Swollen Joint Count Research Articles

Validation of the PsAID-12 Russian questionnaire in patients with psoriatic arthritis

Objective – validation of the Russian-language version of the PsAID-12 questionnaire in patients with psoriatic arthritisMaterials and methods. The study included 187 patients, mostly men (50.2%), with a reliable diagnosis of psoriatic arthritis (PsA) according to the CASPAR criteria (2006), who consistently sought medical help at the V.A. Nasonova Research Institute of Rheumatology and those who signed informed consent to participate in the study. Average age was 45.6±11.7 years, duration of PsA – 113.8±76.7 months, duration of psoriasis – 241±144 months, disease activity according to DAPSA (Disease Activity in Psoriatic Arthritis) – 29.1±22.6. At the initial visit and after 12 months of therapy, all patients underwent a standard rheumatologic examination and assessment of the quality of life. The number of tender joint count (TJC 68), the number of swollen joint count (SJC 66), PGA (patient global assessments) were assessed using a visual analogue scale (VAS) (0–10 cm), VAS pain (0–10 cm), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), PsAID-12 (Psoriatic Arthritis Impact of Disease-12) and EQ-5D (EuroQoL-5D). The EQ-5D was considered the “gold standard” for assessing quality of life. The reliability of the PsAID-12 questionnaire was studied on the basis of its reproducibility by test-retest analysis and internal constancy by calculating the Cronbach’s alpha for each scale. We assessed the validity, i. e., the ability of the PsAID-12 questionnaire to reliably measure its characteristics based on criterional and constructive validity. The criterion validity was calculated by assessing the relationship between PsAID-12 and “external criteria”| reflecting the activity of PsA and interchangeability with the EQ-5D questionnaire using correlation analysis. A moderate and strong bond was considered r≥0.30. Constructive validity was assessed by the method of “known groups” and factor analysis. The study of the reliability of the PsAID-12 questionnaire was carried out in 30 PsA patients. Sensitivity – in 172 patients in dynamics after 12 months of various PsA therapy regimens.Results. The study of the reliability of the PsAID-12 questionnaire included 30 patients. According to the results of the test-retest analysis, it was revealed that there were no statistically significant differences between the initial and repeated assessments on all 12 PsAID-12 scales (p>0.05). To assess the internal constancy, the Cronbach’s alpha was calculated for each of the 12 scales of the questionnaire. The value of this coefficient ranged from 0.8 to 0.9 and was quite high. Validity was assessed in 187 patients with PsA. The analysis of the criterion validity of the PsAID-12 questionnaire was studied by assessing the relationship of its scales with the scales of the EQ-5D questionnaire, where it demonstrated a close correlation (r>0.3). That testifies to the good interchangeability of this questionnaire. Also, the criterion validity was carried out by assessing the “external criteria” (TJC 68, SJC 66, DAPSA, VAS global assessments, VAS global pain, BASDAI). Where were identified direct correlations of external criteria with all scales of the questionnaire. The highest correlation coefficient (r=0.8) was found between the BASDAI index and the “Physical performance” scale. When assessing constructive validity by the “known groups” method, patients were divided into 2 groups according to disease activity: with DAPSA index ≥5 and DAPSA index ≤4. Significant differences were revealed between the group of patients with active PsA and the absence of PsA activity on all scales of the questionnaire (p<0.001). Factor analysis revealed two main factors – physical and emotional health; a high level of correlation of the scales with their factor was also shown. To assess the sensitivity of the questionnaire, its changes were analyzed depending on the achieved effect on therapy after 12 months: group I of patients in whom MDA was achieved – 50 patients; group II – 43 patients REM/LDA; group III – 79 patients with no effect on therapy. It was revealed that in groups I and II there was a statistically significant difference on all scales of questionnaires, in group III, “non-responders” to therapy, there were no statistically significant improvements in the scales “Pain” (p=0.37), “Fatigue” (p=0.15), “Skin problems” (p=0.23), “Work and/or leisure activities” (p=0.056), “Functional capacity” (p=0.44). Thus, during treatment, it was noted that the PsAID-12 questionnaire may reflect the dynamics depending on the activity of the disease during treatment, which proves its good sensitivity.Conclusion. The Russian version of the PsAID-12 has good psychometric properties and is able to reflect changes in the patient’s health status over time, along with disease activity and laboratory manifestations.

Ziyuglycoside I attenuates collagen-induced arthritis through inhibiting plasma cell expansion

Ethnobotanical relevanceWith most of the anti-rheumatic drugs having severe adverse drug reactions and poor tolerance, the active components from natural herbs provides a repository for novel, safe, and effective drug development. Sanguisorba officinalis L. exhibits definite anti-inflammatory capacity, however, whether it has anti-rheumatic effects has not been revealed. Aim of the studyIn the present study, the effect of Ziyuglycoside I (Ziyu I), one of the most important active components in Sanguisorba officinalis L., was investigated in treating collagen-induced arthritis (CIA), illuminating its potential pharmacological mechanisms. Material and methodsCIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of MTX, and clinical manifestations as well as pathological changes were observed. T and B cell viability was determined using cell counting kit-8, plasma autoantibodies and cytokines were tested with ELISA, T and B cell subsets were identified by flow cytometry, Blimp1 expression was detected by RT-qPCR and in situ immunofluorescence. The expression of activation-induced cytidine deaminase (AID) was detected by immunohistochemistry. ERK activation in B cells was verified through western blotting and immunofluorescence. Meanwhile, bioinformatics retrieval and molecular docking/molecular dynamics were used to predict the relationship between Blimp1, ERK and Ziyu I with the pharmacokinetics and toxicity of Ziyu I being evaluated in the ADMETlab Web platform. ResultsZiyu I treatment effectively alleviated the joint inflammatory manifestation including arthritis index, global scores, swollen joint count and body weight of CIA mice. It improved the pathological changes of joint and spleen of arthritic mice, especially in germinal center formation. Ziyu I displayed a moderate regulatory effect on T cell activation, the percentage of total T and helper T cells, and tumor necrosis factor-α, but transforming growth factor-β was not restored. Increased spleen index, B cell viability and plasma auto-antibody production in CIA mice were significantly reduced by Ziyu I therapy. Of note, we found that Ziyu I administration substantially inhibited the excessive expansion of plasma cells in spleen through preventing the expression of B lymphocyte induced maturation protein 1 (Blimp1) and AID in B cells. Ziyu I was predicted in silico to directly interact with ERK2, and reduce ERK2 activation, contributing to the depressed expression of Blimp1. Moreover, Ziyu I was predicted to have a favorable pharmacokinetic profile and low toxicity. ConclusionZiyu I effectively ameliorates CIA in mice by inhibiting plasma cell generation through prevention of ERK2-mediated Blimp1 expression in B cells. Therefore, Ziyu I is a promising candidate for anti-arthritic drug development.

Dactylitis Is Associated With More Severe Axial Joint Damage and Higher Disease Activity in Axial Psoriatic Arthritis.

To investigate the association of dactylitis with disease activity and the severity of damage detected by radiography in patients with axial psoriatic arthritis (axPsA). Patients with axPsA who met the Classification Criteria for Psoriatic Arthritis were recruited. Clinical data, radiographic changes, and disease activity in patients with axPsA with or without dactylitis were compared using t tests, Mann-Whitney U tests, or Kruskal-Wallis tests for continuous variables. Chi-square or Fisher exact tests were used for categorical variables, and logistic regression analysis was performed to evaluate the association between dactylitis and damage detected by radiography. A total of 186 patients with axPsA were analyzed and dichotomized according to the presence or absence of dactylitis. Patients with dactylitis, as compared to those without dactylitis, had higher C-reactive protein (P = 0.004), erythrocyte sedimentation rate (P = 0.006), neutrophil-to-lymphocyte ratio (P = 0.04), and platelet-to-lymphocyte ratio (P = 0.02). In addition, patients with dactylitic axPsA, as compared to patients with nondactylitic axPsA, had higher tender joint counts, swollen joint counts, Disease Activity Index for Psoriatic Arthritis (DAPSA) scores, and Health Assessment Questionnaire scores (P < 0.001). Patients with axPsA who had dactylitis, as compared to those who did not, also had higher values for the Disease Activity Score in 28 joints, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Disease Activity Index (P < 0.05), while fewer of these patients met the criteria for minimal disease activity and low disease activity (P < 0.05). Consistently, they had more severe damage as detected by radiography (P < 0.05), higher sacroiliac scores (odds ratio [OR] 2.08, 95% CI 1.14-3.79; P = 0.02), and a more significant reduction in bone mass density (OR 2.42, 95% CI 1.34-4.37; P = 0.003). No statistical differences were observed regarding HLA-B27 and the Leeds Enthesitis Index between these 2 groups of patients. Notably, only half of the patients with dactylitic axPsA had inflammatory back pain. Our study demonstrated that patients with axPsA who had dactylitis had higher disease activity and more severe joint damage compared to those without dactylitis. Careful examination and proper management of axial involvement are recommended.

Monitoring and Management of the Patient with Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Current Perspectives.

In this review, we draw from observational studies, treatment guidelines and our own clinical experience to describe approaches to monitoring and management of immune checkpoint inhibitor (ICI)-induced inflammatory arthritis, including polymyalgia rheumatica. This condition occurs in about 4% of ICI-treated cancer patients and can persist for a year or longer. Mild arthritis can generally be managed with non-steroidal anti-inflammatory drugs, intraarticular steroids injections and/or low dose corticosteroids. Higher grade arthritis should be brought under control with corticosteroids, but early introduction of a steroid-sparing agent is recommended to minimize steroid toxicity. In order to assess the effectiveness of any arthritis treatment, tender and swollen joint counts and patient reported measures of physical function, such as the health assessment questionnaire, should be obtained at each visit. Referral to a rheumatologist is recommended for patients with high grade arthritis to help guide the use of disease-modifying antirheumatic drugs.

Dietary Pattern or Weight Loss: Which One Is More Important to Reduce Disease Activity Score in Patients with Rheumatoid Arthritis? A Randomized Feeding Trial.

Objectives Herein, disease activity score 28 (DAS 28) was compared between patients with rheumatoid arthritis (RA) receiving the Mediterranean dietary pattern (MD) and low-fat diet. Subjects/Methods. Overweight and obese RA patients aged 15–75 y participated in this randomized feeding trial. Participants were randomized to MD (n = 51) and low-fat high-carbohydrate diet (n = 53) for 12 weeks. The control group followed their regular diet (n = 50). Participants completed the form of tender and swollen joint counts before the study enrollment and after 12 weeks to compute DAS 28. Results Weight loss was not statistically significant between the MD and LF-HC groups. DAS 28 significantly decreased in MD compared to the LF-HC group (p=0.02) and controls (p=0.001). Adjusting for the baseline variables, MD reduced DAS 28 by 76% (95% CI = −0.45, −0.2; p=0.03) after 12 weeks of intervention. The baseline serum ESR level showed 99.8% effect on DAS 28 score at the end (95% CI = 0.014, 0.035; p < 0.001). Conclusions The MD showed beneficial effects on DAS 28 compared to the LF-HC diet in patients with RA, regardless of weight loss. It is a better dietary choice for pain reduction in patients with RA. The trial is registered at Iranian Registry of Clinical Trials (IRCT20200929048876N2).

Real-World Effectiveness and Treatment Retention of Secukinumab in Patients with Psoriatic Arthritis and Axial Spondyloarthritis: A Descriptive Observational Analysis of the Spanish BIOBADASER Registry.

Rheumatic diseases are extensively managed with biological disease-modifying antirheumatic drugs (bDMARDs), but a notable proportion of patients withdraw in the long term because of lack of effectiveness, adverse events, or the patient’s decision. The present real-world analysis showed the effectiveness, retention, and safety data collected in the Spanish BIOBADASER registry for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA, including ankylosing spondylitis (AS) and non-radiographic axSpA) treated with secukinumab, a human antibody against interleukin-17A (IL-17A), for more than 12 months. Six hundred and thirty-nine patients were analysed (350, 262, and 27 PsA, AS, and nr-axSpA patients, respectively). The results showed an improvement in the disease activity after 1 year of treatment, in terms of decreases of the mean Disease Activity Score 28 using C-reactive protein (DAS28-CRP), the mean Disease Activity Psoriatic Arthritis (DAPSA) score, swollen joint counts (SJC), and tender joint counts (TJC) in PsA patients and decreases in the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the mean Ankylosing Spondylitis Disease Activity Score (ASDAS) in axSpA patients. This improvement was maintained or increased after 2 and 3 years of treatment, indicating that secukinumab is effective in both naïve and non-responder patients. Retention rates were higher when secukinumab was used as the first-line biological treatment, although they were also adequate in the second and third lines of treatment. Collected safety data were consistent with previous reports. Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00446-9.

P276 Ixekizumab shows a pattern of pain improvement in patients with and without measurable inflammation in psoriatic arthritis

Abstract Background/Aims The efficacy of ixekizumab (IXE) and adalimumab (ADA) in patients with psoriatic arthritis (PsA) has been previously reported using ACR 50 and Psoriasis Area and Severity Index (PASI) 100 responses. To minimize confounding effects, in this analysis we assessed the efficacy of either IXE or ADA monotherapy on reduction of pain beyond measurable inflammation in patients with active PsA and low C-reactive protein (CRP) (&amp;lt;5mg/L) at baseline. Methods SPIRIT-H2H (NCT03151551) was a 52 week (W), multicenter, randomized, open-label, parallel-group, assessor-blinded study evaluating the efficacy and safety of IXE vs ADA. Participants were randomized (1:1) to approved-label dosing of IXE or ADA. This post-hoc analysis included only patients treated with IXE or ADA as monotherapy and with low CRP (&amp;lt;5mg/L) at baseline. Changes in joint pain were measured using PsA Patient’s Assessment of Pain Visual Analog Scale (VAS). We stratified patients into four categories by two measures of inflammation: 1. Sustained low inflammation either by a. CRP&amp;lt;5 mg/L during W4-24 or b. ≥50% improvement in swollen joint count (SJC) during W8-24. 2. Fluctuating inflammation either by a. CRP≥5 mg/L at least once between W4-24 or &amp;lt; 50% improvement in SJC at least once between W8-24. Results 95 monotherapy patients with a CRP &amp;lt;5mg/L at baseline were included in this analysis. Baseline characteristics were similar between both treatment arms. In patients with fluctuating inflammation as measured by CRP, IXE-treated patients demonstrated a numerically greater mean improvement in joint pain VAS vs ADA-treated patients at W16 (IXE: -31.64, ADA: -25.33) that was sustained up to W52 (IXE: -47.69, ADA: -20.67). There was significance in favor of IXE at W32 (p = 0.0045) and W52 (p = 0.0288). In patients with sustained low inflammation as measured by CRP, there was comparable improvement in joint pain between IXE and ADA-treated patients. In patients with sustained improvement in joint swelling as assessed by SJC, IXE-treated patients demonstrated a numerically greater mean improvement in joint pain VAS vs ADA-treated patients from W4 (IXE: -17.47, ADA: -10.42) that was sustained through W52 (IXE: -43.16, ADA: -32.62). In patients with fluctuating improvement in joint swelling as assessed by SJC, IXE-treated patients demonstrated a numerically greater mean improvement in joint pain VAS vs ADA-treated patients from W16 (IXE: -22.00, ADA: -19.31) that was sustained through W52 (IXE: -28.57, ADA: -13.27). Conclusion This analysis suggests a different pattern of pain improvement in patients with low baseline CRP treated with IXE or ADA monotherapy, with a favorable pain reduction outcome for IXE-treated patients, even when inflammation is fluctuating as measured by CRP or SJC improvement. This analysis supports the hypothesis that IXE improves joint pain in PsA patients with and without measurable inflammation. Disclosure N. Maney: None. K. de Vlam: Consultancies; Celgene, Eli Lilly and Company, Galapagos NV, Novartis, Pfizer, and UCB Pharma. Grants/research support; Celgene. G. Gallo: Shareholder/stock ownership; Eli Lilly and Company. P. Mease: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, GlaxoSmithKline. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB Pharma. Grants/research support; Janssen, Merck Sharp &amp; Dohme, Neumentum, Novartis, Pfizer, Sun Pharma, and UCB Pharma. P. Rahman: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and UCB Pharma. Grants/research support; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and UCB Pharma. V. Krishnan: Shareholder/stock ownership; Eli Lilly and Company. D. Sandoval Calderon: Shareholder/stock ownership; Eli Lilly and Company. C. Lin: Shareholder/stock ownership; Eli Lilly and Company. D. Zhu: Shareholder/stock ownership; Eli Lilly and Company. R. Bolce: Shareholder/stock ownership; Eli Lilly and Company. P. Conaghan: Consultancies; Amgen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Novartis, Pfizer, and UCB Pharma.

P271 To what extent are baseline characteristics in biologic-experienced patients with psoriatic arthritis associated with achievement of minimal disease activity at week 24 of guselkumab treatment: a post hoc analysis of the phase IIIb COSMOS clinical trial

Abstract Background/Aims Guselkumab (GUS), a human monoclonal antibody targeting the interleukin-23p19-subunit, has demonstrated efficacy at Week 24 (W24) in the Phase IIIb COSMOS clinical trial of patients with active psoriatic arthritis (PsA) and inadequate response or intolerance to one or two tumour necrosis factor inhibitors (TNFis). This post hoc analysis aimed to identify predictors of minimal disease activity (MDA) with GUS at W24 in this population. Methods Multiple logistic regression analysis was performed to identify potential predictors of MDA with GUS at W24 in TNFi-refractory patients with PsA; odds ratios, 95% confidence intervals and p-values were calculated. Baseline characteristics assessed as predictors included sex, body mass index (BMI), C-reactive protein (CRP), other medication use and disease duration; clinical features included tender and swollen joint counts (TJC/SJC), affected joint location, dactylitis, enthesitis, spondylitis, Psoriasis Area Severity Index (PASI) score and psoriasis (PsO) localisation (Table). Missing data for MDA at W24 were imputed as non-response; missing baseline values were imputed for two patients. Results Patients (n = 187; female, 54.6%; mean disease duration, 8.3 years) had mean TJC 0-68 and SJC 0-66 of 21.0 and 10.3, respectively, mean PASI score of 11.6, and mean BMI of 28.9; 67.9% had enthesitis and 35.8% had dactylitis at baseline. One prior TNFi had been received by 88.2% of patients, with two received by 11.8%. At W24, 17.1% (32/187) of patients achieved MDA. Wrist involvement (p = 0.031) and scalp PsO (p = 0.049) were positive predictors of MDA. Women were significantly less likely to achieve MDA vs. men; other negative predictors included hand small joints or shoulder involvement and hand/foot PsO (all p &amp;lt; 0.05). Age, BMI, CRP, TJC/SJC, HAQ-DI, PASI, spondylitis, enthesitis, dactylitis, other medication and number of prior TNFis were not predictive of MDA (Table). Conclusion Baseline characteristics and clinical features may be positively (wrist involvement, scalp PsO) or negatively (female sex, hand small joints or shoulder involvement, hand/foot PsO) associated with achieving MDA with GUS at W24 in a TNFi-refractory population. Though the low patient number limits the generalisability of this analysis, assessment of Week 48 data may further elucidate potential predictors of MDA after longer-term treatment. Disclosure W. Tillett: Other; William Tillett has received research grants and consulting or speaker fees from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB. S. Ohrndorf: Other; Sarah Ohrndorf has received fees from AbbVie, BMS, Janssen, Novartis and Pfizer. J. Ramírez: Other; Julio Ramírez has received consulting or speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Novartis and UCB. M. Neuhold: Other; Marlies Neuhold is an employee of Janssen and owns stocks in Johnson &amp; Johnson. R. Wapenaar: Other; Robert Wapenaar is an employee of Janssen and owns stocks in Johnson &amp; Johnson. E. Theander: Other; Elke Theander is an employee of Janssen and owns stocks in Johnson &amp; Johnson. C. Contre: Other; Christine Contre is an employee of Janssen and owns stocks in Johnson &amp; Johnson. M. Sharaf: Other; Mohamed Sharaf is an employee of Janssen and owns stocks in Johnson &amp; Johnson. M. Shawi: Other; May Shawi is an employee of Janssen and owns stocks in Johnson &amp; Johnson. M. Vis: Other; Marijn Vis has received research grants and consulting or speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB and the Dutch Arthritis Foundation.

P209 Subgroups of refractory rheumatoid arthritis and difficult to treat features highlight differences in comorbidity and smoking history - a single-centre observational study

Abstract Background/Aims Limited therapeutic efficacy and ‘difficult to treat’ (D2T) characteristics mean some rheumatoid arthritis (RA) patients cycle through multiple therapies to achieve their treatment targets. The aim of this study was to evaluate for subgroups of refractory RA (RefRA) in a real-world population and describe D2T characteristics. Methods Patients on their third or more targeted therapy were identified from the electronic health record (EHR) at Manchester Royal Infirmary. Demographic and clinic information were obtained. Raised disease activity was identified as DAS28ESR&amp;gt;3.2. Findings of power Doppler joint synovitis on ultrasound (PDUS) if undertaken within a month of clinical assessment. These data were used to categorise patients as raised disease activity and PD positive (persistent inflammatory RefRA, PIRRA) or raised disease activity in the absence of PD (non-inflammatory RefRA, NIRRA). Descriptive analyses were used to describe the characteristics in the two groups. Missing data were counted as negative observations. Results 82 patients who were on a third advanced therapy or higher were identified. 41/82 (50%) had raised disease activity and 32/41 (78%) had MSUS performed. 18/32 (56%) of these were PIRRA and 14/32 (44%) were NIRRA. Table 1 details demographic and clinical characteristics in the two groups as well as the controlled RefRA population. The PIRRA group had more erosive disease [13/18 (72%) PIRRA vs 8/14 (57%) NIRRA] and smoking history [9/18 (50%) of PIRRA vs 5/14 (35%) of NIRRA]. The PIRRA group also had greater levels of co-morbidity but previous bDMARD toxicity was comparable between the two groups. Whilst the DAS28ESR was higher in the PIRRA group, there were only marginal differences in the tender and swollen joint counts and CRP compared to NIRRA. The controlled RefRA population as expected showed notably lower DAS28-ESR and individual components although more similar to the PIRRA group with regards to comorbidity. Conclusion Just over half of the ref-RA cohort with raised disease activity had MSUS-detected synovitis and may be regarded as PIRRA. The PIRRA group had higher disease activity although joint counts and even acute phase were comparable. Higher smoking history and comorbidity appear to distinguish PIRRA and NIRRA in this cohort. Disclosure G. Rogers: None. Y. Tan: None. R. Shukla: None. R. Gorodkin: None. B. Parker: None. I. Bruce: None. J. Humphreys: None. A. Barton: None. K. Hyrich: None. E. Bruce: None. P. Ho: None. M.H. Buch: None.

P203 Prevalence of lower limb disease activity and walking disability in the first two years of rheumatoid arthritis: results from the Scottish Early Rheumatoid Arthritis inception cohort

Abstract Background/Aims Lower limb synovitis and walking disability are reported as common in rheumatoid arthritis (RA), however there is a paucity of contemporary longitudinal studies reporting prevalence rates from disease onset. The aims of this study were to determine i) the prevalence of lower limb synovitis and walking disability from first presentation to 2 years, and ii) the prevalence of active foot/ankle disease amongst participants in Disease Activity Score-28 (DAS28)-remission. Methods The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of newly diagnosed inflammatory arthritis patients attending rheumatology units across Scotland. SERA data included demographics and 6-monthly clinical outcome data. Data from participants diagnosed with RA were included. Synovitis was determined using tender and swollen joint counts recorded at hips, knees, ankles and metatarsophalangeal (MTP) joints 2-5, and dichotomised as present (≥1) or absent (0). Walking disability was measured using the Health Assessment Questionnaire (HAQ) walking subscale (range 0-3) and dichotomised at present (≥1) or absent (0). Prevalence rates are expressed as percentages of participants. Subgroup analysis was performed to estimate the prevalence of foot/ankle joint swelling in participants who were in DAS28-remission (&amp;lt;2.6). Results A total of 932 participants (65.9% female) with a median (interquartile range [IQR]) age 59.5 years (49.5-68.1) were included, dropping to 391 at 2 years. Prevalence rates for lower limb synovitis and walking disability are reported in table 1. At 6 months, 138/816 (28.6%) participants met DAS28-remission criteria, followed by 124/691 (31.9%) at 1 year, 118/522 (39.2%) at 18 months, and 88/391 (39.5%) at 2 years. For those in DAS28-remission the prevalence of foot/ankle joint swelling was 10.3% at 6 months, 13.5% at 1 year, 17.6% at 18 months and 12% at 2 years. Conclusion Prevalence rates for knee, ankle and MTP joint swelling are initially high then stabilise, with largest reductions observed at 6 months. Joint tenderness prevalence rates follow a similar course but are consistently higher than joint swelling. Walking disability affects a significant proportion of patients throughout the first 2 years of RA. Clinically important rates of active foot/ankle disease are present amongst those classed in DAS28-remission. Disclosure N. Kelleher: None. G.J. Hendry: None.

P266 Secukinumab provides clinical improvements in patients with active oligoarticular psoriatic arthritis: results from a pooled analysis of five phase 3 studies

Abstract Background/Aims Evidence for the efficacy of biologics in patients with oligoarticular psoriatic arthritis (PsA) is limited. We evaluated the efficacy of the interleukin 17 inhibitor secukinumab in patients with oligoarticular PsA pooled from 5 phase 3 studies. Methods This post hoc analysis included patients with oligoarticular PsA from the FUTURE 2-5 and MAXIMISE trials (NCT01649375, NCT01989468, NCT02294227, NCT02404350, and NCT02721966). Oligoarticular PsA was defined as the presence of 1-4 tender joints and 1-4 swollen joints at baseline as measured by the tender joint count of 78 joints (TJC78) and the swollen joint count of 76 joints (SJC76), respectively. Patients were pooled by treatment received at week 12 and week 52 in the following groups: week 12 (secukinumab 300 mg, secukinumab 150 mg with or without loading dose [LD], or placebo) and week 52 (any secukinumab 300 mg or any secukinumab 150 mg). Efficacy was assessed by the proportion of patients achieving 50% improvement in Disease Activity in Psoriatic Arthritis (DAPSA50), DAPSA75, DAPSA-based low disease activity (LDA; DAPSA ≤14) and remission (REM; DAPSA ≤4), resolution of TJC78, resolution of SJC76, and a ≥ 0.35-point improvement in the Health Assessment Questionnaire-Disability Index score. Descriptive statistics are provided for each endpoint. Logistic regression analysis was used to identify potential predictors of DAPSA response at weeks 12 and 52; multivariate logistic regression analyses were performed thereafter. Results 84 patients were included: 48 with active PsA from the FUTURE 2-5 trials and 36 with active PsA and axial manifestations from the MAXIMISE trial. Demographics and baseline disease characteristics were comparable across groups. At week 12, notable improvements were observed for the secukinumab 300 and 150 mg versus placebo groups across all the assessed outcome measures and were sustained or increased through week 52. More than 78% of patients who received secukinumab 300 mg or secukinumab 150 mg achieved LDA or REM at week 12. More than 90% of patients who received any secukinumab 300 mg or secukinumab 150 mg achieved LDA or REM at week 52. At week 52, a higher proportion of patients who received any secukinumab 300 mg versus any secukinumab 150 mg achieved higher hurdle endpoints of DAPSA75 (58.1% versus 43.6%, respectively) and DAPSA REM (61.3% versus 37.5%, respectively). At week 12, younger age was a predictor for the achievement of DAPSA LDA or REM and the achievement of DAPSA50, while lower baseline SJC was a predictor of the achievement of DAPSA REM (P &amp;lt; 0.05). No predictors were identified at week 52. Conclusion Secukinumab provides greater improvements versus placebo across a number of disease activity and physical function outcome measures in patients with oligoarticular PsA at week 12, with sustained responses through week 52. Disclosure L.C. Coates: Honoraria; AbbVie, Amgen, Celgene, Galapagos, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Celgene, Eli Lilly, Novartis, Pfizer. A. Ogdie: Consultancies; Amgen, AbbVie, BMS, Celgene, Novartis, Lilly, Janssen, Gilead, Pfizer, UCB. Grants/research support; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rheumatology Research Foundation, National Psoriasis Foundation, Amgen, Pfizer, Novartis. D.D. Gladman: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Galapagos, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Amgen, Celgene, Eli Lilly, Novartis, Pfizer, UCB. E. Pournara: Shareholder/stock ownership; Novartis. Other; Employee of Novartis. X. Meng: Other; Employee of Novartis. B. Parikh: Other; Employee of Novartis. P.J. Mease: Consultancies; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, UCB. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Eli Lilly, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, UCB.

Effectiveness of 6-month Use of Secukinumab in Patients With Psoriatic Arthritis in the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

To evaluate clinical and patient-reported outcomes (PROs) at 6 months after secukinumab initiation in US patients with psoriatic arthritis (PsA). Patients with PsA in the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry who initiated secukinumab between April 1, 2017, and December 2, 2019, and maintained secukinumab at their 6-month follow-up visit were included. Achievement of minimal disease activity (MDA) among patients not in MDA at initiation; resolution (ie, no evidence) of tender and swollen joint counts, enthesitis, and dactylitis among patients with ≥ 1 of these at initiation; and change in disease activity and PROs were evaluated at 6 months in all patients and in patients who received secukinumab as a first-line biologic. Of the 100 eligible patients included, most (83.0%) were biologic experienced and 17.0% initiated secukinumab as a first-line biologic. At initiation, 75/90 patients (83.3%) with available data were not in MDA; 26/71 (36.6%) with follow-up data achieved MDA at 6 months. Further, 28/68 patients (41.2%) with ≥ 1 tender joint, 24/54 (44.4%) with ≥ 1 swollen joint, 17/28 (60.7%) with enthesitis, and 9/12 (75.0%) with dactylitis at initiation achieved resolution at 6 months. Improvements in clinical manifestations, PRO measures, and work productivity and activity were observed after 6 months among patients with PsA who initiated and maintained secukinumab. In this real-world population, patients with PsA who received and maintained secukinumab for 6 months achieved MDA in proportions consistent with clinical trials and demonstrated improvements in clinical manifestations and PROs.

Identification of poor prognostic joint locations in an early rheumatoid arthritis cohort at risk of rapidly progressing disease: a post-hoc analysis of the Phase III AGREE study

BackgroundRheumatoid arthritis (RA) is a heterogeneous disease with established poor prognostic factors such as seropositivity, joint damage, and high disease activity at an early, treatment-naïve stage of disease. However, few studies have examined if specific joint locations are correlated with these factors in such a population. This analysis explored the potential correlation of individual swollen and erosive joints with other disease characteristics at baseline and with remission rates in a post-hoc analysis of the Phase III randomized AGREE study.MethodsMethotrexate (MTX)-naïve, erosive, RF- and/or ACPA-positive early RA patients (N = 509) were retrospectively evaluated. Baseline joint swelling was analyzed for large and small joints. Baseline erosions were analyzed for wrist, MCP1–5, IP1, PIP2–5 and MTP1–5. Remission rates were assessed after 6 months of treatment with abatacept (ABA) + MTX (N = 256) or MTX (N = 253). The following statistical tests were used: Chi-Square or Fisher’s exact test (categorical variables); Student’s t-test or Wilcoxon rank-sum test (continuous variables); continuity-corrected Chi-square test (efficacy remission endpoints).ResultsBaseline swelling was most frequent in wrist (91.9%) and MCP2 joint (89.1%), while baseline erosion was most frequent in MTP5 joint (43.5%). Swollen shoulder was significantly correlated (p < 0.0001) with swelling of almost all other large or medium joints. Baseline swelling in the knee, temporomandibular joint (TMJ), wrist and elbow was highly correlated (p < 0.001) with higher tender and swollen joint counts, higher DAS28(CRP) and higher SDAI and CDAI. Baseline swelling was not correlated with erosion per joint, except for MCP2. The largest difference in mean Boolean remission rates at 6 months was in patients with baseline swollen wrist favoring ABA + MTX (14.0% vs 4.4%; p < 0.001).ConclusionsSwelling in the large and medium joints (knee, TMJ, elbow and wrist) was highly correlated with severe disease activity while MCP2 swelling seemed to be correlated with joint damage. The correlation of joint locations at an early, treatment-naïve stage with poor prognostic factors, higher disease activity and joint damage, could establish a rapidly progressing anatomical pattern in early RA.Trial registration: ClinicalTrials.gov NCT00122382, registered July 2005.

Clinical implications of autoantibodies to extractable nuclear antigens in rheumatoid arthritis patients in tertiary care hospital in Riyadh, Saudi Arabia

The purpose of this study was to assess the prevalence of autoantibodies against extractable nuclear antigens (ENAs), anti-Ro/SSA, anti La/SSB, anti Jo-1, ribo-nucleoproteins (anti UI-RNP) and antibodies to Smith (anti-Sm) in rheumatoid arthritis (RA) patients and to detect the relationship between the existence of these autoantibodies and clinical presentation, radiological damage, and disease activity markers. The study, included 57 RA patients and 35 normal controls, was conducted in Al-Quwayiya General Hospital. Sera were obtained from patients and controls to carry out Hs-CRP, ESR, RF factors, ANA and ACPA IgG. Anti-Sm, anti-U1-RNP, anti-Ro/SSA, anti-La/SSB, and anti-Jo-1 were measured using the Alegria® assay. ESR was 23.8±6.5, while CRP was 16.19±7.15 in RA patients. RF was detected in 23 (40.35%) patients and ACPA in 54 (94.73%), while ANA was positive in 14 (24.56%) cases. Anti-Ro/SSA was detected in 8 (14.03%) patients, anti-La/SSB in 3 (5.26%), anti-Jo-1 was found in 2 cases (3.50%), and anti-RNP in 1 (1.75%). Anti-Ro/SSA had a significant negative relationship with sex (r=-0.220, P=0.001), but a positive correlation was observed with sicca symptoms (r=0.149, P=0.02). Anti-La/SSB antibodies correlated positively with swollen joint count (r=0. 0.225, P=0.001), tender joint count (r=0.219, P=0.001) and ANA (r=0.367, P < 0.001). Anti-Jo-1 antibodies showed a significant positive correlation with interstitial lung disease (r=-0.429, P≤0.001). Anti-Ro/SSA had a significant positive correlation with RF titer (r=0.259, P < 0.001) and ANA (r=0.498, P < 0.001). Anti-La/SSB had significant positive correlation with ANA (r=0.372, P < 0.001). Anti-Jo-1 showed a significant positive correlation with RF titer (r=0.141, P < 0.040) and ANA (r=0.249, P < 0.001). Anti-RNP showed a significant positive correlation with ACPA titre (r=0.288, P < 0.001) and ANA (r=0.159, P < 0.018). We conclude that ENA autoantibodies are crucial and need to be correlated with clinical diagnosis and other serological testing for early diagnosis and intervention of the RA.

292 Fibromyalgianess and Glucocorticoid Persistence Among Patients with Rheumatoid Arthritis

OBJECTIVES/GOALS: Over 30% of patients with rheumatoid arthritis (RA) exhibit fibromyalgianess, a symptom cluster associated with increased pain sensitivity. Up to half of RA patients use oral glucocorticoids (GCs) long-term despite their known, dose-dependent toxicity. We examined the association between fibromyalgianess and oral GC persistence in RA patients. METHODS/STUDY POPULATION: We used data from the Central Pain in Rheumatoid Arthritis (CPIRA) cohort to follow participants with active RA on oral prednisone who initiated a new disease-modifying anti-rheumatic drug. We measured fibromyalgianess using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key fibromyalgia features often superimposed upon RA. We stratified fibromyalgianess severity as follows: FSQ&lt;8 low, 8-10 moderate, &gt;10 high/very high. We defined GC persistence as GC use at 3 month followup visit. We assessed the association between baseline fibromyalgianess (exposure) and GC persistence at followup (outcome) using multiple logistic regression, adjusted for demographics, RA duration, serostatus, and inflammatory activity measured by swollen joint count and C reactive protein. RESULTS/ANTICIPATED RESULTS: Of 97 participants on prednisone at baseline, 65% were taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent GC use, compared to 84% with high or very high fibromyalgianess. After adjustment as outlined above, participants with high/very high baseline fibromyalgianess remained more likely to be on prednisone at follow-up, relative to those with low fibromyalgianess (OR 4.99 [95% CI 1.20 – 20.73]). DISCUSSION/SIGNIFICANCE: In this cohort of patients with active RA, high fibromyalgianess is associated with persistent GC use, independent of inflammatory activity. This finding suggests non-inflammatory pain related to fibromyalgianess may be misclassified as inflammatory pain related to RA disease activity.

Efficacy of anifrolumab across organ domains in patients with moderate-to-severe systemic lupus erythematosus: a post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by multisystem involvement. We aimed to evaluate the efficacy of anifrolumab on organ domain-specific SLE disease activity. In this post-hoc analysis, data were pooled from the randomised, placebo-controlled, phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab (300 mg intravenously once every 4 weeks for 48 weeks) in patients aged 18-70 years with moderate-to-severe SLE. We evaluated changes from baseline to week 52 in British Isles Lupus Assessment Group 2004 (BILAG-2004) and SLE Disease Activity Index 2000 (SLEDAI-2K) organ domain scores, Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score (CLASI-A), swollen and tender joint counts, haematology, and serology. Among the 726 patients included, the mean age was 41·8 years (SD 11·9); 674 (93%) were female, 52 (7%) were male, and 479 (66%) were White. 360 patients received anifrolumab 300 mg (180 patients in each trial), and 366 received placebo (184 patients in TULIP-1 and 182 patients in TULIP-2). The most frequently affected organ domains at baseline were musculoskeletal (645 [89%] patients based on BILAG-2004; 684 [94%] with SLEDAI-2K) and mucocutaneous (627 [86%] with BILAG-2004; 699 [96%] based on SLEDAI-2K). At week 52, anifrolumab treatment resulted in greater improvements versus placebo in the musculoskeletal system (176 [56%] of 317 patients vs 143 [44%] of 328 with BILAG-2004; 164 [49%] of 335 vs 141 [40%] of 349 with SLEDAI-2K), the mucocutaneous system (168 [54%] of 315 vs 119 [38%] of 312 with BILAG-2004; 190 [55%] of 348 vs 138 [39%] of 351 SLEDAI-2K), and immunological system (44 [19%] of 237 vs 26 [11%] of 230 with SLEDAI-2K). Less frequently affected domains had varied responses. Among patients with a CLASI-A of 10 or more at baseline, greater proportions of patients receiving anifrolumab than placebo achieved a reduction of 50% or more in CLASI-A at week 52 (49 [46%] of 107 vs 24 [25%] of 94). Among patients with at least six swollen joints, more patients in the anifrolumab group than in the placebo group had a 50% or more reduction from baseline to week 52 in swollen joint count (99 [57%] of 174 vs 92 [46%] of 200), but the difference between groups was not significant for 50% or more reduction in tender joint count. Across the two pivotal phase 3 trials, anifrolumab treatment improved SLE disease activity across multiple organ domains. AstraZeneca.

Real-world treatment patterns for repository corticotropin injection in patients with rheumatoid arthritis

IntroductionRepository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogues and other pituitary peptides with anti-inflammatory and immunomodulatory effects. In a recent clinical trial, RCI was safe and effective for the treatment of refractory rheumatoid arthritis (RA). This study aims to describe real-world use and outcomes of patients with RA who were prescribed RCI in clinical practice through retrospective analysis of an electronic medical record database.MethodsPatients with RA who were prescribed RCI were identified through the ColumbusTM electronic medical record repository, representing approximately 100 rheumatology practices. Demographics, medications, comorbidities, disease histories, laboratory evaluations, clinical outcomes and patient-reported outcomes were evaluated from 12 months pre-RCI to 12 months post-RCI initiation.ResultsThe RCI cohort (n=63) comprised predominantly white women, aged 54 years on average, at 6 years from RA diagnosis, with high disease activity at baseline according to Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) scores. Within the 12 months pre-RCI initiation, 87% of patients were prescribed disease-modifying antirheumatic drugs and 67% were prescribed glucocorticoids. Twelve months post-RCI initiation, glucocorticoid, opioid and non-steroidal anti-inflammatory drug prescriptions decreased; disease-modifying antirheumatic drug prescriptions remained stable. Reductions in CDAI, RAPID3, physician global assessment, tender joint count, swollen joint count, and pain visual analogue scale scores were observed 12 months post-RCI initiation. Few discontinuations were due to side effects. Study limitations included small sample size and incomplete electronic medical record data.ConclusionThese findings support the safety and effectiveness of RCI for short-term adjunctive treatment of refractory RA and provide patient-management insights from routine clinical practice.

The effectiveness and safety of Simiao Xiaobi decoction on rheumatoid arthritis: A study protocol for systematic review and meta-analysis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease that contributes to progressive disability, systemic complications, higher mortality, and societal burden. Typical symptoms of RA include symmetrical pain and swelling in multiple joints, morning stiffness, and elevated levels of erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor. The representative treatment for RA is medication, including disease-modifying antirheumatic drugs, glucocorticoids, and nonsteroidal anti-inflammatory drugs. However, these medications are not yet curative nor preventative and are associated with several adverse effects, leading to their discontinuation. Recent articles reported that Simiao Xiaobi decoction (SXD) could relieve the symptoms of RA by clinical trial and experimental study, but an evidence-based review on the effectiveness and safety of SXD on RA has not yet been provided. Searching for randomized controlled trials on the use of SXD for RA will be performed by using multiple electronic databases, manual search, and contacting the authors by e-mail if needed. Studies will be selected according to the predefined criteria and the data collected on study participants, interventions, control groups, outcome measurements, their results, adverse events, and risk of bias will be summarized. The primary outcome will be the disease activity score (including effective rate, swollen joint count, tender joint count, and morning stiffness), and the secondary outcomes will be blood tests (including erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor) and adverse events. We will use Review Manager software to perform a meta-analysis, the Cochrane Collaboration "risk of bias" tool for assessing the risk of bias, and grades of recommendation, assessment, development and evaluation for the determination of the quality of evidence. https://inplasy.com; INPLASY202230026. We are going to investigate the effectiveness and safety of SXD for RA. This study will provide reliable evidence on whether SXD is effective on RA.

Effects and Safety of the Tripterygium Glycoside Adjuvant Methotrexate Therapy in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Objective This study aimed to systematically review the efficacy and clinical safety of different courses and doses of tripterygium glycoside (TG) adjuvant methotrexate (MTX) therapy in the treatment of rheumatoid arthritis (RA). Methods Randomized controlled trials (RCTs) of TG adjuvant MTX therapy in patients with RA were retrieved from SinoMed, China Network Knowledge Infrastructure, WanFang Data, PubMed, Cochrane Library, and Embase from inception to September 30, 2021. The effects and clinical safety evaluations were conducted using RevMan 5.3 software. Results A total of 9 RCTs and 892 patients with RA were included in this study. In the meta-analysis, a total of 463 and 429 patients were enrolled into the TG adjuvant MTX therapy group and MTX monotherapy group, respectively. In comparison with MTX monotherapy, the results of the analyzed effects showed that the TG adjuvant MTX therapy can achieve 20%, 50%, and 70% improvements in American College of Rheumatology (ACR) criteria ACR20, ACR50, and ACR70 at P = 0.005, P = 0.0001, and P = 0.004, respectively. Simultaneously, the efficacy of the TG adjuvant MTX therapy was improved at either 30 or 60 mg/day over a six-month course compared to MTX monotherapy (P < 0.0001). There was no statistical difference in the effects between the doses of 30 and 60 mg/day after three months (P = 0.82). TG adjuvant MTX also reduced the expression rate of the swollen joint count, tender joint count, erythrocyte sedimentation rate, rheumatoid factor, and C-reactive protein in subgroup analyses with different courses and doses. In terms of hepatic adverse effects (P = 0.28), leukopenia (P = 0.78), gastrointestinal adverse effects (P = 0.17), cutaneous adverse effects (P = 0.94), and irregular menstruation adverse effects (P = 0.29), there was no statistically significant difference with TG adjuvant MTX therapy and MTX monotherapy with different courses and doses. Conclusions TG adjuvant MTX therapy is more effective than MTX monotherapy and is a safe strategy for RA treatment in doses of 30 or 60 mg/day over a treatment course of six months. However, high-quality multicenter RCT studies with large sample sizes are still needed to confirm the effects and clinical safety of different courses and doses of TG adjuvant MTX therapy.

Ultrasonographic evaluation of distal femoral and talar cartilage thicknesses in patients with early rheumatoid arthritis and their relationship with disease activity.

The aims of this study were to compare the distal femoral and talar cartilage thicknesses by ultrasonography (US) between patients with early rheumatoid arthritis (RA) and healthy controls and to investigate the potential relationship of these parameters with disease activity and clinical parameters. Fifty-five patients with RA with a disease duration of up to 12 months (RA group), and 55 healthy volunteers (control group) were included in the study. The bilateral distal femur and talus cartilage thicknesses of all participants were measured by US and compared between the groups. The relationship of the results with the clinical data of the patients with early RA was investigated. The distal femur (medial, central, and lateral) and talus cartilage thicknesses of both extremities were significantly lower in the RA group. The tender joint count was found to be slightly to moderately negatively correlated with cartilage thickness. However, no correlation was found between the swollen joint count and cartilage thickness. In addition, the disease activity scores were moderately and inversely correlated with cartilage thickness in certain areas. The results of this preliminary study using US indicate that the distal femoral and talus cartilage of patients with RA can be affected in the early period, and the cartilage thickness of patients seems to be associated with disease activity. These results may inspire new studies for the evaluation of femoral and talar cartilage with US. Key Points • The distal femoral and talus cartilage thicknesses seem to be affected in the early period of rheumatoid arthritis. • There may be a relationship between the distal femur and talus cartilage thicknesses and disease activity in patients with early rheumatoid arthritis. • The tender joint count appears to be more associated with cartilage thickness than the swollen joint count in patients with early rheumatoid arthritis.