients from a hospital-based population in Taiwan. In this cohort, there was a total of 17065 osteoporosis patients with or without pathological fracture. In these patients, 7180 patients were osteoporosis medication users, and 9605 patients were non-osteoporosis medication users, after exclusion of previous RA. The risk of RA in the patients with osteoporosis medications was assessed, and stratified by sex and different medications, including bisphosphonates, denosumab, raloxifene and teriparatide. RESULTS: Patients with osteoporosis medication use had a reduced risk of RA compared with non-osteoporosis medication users [adjusted hazard ratio (aHR)=0.484, 95%CI: 0.270-0.867, p<0.05), after adjusting for age, comorbidites and medications. Specifically, patients with ever use of bisphosphonates (n=2069) or denosumab (n=4510) had a reduced risk of RA (aHR=0.405, 95%CI: 0.173-0.951, p<0.05, and aHR=0.394, 95%CI: 0.192-0.809, p<0.05, respectively). Notably, patients that only used denosumab (n=2938) had a further reduced risk of RA (aHR=0.32, 95%CI: 0.12-0.83, p<0.05), particularly in female patients (aHR=0.26, 95%CI: 0.09-0.74, p<0.05). Patients taking raloxifene or teriparatide did not have a significantly reduced risk of RA. CONCLUSIONS: Denosumab use reduces the risk of RA in patients with osteoporosis. Receptor activator of nuclear factor kappa B ligand (RANKL) mediated osteoclast joint damage may be involved in the pathogenesis of RA during the preclinical stage.

Hydroxychloroquine exposure reduces the risk of cardiovasular disease events in patients with hypertension or diabetes mellitus.

OBJECTIVES: To investigate the association of hydroxychloroquine (HCQ) with the risk of cardiovascular disease (CVD) events in patients with traditional risk factors, hypertension (HTN) or diabetes mellitus (DM). METHODS: We conducted a retrospective cohort study from 1 January, 2010 to 30 September, 2022. There was a total of 1007585 patients from a hospital-based population. In this cohort, 146862 patients had newly diagnosed HTN or DM. Among these patients, 1903 patients had HCQ exposure and 136396 patients had no HCQ exposure after exclusion of previous CVD events or invasive cardiovascular procedures. The risk of developing CVD events, a composite of acute myocardial infarction (AMI) and ischaemic stroke was evaluated. RESULTS: The patients with HCQ exposure had reduced risk of CVD events [HR (hazard ratio)=0.67 95%CI: 0.55-0.83], AMI (HR=0.61, 95%CI: 0.41-0.90) and ischaemic stroke (HR=0.74, 95%CI:0.59-0.93), when compared with non-HCQ exposure, after adjusting for age, sex, rheumatic diseases, comorbidities and medications. Specifically, reduced risk for CVD events (HR=0.67, 95%CI: 0.54-0.83), including AMI (HR=0.67, 95%CI: 0.44-1.00) and ischaemic stroke (HR=0.71, 95%CI: 0.55-0.90) were observed in older patients (age ≥50 yrs) with HCQ exposure, and reduced risk for AMI also observed in younger patients (age <50 yrs) (HR=0.28, 95%CI: 0.08-0.97). Reduced risk for CVD events (HR=0.63, 95%CI: 0.48-0.82) and ischaemic stroke (HR=0.63, 95%CI: 0.47-0.85) were observed particularly in female patients with HCQ exposure. Reduced risk for AMI was observed particularly in male patients with HCQ exposure (HR=0.44, 95%CI: 0.22-0.87). CONCLUSIONS: HCQ has protective effect on CVD events, including both AMI and ischaemic stroke in the patients with traditional risk factors. The protective effect of HCQ on CVD events is prominent in older patients.

Recommendations for psoriatic arthritis management: A joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology.

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

Janus kinase-1 and 3 in ankylosing spondylitis.

BACKGROUND/PURPOSE: To investigate the Janus kinase-1 and 3 (JAK-1 and 3) expression in peripheral blood mononuclear cells (PBMCs) in ankylosing spondylitis (AS). METHODS: The levels of JAK-1 and JAK-3 mRNA in PBMCs, CD3+ T cells and CD14+ monocytes were measured by RT-PCR in 52 AS patients and 31 healthy controls (HCs). The demographic features, BASDAI, BASFI, HLA-B27, ESR, CRP and serum immunoglobulin A (IgA) level were recorded and correlated with the JAK-1 & JAK-3 transcripts in patients and HCs as appropriate. RESULTS: JAK-1 and JAK-3 expression in PB CD3+ T cells plus CD14+ monocytes was significantly higher in AS patients than in HCs (p < 0.05). There is a positive correlation between JAK-1 expression in CD3+ T cells plus CD14+ monocytes and ESR, CRP, IgA, HLA-B27, peripheral arthritis, enthesitis and uveitis (all p < 0.05), respectively. JAK-1 transcript was also increased in CD14+ monocytes from patients and correlated well with ESR and CRP as the disease deteriorated. Conversely, JAK-1 was negatively correlated to chest expansion. Area under the curve of standard receiver operating characteristic suggested that JAK-1 transcript in CD3+ T cells plus CD14+ monocytes is better to predict the higher BASDAI (>4) and BASFI (>4) than ESR or CRP in AS patients. CONCLUSION: In AS, JAK-1 expression in PB cells rather than ESR or CRP might be regarded as a bio-marker for monitoring disease activity and functional index in AS. These findings have also suggested that JAK-1 and JAK-3 expression may play a role in the inflammatory processes in patients with AS.

Suppressors of cytokine signalling in ankylosing spondylitis and their associations with disease severity, acute-phase reactants and serum cytokines.

OBJECTIVES: To investigate the suppressors of cytokine signalling (SOCS1 and SOCS3) expression in peripheral blood cells in ankylosing spondylitis (AS), and their associations with clinical and laboratory manifestations. METHODS: The levels of SOCS1 and SOCS3 mRNA in peripheral blood mononuclear cells (PBMCs), T cells and monocytes were measured by RT-PCR in 53 AS patients and 31 healthy controls. Patient's serum IL-6, IL-10 and IL-17A levels were determined by ELISA. We evaluated patient's disease activity, functional ability and global assessment, and tested their ESR, CRP and IgA levels. RESULTS: Cellular SOCS1 expression did not show significant differences between AS patients and controls. However, T cells SOCS1 decreased significantly in the AS subgroup with lower ESR than controls (p=0.013). PBMCs (p=0.047) and T cells (p=0.035) SOCS1 decreased significantly in the AS subgroup with lower CRP than controls. Importantly, SOCS3 expression increased significantly in AS patients compared to the controls in PBMCs (p=0.025), T cells (p=0.003) and monocytes (p=0.009). Moreover, PBMCs SOCS3 correlated with ESR (r=0.297, p=0.031) and CRP (r=0.320, p=0.019). T cells SOCS3 correlated with BASFI (r=0.337, p=0.015), ESR (r=0.435, p=0.001) and CRP (r=0.300, p=0.029). Monocytes SOCS3 correlated with ESR (r=0.281, p=0.041) and IgA (r=0.426, p=0.006). Furthermore, T cells SOCS1 (r=-0.454, p=0.023) and T cells SOCS3 (r=-0.405, p=0.045) negatively correlated with serum IL-17A. Monocytes SOCS3 negatively correlated with serum IL-6 (r=-0.584, p=0.002). CONCLUSIONS: The decreased SOCS1 and increased SOCS3 expression in AS PBMCs and T cells, and their correlation with patient's functional ability, acute-phase reactants and serum pro-inflammatory cytokines suggested that SOCS may participate in the pathogenesis of AS.

The clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis: the product of these acute-phase reactants and disease duration is associated with patient's poor physical mobility.

We evaluated the clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis (AS) disease severity. There were 156 Chinese AS patients included in Taiwan. Patients completed the questionnaires, containing demographic data, disease activity (BASDAI), functional status (BASFI), and patient's global assessment (BASG). Meanwhile, patient's physical mobility (BASMI) and acute-phase reactants, including ESR and CRP levels were measured. Receiver operating characteristic (ROC) plot analysis was used to evaluate the performance of ESR, CRP, and disease duration in the AS patients. ESR mildly correlated with BASFI (r = 0.176, p = 0.028) and disease duration (r = 0.214, p = 0.008), and moderately correlated with BASMI (r = 0.427, p < 0.001). CRP moderately correlated with BASMI (r = 0.410, p < 0.001). By using ROC plot analysis, ESR, CRP, and disease duration showed the best and significant "area under the curve (AUC)", in distinguishing the AS patients with poor physical mobility (BASMI ≥ 3.6, the Median) (AUC = 0.748, 0.751 and 0.738, respectively, all p < 0.001), as compared to BASDAI, BASFI, and BASG. ESR × disease duration (AUC = 0.801, p < 0.001) and CRP × disease duration (AUC = 0.821, p < 0.001) showed higher AUC values than ESR or CRP alone in indicating poor physical mobility. For detecting poor physical mobility (BASMI ≥ 3.6) in the AS patients: ESR × disease duration (≥60.0 mm/h × year): sensitivity = 72.7 % and specificity = 72.8 %; CRP × disease duration (≥8.3 mg/dl × year): sensitivity = 72.7 % and specificity = 74.6 %. ESR, CRP, and disease duration are particularly related to AS patient's poor physical mobility. Combining the usefulness of acute-phase reactants and disease duration, the values of ESR × disease duration and CRP × disease duration demonstrate better association with poor physical mobility in AS patients.

Bruton's Tyrosine Kinase in Ankylosing Spondylitis.

STUDY DESIGN: Prospective case-control study. OBJECTIVE: To explore the role of Bruton's tyrosine kinase (BTK) in ankylosing spondylitis (AS). SUMMARY OF BACKGROUND DATA: AS substantially affects patients, impairing range of motion in the whole spine and peripheral joints, as well as overall quality of life. However, surveillance for this condition is limited and biomarkers that can predict disease activity are not well documented. METHODS: The expression of the BTK gene in peripheral blood mononuclear cells was measured using flow cytometry and real time quantitative polymerase chain reaction (qPCR) in 36 AS patients and 30 healthy controls. Demographic features, Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP based, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, HLA-B27, ESR, and CRP were evaluated to identify factors associated with BTK expression. Analyses were performed using Spearman's rank correlation test for continuous data, the chi-test for categorical data, and that between continuous and dichotomous variables was measured using a point-biserial correlation test. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to assess the performance of each candidate biomarker. RESULTS: BTK gene expression was significantly higher in AS patients than in controls (P=0.042) according to qPCR results. BTKY223 was also high in CD19+ peripheral blood mononuclear cells (PBMCs) from AS patients, with CD19+BTKY223+high cells being significantly positive correlated to ESR, CRP, and ASDAS. A negative association was observed between BTK expression and the chest expansion distance. The AUC for CD19+BTKY223+ was larger than that for ESR, but CRP still had the largest area. CONCLUSIONS: BTK expression was higher in PBMCs from AS patients when compared to controls, and was associated with a higher disease activity index, inflammatory reactants, arthritis and extra-articular manifestations. These findings suggest that BTK expression may play a crucial role in the inflammatory process in individuals with AS.

Overexpression of decoy receptor 3 in synovial tissues of inflammatory arthritis.

OBJECTIVES: Decoy receptor 3 (DCR3) was a newly identified soluble receptor which was reported to modulate the function of T cells, dendritic cells and macrophages. The aim of this study was to investigate DCR3 expression on the synovial tissue in different types of arthritis. METHODS: We obtained synovial tissues from 17 rheumatoid arthritis (RA), 17 ankylosing spondylitis (AS) and 17 osteoarthritis (OA) patients. Synovial specimens were stained with hematoxylin and eosin. The amount of lymphocytes and mononuclear cells infiltration and vascularity during light microscopic examination was scored from 0-4. The expression of CD3, CD4, CD8, CD68 and DCR3 in lining layer (LL) and sublining layer (SL) cells was stained using the immunohistochemical method and analysed by microscopic examination (score from 0-4, 0=absent, 1=slight, 2=moderate, 3=large, 4=extreme). RESULTS: OA patients were older than the RA and AS patients (65.9±10.3 years for OA, 58.4±17.7 for RA, and 43.2±16.4 for AS). Synovial tissues in RA patients had significantly increased mononuclear cells infiltration when compared to AS and OA patients (2.3±0.6, 1.9±0.5, 1.6±0.5, respectively, p<0.05). There was no striking difference in DCR3 expression in the synovial LL between RA, AS, and OA patients. CD4+ T cells and CD68+ monocytes/macrophages in the SL were more prominent in RA and AS than in OA (p<0.05). Similarly, DCR3 in the SL was more overexpressed in RA and AS than in OA (1.83±0.21, 1.71±0.36, 1.39±0.31, respectively, p<0.01). CONCLUSIONS: The increased synovial inflammatory cells infiltration in RA and AS was associated with the elevated DCR3 expression.

Association of blood pressure and hypertension with radiographic damage among the patients with ankyloing spondylitis.

To investigate the association of blood pressure and hypertension with disease severity among the patients with ankyloing spondylitis (AS). There were 167 AS patients enrolled in the cross-sectional study. Blood pressure was measured and the presence of hypertension was recorded. Patient's disease severity, including disease activity, functional ability, patient's global assessments, physical mobility and radiographic damage were evaluated. ESR and CRP levels were tested. We recorded patient's medication use of NSAIDs, DMARDs and TNF-α blockers. Smoking, exercise habit, diabetes mellitus, hypercholesterolemia and obesity indices were assessed. Multivariate linear regression showed that systolic blood pressure was associated with TNF-α blocker [standard coefficient (ß) = 0.194, P = .007], DMARDs (ß = 0.142, P = .046), age (ß = 0.211, P = .003), male gender (ß = 0.242, P = .001) and body mass index (BMI) (ß = 0.245, P = .001). Diastolic blood pressure was associated with cervical rotation (ß = -0.174, P = .037), lateral lumbar flexion (ß = -0.178, P = .019), m-SASSS (ß = 0.198, P = .038) and BMI (ß = 0.248, P = .003). Notably, multivariate logistic regression showed that hypertension was associated with m-SASSS (OR = 1.033, P = .033), age (OR = 1.098, P = .0010) and BMI (OR = 1.210, P = .003). Using ROC cure analyses, age, BASMI, BASRI-Total, m-SASSS, waist circumference, BMI and waist-to-height ratio were useful in predicting hypertension, and m-SASSS is the best (AUC = 0.784, P < .001). Advanced radiographic damage is an independent risk factor of hypertension in AS, and m-SASSS is the most useful disease severity parameter in predicting the presence of hypertension. Advanced radiographic damage, poor cervical rotation, lateral lumbar flexion, older age, male gender, TNF-α blocker, DMARDs use and obesity are associated with increased blood pressure.

Listeria monocytogenes meningitis in a young woman with systemic lupus erythematosus.

Listeria meningitis, a rare but life-threatening infection in patients with systemic lupus erythematosus, often represents a diagnostic and therapeutic challenge because of its rarity and non-representative manifestations. L. monocytogenes is an intracellular pathogen capable of spreading directly from cell to cell without exposure to the extracellular humoral immune system. With the evolving trend of intense immunosuppressive therapy, patients with SLE usually have abnormal cell-mediated immunity and are susceptible to L. monocytogenes infections. The gastrointestinal tract is usually the portal of entry, and a transient gastroenteritis may precede the full-blown meningitides. Ampicillin and penicillin G are the drugs of choice. For patients who are allergic to penicillin, trimethoprim-sulfamethoxazole is an eligible alternative. Delay in diagnosis and inappropriate antibiotics are detrimental to the outcome. Herein, we report a young woman with systemic lupus erythematosus who developed listeria meningitis. Clinicians are advised to be aware of the clinical presentations of this disease.

Association of sleep disturbance with calcitonin, disease severity and health index among patients with ankylosing spondylitis.

ABSTRACT: To investigate the association of sleep disturbance with calcium regulatory hormones, disease severity and health index among the patients with ankylosing spondylitis (AS).There were 104 AS patients enrolled in the cross-sectional study, and their sleep quality was recorded. Serum levels of calcium, parathyroid hormone, vitamin D3 and calcitonin were measured. We evaluated patient's disease activity, functional ability, patient's global assessment, physical mobility, radiographic damage and health index. Blood ESR and CRP levels were tested.Sleep quality was positively correlated with serum calcitonin levels (r = 0.260, P = .008). Bad sleep and advanced radiographic damage were found among the AS patients with detectable serum calcitonin levels (P < .05). Sleep quality was significantly correlated with disease duration, CRP, BASDAI, ASDAS-ESR, ASDAS-CRP, BASFI, BAS-G, BASMI and ASAS-HI among the AS patients (all P < .05). Female gender, longer disease duration, higher ASDAS-CRP and serum calcitonin levels (OR [95% CI] = 3.210 [1.012-10.181], P = .048) were independent factors associated with bad sleep. Inflammation, disease activity, functional ability, patient's global assessment and cervical rotation were useful in predicting bad sleep among the AS patients, and ASDAS-CRP was the best predictor (AUC = 0.772, P < .001).Serum calcitonin levels was elevated in the AS patients with bad sleep, and may participate in the pathophysiology of sleep disturbance. Bad sleep was associated with female gender, longer disease duration, higher inflammation, disease activity, functional impairment, mobility restriction, poor patient's global assessment and health index in AS. ASDAS-CRP was best in predicting bad sleep.

Human leukocyte antigen-G in ankylosing spondylitis and the response after tumour necrosis factor-alpha blocker therapy.

OBJECTIVE: To investigate the role of HLA-G in AS. METHODS: Serum levels of soluble HLA-G (sHLA-G) were measured in 80 AS patients and 30 healthy controls. The expression of HLA-G on the peripheral blood mononuclear cell (PBMC) surface was investigated in the same 80 AS patients and 40 healthy controls by flow cytometry. The response of HLA-G after 3 months of TNF-alpha blocker therapy (adalimumab) was evaluated in 14 AS patients. We evaluated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Patient Global Score (BAS-G), physical mobility, ESR and CRP levels. RESULTS: Serum levels of sHLA-G were significantly lower in 80 AS patients than 30 healthy controls [mean (s.d.) 22.47 (26.8) vs 34.78 (32.01) U/ml, P = 0.028], and correlated significantly with modified Schober index (r = 0.326; P = 0.009), chest expansion (r = 0.319; P = 0.011), lateral lumbar flexion (r = 0.377; P = 0.002), cervical rotation (r = 0.396; P = 0.004), whereas inversely correlated with fingertip-to-floor distance (r = -0.282; P = 0.026) and tragus-to-wall distance (r = -0.270; P = 0.031). The expression of HLA-G on PBMCs was significantly higher in 80 AS patients than 40 healthy controls [mean (s.d.) 18.5 (6.10)% vs 15.41 (4.84)%; P = 0.012], and correlated significantly with ESR (r = 0.421; P < 0.001) and CRP (r = 0.419; P < 0.001). The expression of HLA-G on PMBCs decreased significantly after 3 months of adalimumab therapy [third month vs baseline, 13.46 (5.38)% vs 19.87 (7.31)%; P = 0.016]. CONCLUSIONS: Lower serum levels of sHLA-G contribute to susceptibility to AS, and predispose to poor spinal mobility. The expression of HLA-G on PMBCs is up-regulated in AS, correlates with acute phase reactants and decreases after TNF-alpha blocker therapy, suggesting an index of disease activity.

Association of obesity with inflammation, disease severity and cardiovascular risk factors among patients with ankylosing spondylitis.

AIM: To investigate total and central obesity in ankylosing spondylitis (AS), and assess the association with inflammation, disease severity and cardiovascular risk factors. METHODS: There were 105 AS patients enrolled. Anthropometry was measured to determine total (body mass index [BMI]) and central obesity (waist circumference [WC], waist-to-height ratio [WHtR]). We evaluated patients' disease activity, functional ability, global assessment, physical mobility, radiographic damage and health index. Erythrocyte sedimentation rate, C-reactive protein (CRP) and blood biochemistry profile were tested. Retrospective radiographic change was assessed in 39 patients. Presence of diabetes and hypertension were examined. RESULTS: The obese AS patients had higher inflammation (CRP), disease activity (Ankylosing Spondylitis Disease Activity Score [ASDAS] - CRP), physical mobility (Bath Ankylosing Spondylitis Metrology Index [BASMI]), radiographic damage (modified Stoke Ankylosing Spondylitis Spinal Score [m-SASSS]), liver function and blood pressure (all P < .05). Obesity (BMI, WC, WHtR) positively correlated with inflammation (CRP), physical mobility (BASMI), radiographic damage (m-SASSS), health index (Assessment of SpondyloArthritis International Society Health Index), liver function and blood pressure (all P < .05). Moreover, presence of central obesity (WC, WHtR) had correlation with disease activity (ASDAS-CRP) (r = .218, P = .027; r = .221, P = .025), and predicted longitudinal radiographic change (m-SASSS) (standard coefficient = 0.300, P = .041; standard coefficient = 0.288, P = .045). Importantly, central obesity was better in predicting high inflammation, disease activity, physical mobility, radiographic damage and health index in AS, and WHtR was the best for predicting m-SASSS (area under the curve = 0.734, P < .001). Obesity was associated with increased risk of diabetes and hypertension in AS. CONCLUSION: Obesity was associated with higher inflammation, disease activity, physical mobility, radiographic damage, health index, liver function and cardiovascular risk factors in AS. Central obesity could predict a patient's longitudinal radiographic change. Central obesity is a useful predictor for high disease severity in AS.

Aberrant distribution and function of plasmacytoid dendritic cells in patients with ankylosing spondylitis are associated with unfolded protein response.

Although human leucocyte antigen (HLA)-B27 is strongly associated with ankylosing spondylitis (AS), the association of unfolded protein response (UPR) induced by HLA-B27 misfolding in AS remains controversial. Since dendritic cells (DCs) are crucial in induction of AS in HLA-B27-transgenic rats, and plasmacytoid DCs (pDCs) belong to one type of DCs, we here aim to study the relevance of pDCs and UPR in AS. Peripheral pDCs were isolated from 27 HLA-B27(+) AS patients and 37 controls. The bone marrow (BM) and synovium of inflamed hips from AS patients and controls were obtained. We found a significantly higher frequency of pDCs in the peripheral blood, BM, or inflamed synovium of hips, which is associated with the enhanced expression of pDC trafficking molecules, CCR6 and CCL20 in the synovium of AS patients. Functional analysis further revealed that several inflammatory cytokines, including TNFα, IL-6, and IL-23, secreted by pDCs were significantly increased in AS patients as compared with those in controls. Remarkably, protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in UPR was up-regulated in pDCs of AS patients. Notably, PERK inhibitor treatment significantly inhibited the enhanced cytokine production by pDCs of AS patients. Further, the extent of PERK activation was significantly associated with the increased disease severity of AS patients. Our data uncover the aberrant distribution and function of pDCs in AS patients. The up-regulated PERK pathway in UPR of pDCs not only contributes to enhanced cytokine production of pDCs, but also is associated with increased disease activity of AS patients.

Taiwan Rheumatology Association consensus recommendations for the management of axial spondyloarthritis.

AIM: To establish guidelines for the clinical management of axial spondyloarthritis that take into account local issues and clinical practice concerns for Taiwan. METHOD: Overarching principles and recommendations were established by consensus among a panel of rheumatology and rehabilitation experts, based on analysis of the most up-to-date clinical evidence and the clinical experience of panelists. All Overarching Principles and Recommendations were graded according to the standards developed by the Oxford Centre for Evidence Based Medicine, and further evaluated and modified using the Delphi method. RESULTS: The guidelines specifically address issues such as local medical considerations, National Health Insurance reimbursement, and management of extra-articular manifestations. CONCLUSION: It is hoped that this will help to optimize clinical management outcomes for axial spondyloarthritis in Taiwan.

Biomarkers in spondyloarthropathies.

The study of biomarkers in spondyloarthropathy (SpA) has emerged to be a very important field of research. This is particularly because the two commonly used biomarkers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are of very low sensitivity and specificity. The second reason is, with advances in the treatment of SpA by the very expensive tumor necrosis factor-alpha (TNF-alpha) blockers, for cost-effectiveness, clinicians need to be much more accurate in predicting disease progression, evaluating disease activity and monitoring therapeutic efficacy. This review focuses on several biomarkers of promise: matrix metalloproteinases 3 (MMP-3), Type II collagen neoepitope (C2C and C1-2C), C-propeptide of Type II collagen (CPII), aggrecan 846 epitope, macrophage colony stimulating factor (M-CSF), serum amyloid A (SAA) and Interleukin-6 (IL-6). The results summarized in Table 1 call for a co-ordinated effort for systematic studies of existing biomarkers and for search for new candidates.

HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-ß (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

Human leukocyte antigens in undifferentiated spondyloarthritis.

OBJECTIVES: Undifferentiated spondyloarthritis (USpA) is a major member of the spondyloarthritis family. Ankylosing spondylitis (AS), the prototype of the family, is a largely genetic disease, with human leukocyte antigens (HLA)-B27 being the essential gene. Other genes in the HLA region have also been implicated. The purpose of this study was to identify the alleles of the HLA-A, -B, -C, -DR, and -DQ, which are present at higher frequencies in USpA patients compared with an ethnically matched control population. METHODS: Sixty-three Taiwanese patients with USpA were compared with 75 matched healthy controls. HLA typing was performed by polymerase chain reaction-sequence specific oligo-nucleotide genotyping. RESULTS: The frequencies of HLA-B27, -B60, -C3, and -DR12 were strikingly higher in USpA patients compared with healthy subjects, with odds ratios of 75.4, 14.0, 9.6, and 7.0, respectively. When USpA patients with axial involvement were compared with those with peripheral arthritis, the following were more marginally frequent in those with axial involvement: HLA-B27 and -DR12 (odds ratios, 4.0 and 4.0, respectively). There was no association of HLA typing with other variables, including enthesitis, uveitis, erythrocyte sedimentation rate, and serum C-reactive protein. Interestingly, in 12 HLA-B27-negative USpA patients, HLA-B60, -C3, and -DR12 were more frequent compared with controls (odds ratios, 35, 16.2, and 8.1, respectively). CONCLUSIONS: Similar to AS, USpA is also linked to HLA-B27. A linkage to other HLA alleles observed here, even in our HLA-B27-negative USpA patients, strongly suggests that USpA in general is a genetic disease.

Association of acute anterior uveitis with disease activity, functional ability and physical mobility in patients with ankylosing spondylitis: a cross-sectional study of Chinese patients in Taiwan.

Acute anterior uveitis (AAU) is the most frequently extra-articular manifestation of ankylosing spondylitis (AS). To investigate whether AAU has an association with disease activity, functional ability and physical mobility in AS patients, 146 Chinese AS patients in Taiwan were enrolled in a cross-sectional study. These patients fulfilled the 1984 modified New York criteria and visited the Outpatient Department of the Veterans General Hospital-Taipei from April 2004 to July 2005. Patients completed questionnaires assessing disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)], functional ability [Bath Ankylosing Spondylitis Functional Index (BASFI)] and patient's global assessment [Bath Ankylosing Spondylitis Patient Global Score (BAS-G)]. Meanwhile, physical examinations were performed, including Schober test, finger-to-floor, lateral spinal flexion, occiput-to-wall and chest expansion. The history of AAU was accepted only if diagnosed by an ophthalmologist. The prevalence of AAU in this Chinese AS cohort was 15.8% (23/146). Patients with AAU had a significantly higher BASDAI than those without [absolute differences=0.96, 95% confidence intervals (CI): 0.35-1.88]. Additionally, patients with AAU had significantly increased BASFI than those without (absolute differences=1.46, 95% CI: 0.33-2.59). Moreover, there was advanced limitation of physical motility in patients with AAU, including finger-to-floor, occiput-to-wall distances and Schober test, (95% CI: 3.89-16.95 and p=0.046, respectively). Disease duration mildly correlated with BASFI (r=0.24, p=0.003) but not with BASDAI (p=0.838). There was no difference of disease duration between patients with and without AAU (p=0.343). These results suggested that the presence of AAU in AS patients may be associated with higher disease activity, poor functional ability and advanced physical impairment.

Undifferentiated spondyloarthropathy in Chinese patients.

BACKGROUND: Undifferentiated spondyloarthropathy (USpA) is a unique group in spondyloarthropathy (SpA). This study will investigate the clinical and laboratory characteristics of USpA in the Chinese population. METHODS: Forty two patients with USpA were enrolled from our rheumatology outpatient facility in this retrospective study. SpA was diagnosed according to the European Spondyloarthropathy Study Group (ESSG) criteria. Patients were considered having USpA when they had SpA but did not meet the criteria for the diagnosis of ankylosing spondylitis (AS), Reiter's syndrome or reactive arthritis (ReA), psoriatic arthritis (PsA), and inflammatory bowel diseases (IBD)-related arthritis, etc. Laboratory tests included erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), immunoglobulin A (IgA), and human leukocyte antigen B27 (HLA-B27). RESULTS: Among the 42 USpA patients, the ratio of men to women was 1.47:1, and the age at onset was 32.33 +/- 10.83 years old. Approximately 61.9% of patients had peripheral arthritis, 30.95% had uveitis, and 64.29% had positive HLA-B27. Among these female USpA patients, compared to males, there is a trend of older age at disease onset, higher percentage of HLA-B27 positive, more peripheral arthritis and uveitis, longer disease duration, and higher level of ESR, and IgA and CRP in serum. The items reaching significant difference between males and females were longer disease duration (p < 0.001), higher level of ESR (p < 0.001), and serum IgA (p = 0.03). There was no significant difference in clinical and laboratory characteristics between HLA-B27-positive and -negative groups. CONCLUSIONS: Studies on USpA patients have not been reported in the Chinese population. In this study, we demonstrate the unique demographic characteristics, clinical and laboratory data of USpA in the Chinese population. These findings should be confirmed by analyzing larger number of patients and longer time for further follow-up. Such studies are crucial to understand the pathogenesis of USpA and evaluate its prognosis.