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 this study, we report a high genetic contribution (69%) to anterior cruciate ligament (ACL) injury among 88 414 twins from the Swedish Twin Register. Twins were followed from 17 years of age until ACL injury or death. Results were obtained by comparing the occurrence of ACL injury in identical vs. fraternal twin pairs, who share 100% and 50% of their genes, respectively. The high genetic contribution to ACL injury suggests strong familial clustering of this common knee injury.
In this longitudinal study based on the entire population of Skåne, we estimated the risk of clinically diagnosed knee osteoarthritis (OA) after different types of knee injuries in young adults. We found that in young adults, knee injury increases the risk of future diagnosed knee OA about sixfold, with highest risks found after cruciate ligament injury, meniscal tear and intra-articular fracture.
In this 5-year follow up of a double-blinded, randomized clinical trial, we assessed the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee OA, and on knee symptoms and function. We found that APM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.
In this study, we examined mortality in patients with gout compared to the general population, studying the entire population of Skåne using a register-based approach. We found that persons with gout had a higher prevalence of metabolic, cardiovascular, and renal disease. Gout patients showed 17% increased hazard of all-cause mortality, with strongest risks of death associated with renal disease, diseases of the digestive system, cardiovascular diseases, and infections, in that order.
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.
We're recruiting volunteers. In January 2020, we launched an ambitious new project to follow the earliest changes in the knees of patients at risk for OA, compared to healthy volunteers. If you have healthy knees and would like to participate in our study, follow this link to find out more and participate!
Proteomill is launched! We have developed an interactive proteomic analysis tool, ProteoMill, which contains a complete pipeline from dataset upload, to differential expression, enrichment- and network analysis. The tool is easily accessible, fast and uses data sources that are always up to date. Its innovative interactive visualization methods enable researchers to quickly inspect data quality and gain comprehensive insight into the molecular events of their data. Read our preprint article decribing Preoteomill on bioRxiv or start using it at proteomill.com.
2021-10-06: Martin Englund, Lotte Höjgård Hansen, and Jenny Power help organize a webinar of lectures on osteoarthritis and dementia for the public. The series of 5 lectures by leading researchers in these topics at Lund University are available here (lectures in Swedish).
2021-09-01:The Arthritis Portal, an initiative to share accurate and up-to-date information on osteoarthritis, has been launched in English. This follows the successful launch of Artrosportalen in Swedish last year.
2021-09-17: Our group kicked off the new academic year with a hike through an enchanting forest, where we got to enjoy local delicacies from around Skåne at scenic stops. We look forward to an exciting new year of research, with more interactions with colleagues at home and abroad after a year of remote work.
Hiking in beautiful Genarp.
A tasting tour of Skåne's local delicacies.
We even foraged some delicacies of our own - chanterelles.
2020-12-02: In a new collaboration with the Faculty of Engineering, we welcome Lykke Månsson and Kristina Gehrisch, Masters students in the field of biomedical engineering. This term, they will perform studies in the field of proteomics and biomechanics focusing on human meniscal tissue. Prof. Hanna Isaksson (Faculty of Enginnering, LTH) will lead the biomechanical analyses, while Neserin Ali will lead the proteomics.
Lykke and Kristina preparing meniscus samples for mass spectrometry and biomechanical experiments.
2020-11-01: We initiate a new FOREUM project to look at the impact of COVID-19 and its policies on people with rheumatic diseases. This is an international collaboration with researchers at the Norwegian Institute of Public Health and Erasmus MC in the Netherlands.
2020-09-01: Under the leadership of Prof. Englund, in partnership with the researchers of the Lund University Osteoarthritis Division, we have launched a new public health initiative - Artrosportalen (website in Swedish) - to share accurate and up-to-sate information on osteoarthritis direct from researchers.
2020-08-20: Our annual kickoff activity involved cycling around the beautiful Scanian island of Ven, with a guided tour learning about Tycho Brahe and his vast contributions to astronomy. We also went swimming in the sea and enjoyed some locally crafted ice cream. A great start to the academic year together with old and new colleagues.
The Clin Epi team in beautiful Ven.
2020-02-18: Bioinformatics PhD student Martin Rydén is featured in Vetenskap & Hälsa, where he describes how network analysis can reveal relationships between different components in complex biological systems. Read the full article here (in Swedish).
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: TTo 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: HIn 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.
The relationship between MRI 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.
To explore whether MRI features suggestive of knee OA are associated with presence of knee pain in possible early-stage OA development.
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).
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).
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.
Arthroscopic partial meniscectomy for a degenerative meniscus tear: a 5 year follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial. Raine Sihvonen, Mika Paavola, Antti Malmivaara, Ari Itälä, Antti Joukainen, Juha Kalske, Heikki Nurmi, Jaanika Kumm, Niko Sillanpää, Tommi Kiekara, Aleksandra Turkiewicz, Pirjo Toivonen, Martin Englund, Simo Taimela, Teppo Järvine, FIDELITY (Finnish Degenerative Meniscus Lesion Study) Investigators. British Journal of Sports Medicine, 54(22):1332-1339, November 2020.
To assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up.
Multicentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial. Setting: Orthopaedic departments in five public hospitals in Finland.
146 adults, mean age 52 years (range 35-65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised.
APM or placebo surgery (diagnostic knee arthroscopy).
Main outcome measures:
We used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade ≥1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function (Western Ontario Meniscal Evaluation Tool (WOMET), Lysholm, and knee pain after exercise using a numerical rating scale).
There was a consistent, slightly greater risk for progression of radiographic knee osteoarthritis in the APM group as compared with the placebo surgery group (adjusted absolute risk difference in increase in Kellgren-Lawrence grade ≥1 of 13%, 95% CI -2% to 28%; adjusted absolute mean difference in OARSI sum score 0.7, 95% CI 0.1 to 1.3). There were no relevant between-group differences in the three patient-reported outcomes: adjusted absolute mean differences (APM vs placebo surgery), -1.7 (95% CI -7.7 to 4.3) in WOMET, -2.1 (95% CI -6.8 to 2.6) in Lysholm knee score, and -0.04 (95% CI -0.81 to 0.72) in knee pain after exercise, respectively. The corresponding adjusted absolute risk difference in the presence of mechanical symptoms was 18% (95% CI 5% to 31%); there were more symptoms reported in the APM group. All other secondary outcomes comparisons were similar.
APM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.
Proteomic comparison of osteoarthritic and reference human menisci using data-independent acquisition mass spectrometry. Elin Folkesson, Aleksandra Turkiewicz, Neserin Ali, Martin Rydén, H. Velocity Hughes, Jon Tjörnstrand, Patrik Önnerfjord, Martin Englund. Osteoarthritis and Cartilage, 28(8):1092-1101, August 2020.
Recent research in knee osteoarthritis (OA) highlights the role of the meniscus in OA pathology. Our aim was to compare the proteomes of medial and lateral menisci from end-stage medial compartment knee OA patients, with reference menisci from knee-healthy deceased donors, using mass spectrometry.
Tissue plugs of Ø3 mm were obtained from the posterior horns of the lateral and medial menisci from one knee of 10 knee-healthy deceased donors and 10 patients undergoing knee replacement. Proteins were extracted and prepared for mass spectrometric analysis. Statistical analysis was conducted on abundance data that was log2-transformed, using a linear mixed effects model and evaluated using pathway analysis.
We identified a total of 835 proteins in all samples, of which 331 were included in the statistical analysis. The largest differences could be seen between the medial menisci from OA patients and references, with most proteins showing higher intensities in the medial menisci from OA patients. Several matrix proteins, e.g., matrix metalloproteinase 3 (MMP3) (4.3 times higher values [95%CI 1.8, 10.6]), TIMP1 (3.5 [1.4, 8.5]), asporin (4.1 [1.7, 10.0]) and versican (4.4 [1.8, 10.9]), all showed higher abundance in medial menisci from OA patients compared to medial reference menisci. OA medial menisci also showed increased activation of several pathways involved in inflammation.
An increase in protein abundance for proteins such as MMP and TIMP1 in the medial menisci from OA patients suggests simultaneous activation of both catabolic and anabolic processes that warrants further attention.
Proteomic characterization of the normal human medial meniscus body using data-independent acquisition mass spectrometry. Elin Folkesson, Aleksandra Turkiewicz, Martin Rydén, H. Velocity Hughes, Neserin Ali, Jon Tjörnstrand, Patrik Önnerfjord, Martin Englund. Journal of Orthopaedic Research, 38(8):1735-1745, August 2020.
Recent research suggests an important role of the meniscus in the development of knee osteoarthritis. We, therefore, aimed to analyze the proteome of the normal human meniscus body, and specifically to gain new knowledge on global protein expression in the different radial zones. Medial menisci were retrieved from the right knees of 10 human cadaveric donors, from which we cut a 2 mm radial slice from the mid-portion of the meniscal body. This slice was further divided into three zones: inner, middle, and peripheral. Proteins were extracted and prepared for mass spectrometric analysis using data-independent acquisition. We performed subsequent data searches using Spectronaut Pulsar and used fixed-effect linear regression models for statistical analysis. We identified 638 proteins and after statistical analysis, we observed the greatest number of differentially expressed proteins between the inner and peripheral zones (163 proteins) and the peripheral and middle zones (136 proteins), with myocilin being the protein with the largest fold-change in both comparisons. Chondroadherin was one of eight proteins that differed between the inner and middle zones. Functional enrichment analyses showed that the peripheral one-third of the medial meniscus body differed substantially from the two more centrally located zones, which were more similar to each other. This is probably related to the higher content of cells and vascularization in the peripheral zone, whereas the middle and inner zones of the meniscal body appear to be more similar to hyaline cartilage, with high levels of extracellular matrix proteins such as aggrecan and collagen type II.
Risk of knee osteoarthritis after different types of knee injuries in young adults: a population-based cohort study. Barbara Snoeker, Aleksandra Turkiewicz, Karin Magnusson, Richard Frobell, Dahai Yu, George Peat, Martin Englund. British Journal of Sports Medicine, 54(12):725-730, June 2020.
Objectives: To estimate the risk of clinically diagnosed knee osteoarthritis (OA) after different types of knee injuries in young adults.
Methods: In a longitudinal cohort study based on population-based healthcare data from Skåne, Sweden, we included all persons aged 25-34 years in 1998-2007 (n=149 288) with and without diagnoses of knee injuries according to International Classification of Diseases (ICD)-10. We estimated the HR of future diagnosed knee OA in injured and uninjured persons using Cox regression, adjusted for potential confounders. We also explored the impact of type of injury (contusion, fracture, dislocation, meniscal tear, cartilage tear/other injury, collateral ligament tear, cruciate ligament tear and injury to multiple structures) on diagnosed knee OA risk.
Results: We identified 5247 persons (mean (SD) age 29.4 (2.9) years, 67% men) with a knee injury and 142 825 persons (mean (SD) age 30.2 (3.0) years, 45% men) without. We found an adjusted HR of 5.7 (95% CI 5.0 to 6.6) for diagnosed knee OA in injured compared with uninjured persons during the first 11 years of follow-up and 3.4 (95% CI 2.9 to 4.0) during the following 8 years. The corresponding risk difference (RD) after 19 years of follow-up was 8.1% (95% CI 6.7% to 9.4%). Cruciate ligament injury, meniscal tear and fracture of the tibia plateau/patella were associated with greatest increase in risk (RD of 19.6% (95% CI 13.2% to 25.9%), 10.5% (95% CI 6.4% to 14.7%) and 6.6% (95% CI 1.1% to 12.2%), respectively).
Conclusion: In young adults, knee injury increases the risk of future diagnosed knee OA about sixfold with highest risks found after cruciate ligament injury, meniscal tear and intra-articular fracture.
Does early anterior cruciate ligament reconstruction prevent development of meniscal damage? Results from a secondary analysis of a randomised controlled trial. Barbara A. Snoeker, Frank W. Roemer, Aleksandra Turkiewicz, Stefan Lohmander, Richard B. Frobell, Martin Englund. British Journal of Sports Medicine, 54(10):612-617, May 2020.
Objectives: To determine development of new and worsening meniscal damage over 5 years after acute anterior cruciate ligament (ACL) injury comparing rehabilitation plus early ACL reconstruction ('early-ACLR') versus rehabilitation with optional delayed ACL reconstruction ('optional-delayed-ACLR').
Methods: We used knee MRIs from the only randomised controlled trial in the field including 121 young adults. One musculoskeletal radiologist read baseline and 5-year follow-up images using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS). We defined development (ie, new and worsening) of meniscal damage both dichotomously and as a sum score representing severity (based on the reclassified ACLOAS meniscus grades). In the full analysis set, we analysed development of meniscal damage (yes/no) with logistic regression and severity with zero-inflated Poisson regression and adjusted for age, sex and baseline meniscal damage.
Results: Over 5 years, new or worsening meniscal damage developed in 45% of subjects with early-ACLR and in 53% of subjects with optional-delayed-ACLR. The relative risk for development of meniscal damage on knee level was 1.3 (95% CI 0.9 to 1.9) in optional-delayed-ACLR versus early-ACLR. For medial and lateral meniscal damage, respectively, the relative risks were 2.1 (95% CI 1.1 to 3.9) and 1.0 (95% CI 0.6 to 1.5). The mean severity score was 1.5 higher (more severe damage) on knee level in optional-delayed-ACLR versus early-ACLR (95% CI 1.1 to 1.9) among those with meniscal damage at 5 years. For medial and lateral meniscal damage, respectively, the corresponding scores were 1.7 (95% CI 1.2 to 2.5) and 1.1 (95% CI 0.8 to 1.4).
Conclusion: A strategy of early-ACLR may reduce development of medial meniscal damage following acute ACL injury. For the lateral meniscus, ACLR seems neither to be protective nor to increase the risk of damage.
Molecular and imaging biomarkers of local inflammation at 2 years after anterior cruciate ligament injury do not associate with patient reported outcomes at 5 years.
André Struglics, Aleksandra Turkiewicz, Staffan Larsson, L. Stefan Lohmander, Frank W. Roemer, Richard Frobell, Martin Englund. Osteoarthritis and cartilage, 28(3):356-362, March 2020.
Objective: To estimate the association between molecular or imaging inflammatory biomarkers at 2 years after anterior cruciate ligament (ACL) injury and patient-reported outcomes at 5 years.
Methods: For 116 ACL-injured patients, molecular biomarkers of inflammation (synovial fluid and serum cytokines) and Hoffa- and effusion-synovitis as visualized on magnetic resonance imaging (MRI) were assessed 2 years post-injury. Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-36 were assessed at 2 and 5 years. We used multiple imputation to handle biomarker values that were below the level of detection or missing, and linear regression for statistical analyses.
Results: None of the synovial fluid cytokines or imaging biomarkers of inflammation at 2 years were associated with any of the patient-reported outcomes at 5 years. With each log10 unit higher of serum tumor necrosis factor concentration the knee-related quality of life of KOOS was increased (i.e., better outcome) by 35 (95% confidence interval 7 to 63) points. No other serum biomarker measured at 2 years was associated with patient-reported outcome at 5 years.
Conclusion: Local joint inflammation assessed by biomarkers in synovial fluid and Hoffa- and effusion-synovitis on MRI at 2 years after an ACL injury did not associate with patient-reported outcomes at 5 years. Thus, chronic inflammation in the ACL-injured knee, as reflected by the biomarkers studied here, seems not to be a key determinant for the long-term patient-reported outcomes.
Inappropriate opioid dispensing in patients with knee and hip osteoarthritis: a population-based cohort study. Jonas B. Thorlund, Aleksandra Turkiewicz, Daniel Prieto-Alhambra, Martin Englund. Osteoarthritis and Cartilage, 28(2):146-153, February 2020.
Objectives: To estimate inappropriate opioid dispensing in patients with knee or hip osteoarthritis (OA) defined as (1) dispensing of opioids within the first year of diagnosis or (2) long-term opioid use.
Design: Data from Skåne Healthcare Register was linked with the Swedish Prescribed Drug Register. Incidence proportion of dispensed opioids within first year of incident knee or hip OA diagnosis was determined in knee (n = 399,670) and hip (413,216) OA cohorts without a history of OA. The 1-year period prevalence of long-term opioid dispensing was determined in a prevalence cohort (n = 48,574 with knee and/or hip OA and n = 457,587 without OA). The proportion of OA patients with excess opioid dispensing attributable to OA was estimated using inverse probability weighted regression adjustment.
Results: In the incident cohorts, 5866 and 2359 developed knee and hip OA, respectively. Within the first year after OA diagnosis 14.7% patients with knee OA and 20.7% with hip OA had an opioid dispensed. The estimated inappropriate dispensing attributable to OA was 7.4% (95% CI 6.5-8.4) for knee OA and 12.8% (95% CI 11.1-14.4) for hip OA. Among persons with prevalent knee, hip or knee and hip OA inappropriate, long-term opioid use attributable to OA was 1.3%, 2.0% and 2.4% of, respectively.
Conclusions: More than half the incident opioid dispensations to patients within their first year after knee or hip OA diagnosis are inappropriate according to current treatment guidelines. Furthermore, 2% of patients with prevalent knee or hip OA have inappropriate long-term dispensing of opioids.