Predicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although... Show morePredicting the development of rheumatoid arthritis (RA) in an early stage through magnetic resonance imaging (MRI) can initiate timely treatment and improve long-term patient outcomes. Although manual prediction is time-consuming and requires expert knowledge, automatic RA prediction has not been fully investigated. While standard models fail to achieve acceptable performance, we present a consistency-based deep learning framework to classify and predict RA automatically and precisely, including an output-standardized model, customized self-supervised pretraining and a loss function that is based on label consistency between original and augmented inputs. For training and evaluation, we used a database, containing 5945 MRI scans of carpal, metacarpophalangeal (MCP), and metatarsophalangeal (MTP) joints, from 2151 subjects obtained over a period of ten years. Four (three classification- and one prediction-) tasks were defined to distinguish two patient groups (with recent-onset arthritis and clinically suspect arthralgia) from healthy controls and RA from other arthritis patients within the recent-onset arthritis group, and predict RA development in a period of two years within the clinically suspect arthralgia group. The proposed method was evaluated with the area under the receiver operating curve (AUROC) on a separate test set, achieving mean AUROCs of 83.6%, 83.3%, and 69.7% in the three classification tasks, and 67.8% in the prediction task. This proves the existence of early signs of RA in MRI and the potential of a consistency-based deep learning model to detect these early signs and predict RA Show less
Stoel, B.C.; Staring, M.; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2024
Artificial intelligence techniques, specifically deep learning, have already affected daily life in a wide range of areas. Likewise, initial applications have been explored in rheumatology. Deep... Show moreArtificial intelligence techniques, specifically deep learning, have already affected daily life in a wide range of areas. Likewise, initial applications have been explored in rheumatology. Deep learning might not easily surpass the accuracy of classic techniques when performing classification or regression on low-dimensional numerical data. With images as input, however, deep learning has become so successful that it has already outperformed the majority of conventional image-processing techniques developed during the past 50 years. As with any new imaging technology, rheumatologists and radiologists need to consider adapting their arsenal of diagnostic, prognostic and monitoring tools, and even their clinical role and collaborations. This adaptation requires a basic understanding of the technical background of deep learning, to efficiently utilize its benefits but also to recognize its drawbacks and pitfalls, as blindly relying on deep learning might be at odds with its capabilities. To facilitate such an understanding, it is necessary to provide an overview of deep-learning techniques for automatic image analysis in detecting, quantifying, predicting and monitoring rheumatic diseases, and of currently published deep-learning applications in radiological imaging for rheumatology, with critical assessment of possible limitations, errors and confounders, and conceivable consequences for rheumatologists and radiologists in clinical practice.Deep learning is a powerful technique with great potential for the analysis and interpretation of rheumatological images. To successfully use deep learning, rheumatologists should understand the tasks involved in image processing and the potential confounders and limitations that can affect the analysis of clinical data.The number of research studies on deep learning in rheumatological imaging has grown rapidly during the past 5 years, but they mainly consist of pilot studies that require external validation.Confounding factors and errors in deep-learning methods need to be ruled out before deep learning can be applied in clinical practice, for which the intended use should be strictly defined.Deep-learning techniques, together with mapping to explain their reasoning, will enable hypothesis-free image analysis and could identify new imaging biomarkers.Deep learning might assist rheumatologists and radiologists in interpreting rheumatological images, increasing their diagnostic, prognostic and monitoring accuracy, and decreasing workloads and costs. Show less
Hassanzadeh, T.; Shamonin, D.P.; Li, Y.L.; Krijbolder, D.I.; Reijnierse, M.; Helm-van Mil, A.H.M.V. van der; Stoel, B.C. 2024
Rheumatoid Arthritis (RA) is an autoimmune disease that mainly affects joints in the wrist and hands. It typically results in inflamed and painful joints. MRI is one of the most common imaging...Show moreRheumatoid Arthritis (RA) is an autoimmune disease that mainly affects joints in the wrist and hands. It typically results in inflamed and painful joints. MRI is one of the most common imaging modalities to detect and monitor possible inflamed RA-related areas, enabling rheumatologists to treat patients more timely and efficiently. Despite the importance of finding and tracking inflamed areas associated with RA in MRI, there is no previously published work on finding pixel-by-pixel changes related to RA between baseline and follow-up MRIs. Therefore, this paper proposes a hypothesis-free deep learning-based model to discover changes in wrist MRIs on a pixel level to detect changes in inflamed areas related to RA without using prior anatomical information. To do this, a combination of a U-Net-based network and image thresholding was utilised to find pixel-level non-trivial changes between baseline and follow-up MRI images. A wrist MRI dataset including 99 individual pairs of MRI images (each pair constructed of baseline and follow-up images) was used to evaluate the proposed model. Data were collected from patients with clinically suspected arthralgia (CSA), defined as patients at risk of developing RA according to their rheumatologist and already had subclinical inflammation on MRI but could not be diagnosed with RA (yet) since they had not developed clinically detectable arthritis. The obtained results were evaluated using an observer study. The evaluation showed that our proposed model is a promising first step toward developing an automatic model to find RA-related inflammatory changes. Show less
Marques, M.L.; Silva, N.P. da; Heijde, D. van der; Reijnierse, M.; Baraliakos, X.; Braun, J.; ... ; Ramiro, S. 2022
Objectives: To describe low dose Computed Tomography (ldCT) Hounsfield Units (HU) two-year change-from -baseline values (expressing trabecular bone density changes) and analyse their inter-reader... Show moreObjectives: To describe low dose Computed Tomography (ldCT) Hounsfield Units (HU) two-year change-from -baseline values (expressing trabecular bone density changes) and analyse their inter-reader reliability per vertebra in radiographic axial spondyloarthritis (r-axSpA). Methods: We used 49 patients with r-axSpA from the multicentre two-year Sensitive Imaging in Ankylosing Spondylitis (SIAS) study. LdCT HU were independently measured by two trained readers at baseline and two years. Mean (standard deviation, SD) for the change-from-baseline HU values were provided per vertebra by reader. Intraclass correlation coefficients (ICC; absolute agreement, two-way random effect), Bland-Altman plots and smallest detectable change (SDC) were obtained. Percentages of vertebrae in which readers agreed on the direction of change and on change >|SDC| were computed. Results: Overall, 1,053 (98% of all possible) vertebrae were assessed by each reader both at baseline and two years. Over two years, HU mean change values varied from-23 to 28 and 29 for reader 1 and 2, respectively. Inter-reader reliability of the two-year change-from-baseline values per vertebra was excellent: ICC:0.91-0.99; SDC:6-10; Bland-Altman plots were homoscedastic, with negligible systematic error between readers. Readers agreed on the direction of change in 88-96% and on change >|SDC| in 58-94% of vertebrae, per vertebral level, from C3 to L5. Overall, similar results were obtained across all vertebrae. Conclusion: LdCT measurement of HU is a reliable method to assess two-year changes in trabecular bone density at each vertebra from C3-L5. Being reliable across all vertebrae, this methodology can aid the study of trabecular bone density changes over time in r-axSpA, a disease affecting the whole spine. Show less
Boeren, A.M.P.; Niemantsverdriet, E.; Verstappen, M.; Wouters, F.; Bloem, J.L.; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objective MRI of small joints plays an important role in the early detection and early treatment of rheumatoid arthritis. Despite its sensitivity to demonstrate inflammation, clinical use is... Show moreObjective MRI of small joints plays an important role in the early detection and early treatment of rheumatoid arthritis. Despite its sensitivity to demonstrate inflammation, clinical use is hampered by accessibility, long scan time, intravenous contrast, and consequent high costs. To improve the feasibility of MRI implementation in clinical practice, we introduce a modified Dixon sequence, which does not require contrast and reduces total acquisition time to 6 min. Because the reliability in relation to conventional MRI sequences is unknown, we determined this. Methods In 29 consecutive early arthritis patients, coronal and axial T2-weighted modified Dixon acquisitions on 3.0 T MRI scanner were acquired from metacarpophalangeal 2-5 to the wrist, followed by the standard contrast-enhanced protocol on 1.5 T extremity MRI. Two readers scored osteitis, synovitis and tenosynovitis (summed as total MRI-inflammation), and erosions (all summed as total Rheumatoid Arthritis MRI Score (RAMRIS)). Intraclass correlation coefficients (ICCs) between readers, and comparing the two sequences, were studied. Spearman correlations were determined. Results Performance between readers was good/excellent. Comparing modified Dixon and conventional sequences revealed good/excellent reliability: ICC for total MRI-inflammation score was 0.84 (95% CI:0.70-0.92), for erosions 0.90 (95% CI:0.79-0.96), and for the total RAMRIS score 0.88 (95% CI:0.77-0.94). The scores of total MRI-inflammation, total erosions, and total RAMRIS were highly correlated (rho = 0.80, rho = 0.81, rho = 0.82, respectively). Conclusion The modified Dixon protocol is reliable compared to the conventional MRI protocol, suggesting it is accurate to detect MRI inflammation. The good correlation may be the first step towards a patient-friendly, short and affordable MRI protocol, which can facilitate the implementation of MRI for early detection of inflammation in rheumatology practice. Show less
Dijk, B.T. van; Dakkak, Y.J.; Matthijssen, X.M.E.; Niemantsverdriet, E.; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objective: Intermetatarsal bursae in the forefeet possess a synovial lining similar to joints and tendon sheaths. Inflammation of these bursae (intermetatarsal bursitis [IMB]) was recently... Show moreObjective: Intermetatarsal bursae in the forefeet possess a synovial lining similar to joints and tendon sheaths. Inflammation of these bursae (intermetatarsal bursitis [IMB]) was recently identified as specific for early rheumatoid arthritis (RA). The present study was undertaken to determine if IMB is indeed an RA feature by assessing the following: 1) the association with other local inflammatory measures (synovitis, tenosynovitis, and osteitis), 2) the association with clinical signs, and 3) whether it responds to disease-modifying antirheumatic drug (DMARD) therapy similarly to other local inflammatory measures. Methods: One hundred fifty-seven consecutive early RA patients underwent unilateral contrast-enhanced 1.5T forefoot magnetic resonance imaging (MRI) at diagnosis. MRIs were evaluated for IMB presence and for synovitis, tenosynovitis, and osteitis in line with the RA MRI Scoring (RAMRIS) system (summed as RAMRIS inflammation). MRIs at 4, 12, and 24 months were evaluated for IMB presence and size in patients who had IMB at baseline and received early DMARD therapy. Logistic regression and generalized estimating equations were used. Anti-citrullinated protein antibody (ACPA) stratification was performed. Results: Sixty-nine percent of RA patients had >= 1 IMB. In multivariable analysis on bursa level, presence of IMB was independently associated with local presence of synovitis and tenosynovitis, with odds ratios (OR) of 1.69 (95% confidence interval [95% CI] 1.12, 2.57) and 2.83 (95% CI 1.80, 4.44), respectively, but not osteitis. On the patient level, IMB presence was most strongly associated with tenosynovitis (OR 2.92 [95% CI 1.62, 5.24]). IMB presence was associated with local joint swelling (OR 2.7 [95% CI 1.3, 5.3]) and tenderness (OR 1.7 [95% CI 1.04, 2.9]) independent of RAMRIS inflammation. During treatment, IMB size decreased between 0 and 12 months. This decrease associated with decrease in RAMRIS inflammation, which was driven by synovitis decrease. Within ACPA-positive and ACPA-negative RA, similar results were obtained. Conclusion: IMB particularly accompanies inflammation of the synovial lining of joints and tendon sheaths, showed a similar treatment response after DMARD initiation, and associates with typical clinical signs. These findings suggest that IMB represents a frequently present novel RA feature of juxtaarticular synovial inflammation. Show less
Stal, R.; Baraliakos, X.; Heijde, D. van der; Gaalen, F. van; Ramiro, S.; Berg, R. van den; ... ; Sepriano, A. 2022
Objectives To investigate the associations between MRI detected vertebral corner inflammation (VCI) and vertebral corner fat deposition (VCFD) on whole spine low-dose CT scan (ldCT) detected... Show moreObjectives To investigate the associations between MRI detected vertebral corner inflammation (VCI) and vertebral corner fat deposition (VCFD) on whole spine low-dose CT scan (ldCT) detected syndesmophyte formation and growth. Methods Patients from the Sensitive Imaging in Ankylosing Spondylitis cohort underwent MRI (baseline, 1 year and 2 years) and ldCT (baseline and 2 years). MR images were scored by three readers for VCI and VCFD, MRI patterns were defined by presence of VCI and/or VCFD over 2 years. LdCT images were scored by two central readers for presence and size of syndesmophytes and change was calculated for new or new/grown syndesmophytes. Multilevel generalised estimated equations were used to test the associations between VCI and VCFD and syndesmophyte development. Results Fifty radiographic patients with axial spondyloarthritis were included (mean age 49 years, 86% male, 78% HLA-B27+). Absence of both VCI and VCFD protected against syndesmophyte development (ORs 0.36-0.37). Presence of VCI and/or VCFD increased the risk of syndesmophyte development (ORs 1.73-2.60). Out of all corners with a new or new/grown syndesmophyte, 47% of corners according to reader 1 and 44% according to reader 2 had neither VCI nor VCFD preceding the bone formation. Conclusions VCI and VCFD were positively associated with syndesmophyte development. This has been shown for the first time for syndesmophytes detected on ldCT and also in the thoracic spine. However, almost half of all bone formation occurred in corners without VCI or VCFD, suggesting the presence of these lesions in yearly MRIs does not fully clarify the development of syndesmophytes. Show less
Dakkak, Y.J.; Dijk, B.T. van; Jansen, F.P.; Wisse, L.J.; Reijnierse, M.; Helm-van Mil, A.H.M. van der; DeRuiter, M.C. 2022
MRI-detected inflammation around the extensor tendons of metacarpophalangeal (MCP-) joints is prevalent in RA and poses a markedly increased risk of RA development when present in arthralgia... Show moreMRI-detected inflammation around the extensor tendons of metacarpophalangeal (MCP-) joints is prevalent in RA and poses a markedly increased risk of RA development when present in arthralgia patients. Such inflammation is called 'peritendinitis' since anatomy literature reports no presence of a tenosynovial sheath at these tendons. However, the presence or absence of tenosynovium at these extensor tendons has never been studied. Therefore, an anatomical and histological study of extensor tendons at the MCP-joints of three embalmed human hands was performed. Immunohistochemical staining showed the presence of markers for synovial macrophages and fibroblast-like synoviocytes bordering a natural dorsal space next to the extensor tendon, suggesting the presence of a synovial lining. This implies that contrast-enhancement on MRI around extensor tendons at MCP-joints observed in early RA and pre-RA likely represents tenosynovitis and that inflammation of this synovial tissue is an early feature of RA. Show less
Meulen, C. van der; Stadt, L.A. van de; Kroon, F.P.B.; Kortekaas, M.C.; Boonen, A.E.R.C.H.; Bohringer, S.; ... ; Kloppenburg, M. 2022
Background: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life ... Show moreBackground: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. Methods: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). Results: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI -10.4 to -2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. Conclusions: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. Significance: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone. Show less
Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints, which lead to joint destruction and soft tissue masses. Clinical presentation is variable... Show moreCrystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints, which lead to joint destruction and soft tissue masses. Clinical presentation is variable and diagnosis might be challenging. Therefore, first-line imaging of ultrasound in accessible joints is recommended to assess crystal arthropathies; however, DECT is a useful adjunct to differentiate gout from CPPD. Show less
Marques, M.L.; Silva, N.P. da; Heijde, D. van der; Reijnierse, M.; Baraliakos, X.; Braun, J.; ... ; Ramiro, S. 2022
Objective: Studying vertebral bone loss in radiographic axial spondyloarthritis (r-axSpA) has been challenging due to ectopic bone formation. We cross-sectionally analysed low-dose CT (ldCT)... Show moreObjective: Studying vertebral bone loss in radiographic axial spondyloarthritis (r-axSpA) has been challenging due to ectopic bone formation. We cross-sectionally analysed low-dose CT (ldCT) trabecular bone density Hounsfield units (HU) measurements and calculated inter-reader reliability at the vertebral level in patients with r-axSpA. Methods: LdCT scans of 50 patients with r-axSpA from the sensitive imaging in ankylosing spondylitis study, a multicentre 2-year prospective cohort were included. Trabecular bone HU taken from a region of interest at the centre of each vertebra (C3-L5) were independently assessed by two trained readers. HU mean (SD), and range were provided at the vertebral level, for each reader and centre separately. Inter-reader reliability and agreement were assessed using intraclass correlation coefficients (ICC; single measurements, absolute agreement, two-way mixed effects models); smallest detectable difference and Bland-Altman plots. Results: Overall, 1100 vertebrae were assessed by each reader. HU values decreased from cranial to caudal vertebrae. For readers 1 and 2 respectively, the highest mean (SD) HU value was obtained at C3 (354(106) and 355(108)), and the lowest at L3 (153(65) and 150 (65)). Inter-reader reliability was excellent (ICC(2,1):0.89 to 1.00). SDD varied from 4 to 8. For most vertebrae, reader 1 scored somewhat higher than reader 2 (mean difference of scores ranging from -0.6 to 2.9 HU). Bland-Altman plots showed homoscedasticity. Conclusion: LdCT measurement of HU is a feasible method to assess vertebral bone density in r-axSpA with excellent inter-reader reliability from C3 to L5. These results warrant further validation and longitudinal assessment of reliability. Show less
Stal, R.; Sepriano, A.; Gaalen, F.A. van; Baraliakos, X.; Berg, R. van den; Reijnierse, M.; ... ; Heijde, D. van der 2022
Objectives In radiographic axial spondyloarthritis (r-axSpA), spinal damage manifests as syndesmophytes and facet joint ankylosis (FJA). We evaluated whether the presence of one lesion increased... Show moreObjectives In radiographic axial spondyloarthritis (r-axSpA), spinal damage manifests as syndesmophytes and facet joint ankylosis (FJA). We evaluated whether the presence of one lesion increased the risk of the other lesion. Methods Patients with r-axSpA underwent low-dose CT (ldCT) and MRI of the whole spine at baseline and 2 years. On ldCT, vertebrae were scored for presence and size of syndesmophytes; facet joints were assessed for ankylosis. MR images were assessed for inflammation. Two hypotheses were tested: (i) presence of FJA is associated with new syndesmophyte(s) on the same vertebral unit (VU) 2 years later, and (ii) presence of bridging syndesmophyte(s) is associated with new FJA on the same VU 2 years later. Two generalized estimating equations models were tested per hypothesis using increase of FJA/syndesmophytes (model A) or presence of FJA/syndesmophytes (model B) as outcome, adjusted for inflammation at baseline. Secondary analyses tested the hypotheses with outcomes on adjacent VUs and dose-response effects. Results Fifty-one patients were included (mean age 49, 84% male, 82% HLA-B27(+)). Baseline bridging syndesmophytes occurred more often (range: 10-60% per VU) than FJA (range: 8-36%). Odds ratios (ORs) (95% CI) for presence of bridging syndesmophytes on development of FJA were 3.55 (2.03, 6.21) for model A and 3.30 (2.14, 5.09) for model B. ORs for presence of baseline FJA on new syndesmophytes were 1.87 (1.20, 2.92) for model A and 1.69 (0.88, 3.22) for model B. Secondary analyses yielded positive ORs for both hypotheses. Conclusions Bone formation in vertebrae and in facet joints influence each other's occurrence, with the effect of syndesmophytes being larger than that of FJA. Show less
Background: Dual-energy computed tomography (DECT) allows direct visualization of monosodium urate (MSU) deposits in joints and soft tissues. Purpose: To describe the distribution of MSU deposits... Show moreBackground: Dual-energy computed tomography (DECT) allows direct visualization of monosodium urate (MSU) deposits in joints and soft tissues. Purpose: To describe the distribution of MSU deposits in cadavers using DECT in the head, body trunk, and feet. Materials and Methods: A total of 49 cadavers (41 embalmed and 8 fresh cadavers; 20 male, 29 female; mean age, 79.5 years; SD +/- 11.3; range 52-95) of unknown clinical history underwent DECT to assess MSU deposits in the head, body trunk, and feet. Lens, thoracic aorta, and foot tendon dissections of fresh cadavers were used to verify MSU deposits by polarizing light microscopy. Results: 33/41 embalmed cadavers (80.5%) showed MSU deposits within the thoracic aorta. 11/41 cadavers (26.8%) showed MSU deposits within the metatarsophalangeal (MTP) joints and 46.3% of cadavers demonstrated MSU deposits within foot tendons, larger than and equal to 5 mm. No MSU deposits were detected in the cranium/intracerebral vessels, or the coronary arteries. Microscopy used as a gold standard could verify the presence of MSU deposits within the lens, thoracic aorta, or foot tendons in eight fresh cadavers. Conclusions: Microscopy confirmed the presence of MSU deposits in fresh cadavers within the lens, thoracic aorta, and foot tendons, whereas no MSU deposits could be detected in cranium/intracerebral vessels or coronary arteries. DECT may offer great potential as a screening tool to detect MSU deposits and measure the total uric acid burden in the body. The clinical impact of this cadaver study in terms of assessment of MSU burden should be further proven. 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
Sepriano, A.; Ramiro, S.; Heijde, D. van der; Dougados, M.; Claudepierre, P.; Feydy, A.; ... ; Landewe, R. 2022
Objective To compare the sensitivity to change of different imaging scoring methods in patients with early axial spondyloarthritis (SpA). Methods Patients from the Devenir des Spondylarthropathies... Show moreObjective To compare the sensitivity to change of different imaging scoring methods in patients with early axial spondyloarthritis (SpA). Methods Patients from the Devenir des Spondylarthropathies Indiffererenciees Recentes (DESIR) cohort fulfilling the Assessment of SpondyloArthritis international Society criteria for axial SpA were included. Radiographs and magnetic resonance imaging (MRI) of the sacroiliac (SI) joints and spine were obtained at baseline, 1, 2, and 5 years. Each image was scored by 2 or 3 readers in 3 separate reading waves. The rate of change of outcomes measuring inflammation of the spine and SI joints (e.g., Spondyloarthritis Research Consortium of Canada [SPARCC] score) and structural damage on MRI (e.g., >= 3 fatty lesions) and radiographs (e.g., modified New York grading) was assessed using multilevel generalized estimating equation models (taking all readers and waves into account). To allow comparisons across outcomes, rates were standardized (difference between the individual's value and the population mean divided by the SD). Results In total, 345 patients were included. Inflammation detected on MRI of the SI joints (MRI-SI joints) (standardized rate range -0.278, -0.441) was more sensitive to change compared to spinal inflammation (range -0.030, -0.055). Structural damage in the SI joints showed a higher standardized rate of change on MRI-SI joints (range 0.015, 0.274) compared to radiography of the SI joints (range 0.043, 0.126). MRI-SI joints damage defined by >= 3 fatty lesions showed the highest sensitivity to change (0.274). Spinal structural damage slowly progressed over time with no meaningful difference between radiographic (range 0.037, 0.043) and MRI structural outcomes (range 0.008, 0.027). Conclusion Structural damage assessed in pelvic radiographs has low sensitivity to change, while fatty lesions detected on MRI-SI joints are a promising alternative. In contrast, MRI of the spine is not better than radiography of the spine in detecting structural changes in patients with early axial SpA. Show less
Dakkak, Y.J.; Wouters, F.; Matthijssen, X.M.E.; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objective The relationship between functional disability and magnetic resonance imaging (MRI) inflammation has been studied for the hands, but has not been well established for the feet, even... Show moreObjective The relationship between functional disability and magnetic resonance imaging (MRI) inflammation has been studied for the hands, but has not been well established for the feet, even though walking difficulties are common. Therefore, our objective was to study whether walking difficulties were associated with MRI inflammation at metatarsophalangeal (MTP) joints in early arthritis patients, at diagnosis and during 24 months of follow-up. Methods A total of 532 consecutive patients presenting with early arthritis reported on the presence and severity of walking difficulties (Health Assessment Questionnaire question 4a, scale 0-3), and underwent unilateral contrast-enhanced MRI of MTP joints 1-5 at baseline. In total, 107 patients had clinical and MRI data at follow-up (4, 12, and 24 months). MRI inflammation (synovitis, tenosynovitis, and osteitis) was scored in line with the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system. At baseline, the association of walking disability with MRI inflammation was assessed using regression. Longitudinally, the association between a change in walking disability with a change in MRI inflammation was studied with linear mixed models. Results At baseline, 81% of patients with walking disabilities had MRI inflammation at MTP joints, versus 68% without walking disabilities (P < 0.001). Total MRI inflammation (i.e., the sum of tenosynovitis, synovitis, and osteitis) was associated with severity of walking disability (beta = 0.023, P < 0.001). Studying the MRI features separately, tenosynovitis, synovitis, and osteitis were all univariably associated with severity of walking disability (P < 0.001, P < 0.001, and P = 0.014, respectively). In multivariable analysis, the association was strongest for tenosynovitis. During follow-up, a decrease in MTP inflammation was associated with a decrease in walking disability (beta = 0.029, P = 0.001); in multivariable analyses only, tenosynovitis was independently associated (beta = 0.073, P = 0.049). Conclusion Of the different inflamed tissues in MTP joints, predominantly MRI-detected tenosynovitis was associated with walking disabilities. Likewise a reduction in tenosynovitis related to a decrease in walking disabilities. These results increase our understanding of the involvement of tenosynovitis in walking disabilities in early arthritis. Show less
Objective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)... Show moreObjective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-beta, under the transcriptional control of nuclear factor kappa-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.Methods: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 x 10(12)-1.2 x 10(13) genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-beta immune responses were evaluated. A data review committee provided safety recommendations.Results: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-beta, nor IFN-beta antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.Conclusion: Single IA doses of 0.6 x 10(12) or 1.2 x 10(12) ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. (C) 2021 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
ObjectiveInflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β,... Show moreObjectiveInflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.MethodsIn this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations.ResultsFour patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.ConclusionSingle IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. 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
