Showing papers in "International Journal of Rheumatic Diseases in 2019"

2018 update of the APLAR recommendations for treatment of rheumatoid arthritis

Abstract: Aim: To update recommendations based on current best evidence concerning the treatment of rheumatoid arthritis (RA), focusing particularly on the role of targeted therapies, to inform clinicians on new developments that will impact their current practice. Materials and methods: A search of relevant literature from 2014 to 2016 concerning targeted therapies in RA was conducted. The RA Update Working Group evaluated the evidence and proposed updated recommendations using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, to describe the quality of evidence and strength of recommendations. Recommendations were finalized through consensus using the Delphi technique. Results: This update provides 16 RA treatment recommendations based on current best evidence and expert clinical opinion. Recommendations 1-3 deal with the use of conventional synthetic disease-modifying antirheumatic drugs. The next three recommendations (4-6) cover the need for screening and management of infections and comorbid conditions prior to starting targeted therapy, while the following seven recommendations focus on use of these agents. We address choice of targeted therapy, switch, tapering and discontinuation. The last three recommendations elaborate on targeted therapy for RA in special situations such as pregnancy, cancer, and major surgery. Conclusion: Rheumatoid arthritis remains a significant health problem in the Asia-Pacific region. Patients with RA can benefit from the availability of effective targeted therapies, and these updated recommendations provide clinicians with guidance on their use.

2018 APLAR axial spondyloarthritis treatment recommendations.

Abstract: Introduction Despite the availability of axial spondyloarthritis (SpA) recommendations proposed by various rheumatology societies, we considered that a region-specific guideline was of substantial added value to clinicians of the Asia-Pacific region, given the wide variations in predisposition to infections and other patient factors, local practice patterns, and access to treatment across countries. Materials and methods Systematic reviews were undertaken of English-language articles published between 2000 and 2016, identified from MEDLINE using PubMed, EMBASE and Cochrane databases. The strength of available evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Recommendations were developed through consensus using the Delphi technique. Results Fourteen axial SpA treatment recommendations were developed based on evidence summaries and consensus. The first 2 recommendations cover non-pharmacological approaches to management. Recommendations 3 to 5 describe the following: the use of non-steroidal anti-inflammatory drugs as first-line symptomatic treatment; the avoidance of long-term corticosteroid use; and the utility of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for peripheral or extra-articular manifestations. Recommendation 6 refers to the indications for biological DMARDs (bDMARDs). Recommendation 7 deals specifically with screening for infections endemic to Asia, prior to use of bDMARDs. Recommendations 7 to 13 cover the role of bDMARDs in the treatment of active axial SpA and include related issues such as continuing therapy and use in special populations. Recommendation 14 deals with the utility of surgical intervention in axial SpA. Conclusion These recommendations provide up-to-date guidance for treatment of axial SpA to help meet the needs of patients and clinicians in the Asia-Pacific region.

Effect of curcumin nanomicelle on the clinical symptoms of patients with rheumatoid arthritis: A randomized, double‐blind, controlled trial

Abstract: Aim Rheumatoid arthritis (RA) is a systemic inflammatory disease. In recent years, new drugs with novel targets have been developed to increase the efficacy of drugs in the treatment of RA. Curcumin has shown potent anti-inflammatory effects and is considered an anti-tumor necrosis factor. The present study was conducted to determine the effect of curcumin nanomicelle on the clinical symptoms of patients with RA. Methods This randomized, double-blind, controlled trial selected 65 eligible RA patients and randomly divided them into a curcumin nanomicelle group (n = 30) and a placebo group (n = 35). Curcumin nanomicelle (40 mg) and placebo capsules were administrated to the RA patients 3 times a day for 12 weeks. The Disease Activity Score of 28 joints (DAS-28) and erythrocyte sedimentation rate (ESR) were measured at baseline and after 12 weeks. Results The DAS-28, tender joint count (TJC) and swollen joint count (SJC) at baseline and the end of the study were not significant between the curcumin nanomicelle and placebo groups. After the intervention, the within-group DAS-28, TJC and SJC in the curcumin nanomicelle and placebo groups reduced significantly compared to the baseline. The difference in changes between the two groups was not significant. Nonetheless, this change was greater in the case group than in the placebo group. No significant changes were observed in terms of ESR between the two groups of RA patients. Conclusion Adding curcumin nanomicelle to the RA patients' medication led to some positive changes in the DAS-28, IJC and SJC, although not significantly.

Recent advances in the management of Takayasu arteritis.

Abstract: Takayasu arteritis (TA) is a challenging large vessel vasculitis to treat. Distinguishing disease activity from vascular damage is difficult, often relying on clinician judgement aided by composite clinical disease activity indices with angiographic evidence of vessel wall thickening or vessel wall hypermetabolism demonstrable on positron emission tomography computerized tomography (PET CT). Glucocorticoids form the mainstay of remission induction. While other conventional disease modifying anti-rheumatic drugs (cDMARDs) or biologic DMARDs (bDMARDs) are commonly used, evidence supporting their usefulness is sparse and generally of low quality. The only two randomized controlled trials (RCT) of a DMARD in TA failed to show efficacy of abatacept in reducing relapses of TA, however, tocilizumab showed a trend towards reduction in time to relapses. Of the cDMARDs, methotrexate, azathioprine, mycophenolate mofetil (MMF), leflunomide and cyclophosphamide have shown clinical efficacy in case series, with some evidence that methotrexate, azathioprine and MMF might retard angiographic progression. Among bDMARDs, anti-tumor necrosis factor alpha agents and tocilizumab may be useful in patients refractory to cDMARDs with retardation of angiographic progression, based on evidence derived from mostly retrospective case series, whereas the role of rituximab and ustekinumab needs further elucidation. Revascularization, either surgical or endovascular, is the treatment of choice to relieve critical, symptomatic stenoses and are best undertaken during inactive disease. Emerging evidence suggests that patients with TA also have increased cardiovascular risk and this requires appropriate management. Large studies involving multiple centers are the need of the hour to appropriately evaluate utility of currently available immunosuppressive therapy in TA.

Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.

Abstract: Aim To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer. Method This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized. Results Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64). Conclusion Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.

Elevated expression of miR-21 and miR-155 in peripheral blood mononuclear cells as potential biomarkers for lupus nephritis.

Abstract: Aim Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). There is a great interest in using microRNAs (miRNAs) as diagnostic and prognostic biomarkers in autoimmune diseases. Materials and methods This study evaluated miR-16, miR-21, miR-141, miR-146a, and miR-155 expression levels in peripheral blood mononuclear cells (PBMCs) of 55 female SLE patients with absent, inactive, or active nephritis, and 30 healthy controls (HCs) using quantitative polymerase chain reaction. Results MiR-21 and miR-155 levels were significantly greater in the active nephritis group than in the absent, inactive or HC groups. Moreover, receiver operating characteristic and logistic regression analyses revealed miR-21 and miR-155 were significant risk factors for LN. Conclusion Overexpression of miR-21 and miR-155 in PBMCs may participate in LN pathophysiology and these miRNAs could be used as biomarkers for the condition.

Takayasu arteritis and giant cell arteritis: are they a spectrum of the same disease?

Abstract: Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are forms of large-vessel vasculitides that affect the aorta and its branches. There is ongoing debate about whether they are within a spectrum of the same disease or different diseases. Shared commonalities include clinical features, evidence of systemic inflammation, granulomatous inflammation on biopsy, role of T-helper (Th)-1 and Th17 in the pathogenesis, and, abnormalities of the aorta and its branches on imaging. However, there are also several differences in the geographic distribution, genetics, inflammatory cells and responses to treatment. This review highlights the similarities and differences in the epidemiology, pathogenesis, clinical manifestations, imaging findings and treatment responses in these conditions. Current data supports that they are two distinct conditions despite the numerous similarities.

Interleukin-6 and interleukin-17 are related to depression in patients with rheumatoid arthritis.

Abstract: Aim Mood disorders are a serious issue for patients with rheumatoid arthritis (RA) because poor mental health can exacerbate the disease course. This study aimed to identify the effect of proinflammatory cytokines on the mood of patients with RA. Methods This study was conducted at a rheumatology clinic in Northern Taiwan. In total, 113 patients with RA and 42 healthy controls were assessed for anxiety and depression symptoms using Hospital Anxiety and Depression Scale (HADS). RA was assessed using the Disease Activity Score of 28 joints (DAS28). Serum proinflammatory cytokine levels, including interleukin (IL)-1β, IL-6, IL-17 and tumor necrosis factor alpha (TNF-α) were measured and compared between different patient groups according to disease activity and pain level. Results Serum IL-1β, IL-6, IL-17 and TNF-α levels were significantly higher in patients with RA than in healthy controls, as were the mean anxiety and depression subscale scores. In patients with RA who had different disease activities, pain severity correlated with both anxiety and depression symptoms. When HADS scores were analyzed according to pain levels, age was correlated with depression in the severe pain group. In the mild pain group, patients with higher IL-6 or higher IL-17 had a higher risk of depression. There was no correlation between mood symptoms and cytokine levels in healthy controls. Conclusion Elevated serum IL-6 and IL-17 levels in patients with RA induce arthritis and cause mood symptoms, especially depression symptoms.

Rosmarinic acid attenuates inflammation in experimentally induced arthritis in Wistar rats, using Freund's complete adjuvant.

Abstract: AIM The purpose of our investigation is to evaluate the anti-arthritic potential of isolated rosmarinic acid from the rind of Punica granatum. METHOD Rosmarinic acid was isolated by bioactivity-guided isolation from butanolic fraction of Punica granatum and acute toxicity of rosmarinic acid was carried out. The experiment was conducted at doses of 25 and 50 mg/kg, in Freund's complete adjuvant (FCA)-induced arthritic rats. Various parameters, that is arthritic score, paw volume, thickness of paw, hematological, antioxidant and inflammatory parameters such as glutathione (GSH), superoxide dismutase (SOD), malonaldehyde (MDA) and tumor necrosis factor-α (TNF-α) were also estimated. RESULTS Rosmarinic acid significantly decreased the arthritic score, paw volume, joint diameter, white blood cell count and erythrocyte sedimentation rate. It also significantly increased body weight, hemoglobin and red blood cells. The significantly decreased levels of TNF-α were observed in treated groups as compared to arthritic control rats (P < 0.001). At the same time antioxidant parameters (like GSH and SOD) were increased significantly while levels of MDA were significantly decreased (P < 0.001). CONCLUSION The outcome of the present research concludes that rosmarinic acid showed significant anti-arthritic potential in FCA-induced arthritis in Wistar rats. This study represented the therapeutic role of rosmarinic acid from Punica granatum for the management of arthritis/rheumatoid arthritis/osteoarthritis and related inflammatory complications with negligible side effects which was still far from complete mitigation with available conventional medicines.

Association between circulating 25-hydroxyvitamin D and systemic lupus erythematosus: A systematic review and meta-analysis.

Abstract: Aim The indicators for measuring vitamin D are various, and 25-hydroxyvitamin D (25(OH)D) is considered as the optimal indicator of total vitamin D levels. In this study, we aim to deeply explore the 25(OH)D status in systemic lupus erythematosus (SLE) patients, and evaluate its relation to SLE risk and disease severity. Methods Literature about 25(OH)D status and its associations with SLE were searched in Pubmed, Embase and Cochrane Library databases. Standardized mean difference (SMD), odds ratio (OR) and corresponding 95% confidence interval (95% CI) were illustrated by forest plots, and correlation coefficients (r) were combined by generic inverse variance method. Heterogeneity and publication bias were quantified by I-squared (I2 ) test, funnel plot and Egger's test, respectively. Sensitivity analyses were further examined by leave-one-out method. Results Nineteen articles were included into our meta-analysis. The overall results showed that compared with the healthy controls, the circulating 25(OH)D levels were significantly lower in SLE patients (pooled SMD = -1.63, 95% CI: -2.51 to -0.76). Subgroup analysis revealed that compared with the healthy controls, SLE patients of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) ≥ 10, Arab and European ethnicity, all 4 seasons, no vitamin D supplement, had significantly lower circulating 25(OH)D levels; no significant differences were observed in SLE patients of SLEDAI Conclusions Compared with healthy controls, 25(OH)D levels are significantly lower in SLE patients, which is influenced by disease activity, ethnicity, seasons and vitamin D supplement; no matter the change of age, diseases duration and therapy of corticosteroid or immunosuppressive or neither, 25(OH)D levels are significantly decreased in SLE patients; the deficiency, insufficiency and sufficiency of vitamin D could significantly elevate, slightly decrease, and significantly decrease SLE risk, respectively; and 25(OH)D levels inversely correlate with SLEDAI.

Regulation of osteoblasts by alkaline phosphatase in ankylosing spondylitis

Abstract: Aim Ankylosing spondylitis (AS) is characterized by excessive spinal ankylosis and bone formation. Alkaline phosphatase (ALP) activity is reported to be high in AS, but little is known about the molecular relationship between ALP and AS. The aims of this study were to investigate the relevance of ALP to AS and the role of ALP in the regulation of osteoblast differentiation in AS. Methods High-throughput data with accession numbers GSE73754 and GSE41038 were downloaded from the Gene Expression Omnibus. We retrospectively collected and compared the ALP levels of male patients with AS to those of sex- and age-matched healthy controls (HC) and rheumatoid arthritis (RA) patients. Total serum ALP and ALP activity were measured in the AS and RA groups. ALP gene expression and intracellular ALP activity were analyzed in microarray data from primary diseases control (Ct) and AS-bone-derived cells (BdCs) and in vitro experiments. Furthermore, the effect of ALP inhibitor was examined in both primary Ct- and AS-BdCs under osteoblast differentiation. Regulation of runt-related transcription factor 2 (RUNX2) by ALP was also analyzed. Results Alkaline phosphatase level was higher in AS compared with RA and HC and was associated with radiograph progression. ALP expression was also enriched in the bone tissue of AS patients. Furthermore, AS-BdCs exhibited increasing ALP activity, leading to accelerated osteoblastic activity and differentiation. Intriguingly, inhibition of ALP reduced RUNX2 expression, a master transcriptional factor in osteoblasts, and differentiation status of both primary Ct- and AS-BdCs. Treatment of ALP activator or inhibitor modulated RUNX2 protein level and RUNX2 regulated ALP promoter activity, indicating a reciprocal ALP-RUNX2 positive feedback to regulate osteoblast differentiation. Conclusion Alkaline phosphatase was highly expressed in AS patients, may be involved in the ankylosis of AS, and represents a possible therapeutic target for ankylosis.

Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.

Abstract: Aim To identify the incidence and risk factors for hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with resolved HBV receiving biological disease-modifying antirheumatic drugs (bDMARDs). Method Rheumatoid arthritis patients in whom bDMARD therapy was initiated in our departments from April 2009 to July 2016 were reviewed. The patients diagnosed with resolved HBV and whose HBV-DNA levels had been repeatedly measured were enrolled. The endpoint was HBV reactivation (a positive conversion of HBV-DNA or unquantifiable cases with positivity Results One hundred and fifty-two RA patients with resolved HBV were enrolled; 133 (88%) patients had antibodies against HBV surface antigen (anti-HBs). The medicines that were administered included: abatacept (n = 29), golimumab (n = 26), etanercept (n = 25), tocilizumab (n = 25), adalimumab (n = 19), infliximab (n = 17) and certolizumab pegol (n = 11). During the observation period (15 [interquartile range 4.0-34] months), 7 (4.6%) patients developed HBV reactivation. In 5 of these patients, the HBV-DNA levels became negative or remained at 20 IU/mL were observed in 2 patients but the HBV-DNA levels became negative after NAA treatment. Patients who were negative for anti-HBs showed a significantly higher incidence of HBV reactivation (P = 0.013). Conclusion HBV reactivation occurred in 4.6% of RA patients with resolved HBV during the treatment with bDMARDs and the absence of anti-HBs may be a risk factor for the reactivation of resolved HBV.

Elderly onset of early rheumatoid arthritis is a risk factor for bone erosions, refractory to treatment: KURAMA cohort

Abstract: AIM Age at disease onset has been implicated as an indicator of disease activity and severity in rheumatoid arthritis (RA). This study aimed to investigate how old age at disease onset affects patient treatment and prognosis in early RA. METHODS Data from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. From 2011 to 2015, a total of 2182 patients with RA were enrolled in the cohort; 239 patients were newly diagnosed with RA and were followed up for 2 years. The patients were divided into the following two groups: the young-onset RA (YORA) which included patients <60 years old (n = 117) and elderly-onset RA (EORA) which comprised patients ≥60 years old (n = 122). The clinical and laboratory data were compared at baseline, at 1 year, and at 2 years after onset. RESULTS Disease activity was higher in EORA than in YORA at baseline. Although disease activity was equivalent between EORA and YORA at 1 or 2 years, more EORA patients had bone erosions at baseline and at 2 years. More than 25% of the anti-citrullinated protein autoantibody (ACPA)-positive EORA patients without erosions at baseline had bone erosions even if they attained clinical remission at 1 or 2 years, while ~10% of YORA patients had erosions. CONCLUSION Bone erosions were more frequently found in EORA. Clinical remission at 1 or 2 years was not enough to protect bone erosions in the ACPA-positive EORA patients. Optimal treatment strategies preventing radiological damage should be considered for EORA.

Polyautoimmunity in rheumatological conditions

Abstract: Co-occurrence of autoimmune diseases (ADs) within an individual is postulated to be a frequent phenomenon in rheumatic diseases. Similar clinical signs and symptoms, pathophysiological mechanisms, genetic factors within autoimmune diseases and aggregation of diverse ADs within families sustain the theory of shared pathogenesis of several ADs (autoimmune tautology). Polyautoimmunity (PA) is defined as the presence of more than one autoimmune disease in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). This analysis summarizes an estimated prevalence of PA in the most common rheumatic diseases, the presumable risk factors for PA and influence of concomitant diseases on the course of disease.

Diagnosis and management of ADA2 deficient polyarteritis nodosa.

Abstract: Deficiency of ADA2 (DADA2) is a recently described systemic inflammatory vasculopathy caused by mutations in the CERC1 gene that often, but not always, clinically resembles polyarteritis nodosa (PAN). The condition was originally characterized by livedoid rash, systemic inflammation, variable hypogammaglobulinemia, and early-onset stroke. The phenotypic spectrum has expanded to include patients with immunodeficiency syndromes and bone marrow dysfunction, which are not typical features of PAN. Exploration into the pathogenesis and treatment options of DADA2 has added to our understanding of this condition, but more studies are needed. The purpose of this article is to review the various clinical phenotypes of DADA2, and raise awareness among rheumatologists to consider DADA2 when evaluating patients presenting with PAN-like disease.

Prevalence and incidence of systemic sclerosis: A systematic review and meta-analysis.

Abstract: Objective Systemic sclerosis (SSc) is a rare debilitating autoimmune disease of the connective tissue. This study aimed to assess the recent prevalence and incidence of SSc across the world. Methods Using a systematic search strategy, PubMed/MEDLINE and EMBASE were searched to identify relevant studies published between 2006 and 2016. Two reviewers independently evaluated studies for inclusion based on inclusion/exclusion criteria and performed data extraction. The review was conducted and reported following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The pooled prevalence of SSc was calculated by meta-analysis using a random-effects model. Results There were 1364 references retrieved using the initial searching strategy, and 20 epidemiological publications were selected for data extraction. The identified studies reported prevalence ranging from 3.8 per 100 000 in Taiwan to 50 per 100 000 in the USA. The prevalence was 23 per 100 000 (95% CI: 16-29 per 100 000; 18 studies) in a pooled sample of 11 574 individuals. Incidence rate of SSc ranges from 0.77 per 100 000 person-years in the Netherlands to 5.6 per 100 000 person-years in the USA. SSc predominates in females with higher prevalence and incidence rates. It is important to note that different methodologies were used to derive these numbers so comparisons were made with caution. Conclusion This review provides an assessment of the current estimates of disease prevalence and incidence of SSc. The epidemiological burdens of SSc vary among different regions of the world. The epidemiological data need to be interpreted with caution considering the methodological differences in deriving these estimates.

Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: A single-center experience

Abstract: Aim Systemic juvenile idiopathic arthritis (sJIA) is a distinctive subtype of JIA characterized by systemic features and poor outcome. We aimed to investigate demographic and clinical features, long-term treatment response and disease complications in a large sJIA cohort. Methods Patients diagnosed with sJIA followed up at a pediatric rheumatology outpatient department from January 2003 to December 2017 were included. Demographic and clinical features, long-term treatment response and disease complications were retrospectively collected. Results A total of 168 sJIA patients (51.8% female, 48.2% male) were included: 31.5% with monocyclic, 13.7% polycyclic and 54.8% with persistent clinical course. Corticosteroids were initially used in all patients. Methotrexate was used in 75% and cyclosporine A was used in 17.3% patients. Biological drugs were used in 42.8% patients; etanercept in 29.7%, anakinra in 16%, canakinumab in 16%, tocilizumab in 10% patients. Remission off medication was achieved in 82 (48.8%). Macrophage activation syndrome (MAS) was present in 11.9%, growth retardation in 11.3% patients. Eight percent (4/50) of patients had low bone mineral density. Three patients (1.78%) died due to MAS secondary multiorgan insufficiency and infection. Conclusion The disease is characterized with diverse clinical presentation and possibly severe complications. MAS complicated with multiorgan insufficiency is the major mortality factor. Corticosteroids represent the mainstay of the initial treatment. In patients resistant to classic treatment, biological drugs should be timely introduced.

Evaluation of monosodium iodoacetate dosage to induce knee osteoarthritis: Relation with oxidative stress and pain

Abstract: Aim To determine the dose of monosodium iodoacetate (MIA) required to induce oxidative stress, as well as pain and edema; to confirm the induction of knee osteoarthritis (OA) symptoms in rats by the presence of reactive oxygen species (ROS) and reduction of antioxidant agents; and to verify the presence of histopathological injury in these affected joints. Method Biological markers of oxidative stress, pain, knee edema, and cartilage degeneration provided by different doses of MIA (0.5; 1.0 or 1.5 mg) in rat knee joints were analyzed. The animal evaluations were conducted during 15 days for mechanical and cold hypersensitivity, spontaneous pain and edema. After that, blood serum, intra-articular lavage and structures of knee, spinal cord and brainstem were collected for biochemical analysis; moreover, the knees were removed for histological evaluation. Results This study demonstrates that the highest dose of MIA (1.5 mg) increased the oxidative stress markers and reduced the antioxidant reactions, both in the focus of the lesion and in distant sites. MIA also induced the inflammatory process, characterized by pain, edema, increase in neutrophil count and articular damage. Conclusion This model provides a basis for the exploration of underlying mechanisms in OA and the identification of mechanisms that may guide therapy and the discovery of OA signals and symptoms.

Systematic review of depression and anxiety in psoriatic arthritis

Abstract: Aim To investigate the point prevalence of depression and anxiety in psoriatic arthritis and putative reductions in these comorbidities with the treatment of psoriatic arthritis. Method We performed a systematic review in accordance with PRISMA guidelines examining point prevalence of depression and anxiety in psoriatic arthritis as well as effects of treatment for psoriatic arthritis on these psychiatric comorbidities. MEDLINE, EMBASE, EBM Reviews and Cochrane, and PsycINFO were searched from inception to October 2017. Quality of studies was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. Study and population characteristics were extracted and entered into an electronic database for subsequent descriptive and meta-analysis of point prevalence. Result Three studies matched inclusion criteria with significant statistical heterogeneity. The prevalence of depression ranged between 9%-22% and anxiety between 15%-30% in patients with psoriatic arthritis. One study matched inclusion criteria for treatment effect analysis, albeit with a high risk of bias and illustrated a benefit of etanercept on the prevalence of depression (9% vs 16%) and anxiety (14% vs 30%) after 24 weeks of treatment. Conclusion This is the first systematic review of point prevalence of depression and anxiety in patients with psoriatic arthritis. There is a moderate point prevalence of both depression and anxiety in patients with psoriatic arthritis, which is similar or slightly higher than the general population and comparable to that seen in other rheumatic diseases. The effects of treatment for psoriatic arthritis on comorbid depression and anxiety remain unclear.

Do ANCA-associated vasculitides and IgG4-related disease really overlap or not?

Abstract: Background Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and immunoglobulin G4-related disease (IgG4-RD) have some common features. The co-occurrence/concurrence of AAV and IgG4-RD was recently published by the collaborative European Vasculitis Study Group. First, we aimed to investigate ANCA positivity of our IgG4-RD cohort. Second, a literature review of co-occurrence/concurrence of AAV and IgG4-RD was done. Methods Data of 62 patients with IgG4-RD in Hacettepe Vasculitis Center Database were used. Patient dataset was designed to include demographic data, clinical characteristics, imaging and IgG4-RD, AAV and ANCA test results. At the next step, we performed a systematic literature review in PUBMED database covering the time period from 1976 until April 2018. Relevant publications were searched using these MeSH terms ''IgG4-related disease and Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis'', "IgG4-related disease and Eosinophilic Granulomatosis with Polyangiitis", "IgG4-related disease and Microscopic Polyangiitis" and "IgG4-related disease and Granulomatosis with Polyangiitis". Results Three (10.3%) of 29 patients had low titer ANCA positivity. These three patients didn't have any findings of vasculitis and no granuloma was seen in biopsy. In the literature review, we found 17 cases had features of both IgG4-RD and AAV. These cases were re-evaluated according to the Comprehensive Diagnostic Criteria for IgG4-RD. ANCA were positive in 15 of 17 patients (88%). Conclusion None of our IgG4-RD patients overlapped with AAV. Only two patients in the literature review seemed to be fully compatible with both diseases. Even though AAV and IgG4-RD share similar clinical features, we think this might be a co-occurrence instead of a histopathological link.

Aerobic exercise for axial spondyloarthritis - its effects on disease activity and function as compared to standard physiotherapy: A systematic review and meta-analysis.

Abstract: Aim To evaluate the impact of an aerobic fitness program on disease activity, defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and on C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and the Bath Ankylosing Spondylitis Functional Index (BASFI) in case of axial spondyloarthritis Methods A systematic review of the literature, following the Prisma recommendations, was performed by two reviewers on the PubMed and Embase databases Controlled trials assessing the efficacy of aerobic exercises compared to physiotherapy on axial spondyloarthritis disease activity were included The diagnosis of axial spondyloarthritis was meeting the New York criteria and/or the Assessment in Axial Spondyloarthritis International Working Group criteria Aerobic fitness was defined as an exercise performed at 50%-90% of the maximal heart rate or between 50% and 80% oxygen consumption (VO2 ) peak Results Five hundred and twenty abstracts were identified and 93 abstracts were analyzed Eight studies met the selection criteria and 6 were finally included in this study because of the presence of a control group Both groups were similar in terms of age, sex ratio, disease duration Aerobic exercise provided a positive impact on the BASDAI in the intervention group (148 patients) (weighted mean difference [WMD]: -052 [95% CI: -09 to -013]) (I2 : 103%, P = 035) However, when compared to a control group (152 patients), the improvement of BASDAI didn't reach significance (WMD: -025 [95% CI: -083 to 032]) (I2 : 0%, P = 041) Aerobic exercise did not improve BASFI, CRP or ESR Conclusion Aerobic exercise did not provide beneficial effects either on disease activity or on physical function and biological parameters when compared to a control group in axial spondyloarthritis

Development of the Asia Pacific Lupus Collaboration cohort.

Abstract: Aim The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. Method The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. Results The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. Conclusion The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

Overlap myositis, a distinct entity beyond primary inflammatory myositis: A retrospective analysis of a large cohort from the REMICAM registry.

Abstract: Background Inflammatory idiopathic myositis (IIM) comprises a heterogeneous group of systemic muscular diseases that can occur together with other connective tissue diseases (CTD), named overlap myositis (OM). The question of whether OM is a distinct entity still remains controversial. Aim The present study was conducted to assess the clinical and prognostic differences between patients diagnosed with OM, primary polymyositis (PM) and primary dermatomyositis (DM). Method The study consists of a retrospective longitudinal and multicenter series of IIM patients. Patients were classified as OM, PM and DM. Overlap myositis was defined as patients fulfilling criteria for IIM plus criteria for other CTD (namely systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and primary Sjogren's syndrome). Result A total of 342 patients were included (98 OM, 137 PM and 107 DM). Overlap myositis patients, in comparison with PM and DM, showed significant differences, with more extramuscular involvement, particularly more arthritis (66%, 34.6% and 48.1%, respectively), puffy fingers (49.5%, 11.1% and 24.3%), sclerodactyly (45.4%, 2.2% and 2%), dysphagia (41.8%, 18.2% and 26.4%), Raynaud phenomenon (65.3%, 16.9% and 19.8%), leucopenia (28.9%, 2.2% and 8.4%), thrombocytopenia (8.2%, 2.2% and 1.9%), interstitial lung disease (ILD) (48%, 35% and 30.8%), renal manifestations (13.4%, 3.7% and 1.9%), and more severe infections (41.3%, 26.7% and 21%). No significant differences were found in survival between groups in log rank test (P = 0.106). Multivariate adjusted survival analyses revealed a worse prognosis for severe infections, ILD and baseline elevation of acute phase reactants. Conclusion Overlap myositis stands out as a distinct entity as compared to PM and DM, featuring more extramuscular involvement and more severe infections. Close monitoring is recommended in this subset for early detection and treatment of possible complications.

Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg-negative, HBcAb-positive rheumatoid arthritis patients: A long-term, real-world observation.

Abstract: AIM Longitudinal data of the reactivation of hepatitis B virus (rHBV) and serial serological markers or HBV-DNA has been limited. This study aimed to investigate the temporal course of rHBV development in rheumatoid arthritis (RA) patients undergoing long-term rituximab therapy. METHODS The occurrence of rHBV was examined in 157 RA patients during rituximab therapy. Serum levels of HBV surface antigen (HBsAg), HBV core antibody (HBcAb), and HBsAb were determined by electrochemiluminescence immunoassays, and viral loads by real-time polymerase chain reaction assay. RESULTS Among 157 patients undergoing rituximab therapy, 103 (65.6%) were HBsAg-negative and HBcAb-positive. Before rituximab therapy, 20 (19.4%) of these 103 patients were HBsAb-negative, while 83 (80.1%) were HBsAb-positive. Five (20%) HBsAb-negative patients developed rHBV after rituximab therapy. Among 83 HBsAb-positive patients, 4 (4.8%) developed rHBV. Among 9 patients with rHBV, 7 (77.7%) exhibited HBsAg seroreversion. Significant decline of HBsAb titers (mean ± SD, 296.0 ± 417.3 mIU/mL at baseline vs 187.0 ± 332.5 mIU/mL after rituximab therapy, P < 0.001) was observed in HBsAg-/HBsAb + patients. All HBsAg-negative patients who developed rHBV during rituximab therapy were characterized by baseline HBsAb titers < 100 mIU/mL and negative HBsAb at the time of rHBV. HBsAb positivity was an independent protective factor for rHBV (hazards ratio: 0.14, 95% CI: 0.03-0.62, P = 0.009). CONCLUSION Baseline HBsAb positivity was a significant protective factor for rHBV in HBsAg-negative, HBcAb-positive RA patients receiving rituximab therapy.

Clinical utility of red blood cell distribution width in inflammatory and non-inflammatory joint diseases.

Abstract: AIM Current studies demonstrate red blood cell distribution width (RDW) as a possible surrogate biomarker of inflammation The objectives of the present study were to examine RDW in patients with osteoarthritis (OA), fibromyalgia (FM), rheumatoid arthritis (RA) and spondyloarthritis (SpA) and to evaluate its clinical importance METHODS Six hundred and ninety-nine ambulatory patients were evaluated RDW, hemoglobin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were assessed In order to compare groups, a Kruskall-Wallis test with post hoc Dunn's test was applied A multiple logistic regression analysis was used to evaluate anisocytosis explanatory variables RESULTS Red blood cell distribution width values differed significantly among groups Post hoc analysis demonstrated a significant increase in RDW within RA versus OA groups (P < 0001), active SpA versus OA (P < 0001), RA versus FM (P < 0001) and active SpA versus FM groups (P = 0001) Presence of anisocytosis was useful to discriminate between active articular inflammatory versus non-inflammatory diseases with 48-95% sensitivity and 66-95% specificity Multivariate analysis showed a six-fold increase in anisocytosis for the presence of a possible articular inflammatory disease CONCLUSION In subjects with articular pain, RDW interpretation is a useful tool in clinical practice to distinguish between articular inflammatory and non-inflammatory joint diseases, as with CRP RDW seems to be a surrogate marker of the inflammatory process

Associations between blood lead, cadmium, and mercury levels with hyperuricemia in the Korean general population: A retrospective analysis of population-based nationally representative data.

Abstract: Aim An elevated serum uric acid level is associated with various diseases, such as gout, hypertension, renal impairment, and diabetes. Heavy metals, including lead and cadmium, are suspected to increase serum uric acid levels, but evidence regarding this is not sufficient, particularly in the Asian population. Therefore, this study aimed to evaluate the association between lead, cadmium and mercury exposure and hyperuricemia in the Korean general population. Methods We enrolled 2682 participants (1124 men and 1528 women) aged ≥19 years from The Korean National Health and Nutrition Examination Survey. Sex- and hyperuricemic state-stratified general characteristics of study participants were compared using the Chi-square test, Student's t test, and Mann-Whitney U test for categorical, continuous, and non-normally distributed continuous variables, respectively. Multivariate logistic regression analysis was performed to evaluate the association between blood lead and cadmium levels and hyperuricemia. Results Subjects with hyperuricemia had higher blood lead and cadmium levels than those without hyperuricemia. Lead and cadmium exposure had a positive association with serum uric acid levels in a dose-response manner in the nationally representative Korean population. In logistic analysis, blood cadmium levels had a positive association with increasing risk for hyperuricemia only in men, and this association was more evident in cotinine-verified non-smokers. Although an incremental trend of hyperuricemia in relation to lead exposure was observed, it was not statistically significant. Conclusion Further studies are necessary to clarify the observed association, and public health strategies to reduce heavy metal exposure may be necessary for decreasing the potential harmful effects of hyperuricemia.

Validity and reliability of the Ankylosing Spondylitis Disease Activity Score with C‐reactive protein (ASDAS‐CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with axial spondyloarthritis (axSpA) in Singapore

Abstract: INTRODUCTION The Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) are commonly used instruments for measuring disease activity. However, few studies have assessed their psychometric properties in patients with axial spondyloarthritis (axSpA). We aimed to assess the validity and reliability of ASDAS-CRP and BASDAI in patients with axSpA in Singapore. METHODS Cross-sectional data from 280 patients with axSpA from a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2011 to 2019 were used. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed through 12 a priori hypotheses by correlation of overall ASDAS-CRP and BASDAI score with other patient-reported outcomes measures (PROMs). Structural validity was evaluated via confirmatory factor analysis using maximum-likelihood method, where Comparative Fit Index (CFI) >0.95, Tucker-Lewis Index (TLI) >0.95, Root Mean Square Error of Approximation (RMSEA) <0.06 and Standardized Root Mean Residuals (SRMR) <0.08 were indicative of good fit. RESULTS Among 280 patients (78.2% Male; 92.5% Chinese), ASDAS-CRP showed poor internal consistency of 0.33, while BASDAI showed high internal consistency of 0.87. Convergent and divergent construct validity were demonstrated by fulfillment of 11 out of 12 a priori hypotheses when ASDAS-CRP and BASDAI were compared with other PROMs. Our proposed ASDAS-CRP and BASDAI model showed good fit for a 1-factor structure respectively (CFI = 0.993, TLI = 0.984, RMSEA = 0.036, SRMR = 0.026 for ASDAS-CRP; CFI = 0.993, TLI = 0.985, RMSEA = 0.057, SRMR = 0.022 for BASDAI), demonstrating structural validity. CONCLUSION This study supports the use of both ASDAS-CRP and BASDAI in measuring disease activity in patients with axSpA in Singapore.

Childhood-onset Takayasu arteritis: A 15-year experience from a tertiary referral center.

Abstract: Aim To describe clinical manifestations, angiographic findings, treatment, activity and damage of our Takayasu arteritis patients. Method The patients who met European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society classification criteria for childhood-onset Takayasu arteritis were reviewed in a retrospective longitudinal manner from 2002 to 2017. Extent of the disease was assessed by Disease Extent Index for Takayasu Arteritis (DEI.Tak), activity by Pediatric Vasculitis Activity Score and Indian Takayasu's Arteritis Activity Score (ITAS 2010) and damage by Pediatric Vasculitis Damage Index and Takayasu Arteritis Damage Score (TADS). Results Sixteen subjects (75% female) with a median disease duration of 3.1 years were enrolled in this study. While the median age at disease onset was 12.1 years, there was only a 2.5 months diagnostic delay. Treatment regime included corticosteroids (100%), which were combined with azathioprine or methotrexate in 93.8% and 37.5% of the subjects, respectively. Severe and refractory cases were treated with cyclophosphamide (62.5%) and subsequently with tocilizumab (37.5%). Seven patients (43.8%) required either percutaneous endovascular intervention or bypass for severe disease refractory to medications. The correlation of the activity and damage scores with each other was fairly good. Damage was found to be associated only with high disease activity and extensive disease at disease onset, but not with other parameters. Conclusion Despite high usage rates of aggressive immunosuppressive therapy and biologic agents, almost half of the patients underwent interventional procedures. When medications failed, endovascular and surgical interventions were of great importance to avoid end-organ ischemia. The performance of the new activity (DEI.Tak and ITAS2010) and damage indices (TADS) seems satisfactory.

Musculoskeletal healthcare: Have we over‐egged the pudding?

Abstract: The phrase “to over-egg the pudding” is a terrific analogy for what is now increasingly common in health care: medical overuse. Cooks would know that if you skimp with the eggs a pudding won't hold together and if you use too many eggs the pudding will go rubbery. And in musculoskeletal health care we also need to get the balance right. People's health can suffer when they receive too little health care and also if they receive too much health care. The problem of too little health care is well recognized and it is easy to understand that patients’ health can be put at risk by underuse of proven healthcare services. However, the opposite problem is also possible but is less well recognized.1 In this editorial we adopt some perspectives from the field of overdiagnosis to consider overuse in musculoskeletal health care. Overdiagnosis2 is an unwarranted diagnosis that leads to unnecessary treatments that do not benefit patients and that wastes health resources that could be better used elsewhere. Overdiagnosis also may cause harms: direct effects, unintended/indirect consequences, psychological impact, costs and resource implications, opportunity cost. We focus on 4 aspects of overdiagnosis that can lead to medical overuse in musculoskeletal health care:

Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis

Abstract: Aim The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. Method The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. Results Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. Conclusion Our new criteria are useful for diagnosing PFAPA.