Objective Mucosal initiated immune responses may be involved in the pathophysiology of RA. The most abundant immunoglobulin at mucosal surfaces is IgA, of which two subclasses exist: IgA1 and IgA2.... Show moreObjective Mucosal initiated immune responses may be involved in the pathophysiology of RA. The most abundant immunoglobulin at mucosal surfaces is IgA, of which two subclasses exist: IgA1 and IgA2. IgA2 is mainly present at mucosal sites and has been ascribed pro-inflammatory properties. As IgA subclasses might provide insights into mucosal involvement and pro-inflammatory mechanisms, we investigated IgA responses in sera of RA patients. Methods In two cohorts of RA patients, the EAC and IMPROVED, total IgA1 and IgA2 were measured by ELISA. Furthermore, IgA subclass levels of RF and anti-citrullinated protein antibodies (anti-CCP2) were determined. The association of these IgA subclass levels with CRP and smoking was investigated. Results Total IgA1 and IgA2 were increased in RA patients compared with healthy donors in both cohorts. This increase was more pronounced in seropositive RA vs seronegative RA. For RF and anti-CCP2, both IgA1 and IgA2 could be detected. No strong associations were found between IgA subclasses (total, RF and anti-CCP2) and CRP. In smoking RA patients, a trend towards a selective increase in total IgA2 and RF IgA1 and IgA2 was observed. Conclusion RA patients have raised IgA1 and IgA2 levels. No shift towards IgA2 was observed, indicating that the increase in total IgA is not due to translocation of mucosal IgA into the bloodstream. However, mucosal inflammation might play a role, given the association between smoking and total IgA2 levels. Despite its pro-inflammatory properties, IgA2 does not associate strongly with pro-inflammatory markers in RA patients. Show less
Houtman, E.; Tuerlings, M.; Suchiman, H.E.D.; Lakenberg, N.; Cornelis, F.M.F.; Mei, H.L.; ... ; Meulenbelt, I. 2022
Objectives To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both... Show moreObjectives To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both repeated dosing and slow release of IOP. Methods Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP encapsulated in poly lactic-co-glycolic acid-polyethylene glycol nanoparticles (NP-IOP). Changes to cartilage integrity and signalling were determined by Mankin scoring of histology, sulphated glycosaminoglycan (sGAG) release and expression levels of catabolic, anabolic and hypertrophic markers. Subsequently, on a subgroup of samples, RNA sequencing was performed on 65%MS (n = 14) and 65%MS+IOP (n = 7) treated cartilage to identify IOP's mode of action. Results Damage from injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, and consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, NP-IOP treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and NP-IOP reduced cartilage surface damage induced by 65%MS, while only IOP reduced sGAG release from explants subjected to 65%MS. Lastly, differential expression analysis identified 12 genes in IOP's mode of action to be mainly involved in reducing metabolic processes (INSIG1, DHCR7, FADS1 and ACAT2) and proliferation and differentiation (CTGF, BMP5 and FOXM1). Conclusion Treatment with the deiodinase inhibitor IOP reduced detrimental changes of injurious mechanical stress. In addition, we identified that its mode of action was likely on metabolic processes, cell proliferation and differentiation. Show less
Objectives: To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression and... Show moreObjectives: To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression and determine the impact of standard of care treatment. Methods: SSc patients from the Leiden and Oslo cohorts were included. We assessed clinical data and patient-reported GIT symptoms measured by the validated University of California, Los-Angeles Gastrointestinal-tract (UCLA-GIT) score at baseline and annually. GIT severity and progression was determined. Logistic regression was applied to identify risk factors associated with baseline GIT symptom severity. Linear mixed-effect models were applied to assess progression in GIT symptom burden and to identify predictive factors. We repeated all analysis in patients with early disease (inception cohort) to exclude the effect of longstanding disease and increase insights in development of GIT symptom burden early in the disease course. Results: We included 834 SSc patients with baseline UCLA GIT scores, 454 from Leiden and 380 from Oslo. In the total cohort, 28% reported moderate-severe GIT symptoms at baseline, with increased risk for severity conferred by ACA, smoking and corticosteroid use, while use of calcium channel blockers appeared protective. In the inception cohort, 23% reported moderate-severe GIT symptoms at baseline, with increased risk for females and with smoking. Over time, symptom burden increased mainly for reflux/bloating. Female sex and ACA predicted GIT symptom progression. Conclusion: High GIT symptom burden is present early in SSc disease course. Both for prevalence and for progression of GIT symptom burden, female sex and smoking were identified as risk factors. Show less
Objectives: Clinical phenotyping and predicting treatment responses in SLE patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising... Show moreObjectives: Clinical phenotyping and predicting treatment responses in SLE patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients. We aimed to translate existing transcriptomic data into simpler gene signatures suitable for daily clinical practice. Methods: Real-time PCR of multiple genes from the IFN M1.2, IFN M5.12, neutrophil (NPh) and plasma cell (PLC) modules, followed by a principle component analysis, was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood-onset SLE cohorts (n = 101 and n = 34, respectively), and associations with clinical features were assessed. Disease activity was measured using Safety of Estrogen in Lupus National Assessment (SELENA)-SLEDAI. Cluster analysis subdivided patients into three mutually exclusive fingerprint-groups termed (1) all-signatures-low, (2) only IFN high (M1.2 and/or M5.12) and (3) high NPh and/or PLC. Results: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Interestingly, in longitudinally collected samples, the PLC-signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution was reproduced in samples from an independent SLE cohort. Conclusions: The identified gene signatures were associated with disease activity and were indicated to be suitable tools for stratifying SLE patients into groups with similar activated immune pathways that may guide future treatment choices. Show less
Ruiz, A.R.; Tuerlings, M.; A. das; Almeida, R.C. de; Suchiman, H.E.D.; Nelissen, R.G.H.H.; ... ; Meulenbelt, I. 2022
Objectives OA is a complex genetic disease with different risk factors contributing to its development. One of the genes, TNFRSF11B, previously identified with gain-of-function mutation in a family... Show moreObjectives OA is a complex genetic disease with different risk factors contributing to its development. One of the genes, TNFRSF11B, previously identified with gain-of-function mutation in a family with early-onset OA with chondrocalcinosis, is among the highest upregulated genes in lesioned OA cartilage (RAAK-study). Here, we determined the role of TNFRSF11B overexpression in development of OA. Methods Human primary articular chondrocytes (9 donors RAAK study) were transduced using lentiviral particles with or without TNFRSF11B. Cells were cultured for 1 week in a 3 D in-vitro chondrogenic model. TNFRSF11B overexpression was confirmed by RT-qPCR, immunohistochemistry and ELISA. Effects of TNFRSF11B overexpression on cartilage matrix deposition, matrix mineralization, and genes highly correlated to TNFRSF11B in RNA-sequencing dataset (r >0.75) were determined by RT-qPCR. Additionally, glycosaminoglycans and collagen deposition were visualized with Alcian blue staining and immunohistochemistry (COL1 and COL2). Results Overexpression of TNFRSF11B resulted in strong upregulation of MMP13, COL2A1 and COL1A1. Likewise, mineralization and osteoblast characteristic markers RUNX2, ASPN and OGN showed a consistent increase. Among 30 genes highly correlated to TNFRSF11B, expression of only eight changed significantly, with BMP6 showing the highest increase (9-fold) while expression of RANK and RANKL remained unchanged indicating previously unknown downstream pathways of TNFRSF11B in cartilage. Conclusion Results of our 3D in vitro chondrogenesis model indicate that upregulation of TNFRSF11B in lesioned OA cartilage may act as a direct driving factor for chondrocyte to osteoblast transition observed in OA pathophysiology. This transition does not appear to act via the OPG/RANK/RANKL triad common in bone remodeling. Show less
Verstappen, M.; Matthijssen, X.M.E.; Helm-van Mil, A.H.M. van der 2022
Objectives International guidelines stress timely DMARD initiation in early arthritis as well as when classification criteria are not yet fulfilled. Consequently, undifferentiated arthritis (UA)... Show moreObjectives International guidelines stress timely DMARD initiation in early arthritis as well as when classification criteria are not yet fulfilled. Consequently, undifferentiated arthritis (UA) patients may be increasingly treated with DMARDs. Since UA is a diagnosis of exclusion, the introduction of the 2010 classification criteria presumably decreased the UA population, as former UA patients became regarded as RA. Consequently, the contemporary definition of UA has changed into: no clinical diagnosis and not fulfilling the 1987 nor 2010 RA-criteria. Importantly, placebo-controlled trials on DMARD efficacy in contemporary UA are absent. We aimed to study whether enhanced treatment strategies across the last 25 years improved outcomes in contemporary UA, whereby inclusion period was used as instrumental variable for DMARD treatment. Methods UA was defined, retrospectively, as clinical arthritis (joint swelling at physical examination) neither fulfilling the 1987 nor 2010 RA-criteria or any other clinical diagnosis. In total, 1132 UA patients consecutively included in the Leiden Early Arthritis Clinic between 1993 and 2019 were divided into five inclusion periods: 1993-1997, 1998-2005, 2006-2010, 2011-2014 and 2015-2019. The frequency of DMARD initiation was compared across the inclusion periods, as were the following outcomes: 28-joint DAS with CRP (DAS28-CRP) and the HAQ Disability Index (HAQ-DI) during follow-up, prevalence of DMARD-free-status within 10 years (DFS; spontaneous remission or sustained remission after DMARD stop) and progression to RA (according 1987/2010 criteria). Results The contemporary UA population is mainly autoantibody negative, with a median swollen joint count of 2, tender joint count of 3 and HAQ score of 0.6. These characteristics were similar across the inclusion periods. DMARD treatment increased from 17% (1993-1997) to 52% (2015-2019) and methotrexate became more common. The DAS28-CRP during follow-up improved from 2011 onwards (-0.18 to -0.25 DAS units; P < 0.05). Disability scores during follow-up did not significantly improve. DFS prevalence also remained similar: 58%, 57% and 61% for 1993-1997, 1998-2005 and 2006-2010, respectively (P = 0.77). Likewise, the percentages of RA development did not decrease (14%, 21%, 26%, 18% and 27%, respectively). Conclusion Although intensified DMARD treatment slightly improved disease activity scores, physical functioning and long-term outcomes did not improve. This suggests overtreatment in the contemporary UA population and underlines the importance of developing stratification methods suitable for this patient-population. Show less
Dijk, B.T. van; Dakkak, Y.J.; Krijbolder, D.K.; Zeben, D. van; Tchetverikov, I.; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objectives The squeeze test of MTP joints is frequently used because it is easy and cheap. It is traditionally perceived as a test for synovitis. Besides classic intra-articular synovitis, also... Show moreObjectives The squeeze test of MTP joints is frequently used because it is easy and cheap. It is traditionally perceived as a test for synovitis. Besides classic intra-articular synovitis, also tenosynovitis and intermetatarsal bursitis (IMB) represent synovial inflammation, albeit juxta-articularly located. Both are frequently present in RA and occasionally in other arthritides. Therefore we hypothesized that tenosynovitis and IMB contribute to a positive MTP squeeze test. Methods A cross-sectional study design was used. A total of 192 early arthritis patients and 693 clinically suspect arthralgia patients underwent the MTP squeeze test and forefoot MRI at first presentation. MRI measurements in age-matched healthy controls were used to define positivity for synovitis, tenosynovitis and IMB. Logistic regression was used. Results In early arthritis patients, synovitis [odds ratio (OR) 4.8 (95% CI 2.5, 9.5)], tenosynovitis [2.4 (1.2, 4.7)] and IMB [1.7 (1.2, 2.6)] associated with MTP squeeze test positivity. Synovitis [OR 3.2 (95% CI 1.4, 7.2)] and IMB [3.9 (1.7, 8.8)] remained associated in multivariable analyses. Of patients with a positive MTP squeeze test, 79% had synovitis or IMB: 12% synovitis, 15% IMB and 52% both synovitis and IMB. In clinically suspect arthralgia patients, subclinical synovitis [OR 3.0 (95% CI 2.0, 4.7)], tenosynovitis [2.7 (1.6, 4.6)] and IMB [1.7 (1.2, 2.6)] associated with MTP squeeze test positivity, with the strongest association for synovitis in multivariable analysis. Of positive MTP squeeze tests, 39% had synovitis or IMB (10% synovitis, 15% IMB and 13% both synovitis and IMB). Conclusion Besides synovitis, IMB contributes to pain upon compression in early arthritis, presumably due to its location between MTP joints. This is the first evidence showing that MTP squeeze test positivity is not only explained by intra- but also juxta-articular inflammation. Show less
Hollander, N.K. den; Verstappen, M.; Sidhu, N.; Mulligen, E. van; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objectives: Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR... Show moreObjectives: Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR recommendations, this has only been determined in UA patients not fulfilling 1987 RA criteria, while some of these patients are currently considered as RA because they fulfil the 2010 criteria. Therefore, we studied the predictive value of MRI for progression to RA in the current UA population, i.e. not fulfilling RA classification criteria (either 1987 or 2010 criteria) and not having an alternate diagnosis. Additionally, the value of MRI was studied in patients with a clinical diagnosis of UA, regardless of the classification criteria. Methods: Two UA populations were studied: criteria-based UA as described above (n = 405) and expert-opinion-based UA (n = 564), i.e. UA indicated by treating rheumatologists. These patients were retrieved from a large cohort of consecutively included early arthritis patients that underwent contrast-enhanced MRI scans of hand and foot at baseline. MRIs were scored for osteitis, synovitis and tenosynovitis. Patients were followed for RA development during the course of 1 year. Test characteristics of MRI were determined separately for subgroups based on joint involvement and autoantibody status. Results: Among criteria-based UA patients (n = 405), 21% developed RA. MRI-detected synovitis and MRI-detected tenosynovitis were predictive for progression to RA. MRI-detected tenosynovitis was independently associated with RA progression (odds ratio (OR) 2.79; 95% CI 1.40, 5.58), especially within ACPA-negative UA patients (OR 2.91; 95% CI 1.42, 5.96). Prior risks of RA development for UA patients with mono-, oligo- and polyarthritis were 3%, 19% and 46%, respectively. MRI results changed this risk most within the oligoarthritis subgroup: positive predictive value was 27% and negative predictive value 93%. Similar results were found in expert-opinion-based UA (n = 564). Conclusion: This large cohort study showed that MRI is most valuable in ACPA-negative UA patients with oligoarthritis; a negative MRI could aid in preventing overtreatment. Show less
Objectives: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have... Show moreObjectives: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = <0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015]. Conclusions: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates. Show less
Dijk, B.T. van; Wouters, F.; Mulligen, E. van; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2021
Objectives: Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB... Show moreObjectives: Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB. Methods: A total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed. Results: At presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P < 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0-2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0-4.7)], but not in ACPA-negative CSA-patients [0.8(0.4-1.7)]. Conclusion: Approximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development. Show less
Rogier, C.; Jong, P.H.P. de; Helm-van Mil, A.H.M. van der; Mulligen, E. van 2021
Objectives We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis... Show moreObjectives We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis were used as a reference. Methods Three groups of patients were studied: arthralgia patients converting to RA (n = 114), arthralgia patients with spontaneous symptom resolution (n = 57), and early RA patients (n = 617). Both presenteeism (i.e. working while sick, scale 0-10) and absenteeism (i.e. sick leave) were taken into account. Work ability 1 year prior to clinical arthritis was estimated (in absolute numbers). The course of work restriction over time was studied using linear mixed models (beta coefficient; delta per month) within each patient group. Results One-year prior to the development of clinical arthritis, mean presenteeism was 7.0 (95% CI 5.8, 8.1) in patients with arthralgia, indicating 30% loss, and further worsened to 6.1 (95% CI 5.3, 6.6) at RA diagnosis, thus indicating 39% loss. In early RA patients, presenteeism improved over time after DMARD initiation (beta 0.052 per month 95% CI 0.042, 0.061, P < 0.0001). Presenteeism also improved in arthralgia patients who achieved spontaneous symptom resolution (beta 0.063 per month, 95% CI 0.024, 0.10, P = 0.002). Absenteeism did not change significantly in arthralgia patients, but did improve in RA after DMARD-start. ACPA stratification revealed similar results. Conclusion In the months preceding RA, presenteeism was already apparent, and it worsened further during progression to clinical arthritis and diagnosis. This underlines the relevance of the symptomatic pre-RA phase for patients. The observed reversibility in arthralgia patients with symptom resolution may suggest that intervention in pre-RA could improve work participation. Show less
Inglese, F.; Jaarsma-Coes, M.G.; Steup-Beekman, G.M.; Monahan, R.; Huizinga, T.; Buchem, M.A. van; ... ; Bresser, J. de 2021
Objectives Advanced white matter hyperintensity (WMH) markers on brain MRI may help reveal underlying mechanisms and aid in the diagnosis of different phenotypes of SLE patients experiencing... Show moreObjectives Advanced white matter hyperintensity (WMH) markers on brain MRI may help reveal underlying mechanisms and aid in the diagnosis of different phenotypes of SLE patients experiencing neuropsychiatric (NP) manifestations. Methods In this prospective cohort study, we included a clinically well-defined cohort of 155 patients consisting of 38 patients with NPSLE (26 inflammatory and 12 ischaemic phenotype) and 117 non-NPSLE patients. Differences in 3 T MRI WMH markers (volume, type and shape) were compared between patients with NPSLE and non-NPSLE and between patients with inflammatory and ischaemic NPSLE by linear and logistic regression analyses corrected for age, sex and intracranial volume. Results Compared with non-NPSLE [92% female; mean age 42 (13) years], patients with NPSLE [87% female; mean age 40 (14) years] showed a higher total WMH volume [B (95%-CI)]: 0.46 (0.0 7 <-> 0.86); P = 0.021], a higher periventricular/confluent WMH volume [0.46 (0.0 6 <-> 0.86); P = 0.024], a higher occurrence of periventricular with deep WMH type [0.32 (0.1 3 <-> 0.77); P = 0.011], a higher number of deep WMH lesions [3.06 (1.2 1 <-> 4.90); P = 0.001] and a more complex WMH shape [convexity: -0.07 (-0.12 <-> -0.02); P = 0.011, concavity index: 0.05 (0.0 1 <-> 0.08); P = 0.007]. WMH shape was more complex in inflammatory NPSLE patients [89% female; mean age 39 (15) years] compared with patients with the ischaemic phenotype [83% female; mean age 41 (11) years] [concavity index: 0.08 (0.0 1 <-> 0.15); P = 0.034]. Conclusion We demonstrated that patients with NPSLE showed a higher periventricular/confluent WMH volume and more complex shape of WMH compared with non-NPSLE patients. This finding was particularly significant in inflammatory NPLSE patients, suggesting different or more severe underlying pathophysiological abnormalities. Show less
Runhaar, J.; Ozbulut, O.; Kloppenburg, M.; Boers, M.; Bijlsma, J.W.J.; Bierma-Zeinstra, S.M.A.; CREDO Expert Grp 2021
Objectives. Although there is a general focus on early diagnosis and treatment of hip OA, there are no validated diagnostic criteria for early-stage hip OA. The current study aimed to take the... Show moreObjectives. Although there is a general focus on early diagnosis and treatment of hip OA, there are no validated diagnostic criteria for early-stage hip OA. The current study aimed to take the first steps in developing diagnostic criteria for early-stage hip OA, using factors obtained through history taking, physical examination, radiography and blood testing at the first consultation in individuals presenting with hip pain, suspicious for hip OA, in primary care.Methods. Data of the 543 individuals with 735 symptomatic hips at baseline who had any follow-up data available from the prospective CHECK cohort study were used. A group of 26 clinical experts [general practitioners (GPs), rheumatologists and orthopaedic surgeons] evaluated standardized clinical assessment forms of all subjects on the presence of clinically relevant hip OA 5-10 years after baseline. Using the expert-based diagnoses as reference standard, a backward selection method was used to create predictive models based on pre-defined baseline factors from history taking, physical examination, radiography and blood testing.Results. Prevalence of clinically relevant hip OA during follow-up was 22%. Created models contained four to eight baseline factors (mainly WOMAC pain items, painful/restricted movements and radiographic features) and obtained area under the curve between 0.62 (0.002) and 0.71 (0.002).Conclusion. Based on clinical and radiographic features of hip OA obtained at first consultation at a GP for pain/stiffness of the hip, the prediction of clinically relevant hip OA within 5-10 years was 'poor' to /fair'. Show less
Hartman, L.; Cutolo, M.; Bos, R.; Opris-Belinski, D.; Kok, M.R.; Griep-Wentink, H.J.R.M.; ... ; Boers, M. 2021
Objectives. Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to... Show moreObjectives. Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods.Methods. The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken.Results. Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1-8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user (<20% of days an opening) and 40% as irregular user (different adherence patterns, in or between periods).Conclusion. In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so. Show less
Sidhu, N.; Wouters, F.; Niemantsverdriet, E.; Helm-van Mil, A.H.M. van der 2021
Objectives: New onset undifferentiated large joint inflammatory arthritis can be diagnostically challenging. It is unknown how often these patients progress to RA, and how they can be identified at... Show moreObjectives: New onset undifferentiated large joint inflammatory arthritis can be diagnostically challenging. It is unknown how often these patients progress to RA, and how they can be identified at first presentation. We assessed clinical and serological features associated with RA development in patients with an undifferentiated mono- or oligo-articular large joint arthritis, and with keen interest in whether an MRI of the small joints of the hand and foot would aid diagnosis. Methods: Leiden Early Arthritis Clinic includes 4018 patients; this prospective study follows 221 consecutively included patients with new onset undifferentiated large joint arthritis. Baseline clinical data and serology were obtained. Forty-five patients had MRIs (hand and foot). MRIs were scored according to the OMERACT RAMRIS. Univariable and multivariable logistic regression were assessed. Test characteristics, predictive values and net reclassification index (NRI) for RA were determined. Results: Patients mostly presented with knee or ankle mono-arthritis. During the 12 months' follow-up 17% developed RA. Autoantibody positivity (ACPA and/or RF) and MRI-detected synovitis in hands and feet were independently associated with RA development in multivariable analyses [odds ratio 10.29 (P = 0.014) and 7.88 (P = 0.017), respectively]. Positive predictive value of autoantibodies, MRI-detected synovitis and combination of both features was 63%, 55% and 100%, respectively. The addition of MRI-detected synovitis to autoantibody status improved diagnostic accuracy (NRI 18.1%). Conclusion: In patients presenting with undifferentiated large joint arthritis, 17% will develop RA. Autoantibody positivity and subclinical synovitis are independent predictors. The data suggest MRI of small joints is beneficial for early identification of RA in large joint arthritis. Show less
Objective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice... Show moreObjective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.Results. The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant.Conclusion. In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ. Show less
Objectives. To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict... Show moreObjectives. To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict clinical diagnosis.Methods. The Assessment of SpondyloArthritis international Society (ASAS) MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises where (A) 169 cases and 7 central readers; (B) 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SI joint quadrants or slices with bone marrow oedema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with >= 95% specificity were analysed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPVs/NPVs) and selecting cut-offs with PPV >= 95%.Results. Active or structural lesions typical of axSpA on MRI had PPVs >= 95% for clinical diagnosis of axSpA. Cut-offs that best reflected a definite active lesion typical of axSpA were either >= 4 SI joint quadrants with BME at any location or at the same location in >= 3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of >= 3 SI joint quadrants with erosion or >= 5 with fat lesions, erosion at the same location for >= 2 consecutive slices, fat lesions at the same location for >= 3 consecutive slices, or presence of a deep (i.e. >1 cm depth) fat lesion.Conclusion. We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPVs for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research. Show less
Lerkvaleekul, B.; Veldkamp, S.R.; Wal, M.M. van der; Schatorje, E.J.H.; Kamphuis, S.S.M.; Berg, J.M. van den; ... ; Wijk, F. van 2021
Objective JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a... Show moreObjective JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM. Methods Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay. Results Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (r(s) = 0.81, P < 0.0001) and galectin-9 (r(s) = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01). Conclusion Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential. Show less
Nikiphorou, E.; Boonen, A.; Fautrel, B.; Richette, P.; Landewe, R.; Heijde, D. van der; Ramiro, S. 2021
Objectives: To investigate the impact of clinical and socioeconomic factors on work disability (WD) in early axial spondyloarthritis (axSpA). Methods: Patients from the DESIR cohort with a clinical... Show moreObjectives: To investigate the impact of clinical and socioeconomic factors on work disability (WD) in early axial spondyloarthritis (axSpA). Methods: Patients from the DESIR cohort with a clinical diagnosis of axSpA were studied over 5 years. Time to WD and potential baseline and time-varying predictors were explored, with a focus on socioeconomic (including ethnicity, education, job-type, marital/parental status) and clinical (including disease activity, function, mobility) factors. Univariable analyses, collinearity and interaction tests guided subsequent multivariable time-varying Cox survival analyses. Results: From 704 patients eligible for this study, the estimated incidence of WD among those identified as at risk (n = 663, 94%), and across the five years of DESIR, was 0.05 (95% CI 0.03, 0.06) per 1000 person-days. Significant differences in baseline socioeconomic factors, including lower educational status and clinical measures, including worse disease activity, were seen in patients developing WD over follow-up, compared with those who never did. In the main multivariable model, educational status was no longer predictive of WD, whereas the AS disease activity score (ASDAS) and the BASFI were significantly and independently associated with a higher hazard of WD [HR (95%CI) 1.79 (1.27, 2.54) and 1.42 (1.22, 1.65), respectively]. Conclusion: WD was an infrequent event in this early axSpA cohort. Nevertheless, clinical factors were among the strongest predictors of WD, over socioeconomic factors, with worse disease activity and function independently associated with a higher hazard of WD. Disease severity remains a strong predictor of adverse work outcome even in early disease, despite substantial advances in therapeutic strategies in axSpA. Show less
