The epidemiology of muskuloskeletal disease Molecules, structures, patients and society
Musculoskeletal diseases are a rapidly growing cause of disability, chronic pain, and reduced quality of life in our ageing populations worldwide. Our aims are to gain novel insights into these diseases - their etiology, occurrence, natural history, treatments, prediction, disease monitoring, and disease burden - to allow for better healthcare decision-making and disease prevention.
To accomplish these goals, we use a multidisciplinary approach. For research on osteoarthritis, a chronic degenerative joint disease, we use human tissue biobanking, proteomics, and MR imaging to characterize the molecular and structural aspects of tissue degradation associated with the earliest stages of the disease. We are especially interested in the role of the meniscus in early knee osteoarthritis. Further, in population-based epidemiologic and health economic studies of musculoskeletal disease, we use physician-coded healthcare data from Sweden to understand the impact of these diseases on patients and society. Our previous work has contributed to improved understanding of musculoskeletal disease and impactful changes in their clinical management. To learn more, read about our projects.
In clinical trials and observational data for osteoarthritis, contextual factors are important to consider in relation to pain outcomes. Reported improvement after an intervention is usually acknowledged to be due, in part, to the placebo effect. However, investigators often overlook improvement that might be explained by regression to the mean. Regression to the mean is a statistical phenomenon that can make natural variation in repeated data mimic a real change. For outcomes that exhibit natural variation, regression to the mean occurs when unusually large or small measurements tend to be followed by measurements that are closer to the mean. In this study, using data from the Osteoarthritis Initiative, we find that the phenomenon typically explains an improvement of ~1 point on a 0–10 point pain scale.
In this secondary analysis of an RCT of anterior cruciate ligament (ACL) injuries, we evaluate the natural course of ACL healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group. MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered.
Osteoarthritis (OA) remains the most challenging arthritic disorder, with a high burden of disease and no available disease-modifying treatments. Symptomatic early-stage OA of the knee urgently needs to be identified and defined, as efficient early-stage case finding and diagnosis in primary care would enable health-care providers to proactively and substantially reduce the burden of disease through proper management including structured education, exercise and weight management (when needed) and addressing lifestyle-related risk factors for disease progression. Efforts to define patient populations with symptomatic early-stage knee OA on the basis of validated classification criteria are ongoing. Such criteria, as well as the identification of biomarkers of disease risk and/or progression, would enable well-designed clinical studies, and aid the discovery and validation of cellular and molecular targets for novel therapies.
The SARS-CoV-2 Omicron variant has been associated with less severe acute disease. In this study, we compare risk for long-term complaints following Omicron infection, compared to earlier variants. Studying over one million adults in Norway, we found that individuals infected with Omicron had a similar risk of post-covid complaints as individuals infected with Delta, from 14 to up to 126 days after testing positive. However, at ≥90 days after testing positive, individuals infected with Omicron had a lower risk of having any complaint, as well as a lower risk of musculoskeletal pain than individuals infected with Delta. Our findings suggest that the acute and sub-acute burden of post-covid complaints on health services is similar for Omicron and Delta. The chronic burden may be lower for Omicron vs Delta when considering musculoskeletal pain, but not when considering other typical post-covid complaints.
Molecular pathogenesis We perform biobanking from orthopaedic surgeries to target better understanding of osteoarthritis aetiology and pathogenesis using proteomics, towards identification of novel biomarkers of the disease.
Structural imaging We use multiple cohort data sets with repeat magnetic resonance imaging and post processing of conventional radiographs to gain new knowledge of early stage osteoarthritis and its prediction.
Burden of disease Using population-based health care registries in Sweden covering in excess of 20 million person-years, we study the epidemiology and burden of musculoskeletal disease, including health economic aspects.
News
We're recruiting volunteers. We have an ambitious project to follow the earliest changes in the knees of persons at risk for OA, compared to healthy volunteers. If you have healthy knees or knees with mild symptoms, and would like to participate in our study, follow this link to find out more and sign up!
Proteomill is launched! We have developed an interactive, easy-to-access proteomic analysis tool, ProteoMill, which contains a complete pipeline from dataset upload, to differential expression, enrichment- and network analysis. Read our article decribing Preoteomill in Bioinformatics or start using it at proteomill.com.
2023-10-19: Martin Rydén has successfully defended his thesis: Proteomic profiling of osteoarthritis, a computational approach to biomarker discovery. We congratulate Martin and thank thesis opponent Professor Mohit Kapoor from University of Toronto in Canada for an interesting and enlightening discussion.
Martin Rydén (4th from the left) together with his supervisors, opponent and the dissertation committee.
2023-09-14: Our group kicked off the new academic year with a trip to Österlen on the eastern coast of Sweden. We visited beautiful Backåkra to learn more about the life of Dag Hammarsjöld, explored the beaches at Sandhammaren and finished off with a tour at Kivik Musteri, where we learned all about apple farming. We look forward to an exciting new year of research with colleagues, following this inspiring day!
Taking a moment at the meditation place at Backåkra.
Learning more about the former UN Secretary-General Dag Hammarskjöld.
Getting our feet wet at Sandhammaren.
How much did we know about apples and pollinators?
2023-06-16: Our research in collaboration with Prof. Hanna Isaksson's team at the Faculty of Engineering, focuses on identifying the earliest biomechanical, structural and molecular changes driving OA onset. Read the press release from Lund University profiling this work (in Swedish) here.
2023-04-24: Aleksandra and Martin report on the illusion of effectiveness in typical osteoarthritis clinical trials, which can arise from the natural fluctuations of pain symptoms in the disease. Read their comment in Lancet Rheumatology here, or the press release from Lund university in Swedish here.
2023-03-31: Clinical PhD student Maria Lindéus successfully defends her thesis on socioeconomic inequality in musculoskeletal disorders. Congratulations Maria! And thank you to thesis opponent Prof. Alma Biecic Pedersen from Aarhus University in Denmark for her insightful questions.
Maria Lindéus (fourth from the left) with her supervisors, opponent and dissertation committee.
2023-03-30: Our article on the risk of comorbidities following OA diagnosis has become a top downloaded article in the journal Arthritis Care & Research! Well done Andrea Dell'Isola and co-authors! Read the article here!
2023-03-20: We've had an interesting and informative OARSI 2023 meeting in Denver, presenting our work and meeting our collaborators! At the meeting, Andrea Dell'Isola was presented the "Publication of the Year" award by the journal Osteoarthritis and Cartilage Open, for his work on preexisting conditions and osteoarthritis. Read the article here!
2023-02-15: Our communicator Ebba Andersson welcomes baby Jayden into the world. We wish her family joy and happiness during this beautiful time!
2023-01-30: Congratulations Andrea Dell'Isola, who has been promoted to Docent in Orthopaedics by the Medical Faculty in Lund University!
2022-12-16: Congratulations Karin Magnusson, who has been named Professor at the Norwegian Institute of Public Health!
2022-11-22: Andrea Dell'Isola gave a public lecture about osteoarthritis, symptoms, treatment methods and exercise to a packed audience of more than 300 at the Helsingborg hospital.
Andrea Dell'Isola talks to the public about osteoarthritis in Helsingborg
Publications
Highlights
Genetic influence to osteoarthritis versus other rheumatic diseases. Karin Magnusson, Alexandra Turkiewicz, Martin Rydén, Martin Englund. Arthritis & Rheumatology, In press, September 2023.
Aim: To compare the genetic contribution to osteoarthritis (OA) vs other rheumatic/musculoskeletal diseases (RMDs) in the same population, and 2) to explore the role for any shared genetics between OA and other RMDs.
Methods: In 59 970 Swedish twins aged 35 years or older, we estimated the heritability (the variance explained by genetic factors) to OA in peripheral joints, back and neck pain, shoulder pain (adhesive capsulitis, impingement syndrome, etc), rheumatoid arthritis (RA), spondyloarthritis and psoriatic arthritis (SpA/PSA), myalgia and osteoporosis diagnosed in specialist and inpatient care. We also studied how much of covariance between OA and each of the RMDs could be explained by genetics, by studying phenotypic correlations in bivariate classical twin models.
Results: Any-site OA and hip OA (50% and 64%) were among the most heritable RMDs (as compared to 23% for fibromyalgia (lowest) and 63% for spondylarthritis (highest)). The highest phenotypic correlations were between OA (any joint site) and shoulder pain in the same individual (r=0.33, 95% CI=0.31-0.35), of which 70% (52-88) could be explained by shared genetics. The phenotypic correlation between OA and back/neck pain was r=0.25, with 25%-75% explained by genetics. Phenotypic correlations between OA and each of the other RMDs were lower (r~0.1 to r~0.2) with inconclusive sources of variation.
Conclusions: OA has relatively large heritability as compared to other RMDs. The co-existence of OA and shoulder pain, as well as back pain, was common and could often be explained by genetic factors. Findings imply similar etiologies of OA and several pain conditions.
Identification and quantification of degradome components in human synovial fluid reveals an increased proteolytic activity in knee osteoarthritis patients vs control. Martin Rydén, Alexandra Turkiewicz, Patrik Önnerfjord, Jon Tjörnstrand, Martin Englund, Neserin Ali. Proteomics, 23(15):e2300040, August 2023.
Synovial fluid (SF) may contain cleavage products of proteolytic activities. Our aim was to characterize the degradome through analysis of proteolytic activity and differential abundance of these components in a peptidomic analysis of SF in knee osteoarthritis (OA) patients versus controls (n = 23). SF samples from end-stage knee osteoarthritis patients undergoing total knee replacement surgery and controls, that is, deceased donors without known knee disease were previously run using liquid chromatography mass spectrometry (LC-MS). This data was used to perform new database searches generating results for non-tryptic and semi-tryptic peptides for studies of degradomics in OA. We used linear mixed models to estimate differences in peptide-level expression between the two groups. Known proteolytic events (from the MEROPS peptidase database) were mapped to the dataset, allowing the identification of potential proteases and which substrates they cleave. We also developed a peptide-centric R tool, proteasy, which facilitates analyses that involve retrieval and mapping of proteolytic events. We identified 429 differentially abundant peptides. We found that the increased abundance of cleaved APOA1 peptides is likely a consequence of enzymatic degradation by metalloproteinases and chymase. We identified metalloproteinase, chymase, and cathepsins as the main proteolytic actors. The analysis indicated increased activity of these proteases irrespective of their abundance.
Pain in clinical trials for knee osteoarthritis: estimation of regression to the mean. Martin Englund, Aleksandra Turkiewicz. The Lancet Rheumatology, 5(6):309-311, April 2023.
Evidence of ACL healing on MRI following ACL rupture treated with rehabilitation alone may be associated with better patient-reported outcomes: a secondary analysis from the KANON trial. Stephanie Filbay, Frank Roemer, Stefan Lohmander, Aleksandra Turkiewicz, Ewa Roos, Richard Frobell, Martin Englund. British Journal of Sports Medicine, 57(2):91-98, November 2022.
Objectives: Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group.
Methods: Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstruction (ACLR) or early ACLR and rehabilitation. ACL continuity on MRI (Anterior Cruciate Ligament OsteoArthritis Score 0-2) was considered evidence of ACL healing. Outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS patient acceptable symptomatic state (PASS) and treatment failure criteria. Linear mixed models were used to estimate adjusted mean differences (95% CIs) in patient-reported sport and recreational function (KOOS-Sport/Rec) and quality of life (KOOS-QOL) at 2 and 5 years, between participants with MRI evidence of ACL healing and those who had (1) no evidence of ACL healing, (2) delayed ACLR or (3) early ACLR.
Results: MRI evidence of ACL healing at 2-year follow-up was observed in 16 of 54 (30%, 95% CI 19 to 43%) participants randomised to optional delayed ACLR. Excluding participants who had delayed ACLR, 16 of 30 (53%, 36-70%) participants managed with rehabilitation-alone displayed MRI evidence of ACL healing. Two-year outcomes were better in the healed ACL group (n=16) compared with the non-healed (n=14) (mean difference (95% CI) KOOS-Sport/Rec: 25.1 (8.6-41.5); KOOS-QOL: 27.5 (13.2-41.8)), delayed ACLR (n=24) (KOOS-Sport/Rec: 24.9 (10.2-39.6); KOOS-QOL: 18.1 (5.4-30.8)) and early ACLR (n=62) (KOOS-Sport/Rec: 17.4 (4.1-30.7); KOOS-QOL: 11.4 (0.0-22.9)) groups. Five-year KOOS-QOL was better in the healed versus non-healed group (25.3 (9.4-41.2)). Of participants with MRI evidence of ACL healing, 63-94% met the PASS criteria for each KOOS subscale, compared with 29-61% in the non-healed or reconstructed groups.
Conclusions: MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered.
Phase-contrast enhanced synchrotron micro-tomography of human meniscus tissue. Emma Einarsson, Maria Pierantoni, Vladimir Novak, Jonas Svensson, Hanna Isaksson, Martin Englund. Osteoarthritis and Cartilage, 30(9):1222-1233, September 2022.
Objective: To investigate the feasibility of synchrotron radiation-based phase contrast enhanced micro-computed tomography (SR-PhC-μCT) for imaging of human meniscus. Quantitative parameters related to fiber orientation and crimping were evaluated as potential markers of tissue degeneration.
Design: Human meniscus specimens from 10 deceased donors were prepared using different preparation schemes: fresh frozen and thawed before imaging or fixed and paraffin-embedded. The samples were imaged using SR-PhC-μCT with an isotropic voxel size of 1.625 μm. Image quality was evaluated by visual inspection and spatial resolution. Fiber voxels were defined using a grey level threshold and a structure tensor analysis was applied to estimate collagen fiber orientation. The area at half maximum (FAHM) was calculated from angle histograms to quantify orientation distribution. Crimping period was calculated from the power spectrum of image profiles of crimped fibers. Parameters were compared to degenerative stage as evaluated by Pauli histopathological scoring.
Results: Image quality was similar between frozen and embedded samples and spatial resolutions ranged from 5.1 to 5.8 μm. Fiber structure, including crimping, was clearly visible in the images. Fibers appeared to be less organized closer to the tip of the meniscus. Fiber density might decrease slightly with degeneration. FAHM and crimping period did not show any clear association with histopathological scoring.
Conclusion: SR-PhC-μCT is a feasible technique for high-resolution 3D imaging of fresh frozen meniscus tissue. Further work is needed to establish quantitative parameters that relate to tissue degeneration, but this imaging technique is promising for future studies of meniscus structure and biomechanical response.
Mineral crystal thickness in calcified cartilage and subchondral bone in healthy and osteoarthritic human knees. Mikko Finnilä, Shuvashis Das Gupta, Mikael Turunen, Iida Hellberg, Aleksandra Turkiewicz, Viviane Lutz-Bueno, Elin Jonsson, Mirko Holler, Neserin Ali, Velocity Hughes, Hanna Isaksson, Jon Tjörnstrand, Patrik Önnerfjord, Manuel Guizar-Sicairos, Simo Saarakkala, Martin Englund. Journal of Bone and Mineral Research, 37(9):1700-1710, September 2022.
Osteoarthritis (OA) is the most common joint disease, where articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. In particular, it is technically challenging to study calcified cartilage, where relevant but poorly understood pathological processes such as tidemark multiplication and advancement occur. Here, we used state-of-the-art microfocus small-angle X-ray scattering with a 5-μm spatial resolution to determine the size and organization of the mineral crystals at the nanostructural level in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from both medial and lateral compartments of medial compartment knee OA patients (n = 15) and cadaver knees (n = 10). Opposing the common notion, we found that calcified cartilage has thicker and more mutually aligned mineral crystals than adjoining bone. In addition, we, for the first time, identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32 nm thicker crystals compared to the rest of calcified cartilage. Finally, we found 0.2 nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process because the lateral compartment is typically less loaded in medial compartment knee OA. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee might be involved with the growth of mineral crystals, which is especially evident in the calcified cartilage.
Proteomics Profiling of Human Synovial Fluid Suggests Increased Protein Interplay in Early-Osteoarthritis (OA) That Is Lost in Late-Stage OA. Neserin Ali, Aleksandra Turkiewicz, Velocity Hughes, Elin Folkesson, Jon Tjörnstrand, Paul Neuman, Patrik Önnerfjord, Martin Englund. Molecular and Cellular Proteomics, 21(3):100200, March 2022.
The underlying molecular mechanisms in osteoarthritis (OA) development are largely unknown. This study explores the proteome and the pairwise interplay of proteins in synovial fluid from patients with late-stage knee OA (arthroplasty), early knee OA (arthroscopy due to degenerative meniscal tear), and from deceased controls without knee OA. Synovial fluid samples were analyzed using state-of-the-art mass spectrometry with data-independent acquisition. The differential expression of the proteins detected was clustered and evaluated with data mining strategies and a multilevel model. Group-specific slopes of associations were estimated between expressions of each pair of identified proteins to assess the co-expression (i.e., interplay) between the proteins in each group. More proteins were increased in early-OA versus controls than late-stage OA versus controls. For most of these proteins, the fold changes between late-stage OA versus controls and early-stage OA versus controls were remarkably similar suggesting potential involvement in the OA process. Further, for the first time, this study illustrated distinct patterns in protein co-expression suggesting that the interplay between the protein machinery is increased in early-OA and lost in late-stage OA. Further efforts should focus on earlier stages of the disease than previously considered.
Elastic, dynamic viscoelastic and model-derived fibril-reinforced poroelastic mechanical properties of normal and osteoarthritic human femoral condyle cartilage. Mohammadhossein Ebrahimi, Mikko Finnilä, Aleksandra Turkiewicz, Martin Englund, Simo Saarakkala, Rami Korhonen, Petri Tanska. Annals of Biomedical Engineering, 2021.
Osteoarthritis (OA) degrades articular cartilage and weakens its function. Modern fibril-reinforced poroelastic (FRPE) computational models can distinguish the mechanical properties of main cartilage constituents, namely collagen, proteoglycans, and fluid, thus, they can precisely characterize the complex mechanical behavior of the tissue. However, these properties are not known for human femoral condyle cartilage. Therefore, we aimed to characterize them from human subjects undergoing knee replacement and from deceased donors without known OA. Multi-step stress-relaxation measurements coupled with sample-specific finite element analyses were conducted to obtain the FRPE material properties. Samples were graded using OARSI scoring to determine the severity of histopathological cartilage degradation. The results suggest that alterations in the FRPE properties are not evident in the moderate stages of cartilage degradation (OARSI 2-3) as compared with normal tissue (OARSI 0-1). Drastic deterioration of the FRPE properties was observed in severely degraded cartilage (OARSI 4). We also found that the FRPE properties of femoral condyle cartilage related to the collagen network (initial fibril-network modulus) and proteoglycan matrix (non-fibrillar matrix modulus) were greater compared to tibial and patellar cartilage in OA. These findings may inform cartilage tissue-engineering efforts and help to improve the accuracy of cartilage representations in computational knee joint models.
The impact of first and second wave of COVID-19 on knee and hip surgeries in Sweden. Andrea Dell'Isola, Ali Kiadaliri, Aleksandra Turkiewicz, Velocity Hughes, Karin Magnusson, Jos Runhaar, Sita Bierma-Zeinstra, Martin Englund. Journal of Experimental Orthopaedics, 2021.
Purpose: To investigate the impact of COVID-19 in Sweden on rates of knee and hip surgeries.
Methods: We used healthcare data for the population of the southernmost region in Sweden (1.4 million inhabitants). We did an interrupted time-series analysis to estimate changes in rates and trends of joint replacements (JR), arthroscopies, and fracture surgeries for knee or hip in April-December 2020 compared to pre-COVID-19 levels adjusting for seasonal variations.
Results: We found a drop of 54% (95% CI 42%; 68%) and 42% (95% CI 32%; 52%), respectively, in the rate of JRs and arthroscopies in April 2020 when compared to the counterfactual scenario. This was followed by an increase that brought the rates of JRs and arthroscopies back to their predicted levels also during the beginning of the second wave (November-December 2020). Acute fracture surgeries were largely unaffected, i.e. did not show any decrease as observed for the other surgeries.
Conclusions: In southern Sweden, we observed a marked decrease in elective knee and hip surgeries following the first wave of Covid-19. The rates remained close to normal during the beginning of the second wave suggesting that important elective surgeries for patients with end-stage osteoarthritis can still be offered despite an ongoing pandemic provided adequate routines and hospital resources.
Relationship between magnetic resonance imaging features and knee pain over 6 years in knees without radiographic osteoarthritis at baseline. Karin Magnusson, Aleksandra Turkiewicz, Jaanika Kumm, Fan Zhang, Martin Englund. Arthritis Care & Research, 73(11):1659-1666, November 2021.
Aim: To explore whether MRI features suggestive of knee OA are associated with presence of knee pain in possible early-stage OA development.
Methods: We included 294 participants from the Osteoarthritis Initiative (mean [SD] age 50 (3) years, 50% women), with baseline Kellgren and Lawrence grade=0 in both knees, and who had all obtained knee MRIs from 4 different time points over 6 years (baseline, 24, 48 and 72 months). Using a linear mixed model (knees matched within individuals), we studied whether MRI features: meniscal body extrusion (millimeter), cartilage area loss (score 0 to 39), cartilage full thickness loss (0-16), osteophytes (0-29), meniscal integrity (0-10), bone marrow lesions (BML) including bone marrow cysts (0-20), Hoffa or effusion synovitis (absent/present) and popliteal cysts (absent/present) were associated with knee-specific pain as reported on the Knee injury and Osteoarthritis Outcomes Score (KOOS) questionnaire on 0-100 scale (worst-best).
Results: The difference in KOOS knee pain for a knee with a one unit higher score on MRI feature was: for meniscal extrusion -1.52 (95% CI -2.35,-0.69), cartilage area loss -0.23 (-0.48,0.02), cartilage full thickness loss: -1.04 (-1.58,-0.50), osteophytes -0.32 (-0.61,-0.03), meniscal integrity -0.28 (-0.58,0.02), BMLs including potential cysts -0.19 (-0.55,0.16), synovitis 0.23 (-1.14,1.60) and popliteal cysts 0.86 (-0.56,2.29).
Conclusions: Meniscal extrusion, full thickness cartilage loss and osteophytes are associated with having more knee pain. Although these features may be relevant targets for future trials, the clinical relevance of our findings is unclear because no feature was associated with a clinically important difference in knee pain.
