BackgroundObese RA patients have higher disease activity scores (DAS). Previous research showed that obese RA patients have higher tender joint count (TJC) and VAS general health. However, it... Show moreBackgroundObese RA patients have higher disease activity scores (DAS). Previous research showed that obese RA patients have higher tender joint count (TJC) and VAS general health. However, it remains unclear whether DAS components measuring local and systemic inflammation (swollen joint count (SJC), CRP) are increased and if this is present in the total RA population or confined to an ACPA subgroup. As ACPA is suggested to enhance inflammatory responses, we hypothesized that the association of obesity with SJC and CRP is present especially in ACPA-positive RA. We therefore studied associations of obesity with courses of DAS components in ACPA subgroups.MethodsWe studied 649 RA patients (291 ACPA-positive), included in the Leiden Early Arthritis Clinic. Five-year courses of DAS44 and DAS44 components (SJC-44, TJC-53, CRP, VAS (0-100)) were compared between RA patients with normal weight (BMI 18.5-24.9), overweight (25.0-29.9), and obesity (>= 30.0), stratified for ACPA. Linear/Poisson mixed models with a knot at 4 months were used.ResultsObese RA patients had + 0.32 higher DAS compared to normal weight during the 5-year follow-up. In ACPA-positive RA, obese patients had + 0.43 (95% CI: 0.22, 0.64) higher DAS, whereas in ACPA-negative RA, this difference was smaller and not statistically significant: + 0.19 (95% CI: - 0.01, 0.38). In ACPA-positive RA, all DAS components were significantly higher in obese patients compared to normal weight: SJC + 60% (IRR1.60; 95% CI: 1.18, 2.16), CRP + 3.7 mg/L (95% CI:0.95, 6.53), TJC + 55% (IRR1.55; 95% CI:1.15, 2.10), and VAS + 9 (95% CI: 4.0, 14.2). ACPA-negative obese RA patients tended to have higher TJC (IRR1.22; 95% CI: 0.96, 1.55) and VAS (beta 4.3; 95% CI: - 0.4, 9.0), while SJC (IRR1.07; 95% CI:0.85, 1.33) and CRP (beta 0.24; 95% CI: - 1.29, 3.32) were unaffected.ConclusionThe association of obesity with a worse DAS course is mainly present in ACPA-positive RA; especially SJC and CRP levels remain higher in ACPA-positive RA patients with obesity but not ACPA-negative RA patients. This is the first demonstration that obesity influences the disease course of ACPA-positive and ACPA-negative RA differently. Show less
Steenbergen, H.W. van; Cope, A.P.; Helm-van Mil, A.H.M. van der 2023
The concept of a ‘window of opportunity’ in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In... Show moreThe concept of a ‘window of opportunity’ in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the ‘arthralgia’ phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease. This Review summarizes the results of these trials and reflects on the outcomes in relation to the patients’ perspectives. Overall, the majority of symptomatic at-risk individuals could benefit from a fixed period treatment, even if RA does not develop. Various factors must be taken into consideration when translating these findings into clinical practice. More evidence is needed to target the individuals at highest risk, and additional tools are needed to monitor treatment and guide decisions about whether treatment can be discontinued. Without these tools, there is a paradoxical risk of seemingly increasing the incidence of the disease and prolonging disease duration, which is the opposite of what the concept of intervening in the window of opportunity entails. Show less
Objective. The natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis,... Show moreObjective. The natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves.Methods. We studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross-lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue).Results. In patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (P < 0.01). In anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4-12 months (P = 0.02 and P < 0.01).Conclusion. We identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis. Show less
ObjectiveThe natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis,... Show moreObjectiveThe natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves.MethodsWe studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross-lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue).ResultsIn patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (P < 0.01). In anti–citrullinated protein antibody (ACPA)-positive and ACPA-negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4–12 months (P = 0.02 and P < 0.01).ConclusionWe identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis. Show less
ObjectiveThe natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis,... Show moreObjectiveThe natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves.MethodsWe studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross-lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue).ResultsIn patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (P < 0.01). In anti–citrullinated protein antibody (ACPA)-positive and ACPA-negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4–12 months (P = 0.02 and P < 0.01).ConclusionWe identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis. Show less
Hollander, N.K. den; Helm-van Mil, A.H.M. van der; Steenbergen, H.W. van 2023
ObjectiveObesity conveys a risk for RA development, while paradoxically, associating with less radiographic progression after RA diagnosis. Using MRI we can study this surprising association in... Show moreObjectiveObesity conveys a risk for RA development, while paradoxically, associating with less radiographic progression after RA diagnosis. Using MRI we can study this surprising association in detail from MRI-detected synovitis and osteitis to MRI-detected erosive progression, which precedes radiographic progression. Previous research suggested obesity associates with less osteitis and synovitis. We therefore aimed to (i) validate the previously suggested association between BMI and MRI-detected osteitis/synovitis; (ii) study whether this is specific for ACPA-positive or ACPA-negative RA or also present in other arthritides; (iii) study whether MRI-detected osteitis associates with MRI-detected erosive progression; and (iv) study whether obesity associates with MRI-detected erosive progression.MethodsWe studied 1029 early arthritis patients (454 RA, 575 other arthritides), consecutively included in Leiden Early Arthritis Clinic. At baseline patients underwent hand-and-foot MRI that were RAMRIS-scored, and 149 RA patients underwent follow-up MRIs. We studied associations between baseline BMI and MRI-detected osteitis/synovitis (using linear regression), and erosive progression (using Poisson mixed models).ResultsIn RA, higher BMI associated with less osteitis at disease onset (β = 0.94; 95% CI: 0.93, 0.96) but not with synovitis. Higher BMI associated with less osteitis in ACPA-positive RA (β = 0.95; 95% CI: 0.93, 0.97), ACPA-negative RA (β = 0.97; 95% CI: 0.95, 0.99) and other arthritides (β = 0.98; 95% CI: 0.96, 0.99). Over 2 years, overweight and obesity associated with less MRI-detected erosive progression (P = 0.02 and 0.03, respectively). Osteitis also associated with erosive progression over 2 years (P < 0.001).ConclusionsHigh BMI relates to less osteitis at disease onset, which is not confined to RA. Within RA, high BMI and less osteitis associated with less MRI-detected erosive progression. This suggests that the protective effect of obesity on radiographic progression is exerted via a path of less osteitis and subsequently fewer MRI-detected erosions. Show less
Background Inflammation around the tendons of interosseous muscles of the hand (interosseous tendon inflammation) was recently observed with MRI for the first time in patients with rheumatoid... Show moreBackground Inflammation around the tendons of interosseous muscles of the hand (interosseous tendon inflammation) was recently observed with MRI for the first time in patients with rheumatoid arthritis and in at-risk individuals with detectable anti-citrullinated protein antibodies, generating the hypothesis that interosseous tendon inflammation precedes clinical arthritis. To better understand the role of interosseous tendon inflammation during the development of rheumatoid arthritis, we studied the frequency of interosseous tendon inflammation in healthy individuals and in those with arthralgia that was suspected of progressing to rheumatoid arthritis (ie, clinically suspect arthralgia) and the association of interosseous tendon inflammation with other symptoms of inflamed joint tissues and with clinical arthritis development.Methods Adult (age >= 18 years) patients who presented with clinically suspect arthralgia and symptom-free (control) individuals underwent contrast-enhanced hand MRI. MRIs were evaluated for interosseous tendon inflammation on the radial and ulnar sides of the second to fifth metacarpophalangeal joints, and for synovitis, tenosynovitis, and osteitis using the rheumatoid arthritis MRI scoring system. Patients with clinically suspect arthralgia were followed up for clinical arthritis development. The presence of local tenosynovium was examined using immunohistochemistry for anti-CD55 and anti-CD68 on tissue from the hands of three embalmed bodies donated for scientific research. The primary outcome for the cross-sectional part of the study was the presence of interosseous tendon inflammation on MRI. The primary outcome for the longitudinal part of the study was development of clinical arthritis.Findings Between April 3, 2012, and May 20, 2020, 667 patients with clinically suspect arthralgia (mean age 44 years [SD 13], 504 [76%] were women and 163 [24%] were men) underwent contrast-enhanced hand MRI. Between Nov 1, 2013, and Nov 30, 2014, 193 symptom-free controls were recruited (mean age 50 years [SD 16], 136 [70%] were women and 57 [30%] were men). Two (1%) of 193 symptom-free controls had interosseous tendon inflammation. Immunohistochemistry of cadaveric hand tissues showed no tenosynovium surrounding interosseous tendons. At inclusion, 67 (10%) of 667 patients with clinically suspect arthralgia had interosseous tendon inflammation (p<00001 vs symptom-free controls). Interosseous tendon inflammation occurred more frequently if synovitis (odds ratio [OR] 22 [95% CI 12-42]), or tenosynovitis (OR 97 [55-170]), was present at metacarpophalangeal joints. A three-dimensional MRI reconstruction suggested confluency of interosseous tendon inflammation with metacarpophalangeal-flexor-tenosynovitis. 91 (16%) of 558 patients with clinically suspect arthralgia developed clinical arthritis during follow-up (median total follow-up 253 months [95% CI 251-255]). Patients with clinically suspect arthralgia with interosseous tendon inflammation had a higher risk of developing clinical arthritis (hazard ratio [HR] 45 [28-72]), which was attenuated but still significant after adjusting for concomitant synovitis, tenosynovitis, or osteitis (HR 17 [102-28]).Interpretation Interosseous tendon inflammation is almost absent in symptom-free individuals but occurs in people with clinically suspect arthralgia, in whom it correlates with symptoms and is associated with the development of clinical arthritis. The absence of local tenosynovium suggests that interosseous tendon inflammation arises from expanding local subclinical inflammation in the pre-arthritis phase of rheumatoid arthritis. Show less
Verstappen, M.; Steenbergen, H.W. van; Jong, P.H.P. de; Helm-van Mil, A.H.M. van der 2022
Background: Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)... Show moreBackground: Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR.Methods: In 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized.Results: ACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30x/1.44x/2.12x/2.24x stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (>= 3 times ULN), and early DAS remission (DAS(4 months) < 1.6). This latter was replicated in independent ACPA-negative RA patients.Conclusions: ACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels >= 3x ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA. Show less
Brinck, R.M. ten; Boeters, D.M.; Steenbergen, H.W. van; Helm-van Mil, A.H.M. van der 2020
Introduction Arthralgia and MRI-detected subclinical inflammation can precede the development of clinically evident rheumatoid arthritis (RA). However, part of the patients presenting with... Show moreIntroduction 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. Show less
Dijk, B. van; Steenbergen, H.W. van; Niemantsverdriet, E.; Brouwer, E.; Helm-van Mil, A. van der 2020
Objectives Healthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly... Show moreObjectives Healthcare 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. Design Cross-sectional derivation and validation study. Setting Data 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. Participants Between 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 measures Physical 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. Results IA 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%. Conclusions Patient-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. Show less
Brinck, R.M. ten; Dijk, B.T. van; Steenbergen, H.W. van; Cessie, S. le; Numans, M.E.; Hider, S.L.; ... ; Helm-van Mil, A. van der 2018
Background: The presence of autoantibodies is considered an important characteristic of rheumatoid arthritis (RA); therefore, both anticitrullinated protein antibodies (ACPA) and rheumatoid factor ... Show moreBackground: 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. Show less
Boeters, D.M.; Trouw, L.A.; Helm-Van Mil, A.H.M. van der; Steenbergen, H.W. van 2018
