Automatic radiographic quantification of hand osteoarthritis; accuracy and sensitivity to change in joint space width in a phantom and cadaver study

This is the final version of the article. Available from Springer Verlag via the DOI in this record.OBJECTIVE: To validate a newly developed quantification method that automatically detects and quantifies the joint space width (JSW) in hand radiographs. Repeatability, accuracy and sensitivity to changes in JSW were determined. The influence of joint location and joint shape on the measurements was tested. METHODS: A mechanical micrometer set-up was developed to define and adjust the true JSW in an acrylic phantom joint and in human cadaver-derived phalangeal joints. Radiographic measurements of the JSW were compared to the true JSW. Repeatability, systematic error (accuracy) and sensitivity (defined as the smallest detectable difference (SDD)) were determined. The influence of joint position on the JSW measurement was assessed by varying the location of the acrylic phantom on the X-ray detector with respect to the X-ray beam and the influence of joint shape was determined by using morphologically different human cadaver joints. RESULTS: The mean systematic error was 0.052 mm in the phantom joint and 0.210 mm in the cadaver experiment. In the phantom experiments, the repeatability was high (SDD = 0.028 mm), but differed slightly between joint locations (p = 0.046), and a change in JSW of 0.037 mm could be detected. Dependent of the joint shape in the cadaver hand, a change in JSW between 0.018 and 0.047 mm could be detected. CONCLUSIONS: The automatic quantification method is sensitive to small changes in JSW. Considering the published data of JSW decline in the normal and osteoarthritic population, the first signs of OA progression with this method can be detected within 1 or 2 years.This work was funded by the Dutch Arthritis Association (Reumafonds). The study sponsor had no involvement in study design, data collection, data analysis, or interpretation of the results

DeepRA: Predicting Joint Damage From Radiographs Using CNN with Attention

Joint damage in Rheumatoid Arthritis (RA) is assessed by manually inspecting and grading radiographs of hands and feet. This is a tedious task which requires trained experts whose subjective assessment leads to low inter-rater agreement. An algorithm which can automatically predict the joint level damage in hands and feet can help optimize this process, which will eventually aid the doctors in better patient care and research. In this paper, we propose a two-staged approach which amalgamates object detection and convolution neural networks with attention which can efficiently and accurately predict the overall and joint level narrowing and erosion from patients radiographs. This approach has been evaluated on hands and feet radiographs of patients suffering from RA and has achieved a weighted root mean squared error (RMSE) of 1.358 and 1.404 in predicting joint level narrowing and erosion Sharp van der Heijde (SvH) scores which is 31% and 19% improvement with respect to the baseline SvH scores, respectively. The proposed approach achieved a weighted absolute error of 1.456 in predicting the overall damage in hands and feet radiographs for the patients which is a 79% improvement as compared to the baseline. Our method also provides an inherent capability to provide explanations for model predictions using attention weights, which is essential given the black box nature of deep learning models. The proposed approach was developed during the RA2 Dream Challenge hosted by Dream Challenges and secured 4th and 8th position in predicting overall and joint level narrowing and erosion SvH scores from radiographs

Knee complaints and prognosis of osteoarthritis at 10 years : impact of ACL ruptures, meniscal tears, genetic predisposition and surgery

In this thesis we demonstrated that several known risk factors for knee OA development i.e. ACL ruptures, meniscal tears, the presence of hand OA and increased BMI, are already associated with knee OA development as demonstrated on radiographs and MR images early in life. Identifying these factors in young to middle aged patients suffering from knee complaints helps to define high risk patients who may benefit from early preventive exercise therapy or maybe disease modifying drugs which might be developed in the future. Meniscectomy and ACL reconstruction have no effect on knee OA development after 10 years in patients with sub-acute knee complaints. The in this thesis validated automatic JSW quantification method is sensitive to small changes in JSW of the finger joints. The first signs of hand OA development with this method can be detected within one or two years. In patients with traumatic meniscal tears but without knee locking symptoms, there may be some benefits from treatment with meniscectomy in long-term Sports and Recreation knee function outcomes compared to conservative treatment. Future randomized controlled trials may elucidate the effect of surgical treatment of traumatic meniscal tears.ReumafondsUBL - phd migration 201

Ultrasound and fluorescence optical imaging biomarkers for early diagnosis and prediction of rheumatoid arthritis

Prevention of rheumatoid arthritis (RA) is most desirable together with curative treatment which is, however, not yet available. Today, the correct timely diagnosis and early treatment interventions to prevent disease progression remain the best options for our patients. In this thesis, I explore the diagnostic and predictive value of musculoskeletal ultrasound (MSUS) and fluorescence optical imaging (FOI) in identifying biological features on images indicative of existing or emerging joint inflammation (synovitis). In study 1, we tested and compared the diagnostic utility of FOI with clinical examination and musculoskeletal ultrasound (MSUS) to detect active synovitis in 872 joints of 26 patients with different rheumatic diseases (46% early RA). Fluorescence optical imaging proved to be 80% sensitive and 96% specific, having a 77% positive predictive value (PPV) and 97% negative predictive value (NPV) for detecting silent synovitis. In study 2 we showed FOI’s ability to quantify digital disease activity (DACT) scores of 1326 joints in 39 early RA patients to be 81% sensitive and 90% specific, with 96% PPV and 61% NPV. These results justify FOI use in clinical practice, to assist the rheumatologist to make an earlier diagnosis with greater confidence. Unsupervised cluster differences emerged for seropositive and seronegative RA patients showing FOI’s ability to objectively quantify hand joint inflammation using novel DACT scoring methods. In study 3 we report good association among the two ultrasound semi-quantitative scoring (SQS) methods to that of a novel quantitative scoring (QS) measure of color Doppler pixel counts in 37 established RA patients. Although SQS well correlated with QS to assess active synovitis, the SQS methods lacked visual perceptions of raters to distinguish between grade cut-offs which may help to further revise the criteria used to objectively quantify disease activity. In study 4, we show the value of ultrasound and immune-inflammatory biomarkers in predicting arthritis onset in individuals positive for Anti-CCP with musculoskeletal complaints at risk of RA development. We propose the recognition of a high-risk RA phase characterized by presence of certain ACPA reactivities, IL15-Rα, IL6; and ultrasound detected tenosynovitis, and possibilities to identify (low and high) risk groups for arthritis progression. Overall, our findings on imaging contribute towards a) silent synovitis detection despite negative clinical investigation, b) objective quantitative measures to monitor the effects of RA therapy and c) early identification of certain predictive imaging and biological features/biomarkers that precede arthritis development (tenosynovitis and/or bursitis) in individuals at risk for developing RA, enabling closer monitoring and early diagnosis

The assessment of the rheumatoid hand : "the assessment of the function of the hand undergoing corrective surgery for rheumatoid disease using specially designed biomechanical instruments and the Colour Television Image Analyser"

Present methods of assessing the function of the hand are reviewed and found to be inadequate. Two new concepts are introduced; the concept of assessing the function of the hand at the digital level, and the concept that hand function and bone density are closely related in both the hypodynamic state of disuse and the hyperdynamic state of improved function following corrective surgery.To investigate hands in this manner, the design and use of two biomechanical instruments, the 'Cybernometer' and the 'Torquemeter', invented by the author, are described. The use of Colour Television Image Analysis as a new method of measuring bone density, developed by the author, is also described.With this equipment a biomechanical study has been performed on normal hands and a positive relationship has been shown between function and bone density in both normal and rheumatoid hands.A statistical analysis has been performed on 51 rheumatoid patients before and after a variety of types of corrective hand surgery in terms of function and bone density. Not only is disuse osteoporosis accompanied by a reduction in hand function but also by surgically improving function osteoporosis in the rheumatoid hand is reversed

Hand osteoarthritis : natural course and determinants of outcome

We investigated the clinical and radiographic disease course of hand osteoarthritis as well as determinants of poor clinical outcome and radiographic progression over a period of six years in 289 patients with hand osteoarthritis. Because these patients had osteoarthritis at multiple joints this enabled us to not only assess the association between progression of osteoarhtiritis in different hand joints groups but also between progression of hand osteoarthritis and osteoarthritis change at the knee. In addition, genetic factors in hand osteoarthritis progression were investigated as well as the influence of illness perceptions. The hand osteoarthritis subsets erosive osteoarthritis and thumb base osteoarthritis are further characterised. In the last part of the thesis the clinimetric properties of a pain score for osteoarthritis and radiographic outcome measures for hand osteoarthritis are evaluated.Reumafonds, stichting Atrosezorg, Pfizer, Abbott B.V., UCB Pharma B.V.UBL - phd migration 201

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Objective: To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis. Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26. Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis

Osteoporosis in rheumatoid arthritis

The literature is replete with reports of osteoporosis in rheumatoid arthritis, but the mechanism of bone loss remains obscure. This is probably due to the overlap with bone loss of aging and the menopause, whose exact mechanisms are also poorly understood. Against this background, a study was designed to evaluate generalised bone loss in young, premenopausal (if female), patients with rheumatoid arthritis. The protocol was designed to record demographic data, as well as information pertaining to the disease. Cortical bone mass was measured at the metacarpals and left femur, using an automated, computer-controlled technique. Trabecular bone was evaluated at the left femur (Singh index) as well as at the 3rd lumbar vertebra (Saville index). Bone kinetics were studied by the measurement of urinary excretion of calcium, phosphate and hydroxy-praline (resorption) and serum alkaline phosphatase (formation). Disease activity was measured clinically and with laboratory indices. Physical activity was indirectly measured by quantitating the disability, using the Keitel function test as well as a modified health assessment questionnaire (HAQ). The radiograph of the right wrist was scored by the Larsen index. The carpometacarpal ratio was also calculated from the radiograph. Numerous statistical techniques were applied in the analysis of the data. Healthy volunteers were used as controls. Patients with SLE were also studied, in order to compare the 2 inflammatory diseases. Patients with RA had generalised cortical bone loss (metacarpal and femur) (p < 0.001). Trabecular bone measurements were not significantly different from normals, using the crude radiographic techniques. Duration of disease was the most important clinical determinant of this bone loss. The relative contributions of disease activity and lack of physical activity to the loss of bone could not be adequately separated using conventional statistical techniques. Corticosteroid therapy did not promote metacarpal bone loss in these subjects, but may have contributed to thinning of the femoral cortex. Nonsteroidal anti-inflammatory drugs and disease modifying agents did not seem to influence the extent of the bone loss. Nutritional status and skinfold thickness did not correlate with bone mass. Dietary factors played no role in the genesis of bone loss, but may have had some effect on disease activity. Metacarpal measurements showed a sensitivity of 80% and specificity of 85% in discriminating between osteopaenic and normopaenic groups with RA. Osteopaenia could not be adequately predicted in the absence of metacarpal measurements. Metacarpal bone loss in RA was due to endosteal resorption, while in SLE it was due to periosteal resorption. The semi-automatic technique for measurement of metacarpal bone mass showed good reproducibility among 5 observers and at 2 different centres. The pathogenesis of bone loss in RA was multifactorial, the largest contribution probably coming from a humoral factor in the circulation, closely related to disease activity. Ionised calcium was elevated in 55% of RA patients, but only 5% of SLE patients. Serum PTH levels were normal in 99% of the RA subjects. Elevations in alkaline phosphatase. (25%) probably reflected disease activity rather than increased bone formation. Factor analysis of 27 variables showed that disease activity was central to the development of OP in RA. CS therapy tended to be used in the presence of active disease. Disability was not an important determinant of bone loss in RA, but may be a useful measure of activity of the disease. This study did not evaluate the relationships with sex hormonal status or vitamin D metabolism. Future research should aim at cohort analysis at 2 different periods, in order to improve our understanding of the pathogenesis of bone loss in RA