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This study aimed to assess the cost-effectiveness of biologic disease-modifying antirheumatic drugs (bDMARDs) for treating patients with psoriatic arthritis who failed conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).A decision tree and Markov model were constructed to capture long-term costs and outcomes from a societal perspective. Patients with psoriatic arthritis who failed 2 previous csDMARDs were modeled over a 3-month cycle with a lifetime horizon. Clinical probabilities were derived from a published meta-analysis. Prices of bDMARDs were proposed by pharmaceutical companies. Other costs and utilities were based on data in Thailand. All costs and outcomes were discounted at a 3% annual rate. Incremental cost-effectiveness ratio and a series of sensitivity analyses were performed.All 11 bDMARDs (3 infliximab originator and biosimilars, 2 etanercept originator and biosimilar, golimumab, 2 secukinumab 150 mg and 300 mg, 3 adalimumab biosimilars) gained better quality-adjusted life-years (QALYs) with more costly than csDMARDs. Infliximab had the highest QALYs compared with other bDMARDs. Only secukinumab 150 mg showed the incremental cost-effectiveness ratio below the Thai threshold of 5152 US dollars per QALY. Cost of bDMARDs was the most influential factor.At the current price, secukinumab 150 mg shows the value for money in the Thai context. Price negotiation is of great importance for other bDMARDs.

Scleroderma is a rare complication in taxanes therapy. Although individual cases of taxanes-induced scleroderma have been reported, the clinical manifestation and treatment outcomes were reviewed and summarized rarely. This study reported a patient who developed diffuse scleroderma and possible scleroderma renal crisis after paclitaxel therapy for ureter cancer.A PubMed literature review on published cases of taxanes-induced scleroderma up until April 2022 was included for analysis.The search identified 27 patients with adequate information for analysis. Of the 28 patients, including the one presented here, 22 were female. Peripheral edema was the most common symptom in all but one patient, and often accompanied by erythema in 11. Symptoms usually occurred in half of the patients within the 4Taxanes-induced scleroderma is different from idiopathic scleroderma. Physicians should be aware of this condition in order to provide early diagnosis and apply appropriate management in order to avoid serious complications from severe skin sclerosis. Key Points • Scleroderma is a rare but unique and serious complication of taxanes therapy • Skin manifestations and distribution are similar to idiopathic scleroderma, but vascular phenomenon, internal organ involvement and scleroderma-associated auto-antibodies are presented rarely. Skin improvement usually occurs shortly after discontinuing taxanes • The role of immunosuppressive therapy in treating taxanes-induced scleroderma is not clear.

Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort.Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity.Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS.Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

To translate the Gout Assessment Questionnaire version 2.0 (GAQ2.0) with Gout Impact (GI) Scale (GIS) into Thai and determine its psychometric property in gout patients with acute arthritis (acute arthritis group) and during the intercritical period (chronic gout group).Translation followed the ISPOR recommendations. Cronbach's α, intraclass correlation coefficient (ICC) and standardized response mean (SRM) were used to determine internal consistency, reliability and responsiveness to change, respectively. Correlations between GI subscales with generic health-related quality of life (HRQoL) questionnaires (SF-36, HAQ-DI and EQ-5D-5L) and gout clinical parameters were determined.The acute arthritis group and the chronic gout group comprised 27 and 92 patients, respectively. Internal consistency was sufficient for all GI subscales (Cronbach's α = 0.80-0.98), reliability was moderate to good in most GI subscales (ICC = 0.54-0.88) and responsiveness to change was moderate to large in most GI subscales (SRM = 0.43-0.98). The GI subscales correlated better with SF-36 than HAQ-DI and EQ-5D-5L. In the acute arthritis group, the unmet gout treatment needs subscale showed large and moderate negative correlation with tophi and serum uric acid, respectively. In the chronic gout group, the gout concern overall subscale had statistically significant, moderate correlation with overall gout severity rated by the patients and number of gout attacks over the past year, while the well-being during attack subscale and total GIS score had statistically significant, moderate correlation with overall gout severity rated by the patients.The Thai GAQ2.0 GIS showed acceptable internal consistency, reliability and responsiveness to change and correlated significantly with generic HRQoL questionnaires and clinical parameters. Key Points • The Thai GAQ2.0 GIS showed acceptable internal consistency, reliability and responsiveness to change in gout patients both during acute attack and during the intercritical period • The GI subscales showed significant correlation with SF-36 and HAQ questionnaires and gout clinical parameters in gout patients both during acute attack and during the intercritical period • The Thai GAQ2.0 GIS subscales should be used in conjunction with generic HRQoL for complete HRQoL assessment in gout patients.

Objectives: This study aims to compare pregnancy outcomes between systemic lupus erythematosus (SLE) patients who attained clinical remission based on the Definition of Remission in SLE (DORIS) and those with lupus low disease activity based on Low Lupus Disease Activity State (LLDAS). Patients and methods: Between January 1993 and June 2017, a total of 90 pregnancies (one twin pregnancy) from 77 patients (mean age: 26.9±4.8 years; range, 17.9 to 37.3 years) were included in the study. The clinical remission and the LLDAS groups were modified into modified clinical remission and LLDAS groups, respectively by omitting Physician Global Assessment (PGA). The clinical SLE disease activity index (cSLEDAI) score was used for LLDAS. Results: Pregnancies in 49 patients occurred, when they were in modified clinical remission and in 57 in modified LLDAS. There was no significant difference in demographic characteristics, disease activity, or medication received at conception between the two groups. Pregnancy outcomes were similar between the modified clinical remission and the modified LLDAS groups in terms of successful pregnancy (83.67% vs. 84.21%), full-term births (38.78% vs. 38.60%), fetal losses (16.33% vs. 15.79%), spontaneous abortions (14.29% vs. 14.04%), small for gestational age infants (18.37% vs. 19.30%), low birth weight infants (42.86% vs. 40.35%), maternal complications (46.94% vs. 49.12%), and maternal flares (36.73% vs. 40.35%). The agreement of pregnancy outcomes was very high between the two groups (91.11% agreement). Conclusion: Pregnancy outcomes in SLE patients who achieved modified clinical remission and modified LLDAS were comparable

Aim To update previous guidance of the Asia Pacific League of Associations for Rheumatology (APLAR) on the management of patients with rheumatic and musculoskeletal diseases (RMD) during the coronavirus disease 2019 (COVID‐19) pandemic. Methods Research questions were formulated focusing on diagnosis and treatment of adult patients with RMD within the context of the pandemic, including the management of RMD in patients who developed COVID‐19. MEDLINE was searched for eligible studies to address the questions, and the APLAR COVID‐19 task force convened 2 meetings through video conferencing to discuss its findings and integrate best available evidence with expert opinion. Consensus statements were finalized using the modified Delphi process. Results Agreement was obtained around key aspects of screening for or diagnosis of COVID‐19; management of patients with RMD without confirmed COVID‐19; and management of patients with RMD with confirmed COVID‐19. The task force achieved consensus on 25 statements covering the potential risk of acquiring COVID‐19 in RMD patients, advice on RMD medication adjustment and continuation, the roles of telemedicine and vaccination, and the impact of the pandemic on quality of life and on treatment adherence. Conclusions Available evidence primarily from descriptive research supported new recommendations for aspects of RMD care not covered in the previous document, particularly with regard to risk factors for complicated COVID‐19 in RMD patients, modifications to RMD treatment regimens in the context of the pandemic, and COVID‐19 vaccination in patients with RMD.

In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up.We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied.We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P 0.05 for damage accrual ORs at all time points).In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

HLA studies in patients with systemic sclerosis (SSc) have shown variable results. This study aimed to examine the association of HLA class I and II risk alleles in Thai SSc patients, and clarify the contribution of risk HLA alleles to the pathogenesis and clinical manifestations. Blood samples from 92 SSc patients and 135 healthy controls (HCs) were collected. Eleven loci of the HLA class I (HLA-A, B, and C) and class II (HLA-DR, DP, and DQ) genes were determined by a 3-field (6-digit) analysis using the Next Generation DNA Sequencing (NGS) method. Anti-topoisomerase-I antibodies (ATA) and anti-centromere antibodies (ACA) were identified by ELISA methods. Allele frequencies (AFs) of HLA-DRB1*15:02:01, DRB5*01:02:01, DQB1*05:01:24, DPB1*13:01:01, and DQA1*01:01:01 were increased significantly in the whole SSc and SSc patients with positive ATA, but with negative ACA (SSc/ATA+/ACA-). Of these, DPB1*13:01:01 was the most susceptible allele. The DRB1*15:02:01, DQB1:05:01:24, and DPB1*13:01:01 alleles were estimated to locate on the unique haplotype, and haplotype frequency was estimated to be significantly higher than those in the HCs (p = 0.002). The linkage analysis of DRB1*15/16 revealed that most of the DRB1*15:02:01 alleles were linked to DRB5*01:02:01 or DRB5*01:08:01N. The linkage of DRB1*16:02:01 to DRB5*01:01:01 was observed frequently. The associations of risk alleles with several SSc clinical features were observed. HLA-DRB1*15:02:01, DRB5*01:02:01, DQB1*05:01:24, and DPB1*13:01:01 on the unique haplotype were associated with the pathogenesis and clinical features of SSc in Thai patients. The linkage of DRB1*15:02:01 to DRB5*01:08:01N was observed commonly in northern Thai patients.

Objective The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. Methods Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013 to 2018, were used. Predictors of lymphopenia (lymphocyte count Results Data from 2330 patients and 18 287 visits were analysed. One thousand and eighteen patients (43.7%) had at least one episode of leucopenia; 867 patients (37.2%) had lymphopenia, observed in 3065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, AZA, MTX, tacrolimus, CYC and rituximab use. MTX and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state was negatively associated with both lymphopenia and neutropenia. Conclusion Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.

Purpose of the study: Parkinsonism in patients with systemic lupus erythematosus (SLE) is rare. This study reported a case of parkinsonism in SLE and reviewed the clinical features and outcomes of ...

Objective To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. Methods Patients’ self-reports of current gout flares were assessed with the question, ‘Are you having a gout flare today?’ which was then compared with a concurrent, blinded, physician’s assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups—patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed—were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. Results Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0–10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. Conclusion Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

Reports of inflammatory rheumatic diseases (IRD) in thalassemia are limited. This study aimed to determine the prevalence and clinical characteristics of IRD in patients with thalassemia disease. Consecutive adult patients with thalassemia disease, confirmed by hemoglobin typing, attending the Hematology Clinic between June 2019 and May 2021 were invited to join this study. All of them had their history taken and a physical examination for IRD. Those with IRD had their medical records reviewed. Sixty-three patients (transfusion-dependent in 50) were included in this study. There was α-, β-, and co-inheritance of α- and β-thalassemia in 22.22%, 73.02%, and 4.76% of the patients, respectively, with β-thalassemia/Hb E disease in 53.97%. Twenty-three patients had IRD (rheumatoid arthritis in 9, gout in 6, systemic lupus erythematosus in 3, spondyloarthropathy in 2, and one patient each with dermatomyositis, overlap syndrome, and unclassified polyarthralgia). Clinical manifestations and laboratory findings were similar to IRD patients in general. In 40 patients without IRD, direct and indirect Coombs tests and antinuclear antibody (ANA) were positive in 51.72%, 27.59%, and 10.26%, respectively. When comparing among these 40 patients, between those with non-transfusion-dependent thalassemia (n = 10) and those with transfusion-dependent thalassemia (n = 30), the latter had non-significantly more positive direct Coombs (60.87% vs. 16.67%), indirect Coombs (30.43% vs. 16.67%), and ANA tests (13.33% vs. 0%). The prevalence of IRD in patients with thalassemia disease was rather high. Positive direct Coombs test and ANA were common in transfusion-dependent patients.

Background: Nowadays, we have standard treatment guidelines for lupus nephritis (LN), a substantial proportion of patients have LN flare. The aims here to determine the incidence of LN flare in patients who had renal complete remission (CR) after receiving induction therapy (IT) and to identify factors associated with renal flare after CR in clinical practice. Methods: Retrospective analysis in a tertiary-level center for the clinical outcomes of patients who had first LN episode, achieved CR (24hr urine protein

Gout is the most prevalent inflammatory arthritis in the Asia-Pacific region and worldwide. This clinical practice guideline (CPG) aims to provide recommendations based on systematically obtained evidence and values and preferences tailored to the unique needs of patients with gout and hyperuricemia in Asia, Australasia, and the Middle East. The target users of these guidelines are general practitioners and specialists, including rheumatologists, in these regions.Relevant clinical questions were formulated by the Steering Committee. Systematic reviews of evidence were done, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation methodology. A multi-sectoral consensus panel formulated the final recommendations.The Asia-Pacific League of Associations for Rheumatology Task Force developed this CPG for treatment of gout with 3 overarching principles and 22 recommendation statements that covered the treatment of asymptomatic hyperuricemia (2 statements), treatment of acute gout (4 statements), prophylaxis against gout flare when initiating urate-lowering therapy (3 statements), urate-lowering therapy (3 statements), treatment of chronic tophaceous gout (2 statements), treatment of complicated gout and non-responders (2 statements), treatment of gout with moderate to severe renal impairment (1 statement), and non-pharmacologic interventions (5 statements).Recommendations for clinically relevant scenarios in the management of gout were formulated to guide physicians in administering individualized care.

Physical disability and severity of skin disease are important factors for evaluating healthy utility in psoriatic arthritis (PsA) patient. This study aims to estimate health utility and its related factors incorporating both rheumatologic and dermatologic factors in PsA. This cross-sectional study performed in PsA patients in Thailand. EQ-5D-5L, Health Assessment Questionnaire Disability Index (HAQ-DI), and Psoriasis Area and Severity Index (PASI) tools were used to collect health utility, physical disability, and severity of psoriatic skin lesions by face-to-face interviewed. Linear regression analysis was performed to relate health utility and its related factors. Of 84 patients enrolled, 49 (58.3%) were female, 67 (79.8%) had remission or low disease activity. Eighty-three patients (98.8%) received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). The mean±SD overall utility was 0.87±0.15. The utility score of patients with low disease activity was significantly greater than those with moderate to severe disease activity (0.89±0.12 vs 0.72±0.19, p

Background The adjusted-Global Antiphospholipid Syndrome Score (aGAPSS) has been validated and used to predict antiphospholipid antibodies (aPL) related to vascular thrombosis (VT). Objective To validate aGAPSS for predicted aPL-related VT and pregnancy complications (PC) in Thai systemic lupus erythematosus (SLE) patients. Methods A cross-sectional study was performed among Thai SLE patients with clinical manifestations; history of VT and PC, cardiovascular risk factors, and aPL profiles were collected. The aGAPSS was calculated from the sum of the risk factors (hyperlipidemia = 3.0, arterial hypertension = 1.0, anti-cardiolipin antibody = 5.0, anti-b2 glycoprotein I antibody = 4.0, and lupus anticoagulant = 4.0). Results Of 132 SLE patients, 12 (9.1%) had VT and 5 (4.1%) had PC. When comparing the aGAPSS (median; interquartile range [IQR]) of patients with events (VT and/or PC) (6.5; IQR 3.3-9.0), VT (8.0; IQR 4.0-9.0), arterial thrombosis (3.5; IQR 1.0-5.8), and PC (9.0; IQR 8.0-11.5), and the aGAPSS of patients without an event (3.0; IQR 0-4.0), aGAPSS of patients with events was significantly higher, except in patients with arterial thrombosis. An aGAPSS of 4.5 or more was associated with risk of aPL-related VT (sensitivity 71.4%, specificity 76.7%), and an aGAPSS of 6.0 or more was associated with risk of aPL-PC (sensitivity 100%, specificity 84.0%). Conclusion The aGAPSS could predict the risk of aPL-PC and aPL-related VT in Thai SLE patients.

AIMS To investigate susceptible human leukocyte antigen (HLA) alleles and their associations with clinical features in Thai patients with Behcet's disease (BD). METHOD Eighteen HLA-A and 36 HLA-B alleles were determined in 42 Thai BD patients and 99 healthy controls (HCs) by reverse line blot assay, and reconfirmed by MICRO SSP assay. RESULTS The BD patients had significantly higher allele frequency (AF) of HLA-B*51 than the HCs (13.10% vs 5.05%, P = .025). The AF of HLA-A*26, -A*26:01 and -B*51:01 also was higher and almost reached statistical significance (5.59% vs 1.52%, P = .054, 5.95% vs 1.52%, P = .054 and 10.71% vs 4.04%, P = .051, respectively). However, the BD patients had significantly higher AF of either HLA-A*26:01 or -B*51:01 (16.67% vs 5.56%, P = .005), or -A*26:01 or -B*51X (19.05% vs 6.56%, P = .003). The AF of HLA-B*51:01 and -B*51X increased significantly in -A*26:01 non-carrier BD patients (12.16% vs 4.17%, P = .024 and 14.86% vs 5.21%, P = .019, respectively); and that of HLA-A*26:01 was significantly higher in -B*51X non-carrier BD patients (7.58% vs 1.67%, P = .034). HLA-B*51:01 associated significantly with the presence of posterior uveitis and visual impairment (18.18% vs 2.50%, P = .031 for both conditions). HLA-B*51:01 was not observed in BD patients with gastrointestinal involvement or arthritis. Furthermore, the AF of HLA-B*51:01 was significantly higher in HLA-A*26:01 non-carrier BD patients without arthritis (17.30% vs 0%, P = .050). CONCLUSION HLA-B*51:01 was a susceptible allele for Thai BD patients, and associated with posterior uveitis and visual impairment. HLA-A*26:01 was another susceptible allele in HLA-B*51X non-carrier patients. The protective effect of HLA-B*51:01 on arthritis needs further investigation.

Summary Background Evaluating the contribution of glucocorticoid use to organ damage in systemic lupus erythematosus is confounded by glucocorticoid use in active disease. We sought to determine the independence of the contribution of glucocorticoid use to damage accrual from associations with disease activity by analysing patients without measurable disease activity. Methods Patients (age >18 years) who met the criteria for systemic lupus erythematosus were recruited from 13 centres in Australia, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand, and followed longitudinally. Disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and Physician Global Assessment [PGA] scores) and treatment details were recorded at each visit (at least once every 6 months), and organ damage measured annually according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Glucocorticoid use during the study period was recorded as any exposure to prednisolone, cumulative prednisolone exposure, and time-adjusted mean daily prednisolone dose. Multivariate survival analyses were used to examine time-dependent associations of glucocorticoid use with damage accrual (defined as an increase of ≥1 on SDI). A SLEDAI-2K score of 0 was taken to indicate the absence of clinical and serological disease activity; a subset of patients without disease activity during the study were defined by a time-adjusted mean SLEDAI-2K (AMS) score of 0. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited. Over a median observation period of 2·2 years (IQR 1·5–3·0), damage accrual events were observed in 255 (14·9%) patients. 1405 (82·3%) of patients were exposed to prednisolone, with a median time-adjusted mean prednisolone dose of 5·0 mg/day (IQR 1·9–8·8). As SLEDAI-2K and PGA scores were highly correlated, two multivariable models were set, each including one of these two variables. In the model including AMS score, baseline SDI damage (SDI >0) was independently associated with damage accrual (HR 1·32 [95% CI 1·01–1·73], p=0·0427). In the other model, time-adjusted mean PGA score was independently associated with damage accrual (1·05 [1·02–1·08], p=0·0012). In both models, factors independently associated with damage accrual included time-adjusted mean prednisolone dose, age at enrolment, and ethnicity (Asian vs non-Asians). 157 (9·2%) patients had an AMS score of 0 (no disease activity), among whom 103 (65·6%) had glucocorticoid exposure and the median time-adjusted mean prednisolone dose was 2·0 mg/day (IQR 0·0–5·0). Accrual of irreversible organ damage occurred in 21 (13·4%) of these patients and was independently associated with time-adjusted mean prednisolone dose (HR 1·14 [95% CI 1·03–1·26], p=0·0117), time-adjusted mean PGA score (1·13 [1·03–1·23], p=0·0144), and age at enrolment (1·04 [1·01–1·07], p=0·0061), but not baseline SDI damage (0·94 [0·43–2·06], p=0·8675). Interpretation Glucocorticoid use contributes to damage accrual in systemic lupus erythematosus independently of the presence of clinical or serological disease activity. Funding UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca (to the Asia-Pacific Lupus Collaboration).

Objective To examine longitudinal associations of active lupus nephritis with organ damage accrual in patients with systemic lupus erythematosus (SLE). Methods This study was performed using data from a large multinational prospective cohort. Active lupus nephritis at any visit was defined by the presence of urinary casts, proteinuria, haematuria or pyuria, as indicated by the cut-offs in the SLE Disease Activity Index (SLEDAI)-2K, collected at each visit. Organ damage accrual was defined as a change of SLICC-ACR Damage Index (SDI) score >0 units between baseline and final annual visits. Renal damage accrual was defined if there was new damage recorded in renal SDI domains (estimated glomerular filtration rate 3.5 g per 24 h/end-stage kidney disease). Time-dependent hazard regression analyses were used to examine the associations between active lupus nephritis and damage accrual. Results Patients ( N = 1735) were studied during 12,717 visits for a median (inter-quartile range) follow-up period of 795 (532, 1087) days. Forty per cent of patients had evidence of active lupus nephritis at least once during the study period, and active lupus nephritis was observed in 3030 (24%) visits. Forty-eight per cent of patients had organ damage at baseline and 14% accrued organ damage. Patients with active lupus nephritis were 52% more likely to accrue any organ damage compared with those without active lupus nephritis (adjusted hazard ratio = 1.52 (95% confidence interval (CI): 1.16, 1.97), p Conclusion Active lupus nephritis measured using the SLEDAI-2K domain cut-offs is associated with renal, but not non-renal, damage accrual in SLE.

Summary Background Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. Methods In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov , NCT03138941 . Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45–0·76; p Interpretation LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. Funding The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Summary Background Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. Methods In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. Interpretation Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions. Funding UCB, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Aims Studies on polymorphisms of the cytotoxic T lymphocytes associated antigen-4 (CTLA-4) genes in rheumatic disease patients are limited in Southeast Asia. This pilot study aimed to determine CTLA-4 polymorphisms in Thai patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and correlate them with serology. Method One-hundred RA, 70 SLE and 50 SSc patients, and 99 healthy controls (HCs) were included in this study. Polymorphisms of the CTLA-4 gene at +49A/G, -318C/T, -1661A/G and -1722T/C loci were determined by polymerase chain reaction restriction fragment length polymorphism methods. Patient serum samples were determined as follows: RA (rheumatoid factor [RF] and anticyclic citrullinated peptide [anti-CCP]), SLE (antinuclear antibodies [ANA], anti-double-stranded DNA [anti-dsDNA], anti-Smith [anti-Sm], anti-ribonucleoprotein [anti-RNP], and anti-Sjogren's syndrome antigen A [SSA]), and SSc (ANA, anti-RNP, anti-SSA, anti-topoisomerase-1 [anti-Scl70], and anti-centromere antibodies [ACA]). Results Among the 4 loci studied (+49A/G, -318C/T, -1661A/G and -1722T/C) only the A allele frequency at the +49A/G was significantly higher in the RA patients than their HCs (47.25% vs 35.86%, P = .029, odds ratio [OR] 1.60; 95% CI 1.04-2.47). It also was significantly higher in the subgroup of RA patients with positive RF and anti-CCP than their HCs (47.50% vs 35.86%, P = .020, OR 1.62; 95% CI 1.06-2.47 and 48.89% vs 35.86%, P = .012, OR 1.71; 95% CI 1.11-2.64, respectively). No polymorphisms at these 4 loci were observed in SLE or SSc patients. Conclusion The A allele at +49A/G locus of the CTLA-4 gene was associated with RA in Thais.

Objective To determine longitudinal associations between Physician Global Assessment (PGA) and patient-reported outcomes (PROs) in patients with systemic lupus erythematosus (SLE). Methods Patients attending a rheumatology clinic between 2013 and 2017 completed specific (SLEQOL) and generic (SF36) health-related quality of life (HRQoL) surveys and rated their global rating of change (GRC) at each visit. PGA, SLEDAI-2K and SLE Flare Index (SFI) were also captured on all visits. Generalised estimating equations (GEE) methods were used to examine longitudinal associations of PGA with PROs and clinical indicators. Results 337 patients were followed for a median [IQR] of 3.2 [1.6, 3.4] years (2,059 visits). High PGA (>1) was strongly associated with high SLEDAI-2K scores, the presence of flares and poor PROs. Odd ratios (OR) [95% CI] of PGA > 1 in patients with SLEDAI-2K >4 & 1 in patients with mild-to-moderate or severe flares were 2.09 [1.62, 2.71], p 1 (OR [95%CI] 1.99 [1.25, 3.16], p = 0.004). Conclusion High PGA was strongly associated with poor mental health, high disease activity and flares. This study confirms the value of PGA as an efficient assessment tool for SLE.

BACKGROUND/OBJECTIVE The aim of this study was to compare disease activity and rate and severity of flares between pregnant and nonpregnant systemic lupus erythematosus (SLE) patients. METHODS Medical records of pregnant SLE patients seen between January 1993 and June 2017 were reviewed. Nonpregnant SLE controls were matched by age at diagnosis and disease duration before pregnancy. Systemic lupus erythematosus disease activity and flares were determined by the cSLEDAI (clinical Systemic Lupus Erythematosus Disease Activity Index) and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index, respectively. Disease activity was measured from 6 months before conception (-6 months) until the postpartum period. The repeated measures mixed model, Cox regression, and cumulative hazard plots were used for statistical analysis. RESULTS Ninety pregnancies occurred in 77 patients. The cSLEDAI scores from -6 months to the postpartum period were comparable between the pregnancy and control group, but slightly yet significantly higher in the controls at conception (mean ± SEM, 3.57 ± 0.45 vs 1.90 ± 0.36; p = 0.019). When compared with the controls, during the pregnancy and postpartum period, the pregnancy group did not have significantly higher incidence of flare (41.11% vs 28.89%, p = 0.086 and 7.78% vs 11.11%, p = 0.445, respectively) or flare category (severe flare) (75.68% vs 53.85%, p = 0.070 and 85.71% vs 70.00%, p = 0.603, respectively). The flare incidence rate (95% confidence interval)/100 patient-months in the pregnancy and control group was 6.75 (4.89-9.32) and 4.34 (2.96-6.38), respectively, giving the adjusted hazards for flare (95% confidence interval) of 1.54 (0.91-2.61) (p = 0.110). CONCLUSIONS There was no overall significant increase in SLE disease activity, flare incidence, and flare severity in pregnant SLE patients when compared with their properly matched nonpregnant SLE controls.

Background: Flares in pregnant patients with systemic lupus erythematosus (SLE) have shown conflicting results. This study aimed to determine the disease activity, and rate and severity of flares in pregnant SLE patients compared with the non-pregnant SLE controls. Methods: The medical records of pregnant patients in the SLE cohort were identified. Controls were non-pregnant female SLE patients who were matched for age at diagnosis and disease duration prior to conception. Disease activity was determined by mSLEDAI-2K. The definition and severity of flares followed the SELANA-SLEDAI Flare Index. The disease activity was measured from 6 months prior to conception (-6M) until termination of pregnancy or delivery.Results: Ninety pregnancies occurred from 77 patients, of whom 36.67% had active disease at the time of conception. The pregnancy group was slightly, but significantly, younger than the control group at diagnosis (21.63 ± 5.89 years vs. 24.05 ± 7.27 years, p = 0.015). The SLE disease activity (mSLEDAI-2K) score was comparable in both groups from -6M to the post-partum period, with that in the control group being slightly but significantly higher than that in the pregnancy group at conception (3.57 ± 4.28 vs. 1.91 ± 3.44, p = 0.003). Of the 90 pregnancies, the overall incidence of flares in both groups was similar during pregnancy (39 vs. 26, p = 0.070). There also was no difference in the incidence of flare during each trimester, with 19 vs.7 flares among 90 pregnancies (p = 0.588) in the 1st, 12 vs. 12 among 82 (p = 0.682) in the 2nd, and 6 vs. 7 among 71 (p = 0.266) in the 3rd trimester. The incidence of flare during the post-partum period also was similar (42 vs. 30 flares among 90 pregnancies, p = 0.091). There was no difference in the severity of flare in each trimester, overall flare during pregnancy or post-partum flare. Conclusions: This study found no difference in flare rate or severity of flares between pregnant SLE patients and non-pregnant SLE controls, who were matched by sex, age at diagnosis and disease duration prior to pregnancy.

The effect of coffee on serum uric acid (SUA) has shown conflicting results. This study was to determine the effects of caffeinated coffee (CC) and decaffeinated coffee (DC) on SUA, serum xanthine oxidase activity (sXOA) and urine uric acid clearance (UAC).This was a prospective randomised within-subject experimental study design of 51 healthy male participants. Each study period consisted of 3 periods, including a control, an intervention, and washout period for 1, 3 and 1 week, respectively. During the intervention period, the participants received 2, 4 or 6 gram/day of coffee, either CC or DC.For DC groups, SUA significantly decreased by 6.5 (±1.1) mg/dL to 6.2 (±1.1) mg/dL during the intervention period (p=0.014). sXOA significantly increased by 0.05 (±0.07) nmol/min/mL to 0.20 (±0.38) nmol/min/mL during the intervention period (p=0.010) of CC. For UAC, there was no significant change with CC or DC. In hyperuricaemic participants, SUA significantly decreased by 7.7 (±0.7) mg/dL to 7.2 (±0.7) mg/dL during the intervention period (p=0.028) of DC. For non-hyperuricaemic, CC significantly increased SUA by 5.9 (±0.7) mg/dL to 6.2 (±0.9) mg/dL during the intervention period (p=0.008) and significantly decreased SUA to 6.0 (±0.8) mg/dL (p=0.049) during the withdrawal period. A significant increase of sXOA according with SUA in CC groups from 0.05 (±0.07) nmol/min/mL to 0.25 (±0.44) nmol/min/mL during the intervention period (p=0.040) was presented in non-hyperuricaemic participants.DC had a significant decrease of SUA during the intervention period. However, in non-HUS participants, SUA significantly increased in CC.

Background:The recent prospectively validated definition of the lupus low disease activity state (LLDAS) allows characterisation of patients not achieving a treatment goal, providing impetus for an analysis of unmet needs in SLE using formal definitions. Other recently described definitions of high disease burden include disease activity over time, high disease activity status (HDAS) episodes, and the combination of high disease activity, serological activity and glucocorticoid (GC) use (HDAS+SA+GC).Objectives:To determine the prevalence of formal categories of unmet need, and the association of these with adverse outcomes, in SLE.Methods:Data from a 13-country longitudinal SLE cohort (ACR/SLICC criteria) were collected between 2013 and 19 using standard templates. Unmet need was defined as (i) patients never attaining LLDAS defined as in Golder et al., 2019 [1], (ii) having persistently active disease (time adjusted mean SLEDAI-2K (AMS) > 4), (iii) ever exhibiting high disease activity status (HDAS; SLEDAI-2K ≥10[2]), or (iv) ever exhibiting all of SLEDAI≥10, serological activity, and glucocorticoid use (HDAS+SA+GC)[3]. Health-related quality of life (HRQoL) was assessed using SF36 (v2) surveys and damage accrual using SLE Damage Index (SDI).Results:3,384 SLE patients were followed for 30,313 visits over median [IQR] 2.4 [0.4, 4.3] years. 53% of all visits were not in LLDAS; 813 patients (24%) never achieved LLDAS during observation. Median AMS was 3.0 [1.4, 4.9] and 34% of patients had AMS > 4 throughout the study. 25% of patients had at least one episode of HDAS, representing 8% of visits. 702 patients (21%) had at least one episode of HDAS+SA+GC, representing 8% of visits. Each of never-LLDAS, AMS>4, ever-HDAS, and ever-HDAS+SA+GC were associated with significantly greater number of physician visits, higher mean glucocorticoid dose, lower HRQoL and higher mortality. 31%, 58% and 83% of never-LLDAS, AMS>4, and ever-HDAS patients respectively were also HDAS+SA+GC on at least one occasion.Conclusion:Data from a multinational longitudinal SLE cohort indicate that unmet need, defined by LLDAS-never, AMS>4, HDAS, or HDAS+SA+GC, is prevalent in SLE, and that these definitions are associated with poor outcomes.References:[1]Golder, V., et al., Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. The Lancet Rheumatology, 2019. 1(2): p. e95-e102.[2]Koelmeyer, R., et al., High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus. Lupus Sci Med, 2020. 7(1).[3]van Vollenhoven, R.F., et al., Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Annals of the Rheumatic Diseases, 2012. 71(8): p. 1343-1349.Acknowledgements:The APLC acknowledges all the Data Collectors and Patients for their valuable contributions to research.Disclosure of Interests:Rangi Kandane-Rathnayake: None declared, Worawit Louthrenoo: None declared, Alberta Hoi Consultant of: Abbvie and GSK, Grant/research support from: AstraZeneca, GSK, BMS, Janssen, and Merck Serono, Vera Golder: None declared, Yi-Hsing Chen Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead, Grant/research support from: Pfizer, Norvatis, BMS, Abbevie, Johnson & Johnson, Roche, Sanofi, Guigai, Roche, Boehringer Ingelheim, UCB, MSD, Astra-Zeneca, Astellas, Gilead, Shue Fen Luo: None declared, Yeong-Jian Jan Wu Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, Aisha Lateef: None declared, Jiacai Cho: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Abbot, Chak Sing Lau Shareholder of: Pfizer, Sanofi, and Janssen, Sandra Navarra Speakers bureau: Pfizer, Johnson & Johnson, Novartis, Astellas, Grant/research support from: Astellas, Johnson & Johnson, Leonid Zamora: None declared, Zhanguo Li Speakers bureau: Eli, Lilly, Novartis, GSK, AbbVie, Paid instructor for: Pfizer, Roche, Johnson., Consultant of: Lilly, Pfizer, Grant/research support from: Pfizer, Yuan An: None declared, Sargunan Sockalingam Speakers bureau: Pfizer, Roche, Novartis, Grant/research support from: Roche and Novartis, Yasuhiro Katsumata Speakers bureau: Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., and Sanofi K.K., masayoshi harigai Speakers bureau: AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang Speakers bureau: Norvatis, GSK, Pfizer, Jun Kikuchi: None declared, Tsutomu Takeuchi Speakers bureau: AbbVie AYUMI Pharmaceutical Corp. Bristol-Myers Squibb Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan, Gilead Sciences, Inc. Mitsubishi-Tanabe Pharma Corp. Pfizer Japan Inc. Sanofi K.K., Consultant of: Astellas Pharma, Inc. Chugai Pharmaceutical Co, Ltd. Eli Lilly Japan, Mitsubishi-Tanabe Pharma Corp., Grant/research support from: AbbVie, Asahikasei Pharma Corp. Chugai Pharmaceutical Co, Ltd. Mitsubishi-Tanabe Pharma Corp. Sanofi K.K., BMDB Basnayake: None declared, Fiona Goldblatt: None declared, Madelynn Chan Speakers bureau: AbbVie, Novartis, Consultant of: Pfizer, Eli-Lilly, Kristine Ng Speakers bureau: Abbvie, Novartis, Janssen, Sang-Cheol Bae: None declared, Shereen Oon: None declared, Sean O’Neill Consultant of: GSK, Kathryn Gibson Speakers bureau: UCB, Consultant of: Novartis, Janssen, Grant/research support from: Novartis, Sunil Kumar: None declared, Nicola Tugnet: None declared, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, Grant/research support from: Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Eric F. Morand Speakers bureau: AstraZeneca, Paid instructor for: Eli Lilly, Consultant of: AstraZeneca, Amgen, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, Janssen, Grant/research support from: AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, Janssen.