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ObjectivesHealthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly considered as helpful and could be incorporated in online tools to assist healthcare professionals, but first their discriminative ability must be assessed. As part of this effort, we evaluated whether inquiring about functional impairments could aid early IA identification.DesignCross-sectional derivation and validation study.SettingData from two Early Arthritis Recognition Clinics (EARC) in the Netherlands were studied, which are easy access outpatient rheumatology clinics intermediary between primary and secondary care for patients in whom general practitioners suspect but are unsure about IA presence.ParticipantsBetween 2010 and 2014, 997 patients consecutively visited the Leiden-EARC (derivation cohort). Patients consecutively visiting the Groningen EARC (2010–2014, n=506) and Leiden-EARC (2015–2018, n=557) served as validation cohorts.Primary and secondary outcome measuresPhysical functioning was assessed with the Health Assessment Questionnaire Disability-Index (HAQ); IA presence by physical joint examination by rheumatologists. HAQ questions were studied individually regarding discriminative ability for IA presence. For the best discriminating question, ORs and positive predictive values (PPVs) for IA presence were determined.ResultsIA was ascertained in 43% (derivation cohort), 53% and 35% (validation cohorts). In the derivation cohort, IA presence associated with higher mean HAQ scores (0.84 vs 0.73, p=0.003). One question on difficulties with dressing equalled discriminative ability of the total HAQ score. ‘Difficulties with dressing’ yielded ORs for IA presence of 1.8 (95% CI 1.4 to 2.4) in the derivation cohort; 2.0 (1.4 to 2.9) and 2.1 (1.5 to 3.1) in the validation cohorts. After adjustments for clinical characteristics these were 1.7 (1.3 to 2.3), 1.6 (1.1 to 2.5) and 1.9 (1.2 to 2.9). PPVs (probabilities of IA for positive answers) ranged 42%–60% and negative predictive values (probabilities of no IA for negative answers) ranged 57%–74%.ConclusionsPatient-reported difficulties with dressing in patients with suspected IA associated with actual IA presence. Although further validation is required, for example, in primary care, this simple question could be of help in future early IA detection tools for healthcare professionals with limited experience in joint examination.

Introduction Arthralgia and MRI-detected subclinical inflammation can precede the development of clinically evident rheumatoid arthritis (RA). However, part of the patients presenting with clinically suspect arthralgia (CSA) do not progress to RA. In these ‘non-progressors’, we aimed to study the frequencies of spontaneous improvement of arthralgia and its relation with the course of subclinical inflammation. Methods Between April 2012 and April 2015, 241 patients were considered at risk for RA based on the clinical presentation and included in the CSA cohort. One hundred fifty-two patients with complete data on clinical follow-up did not develop clinical arthritis, of which 98 underwent serial 1.5T MRI scans (wrist, MCP2–5, and MTP1–5 joints) at baseline and after 2 years. MRI scans were scored for synovitis, tenosynovitis, and bone marrow oedema (summed: MRI inflammation score). MRI scores were compared to scores of symptom-free persons. Results After a 2-year follow-up, 33% of the ‘non-progressors’ had complete resolution of symptoms; 67% had no symptom resolution and were diagnosed as persistent CSA (44%), osteoarthritis (10%), and tendinomuscular complaints (13%). With symptom-free controls as a reference, patients without resolution did not have increased MRI scores at any time point. However, patients achieving resolution of symptoms had increased MRI inflammation scores at baseline (4.0 vs. 2.6, p = 0.037), but not after 2 years (3.0 vs. 2.6; p = 0.57), and during follow-up, their MRI inflammation score decreased significantly (p = 0.036). Conclusions A subgroup of CSA patients that did not progress to RA had spontaneous improvement of symptoms and resolution of subclinical joint inflammation. This time relationship suggests that symptoms and inflammation were causally related in these patients. Further research is needed to identify the mechanisms underlying the resolution of inflammation.

Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umeå university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development

Copyright © 2017 BMJ Publishing Group Ltd & European League Against Rheumatism. All rights reserved., Background: During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience. Methods: The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics. Results: The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration

Background:Early treatment initiation in inflammatory arthritis (IA), and specifically in RA, is associated with improved outcomes but requires early identification of synovitis. However, healthcare professionals other than rheumatologists, e.g. general practitioners (GPs), experience difficulties in detecting early IA by joint examination. In this light, two Early ArthritisRecognitionClinics (EARCs) were initiated in the Netherlands in 2010. EARCs are easy-access outpatient rheumatology clinics, intermediary between primary and secondary care, to which GPs can refer patients when in doubt about the presence of IA (instead of ‘watchful waiting’). Although this approach markedly reduced referral delay,[1] it may not be easily implemented in other places due to shortage of rheumatologists. Therefore, other new tools to support early identification of IA are needed.Objectives:Aiming for simple and time-efficient use in daily practice, we evaluated if just a single question on functional impairments could aid the identification of early IA.Methods:Data from two EARCs in the Netherlands were studied. Between 2010 and 2014, 997 patients with suspected IA visited the Leiden EARC (derivation cohort). Patients visiting the Groningen EARC (2010–2014, n = 506) and Leiden EARC (2015–2018, n = 557) served as validation cohorts. Physical functioning was assessed with the Health Assessment Questionnaire Disability Index (HAQ); IA by joint examination by rheumatologists. Discriminative abilities for IA of the 20 HAQ-questions were compared based on the area under the curve (AUC). For the best discriminating question, test characteristics and odds ratios (ORs) were calculated. ORs were adjusted for clinical characteristics that were previously reported to be predictive of the presence of IA (gender, age ≥60 years, symptom duration, acuteness of symptom onset, morning stiffness >60 minutes, number of painful joints, presence of patient-reported swollen joint(s) and difficulty with making a fist)[2] using multivariable logistic regression.Results:IA was identified in 43% (derivation cohort), 53% and 35% (validation cohorts). In the derivation cohort, presence of IA associated with higher mean HAQ-scores (0.84 versus 0.73, p=0.003). The HAQ-question on difficulties with dressing yielded the highest AUC (0.58), which equalled discriminative ability of the total HAQ-score (AUC 0.55). Responses to this question were dichotomised into a simple binary score since loss of discriminative ability was minimal (AUC 0.57). Presence of any difficulties with dressing yielded ORs for IA of 1.80 (95%CI 1.39–2.33) in the derivation cohort; 2.00 (1.39–2.87) and 2.14 (1.48–3.10) in the validation cohorts. After adjustments for clinical characteristics the presence of any difficulties with dressing remained associated with the presence of IA; OR 1.71 (1.27–2.32) in derivation cohort and 1.64 (1.08–2.50) and 1.87 (1.20–2.92) in the validation cohorts. The prevalence of IA in case of presence of difficulties with dressing (positive predictive value) ranged 42–60% (see Figure).Conclusion:A yes/no answer on a simple question (“Are you able to dress yourself, including shoelaces and buttons?”) was helpful in discriminating patients with and without IA. Findings were validated in independent 1.5-line settings and need to be validated further in primary care. This is a step forward to arrive at practical tools that are helpful for GPs in identifying early IA.References:[1] van Nies JA et al. Improved early identification of arthritis: evaluating the efficacy of Early Arthritis Recognition Clinics. Ann Rheum Dis. 2013;72(8):1295–301.[2] ten Brinck RM et al. Development and validation of a clinical rule for recognition of early inflammatory arthritis. BMJ Open. 2019 Feb 22;8(11):e023552.Disclosure of Interests:Bastiaan van Dijk: None declared, Hanna W. van Steenbergen: None declared, Ellis Niemantsverdriet: None declared, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG), Annette van der Helm - van Mil: None declared

ObjectivesNational and international guidelines recommend prompt referral of patients presenting with inflammatory arthritis (IA), but general practitioners (GPs) feel uncertain in their proficiency to detect synovitis through joint examination, the method of choice to identify IA. Our objective was to develop and validate a rule composed of clinical characteristics to assist GPs and other physicians in identifying IA when in doubt.DesignSplit-sample derivation and validation study.SettingThe Leiden Early Arthritis Recognition Clinic (EARC), a screening clinic for patients in whom GPs suspected but were unsure of the presence of IA.Participants1288 consecutive patients visiting the EARC.Primary and secondary outcome measuresAssociations of clinical characteristics with presence of IA were determined using logistic regression in 644 patients, while validating the results in the other 644 patients (split-sample validation). To facilitate application in clinical practice, a simplified rule (with scores ranging from 0 to 7.5) was derived and validated.ResultsIA was identified by a rheumatologist in 41% of patients. In univariable analysis, male gender, age ≥60 years, symptom duration 60 min, a low number of painful joints (1–3 joints), presence of patient-reported joint swelling and difficulty with making a fist were associated with IA in the derivation data set. Using multivariable analysis, a simplified rule consisting of these seven items was derived and validated, yielding an area under the receiver operator characteristic curve (AUC) of 0.74 (95% CI 0.70 to 0.78) in the derivation data set. Validation yielded an AUC of 0.71 (95% CI 0.67 to 0.75). Finally, the model was repeated to study predicted probabilities with a lower prevalence of inflammatory arthritis to simulate performance in primary care settings.ConclusionsOur rule, composed of clinical parameters, had reasonable discriminative ability for IA and could assist physicians in decision-making in patients with suspected IA, increasing appropriateness of healthcare utilisation.

Objective Subclinical joint inflammation in patients with arthralgia is predictive for progression to rheumatoid arthritis (RA). However, the time course of progression for bone marrow edema (osteitis), synovitis, and/or tenosynovitis is unsettled. This longitudinal study assessed the course of magnetic resonance imaging (MRI)-detected subclinical joint inflammation during progression to RA. Methods Patients that progressed from clinically suspect arthralgia (CSA) to RA underwent 1.5-T MRI of the metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints at presentation with arthralgia and at first identification of synovitis assessed through physical examination (n = 31). MRIs were evaluated for osteitis, synovitis, tenosynovitis, and erosions by two readers, blinded for clinical data and order in time. To estimate changes in MRI scores between the asymptomatic state and CSA onset, scores of MRI features at CSA baseline were compared with scores from age-matched symptom-free persons. Results At presentation with CSA, synovitis and tenosynovitis scores were higher than scores from age-matched symptom-free persons (p = 0.004 and p = 0.001, respectively). Anti-citrullinated protein antibody (ACPA)-positive arthralgia patients also had increased osteitis scores (p = 0.04). Median duration between presentation with arthralgia and RA development was 17 weeks. During progression to RA, synovitis and osteitis increased significantly (p = 0.001 and p = 0.036, respectively) in contrast to tenosynovitis and erosion scores. This pattern was similar in both ACPA subsets, although statistical significance was reached for synovitis and osteitis in ACPA-negative but not ACPA-positive RA. Conclusion Increased tenosynovitis and synovitis scores at CSA onset and the increase in synovitis and osteitis during progression to RA suggest an ‘outside-in’ temporal relationship of arthritis development, in particular for ACPA-negative RA. For ACPA-positive RA, further studies are needed. Electronic supplementary material The online version of this article (10.1186/s13075-018-1756-z) contains supplementary material, which is available to authorized users.

IntroductionSubclinical inflammation, detected by MRI, in patients with arthralgia is predictive for development of inflammatory arthritis (IA). However, within patients that develop IA, the course of inflammation at the joint level during this transition is unknown. This longitudinal study assessed progression of inflammation at the joint level.Methods350 joints (unilateral metacarpophalangeals (MCPs), wrist, metatarsophalangeal (MTP) joints) of 35 patients presenting with clinically suspect arthralgia (CSA) that progressed to IA were studied at presentation with CSA and subsequently when clinical synovitis was first identified at joint examination (median time interval 17 weeks). At both time points, subclinical inflammation (bone marrow oedema, synovitis, tenosynovitis) was evaluated with MRI and joint examination was performed.ResultsAt presentation with CSA, 71 joints showed subclinical inflammation. During progression to IA, 20% of these joints had resolution of inflammation, 60% had persistent inflammation and 20% progressed to clinical synovitis. Of all joints that had developed clinical synovitis (n = 45), no prior subclinical inflammation was detected in 69%. Similar results were observed for anticitrullinated protein antibodies (ACPA)-positive and ACPA-negative patients.ConclusionsThis longitudinal study demonstrated moderate correlations between joints with subclinical inflammation and joints that developed clinical synovitis. These data imply that IA development is a more systemic rather than a locally outgrowing process.

Background It is known that MRI-detected subclinical inflammation in patients with Clinically Suspect Arthralgia (CSA) precedes the development of clinically evident Inflammatory Arthritis (IA). However, there are no longitudinal studies in CSA patients that did not progress to IA. The course of joint symptoms in these patients is unknown. Furthermore, it is unknown if subclinical inflammation resolves spontaneously in parallel with disappearance of joint symptoms. Objectives To determine the course of joint symptoms and of MRI-detected subclinical joint inflammation, and mutual time relationships, in patients that presented with CSA but did not progress to IA during 2 year follow-up. Methods Between April 2012-April 2014, 149 patients were included in the CSA cohort. These patients had no clinically evident arthritis but recent-onset ( Results After 2 year follow-up, 20 patients (33%) had complete resolution of symptoms whereas 40 patients (66%) did not. The remaining symptoms in the latter group were diagnosed as: persistent inflammatory arthralgia (n=26), osteoarthritis (n=6) and tendinomyalgia (n=8). In the total group, the mean total MRI-inflammation score decreased from 3.2 at baseline to 2.5 at 2 years (p=0.046). When the patients with persistent symptoms were studied, there were no significant changes in MRI-inflammation scores. Analysing the patients with resolution of symptoms separately, the total MRI-inflammation score decreased significantly (3.3 to 2.3; p=0.019). Also the total synovitis and tenosynovitis scores decreased significantly (1.3 to 0.82 and 0.83 to 0.30, respectively; p=0.043 and p=0.029), whereas BME scores remained unchanged (1.2 and 1.2; p=0.87). After 2 year follow-up the absolute MR-scores of these patients were compared to data from age-matched symptom-free controls; no differences were found for synovitis, suggesting normalisation. Physical functioning, measured with HAQ, remained similar in patients with persistent symptoms (0.56 to 0.51; p=0.61), whereas HAQ normalised in patients with resolution of symptoms (mean score of 0.15 at 2 years, p=0.053 compared to baseline). Conclusions Approximately one-third of the patients that presented with CSA and that did not convert to IA had resolution of symptoms, this was paralleled by normalisation of MRI-detected inflammation as well as physical functioning. This is the first study showing that subclinical inflammation in individuals at risk for developing RA can resolve spontaneously. The data suggest that subclinical inflammation was causally related to joint pain. Disclosure of Interest None declared

Background: Early treatment of inflammatory arthritis (IA) associates with improved outcomes. Therefore, the first recommendation in the 2016 update of the EULAR guidelines for management of early IA states that patients presenting with IA should be seen by a rheumatologist ≤6 weeks. Data on how to implement this recommendation are lacking. A screening clinic situated in between primary and secondary care, the Early Arthritis Recognition Clinic (EARC), has previously shown to increase early identification of rheumatoid arthritis patients. However, it is unknown if this effect is sustained when applied for several years and if this approach is of added value to identify patients within the 6-week limit set by EULAR. Objectives: To study if an EARC approach can lead to sustained early identification of patients with IA (as compared to regular referral to our Early Arthritis Clinic (EAC)) and to determine the efficacy to identify patients ≤6 weeks after symptom onset. Methods: To promote early recognition of IA, the EARC was initiated in September 2010 in the Netherlands. General practitioners (GPs) were instructed to refer to this screening clinic without a scheduled appointment if they were unsure about the presence of IA (instead of a ‘wait-and-see’ approach or performing additional tests). At the EARC, patients were seen for a 5-minute visit by an experienced rheumatologist who performed a full 66-joint examination for clinical synovitis. GPs can also refer directly to the EAC, where patients are seen Results: Of the 1,151 patients visiting the EARC, 475 (41%) were diagnosed with IA. Firstly, proportions of patients with IA at the EARC were studied per year. These remained stable over time: 45% in 2010, 39% in 2011, 45% in 2012, 42% in 2013 and 36% in 2014. Clinical characteristics of these patients were similar over time. In the same period 675 referred patients were diagnosed with IA at the EAC; these were compared to the 475 IA patients that were identified via the EARC. Demographic characteristics were similar. However, median symptom duration of the IA patients in the EARC-group versus the EAC-group at identification of IA were 10.7 vs 17.0 weeks in 2010 (p Conclusions: A screening clinic in between primary and secondary care has sustainable benefit with regards to early identification of inflammatory arthritis and allows >40% of patients to be identified within the timelines as recommended by EULAR. Disclosure of Interest: None declared

Early treatment is associated with improved outcomes in patients with rheumatoid arthritis (RA), suggesting that a 'window of opportunity', in which the disease is most susceptible to disease-modifying treatment, exists. Autoantibodies and markers of systemic inflammation can be present long before clinical arthritis, and maturation of the immune response seems to coincide with the development of RA. The pre-arthritis phase associated with symptoms such as as joint pain without clinical arthritis (athralgia) is now hypothesized to fall within the aforementioned window of opportunity. Consequently, disease modulation in this phase might prevent the occurrence of clinically apparent arthritis, which would result in a persistent disease course if untreated. Several ongoing proof-of-concept trials are now testing this hypothesis. This Review highlights the importance of adequate risk prediction for the correct design, execution and interpretation of results of these prevention trials, as well as considerations when translating these findings into clinical practice. The patients' perspectives are discussed, and the accuracy with which RA development can be predicted in patients presenting with arthralgia is evaluated. Currently, the best starting position for preventive studies is proposed to be the inclusion of patients with an increased risk of RA, such as those identified as fulfilling the EULAR definition of 'arthralgia suspicious for progression to RA'.

Background The presence of autoantibodies is considered an important characteristic of rheumatoid arthritis (RA); therefore, both anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are included in the 2010 classification criteria for rheumatoid arthritis (RA). However, a considerable number of RA patients lack both these autoantibodies. Recently, several novel autoantibodies have been identified but their value for the classification of RA patients is unclear. Therefore, we studied the value of novel autoantibodies using the presence of anticarbamylated protein (anti-CarP) antibodies as an example for predicting RA development in patients with undifferentiated arthritis (UA). Methods There were 1352 UA patients included in the Leiden Early Arthritis Clinic (EAC) cohort according to the 1987 criteria. When the 2010 criteria were used, there were 838 UA patients. Of these, we evaluated whether they fulfilled the 1987 or 2010 criteria after 1 year, respectively. Logistic regression analyses were performed with RA as outcome and ACPA, RF, and anti-CarP antibodies as predictors. Analyses were repeated after stratification for ACPA and RF. Results Thirty-three percent of the 1987-UA patients and 6% of the 2010-UA patients progressed to RA during the first year of follow-up. For the 1987-UA patients, anti-CarP antibodies were associated with progression to RA, an association which remained when a correction was made for the presence of ACPA and RF (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.2–2.4). After stratification for ACPA and RF, anti-CarP antibodies were associated with progression to RA only for ACPA- and RF-negative patients (OR 2.1, 95% CI 1.3–3.7). For the 2010-UA patients, anti-CarP antibodies were associated with progression to RA; however, they were not when a correction was made for the presence of ACPA and RF (OR 0.8, 95% CI 0.3–2.1). Conclusions Our finding that anti-CarP antibodies have no additional value when RA is defined according to the 2010 criteria might be inherent to the composition of the 2010 criteria and therefore might also apply to other novel autoantibodies. Potentially it would be interesting to evaluate other, non-autoantibody biomarkers.

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are = 500 mL within 24h postpartum and severe PPH as blood loss >= 1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL(-1) cut-off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2-6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population.

INTRODUCTION: Autoantibody testing is helpful to predict the risk of progression to clinical arthritis in subjects at risk. Previous longitudinal studies have mainly selected autoantibody-positive arthralgia patients and, consequently, the predictive values of autoantibodies were evaluated relative to each other. This study assessed risks for arthritis development of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF) and/or anti-carbamylated protein antibodies (anti-CarP) in arthralgia patients considered at risk for RA by rheumatologists based on clinical characteristics (Clinically Suspect Arthralgia, CSA). METHODS: Baseline ACPA, RF and anti-CarP autoantibody-status of 241 patients, consecutively included in the CSA-cohort, was studied for risk of developing clinical arthritis during a median follow-up of 103 (IQR 81-114) weeks. RESULTS: Univariable associations for arthritis development were observed for ACPA, RF and anti-CarP antibodies; Hazard Ratios (95%CI) were 8.5 (4.7-15.5), 5.1 (2.8-9.3) and 3.9 (1.9-7.7) respectively. In multivariable analysis, only ACPA was independently associated (HR 5.1; 2.0-13.2). Relative to autoantibody-negative CSA-patients, ACPA-negative/RF-positive patients had HRs of 2.6 (1.04-6.6), ACPA-positive/RF-negative patients 8.0 (2.4-27.4), and ACPA-positive/RF-positive patients 10.5 (5.4-20.6). Positive predictive values (PPV) for development of clinical arthritis within two years were: 38% for ACPA-negative/RF-positive, 50% for ACPA-positive/RF-negative and 67% for ACPA-positive/RF-positive patients. Higher ACPA-levels were not significantly associated with increased progression to clinical arthritis, in contrast to higher RF-levels. Autoantibody levels were stable during follow-up. CONCLUSION: ACPA conferred the highest risk for arthritis development and had an additive value to RF. However, >30% of ACPA-positive/RF-positive CSA-patients did not develop arthritis during two-year follow-up. Thus, CSA and information on autoantibodies is insufficient to accurately identify imminent autoantibody-positive RA.

Objective Although anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) have different aetiopathology, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic differences in the symptomatic pre-RA phase. Methods Patients with arthralgia included in the Leiden clinically suspect arthralgia cohort who developed arthritis during follow-up were studied (n=67). Symptoms at symptom onset, symptoms and signs at presentation with arthralgia and time to arthritis development were compared between ACPA-positive and ACPA-negative patients. Results In ACPA-negative patients (n=37), the location of initial symptoms less often included the lower extremities (22% vs 50%, p=0.014). At presentation with arthralgia, ACPA-positive patients had a longer symptom duration (median 22 vs 14 weeks, p=0.005), less tender joints (mean 5 vs 9, p=0.007) and less difficulty making a fist (11% vs 43%, p=0.004). However, after presentation with arthralgia, ACPA-positive patients developed arthritis more quickly (median 6 vs 18 weeks, p=0.015). A partial least squares regression analysis showed clustering of ACPA-positive and ACPA-negative patients based on the above-mentioned clinical variables. Conclusion This study is the first showing that ACPA-positive and ACPA-negative patients have clinical differences in the symptomatic phase preceding clinical arthritis. This contributes to the notion that ACPA-positive and ACPA-negative RA develop differently.

Objectives The use of hand and foot MRI in the diagnostic process of RA has been advocated. Recent studies showed that MRI is helpful in predicting progression from clinically suspect arthralgia (CSA) to clinical arthritis, and from undifferentiated arthritis (UA) to RA. Symptom-free persons can also show inflammation on MRI. This study aimed to evaluate if MRI findings in symptom-free volunteers are relevant when defining a positive MRI. Methods Two hundred and twenty-five CSA patients and two hundred and one UA patients underwent MRI of MCP, wrist and MTP joints at baseline and were followed for 1 year on progression to arthritis and RA, respectively, as reported previously. MRI was considered positive if ⩾ 1 joint showed inflammation (called uncorrected definition), or if ⩾ 1 joint had inflammation that was present in < 5% of persons of the same age category at the same location (called 5% corrected definition). Test characteristics were compared for both definitions. Results By using MRI data of symptom-free volunteers as reference, specificity of MRI-detected inflammation increased from 22 to 56% in CSA patients, and from 10 to 36% in UA patients. The sensitivity was not affected; it was 88 and 85% in CSA patients and 93 and 93% in UA patients. The accuracy also increased, from 32 to 60% in CSA patients and 22 to 44% in UA patients. Conclusion The use of a reference population resulted in a substantial reduction of false-positive results, without influencing the sensitivity. Although common for other tests in medicine, this phenomenon is novel for MRI in the early detection of RA.

Objectives Moderate alcohol consumption is protective against rheumatoid arthritis (RA) development and associated with lower levels of systemic inflammation in RA and in the general population. We therefore hypothesised that moderate alcohol consumption is associated with less severe local inflammation in joints in RA, detected by MRI. Since asymptomatic persons can have low-grade MRI-detected inflammation, we also hypothesised that alcohol consumption is associated with the extent of MRI inflammation in asymptomatic volunteers. Methods 188 newly presenting patients with RA and 192 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints. The MRIs were scored on synovitis, bone marrow oedema and tenosynovitis; the sum of these yielded the MRI inflammation score. MRI data were evaluated in relation to current alcohol consumption, categorised as non-drinkers, consuming 1–7 drinks/week, 8–14 drinks/week and >14 drinks/week. Association between C reactive protein (CRP) level and alcohol was studied in 1070 newly presenting patients with RA. Results Alcohol consumption was not associated with the severity of MRI-detected inflammation in hand and foot joints of patients with RA (P=0.55) and asymptomatic volunteers (P=0.33). A J-shaped curve was observed in the association between alcohol consumption and CRP level, with the lowest levels in patients consuming 1–7 drinks/week (P=0.037). Conclusion Despite the fact that moderate alcohol consumption has been shown protective against RA, and our data confirm a J-shaped association of alcohol consumption with CRP levels in RA, alcohol was not associated with the severity of joint inflammation. The present data suggest that the pathophysiological mechanism underlying the effect of alcohol consists of a systemic effect that might not involve the joints.

OBJECTIVES: Magnetic resonance imaging (MRI) is recommended in the diagnostic process of rheumatoid arthritis (RA), to detect joint damage early. MRI-detected erosions are also present in symptom-free controls, especially at older age. It is unclear if RA-specific MRI-detected erosions can be distinguished from ‘physiological’ erosions in symptom-free individuals. This study compared MRI-detected erosions of RA-patients with healthy controls and with other arthritides. METHODS: 589 newly-presenting early arthritis patients (238 RA, 351 other arthritides) and 193 symptom-free controls underwent contrast-enhanced 1.5T MRI of unilateral metacarpophalangeal- and metatarsophalangeal(MTP)-joints. Total erosion score (according to RAMRIS), number, severity, location of erosions and simultaneous presence of MRI-detected inflammation (synovitis and/or bone marrow edema) were compared; participants were categorized in three age-groups (

Background Early initiation of treatment of rheumatoid arthritis is strongly associated with an improved outcome, but requires the early identification of arthritis. Physical examination of joints is crucial to this end, but is difficult for general practitioners (GPs) who have little experience. Another difficulty is that GPs see many persons with musculoskeletal symptoms per year but only few patients with clinical arthritis. To promote early recognition of arthritis, the Early Arthritis Recognition Clinic (EARC) was initiated in Leiden, the Netherlands in 2010. GPs were instructed to refer to this clinic in case of doubt on the presence of arthritis (and not to wait and see, or to perform additional laboratory tests). At this clinic, patients filled out a form with questions on their symptoms and were seen by a rheumatologist in a short visit that comprised a full joint examination. As reported previously, this clinic importantly improved the early identification of arthritis and RA (1), but this approach may not be easily implemented in other centres or regions. Objectives To assess if a combination of symptoms and signs that are easy to assess can differentiate patients with and without clinical arthritis at joint examination. Methods 1,288 patients in whom GPs doubted on the presence of arthritis visited the EARC between 2010 and 2015. Reported symptoms and signs were studied with the presence of synovitis (joint examination by experienced rheumatologist) as outcome. Multivariable logistic regression was used. A model was derived in 644 patients, and validated in the second set of 644 patients. Results 41% of the patients who visited the EARC had arthritis at examination. Age (per year OR 1.02; 95% CI 1.01–1.03), male sex (OR 1.8; 95% CI 1.3–2.7), symptom duration (4–12 weeks OR 3.83; 95% CI 2.22–6.60), morning stiffness >60 min (OR 1.7; 95% CI 0.9–2.9), difficulty with making a fist (OR 1.6; 95% CI 0.97–2.5), number of tender joints (1–3 tender joints OR 9.7; 95% CI 1.1–81.8) and self-reported swollen joints (OR 3.5; 95% CI 1.8–7.0) were associated with the presence of arthritis in multivariable analysis. The AUC was 0.75 (SE 0.02) in the derivation set and 0.71 (SE 0.02) in the validation set. To facilitate application in practice, a simplified model was made. This consisted of 7 variables and the total score ranged between 0–7. The AUC was 0.73 (SE 0.02). Depending on the cut-off, the PPV of the simplified model ranged between 41 and 74% and the NPV between 100 and 62%. With a cut-off of 4, the NPV was 86%, PPV 49%, specificity 35%, and sensitivity 91%. Conclusions A set of clinical characteristics that can be easily assessed by GPs had a reasonable discriminative ability for clinical arthritis, and can be applied by GPs in case of doubt on the presence of arthritis. This model requires further validation in general practices, but may lead to a tool that could assist GPs in their decision making regarding referral or ordering additional tests for patients with suspected early arthritis. References van Nies JA, et al. Ann Rheum Dis. 2013;72(8):1295–301. Disclosure of Interest None declared

Background Autoantibody testing is helpful to predict progression to arthritis in subjects at risk. Previous longitudinal studies mainly focussed on autoantibody-positive arthralgia patients. Consequently predictive values of autoantibodies were evaluated relative to each other. This study assessed risks of having anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and/or anti-carbamylated protein antibodies (anti-CarP) for arthritis development in arthralgia patients considered at risk for RA by rheumatologists based on clinical characteristics (Clinically Suspect Arthralgia, CSA). Objectives To assess risks of having anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and/or anti-carbamylated protein antibodies (anti-CarP) for arthritis development in arthralgia patients considered at risk for RA by rheumatologists based on clinical characteristics (CSA). Methods Baseline ACPA, RF and anti-CarP antibodies of 241 patients, consecutively included in the CSA-cohort, were studied in relation to development of clinical arthritis during a median follow-up of 103 (IQR 81–114) weeks. Results ACPA, RF and anti-CarP antibodies were all univariably associated with arthritis development, hazard ratios (95% CI) were 8.5 (4.7–15.5), 5.1 (2.8–9.3) and 3.9 (1.9–7.7). Only ACPA, and not RF or anti-CarP, was independently associated (HR 5.1, 2.0–13.2). Relative to autoantibody-negative CSA-patients, ACPA-negative/RF-positive patients had HRs of 2.6 (1.04–6.6), ACPA-positive/RF-negative patients 8.0 (2.4–27.4), and ACPA-positive/RF-positive patients 10.5 (5.4–20.6, Figure). PPVs for development of clinical arthritis within two years were: 38% for ACPA-negative/RF-positive, 50% for ACPA-positive/RF-negative, and 67% for ACPA-positive/RF-positive patients. Higher ACPA-levels were not significantly associated with increased progression to clinical arthritis, in contrast to higher RF-levels. Autoantibody levels were stable during follow-up. Conclusions ACPA conferred the highest risk for arthritis development and had an additive value to RF. However, >30% of ACPA-positive/RF-positive CSA-patients did not develop arthritis during two-year follow-up. Thus CSA and information on autoantibodies is insufficient to accurately identify imminent autoantibody-positive RA. Disclosure of Interest None declared

Performance of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis - a longitudinal study

Background The clinical phase of Rheumatoid arthritis (RA) is preceded by a phase with subclinical inflammation. MRI can detect subclinical inflammation and, at patient level, this is predictive for the development of clinical arthritis. However, at joint level it is unknown how arthritis develops. It is unknown how frequently joints with subclinical inflammation progress to clinical arthritis, and vice versa, how often joints that developed clinical arthritis had local subclinical inflammation during the preceding phase of arthralgia. A longitudinal MRI study in patients that developed arthritis can unravel if arthritis development is restricted to some locations in which the severity of inflammation increases over time or, alternatively, if the process is more generalized with a weak association between the locations of subclinical inflammation and subsequent clinical arthritis. Objectives This longitudinal study at joint level during progression from pre-RA to RA determined the relation between the location of subclinical inflammation and clinical arthritis over time. Methods 290 small joints (4 MCPs, 1 wrist, 5 MTPs per person) of 29 patients that presented with arthralgia and developed clinical arthritis were studied with 1.5T MRI at both time-points. MRIs were evaluated for BME, synovitis and tenosynovitis by three readers (ICCs 0.98, 0.96 and 0.97) that were blind to clinical data and the order in time. Subclinical inflammations was defined as presence of BME, synovitis and/or tenosynovitis. Results The median time between presentation with arthralgia and clinical arthritis development was 17 weeks. At presentation with arthralgia 68 joints had subclinical inflammation and no significant association was found between joint tenderness and the presence of local MRI-detected subclinical inflammation (OR 0.98; 95% CI 0.48–1.9). Over time, 21% of 68 joints had resolution of subclinical inflammation, 60% had persistent subclinical inflammation and 19% developed clinical arthritis. At arthritis development 37 joints were swollen. Of these, 24 (65%) had no prior subclinical inflammation at the time of presentation with arthralgia (Figure). Conclusions This first longitudinal MRI-study on joint level in pre-RA suggested that the majority of joints that developed clinical arthritis had no (long-lasting) preceding phase with subclinical inflammation. Disclosure of Interest None declared

Background Subclinical joint inflammation in the phase of arthralgia preceding RA can comprise synovitis, bone marrow edema (BME) and/or tenosynovitis. It is unknown in what time order the different tissues in a joint become inflamed or progress with inflammation. It has been postulated that synovitis is an initial process that is succeeded by bone involvement (“outside-in hypothesis” presuming that synovitis precedes BME and erosions). Alternatively, it is suggested that inflammatory cells in the bone marrow migrate via bone pores to the synovium, promoting synovitis (“inside-out”, then BME precedes synovitis). Thirdly, these processes can occur or progress simultaneously. Serial MRI studies can reveal time-relationships. This longitudinal MRI study on patient-level determined the course of joint inflammation during progression from arthralgia to clinical arthritis. Objectives To increase the comprehension on the course of MRI-detected subclinical joint inflammation during progression from arthralgia to clinical arthritis, both in ACPA-positive and ACPA-negative arthritis patients. Methods We longitudinally followed 29 patients that all progressed from Clinically Suspect Arthralgia to clinical arthritis. 1.5T MRI on hand and foot joints was performed at presentation with arthralgia and subsequently at the development of clinical arthritis. MRIs were evaluated for BME, synovitis and tenosynovitis (summed in the total inflammation score) and erosions by three readers (ICCs 0.98, 0.96 and 0.97) that were blind to clinical data and the order in time. Analyses were repeated in arthritis patients that fulfilled the 2010 criteria for rheumatoid arthritis, and in ACPA-positive and ACPA-negative patients separately. Results At presentation with arthralgia the mean age was 43 years, 72% was female, and 28% was ACPA-positive. Median duration to clinical arthritis was 17 weeks. At the time of arthritis development 65% fulfilled the 2010-criteria. During progression from arthralgia to clinical arthritis the median total inflammation score increased from 4.5 (IQR 2.8–7.8) to 6.0 (IQR 2.0–13.5), p=0.01. The BME score increased over time (p=0.04), as did the synovitis score (p=0.002). The tenosynovitis and erosion scores increased as well, though not statistically significant (p=0.10 and p=0.07 respectively). Analyses within the patients that developed 2010-RA revealed that BME (p=0.047), synovitis (p=0.005) and tenosynovitis (p=0.004) all increased significantly, in contrast to the erosion score. At presentation with arthralgia, BME and synovitis scores were higher in ACPA-positive than in ACPA-negative patients; during progression to clinical arthritis the different types of inflammation increased similarly in ACPA-positive and ACPA-negative patients. Conclusions During progression from arthralgia to clinically evident rheumatoid arthritis, BME, synovitis as well as tenosynovitis progress simultaneously. Disclosure of Interest None declared

Background/Objectives: The epidemiology, natural history, complications, and therapeutic management of chronic pancreatitis (CP) are not well described at the national level. This multi-centre prospective observational study involving eight Belgian hospitals aimed to improve the understanding of these aspects of CP in Belgium. Methods: All patients with a diagnosis of CP based on imaging were eligible for this study. Data were gathered regarding epidemiology, etiology, CP complications, and treatment modalities. Results: A total of 809 patients were included between 1/9/2014 and 31/8/2015. Most patients (794) were adults >= 16-years old, 74% were male, the median age at symptom onset was 47 (38-57) years, the median disease duration was 7 (3-13) years, and the median Izbicki pain score (IPS) was 96 (0-195). The main etiological risk factors according to the TIGAR-O classification were alcohol and tobacco (67%). Current drinkers had lower body mass index (BMI) (21.4 kg/m(2) vs 24.1 kg/m(2)), higher IPS (110 vs 56), and longer inability to work than non-drinkers. Current smokers had lower BMI (21.5 kg/m(2) vs 25 kg/m(2)) and higher IPS (120 vs 30) than non-smokers. Endocrine insufficiency and/or clinical steatorrhea was recorded in 41% and 36% of patients, respectively. The highest IPS was reported in patients with ongoing endotherapy (166 vs 50 for patients who completed endoscopy). Conclusion: This multicentric study on CP patients showed that current alcohol drinking and smoking are associated with pain and malnutrition. Pain scores were higher in patients with ongoing endotherapy, independently of surgery. (C) 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

BackgroundThe phase of arthralgia is the earliest moment to clinically recognize patients who may develop Rheumatoid Arthritis (RA). Previous imaging studies in the arthralgia phase have shown that inflammation precedes RA development. It is unknown which symptoms/characteristics relate to subclinical joint inflammation as measured by MRI. Among all patients with arthralgia, those with clinically suspect arthralgia (CSA) are suspected to progress to arthritis according to the clinical judgement of their rheumatologists. We determined the symptoms/characteristics of patients with CSA who had inflammation on MRI.Methods102 patients with CSA and without clinical arthritis were included. They completed questionnaires, underwent joint counts and unilateral 1.5 T MRI of MCP joints 2–4, wrist and MTP joints 1–5. Synovitis, bone marrow oedema (BME) and tenosynovitis were scored according to the OMERACT rheumatoid arthritis MRI scoring system. Symptoms and signs were related to MRI inflammation (based on MRI scores in symptom-free controls; a sum of synovitis, BME and tenosynovitis scores ≥3 was considered positive). Whether certain clinical characteristics frequently occurred together with MRI inflammation was studied by partial least squares analysis.ResultsMRI was performed in 93 patients with CSA, 44% of whom had subclinical MRI inflammation. Synovitis was the most prevalent inflammatory feature on MRI (20%). Patients with MRI inflammation were older and were more frequently positive for anti-citrullinated peptide antibodies than patients without MRI inflammation (pConclusionsSubclinical inflammation as measured by MRI is present in 44% of patients with CSA. A combination of symptoms/characteristics incompletely differentiated patients with and without MRI inflammation.

OBJECTIVES MRI sensitively detects inflammation, but the clinical relevance of MRI-detected inflammation is undetermined in early arthritis. Therefore, the aim of this cross-sectional study was to investigate the association between MRI-detected inflammation of hands and feet and functional disability in early arthritis. METHODS Five hundred and fourteen early arthritis patients, consecutively included in the Leiden Early Arthritis Clinic, were studied. At baseline a unilateral 1.5 T MRI of the wrist, MCP and MTP joints was performed and functional disability was measured using the HAQ. MRIs were scored for tenosynovitis, synovitis and bone marrow oedema (BME) by two readers. The sum of these types of MRI-detected inflammation yielded the total MRI-inflammation score. Linear and nonlinear regression analyses were performed with HAQ as outcome. RESULTS The total MRI-inflammation score was associated with the HAQ score (β = 0.014, P < 0.001), as were tenosynovitis (β = 0.046, P < 0.001), synovitis (β = 0.039, P < 0.001) and bone marrow oedema scores (β = 0.015, P < 0.001) separately. Analysing these three types of MRI-detected inflammation in one multivariable model revealed that only tenosynovitis was independently associated with the HAQ score (β = 0.039, P < 0.001). Also after correction for age, gender, joint counts, CRP and auto-antibodies, this association remained significant (β = 0.034, P < 0.001). MRI-detected inflammation at wrists or MCP joints associated significantly with impairments in hand functioning (e.g. difficulties with opening milk cartons or jars). Exploring the relation between MRI-detected inflammation and HAQ scores showed no evidence of a floor effect, suggesting that even low scores of MRI-detected inflammation are functionally relevant. CONCLUSION MRI-detected inflammation, and tenosynovitis in particular, is associated with functional disability. This demonstrates the functional relevance of MRI-detected inflammation in early arthritis.

Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures.The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC.HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found.These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA.

Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development.150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons.During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA-positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA-positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA-negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA).Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with arthritis development.

Background In the population a high body mass index (BMI) has been associated with slightly increased inflammatory markers. Within rheumatoid arthritis (RA), however, a high BMI has been associated with less radiographic progression; this phenomenon is unexplained. We hypothesized that the phenomenon is caused by an inverse relationship between BMI and inflammation in hand and foot joints with RA. To explore this hypothesis, local inflammation was measured using magnetic resonance imaging (MRI) in early arthritis patients presenting with RA or other arthritides and in asymptomatic volunteers. Methods A total of 195 RA patients, 159 patients with other inflammatory arthritides included in the Leiden Early Arthritis Clinic, and 193 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5 T MRI scan of metacarpophalangeal, wrist, and metatarsophalangeal joints. Each MRI scan was scored by two readers on synovitis, bone marrow edema (BME), and tenosynovitis; the sum yielded the total MRI inflammation score. Linear regression on log-transformed MRI data was used. Results A higher BMI was associated with higher MRI inflammation scores in arthritides other than RA (β = 1.082, p

Objectives. Despite recent progress in biomarker discovery for RA diagnostics, still over one-third of RA patients-and even more in early disease-present without RF or ACPA. The aim of this study was to confirm the presence of previously identified autoantibodies to novel Hasselt University (UH) peptides in early and seronegative RA. Methods. Screening for antibodies against novel UH peptides UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21, was performed in two large independent cohorts. Peptide ELISAs were developed to screen for the presence of antibodies to UH-RA peptides. First, 292 RA patients (including 39 early patients), 90 rheumatic and 97 healthy controls from UH were studied. Antibody reactivity to two peptides (UH-RA. 1 and UH-RA. 21) was also evaluated in 600 RA patients, 309 patients with undifferentiated arthritis and 157 rheumatic controls from the Leiden Early Arthritis Clinic cohort. Results. In both cohorts, 38% of RA patients were seronegative for RF and ACPA. Testing for autoantibodies to UH-RA. 1 and UH-RA. 21 reduced the serological gap from 38% to 29% in the UH cohort (P = 0.03) and from 38% to 32% in the Leiden Early Arthritis Clinic cohort (P = 0.01). Furthermore, 19-33% of early RA patients carried antibodies to these peptides. Specificities in rheumatic controls ranged from 82 to 96%. Whereas antibodies against UH-RA. 1 were related to remission, anti-UH-RA. 21 antibodies were associated with inflammation, joint erosion and higher tender and swollen joint counts. Conclusion. This study validates the presence of antibody reactivity to novel UH-RA peptides in seronegative and early RA. This might reinforce current diagnostics and improve early diagnosis and intervention in RA.

Objectives To assess the diagnostic value of MRI for early RA. In some RA patients, a classifiable diagnosis cannot be made at first presentation; these patients present with unclassified arthritis (UA). The use of MRI for early diagnosis of RA is recommended, yet the evidence for its reliability is limited. Methods MRI of hand and foot was performed in 589 early arthritis patients included in the Leiden Early Arthritis Clinic (229 presented with RA, 159 with other arthritides and 201 with UA). Symptom-free controls provided a reference for defining an abnormal MRI. In preliminary investigations, MRI of patients who presented with RA was compared with MRI of symptom-free controls and of patients with other arthritides. Thereafter, the value of MRI in early RA diagnosis was determined in UA patients using the 1-year follow-up on fulfilling the 1987 RA criteria and start of disease-modifying drugs as outcomes. Results Preliminary investigations were promising. Of the UA patients, 14% developed RA and 37% started disease-modifying treatment. MRI-detected tenosynovitis was associated with RA development independent of other types of MRI-detected inflammation [odds ratio (OR) = 7.5, 95% CI: 2.4, 23] and also independent of age and other inflammatory measures (swollen joints, CRP) (OR = 4.2, 95% CI: 1.4, 12.9). Within UA patients, the negative predictive value of abnormal tenosynovitis was 95% (95% CI: 89%, 98%) and the positive predictive value 25% (95% CI: 17%, 35%). The performance was best in the subgroup of UA patients presenting with oligoarthritis (18% developed RA): the positive predictive value was 36% (95% CI: 23%, 52%), the negative predictive value was 98% (95% CI: 88%, 100%), the sensitivity was 93% (95% CI: 70%, 99%) and the specificity was 63% (95% CI: 51%, 74%). Conclusion MRI contributes to the identification of UA patients who will develop RA, mostly in UA patients presenting with oligoarthritis.

1. alpha 1-antitrypsin is an antiprotease that inhibits the neutrophil elastase enzyme, and belongs to a family of structurally related serine proteinase inhibitors (serpins). Its methionine358 residue determines the specificity for elastase. 2. The normal M-type alpha 1-antitrypsin is mainly synthesized in the liver parenchymal cells and transported to the plasma. Abnormal Z-mutant alpha 1-antitrypsin is retained in the endoplasmic reticulum, which leads to its intracellular accumulation and to markedly decreased plasma levels. 3. In normal conditions, alpha 1-antitrypsin protects the lungs from destruction by the proteolytic neutrophil elastase. A protease/antiprotease imbalance in the lung is responsible for the development of emphysema in severe alpha 1-antitrypsin deficiency and in cigarette smokers, and accounts for the marked acceleration of the lung disease in smoking alpha 1-antitrypsin deficient patients. Smoking has to be avoided in alpha 1-antitrypsin deficient patients. Replacement therapy with plasma-derived alpha 1-antitrypsin seems indicated in alpha 1-antitrypsin deficient patients with emphysema. 4. Intracellular accumulation of abnormal Z-alpha 1-antitrypsin molecules in liver parenchymal cells may lead to liver disease, ranging from neonatal cholestasis to adulthood cirrhosis and hepatocellular carcinoma. End-stage liver disease can be treated by liver transplantation, which is followed by a phenotypic conversion. 5. Diagnosis of alpha 1-antitrypsin deficiency related disease relies on the presence of a low serum concentration of alpha 1-antitrypsin, and of periodic-acid Schiff positive globules in the liver parenchymal cells. Isoelectric focusing of the serum identifies the protease inhibitor phenotype. The protease inhibitor phenotype is determined by the independent expression of the two parental alpha 1-antitrypsin alleles. It is determinant of the serum level and of the risk for development of lung or liver disease.

Background: Wider utilization of liver grafts from donors

Orthotopic liver transplantation (OLT) (LTx) using donation after circulatory death (DCD) donors is increasingly performed, but still considered to risk of poorer outcomes compared with standard donations after brain death (DBD)-OLT. Therefore we reviewed our results of DCD-OLT.Between 2003 and 2010, we performed 30 DCD-OLT (6% of all OLT). We retrospectively reviewed medical records of donors and recipients after DCD versus DBD-OLT to analyze biliary complications, retransplantation rates, and patient/graft survivals.Median donor age was similar for DCD and DBD-OLT: 51 versus 53 years (P = .244). Median donor warm ischemia time (stop ventilation to cold perfusion in DCD donors) was 24 minutes. Median cold ischemia time was shorter for DCD (6 hours 54 minutes) compared with DBD-OLT (8 hours 36 minutes; P.0001). Median laboratory model of end-stage liver disease score was 15 for DCD, and 16 for DBD-OLT (P = .59). Median post-OLT Aspartate Aminotransferase (AST) peak was higher after DCD: 1178 versus DBD-OLT 651 IU/L (P = .005). The incidence of nonanastomotic strictures was different: 33.3% for DCD versus 12.5% for DBD-OLT (P = .001). The overall retransplantation rate was 3% after both DCD and DBD-OLT. After DCD-LTx actuarial 1, 3- and 5-year patient survivals were 93, 85 and 85%, and corresponding graft survivals, 90%, 82%, and 82% respectively, and not different compared with DBD-OLT: 88%, 78%, and 72% (P = .348) and 85%, 74%, and 68% (P = .524) respectively.Despite substantial ischemic injury (high peak AST and biliary strictures) short- and long-term survival after DCD-OLT was comparable to DBD-OLT. Rapid donor surgery, careful donor and recipient selection, as well as short warm and cold ischemia times are key factors to optimize outcomes after DCD-OLT. However, strategies to reduce biliary complications remain warranted.

Biliary strictures (BS), a major complication after orthotopic liver transplantation (OLT), cause morbidity, mortality, graft loss, and increased costs. The virtually unchanged incidence of BS (approximately 10%-25%) suggests that they are not simply "technical" in origin, but probably represent a mucosa ischemic injury inherent in the transplantation procedure. To study risk factors for BS, we analyzed 403 OLTs performed between January 1, 1997 and December 31, 2006, at a single center, excluding cases of regraft or death within 1 month. The average time to the diagnosis of the BS was 253 days (range, 7-1002 days). Upon univariate analysis, the absence of flushing of donor bile ducts, an imported versus a locally procured liver, and rejection were risk factors for BS. In contrast, the following factors were protective: donor cardiac arrest followed by resuscitation (suggesting an ischemic preconditioning effect) as well as addition of epoprostenol to and pressurization of the preservation solution. Patients with higher postoperative peak values of transaminases, bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase were at greater risk for later development of BS. Donor hypotension, donor age, donor intensive care unit (ICU) stay, type of preservation, positive cross-match, cold and warm ischemia times, sequential versus simultaneous portal/arterial reperfusion, as well as cytomegalovirus (CMV) infection were not risk factors for BS. Upon multivariate analysis, only epoprostenol and pressurization offered protection from BS. In conclusion, this study 2 novel points: (1) patients with high(er) transaminase values and cholestasis early postoperatively are at greater risk to develop later BS and require close monitoring and (2) donor maneuvers for better flushing and preserving peribiliary vascular plexus and biliary mucosa (epoprostenol and pressurization of preservation solution) offer protection from BS.

The probability that a patient has common bile duct stones (CBDS) is a key factor in determining diagnostic and treatment strategies. This prospective cohort study evaluated the accuracy of clinical models in predicting CBDS for patients who will undergo cholecystectomy for lithiasis.From October 2005 until September 2006, 335 consecutive patients with symptoms of gallstone disease underwent cholecystectomy. Statistical analysis was performed on prospective patient data obtained at the time of first presentation to the hospital. Demonstrable CBDS at the time of endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative cholangiography (IOC) was considered the gold standard for the presence of CBDS.Common bile duct stones were demonstrated in 53 patients. For 35 patients, ERCP was performed, with successful stone clearance in 24 of 30 patients who had proven CBDS. In 29 patients, IOC showed CBDS, which were managed successfully via laparoscopic common bile duct exploration, with stone extraction at the time of cholecystectomy. Prospective validation of the existing model for CBDS resulted in a predictive accuracy rate of 73%. The new model showed a predictive accuracy rate of 79%.Clinical models are inaccurate in predicting CBDS in patients with cholelithiasis. Management strategies should be based on the local availability of therapeutic expertise.

Introduction Anti-carbamylated protein (anti-CarP) antibodies have been described in rheumatoid arthritis (RA) and arthralgia patients at risk of developing RA. To what extent these autoantibodies are specific for RA is unknown. Therefore, we investigated the diagnostic performance of the presence of anti-CarP antibodies for RA in a setting of early arthritis. Methods Anti-CarP antibodies were detected using carbamylated fetal calf serum as substrate. Anti-CCP2 antibodies were measured using enzyme-linked immunosorbent assay and immunoglobulin M (IgM) rheumatoid factor (RF) as part of routine care. Sera were derived from patients in the Leiden Early Arthritis Clinic cohort obtained at inclusion. Test characteristics were determined using the fulfillment of the 2010 RA criteria after 1 year as outcome. Results In total 2086 early arthritis patients were studied regarding the presence of anti-CarP antibodies. We observed that the sensitivity and specificity of the presence of anti-CarP antibodies for RA were 44 % and 89 %, respectively. As a reference, sensitivity and specificity of the presence of anti-CCP2 antibodies were 54 % and 96 %, respectively, and of IgM-RF 59 % and 91 %. Patients harboring anti-CarP antibodies not classified as RA were mainly diagnosed with undifferentiated arthritis and less frequently reactive arthritis and psoriatic arthritis. Conclusion Anti-CarP antibodies are predominantly present in RA but can also be detected in other forms of arthritis.

[Introduction] Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA)., [Methods] Six independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance–weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed., [Results] The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05–1.14, p = 2.10 × 10−5), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele., [Conclusions] The PTGER4 gene is a candidate risk factor for radiological progression in RA., This work was supported by the Instituto de Salud Carlos III (ISCIII), Ministry of Health, Spain [Miguel Servet research contract CP12/03129 (to LRR); Fondo de Investigaciones Sanitarias PI11/02413; and Red de Investigación en Inflamación y Enfermedades Reumáticas RD12/0009/0004, RD12/0009/0011, and RD12/0009/0017]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction The western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study. Method 1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used. Results Analysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p

Summary Background Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). Aim To compare PSC/CD with other PSC patients. Methods Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. Results Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. Conclusions The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Objective Fatigue is prevalent and disabling in rheumatoid arthritis (RA). Surprisingly, the long-term course of fatigue is studied seldom and it is unclear to what extent it is influenced by inflammation. This study aimed to determine the course of fatigue during 8 years follow-up, its association with the severity of inflammation and the effect of improved treatment strategies. Methods 626 patients with RA included in the Leiden Early Arthritis Clinic cohort were studied during 8 years. Fatigue severity, measured on a 0–100 mm scale, and other clinical variables were assessed yearly. Patients included in 1993–1995, 1996–1998 and 1999–2007 were treated with delayed treatment with disease-modifying antirheumatic drugs (DMARDs), early treatment with mild DMARDs and early treatment with methotrexate respectively. After multiple imputation, the serial measurements were analysed using linear quantile mixed models. Results Median fatigue severity at baseline was 45 mm and remained, despite treatment, rather stable thereafter. Female gender (effect size=4.4 mm), younger age (0.2 mm less fatigue/year), higher swollen and tender joint counts (0.3 mm and 1.0 mm more fatigue/swollen or tender joint) and C reactive protein-levels (0.1 mm more fatigue per mg/L) were independently and significantly (p

Introduction The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients. Results No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5. Conclusion Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.

International audience; Objective: To group HLA-DRB1 alleles based on acid–base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA).Methods: Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72–74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ2 test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method.Results: After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid–base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)).Conclusions: This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA

Infectious complications after endoscopic retrograde cholangiopancreatography (ERCP) are rare and can mainly be divided into endocarditis and sepsis/cholangitis. There still remains uncertainty about the indications, antibiotic regimens, and timing for antibiotic prophylaxis. Several guidelines for antibiotic prophylaxis have been published. It is the purpose of the present paper to make an extensive review of the literature and to yield general recommendations on antibiotic prophylaxis before ERCP. Antibiotic prophylaxis is recommended for patients at high risk for endocarditis, as well as for patients with a vascular graft less than 1 year old. For sepsis/cholangitis, prophylaxis is mostly recommended for patients with a bile duct obstruction or with a pancreatic pseudocyst. For other conditions, a case-by-case evaluation by the physician/endoscopist is still inevitable.

To study features in older patients with autoimmune hepatitis, as this was considered mainly a disease of young females.Analysis of 28 patients diagnosed at ageor =65 years compared with 84 younger patients.The incidence was similar at all age decades. The ratio M:F was 1:3 (or =65 years) vs. 1:2 (65 years). Presenting symptoms were not different when compared with younger patients and consisted of general malaise and fatigue (36%), jaundice +/- other symptoms (50%), or ascites (11%). Antinuclear antibodies (ANA)or = 1/80 were positive in 93%, smooth muscle antibodies (SMA)1/40 in 50%, anti-liver kidney microsomes (anti-LKM) proved always negative. Histology showed acute necrotizing hepatitis in 19%, severe interphase hepatitis in 15%, chronic hepatitis with plasmo-lymphocytic infiltrate in 30%, cirrhosis in 29% (with active inflammation in one-third); biopsy was refused in 11%. The elderly responded very well to low doses of methylprednisolone (or =8 mg) and azathioprine (1 mg/kg). This schedule obviates side-effects such as infections seen with higher dosages.Autoimmune hepatitis has to be also looked for in the elderly with acute and chronic hepatitis. The steroid therapy should be individualized but kept at a low dose.

The discovery of the gene responsible for most cases of hereditary haemochromatosis has made it possible to evaluate the role of this gene in iron accumulation in other conditions. Previous observations in patients with various inherited anaemias are suggestive of a role of the haemochromatosis gene in the noniatrogenic form of iron overload that may occur in these conditions.We studied two brothers with congenital dyserythropoietic anaemia type II, presenting with marked noniatrogenic iron overload. Young age, familial occurrence, concordance of iron overload, and histology were all suggestive of a genetic basis for the iron overload. A search for C282Y, H63D, S65C, and IVS3 + 1G?T mutations was performed by polymerase chain reaction after extraction of genomic DNA from whole blood.A search for the C282Y, H63D, S65C, and IVS3 + 1G?T mutations in the HFE gene proved to be negative. Despite the existence of ineffective erythropoiesis with mild anaemia, both patients were treated with regular phlebotomies in order to prevent long-term complications of their iron-overload. This treatment was well tolerated.1. C282Y, H63D, S65C, and IVS3 + 1G?T mutations were negative in two brothers with congenital dyserythropoietic anaemia, in whom young age, familial occurrence, concordance of iron overload, and the histological pattern were all suggestive of hereditary haemochromatosis. 2. Treatment with regular phlebotomies, in order to prevent complications of iron overload, was well tolerated despite the existence of mild haemolytic anaemia.

Introduction A phase of arthralgia may precede the emergence of rheumatoid arthritis (RA). Although several studies have focused on biomarkers, the relevance of this phase for patients is less studied. It is unknown if patients already have functional limitations and if this is correlated to the extent of subclinical inflammation. Therefore, we assessed functional disability in patients with clinically suspect arthralgia (CSA), its association with MRI-detected subclinical inflammation and its course during progression to clinical arthritis.Methods From April 2012 to March 2015, 241 patients had arthralgia for Results The median HAQ score at presentation with CSA was 0.50. Higher MRI-inflammation scores were associated with higher HAQ scores (β=0.017, 95% CI=0.004 to 0.030). During median 103 weeks follow-up, 44 patients progressed to clinical arthritis. HAQ scores ≥1.0 were associated with arthritis development (HR=2.50, 95% CI=1.03 to 6.10). Within converters, median HAQ scores did not increase from presentation with CSA to arthritis development (0.88 and 0.75, p=0.36). Conclusions HAQ scores ≥1.0 at presentation were associated with the development of clinical arthritis. Functional limitations in the prearthritis phase of CSA were as serious as in the early clinical phase, demonstrating the relevance of CSA from patients’ perspectives

We describe the case of a 26-year-old man with acute liver failure secondary to ingestion of khat (Catha edulis) leaves. In fact, this is the first case of acute liver failure due to khat reported outside the United Kingdom. The combination of specific epidemiologic data (young man of East African origin) and clinical features (central nervous system stimulation, withdrawal reactions, toxic autoimmune-like hepatitis) led to the diagnosis. Mechanisms of action and potential side effects of khat are elaborated on.