CHICAGO—Joint trauma is one of many potential drivers of osteoarthritis disease activity and structural progression. In Post-Traumatic OA: Pathogenesis, Clinical Evolution and Management, a session at the 2018 ACR/ARHP Annual Meeting, experts discussed the effects of sports and other injuries on even young patients’ joints.
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Post-traumatic osteoarthritis (OA) may account for 12% of hip, knee and ankle OA cases, and in this form of knee OA, “biomechanics [are] important, as well as malalignment, gait abnormalities and tissue-specific effects,” said Tom Appleton, MD, PhD, assistant professor of medicine, Western University in London, Ontario, Canada.1
OA may develop following injury due to unresolved inflammation, hemarthrosis, chronic destabilization and biomechanical effects of the trauma on cartilage and other tissues. Catabolic responses, such as tissue necrosis and acute innate inflammation that never completely resolves, occur shortly after trauma, followed by anabolic responses, including bone remodeling and extracellular matrix (ECM) synthesis.2 Three weeks after anterior cruciate ligament (ACL) tears, patients have elevated cytokines in their synovial fluid.3 Lubricin, a glycoprotein secreted from synovial fibroblasts, may slowly resolve, and inflammatory markers, such as TNF-α or IL-6, may stay elevated.4
“Does severity of the joint injury matter in terms of pathophysiology and overall risk?” asked Dr. Appleton. Osteochondral fractures may lead to cytokine levels elevated in comparison with soft-tissue injury alone, suggesting more injury leads to more inflammation. More severe intra-articular fractures led to more severe synovitis in one study in mice, but “it didn’t translate to any worse damage in terms of the cartilage nor an increase in cell death.5 So it may depend, in a tissue-specific way, on how intense the injury to the cartilage in the joint is.”
‘Soft tissues are important sources of proteases that are known to damage cartilage & joint structures.’ —Tom Appleton, MD, PhD
Severe, repetitive loading may cause dose-dependent changes to cartilage and synovial lining.6 Hemarthrosis after a knee injury may lead to leukocyte activation and reactive oxygen species (ROS) production even in an otherwise healthy person, and this acute, substantial joint bleeding can damage knee cartilage, much more so than microbleeds.7,8
“What about effects on other joint tissues, such as the soft tissues?” asked Dr. Appleton. Gottingen minipigs showed elevated levels of matrix metalloproteinases (MMP) 1, 13 and the aggrecanase ADAMTS-4 in both their cartilage and ligament tissue after ACL injuries in one study.9 “These soft tissues are important sources of proteases that are known to damage cartilage and joint structures.”
A few weeks after joint trauma, subchondral bone may increase in volume, suggesting that bone turnover occurs early after a destabilizing joint injury.10 Gene dysregulation also happens very early in subchondral bone following traumatic injury, with gene signatures consistent with heavy bone turnover, MMP upregulation and osteoclast differentiation.11
Post-traumatic OA inflammation is mechanically induced. After injury, “there is an effect on cartilage with matrix product release, and these can be acting as DAMPs [damage-associated molecular patterns] to activate cell population in the synovium. There is cytokine release, and subchondral bone turnover even in very early stages,” he said. Eleven cartilage-specific genes were dysregulated in the meniscus tissue of rats a few days after knee injury in one study, although not all at the same points in time.12 In post-traumatic OA, an early inflammatory response may be required to usher in a later wound healing response, and that may have important considerations for the timing and mechanism of treatment.
In early post-traumatic OA, cytokines and chemokines are dysregulated weeks after injury, as his research on surgically induced, CCL2-knockout mice shows.13 His group was interested in CCL2 as a potentially structure-modifying target. Blocking CCL2 and CCR2 can reduce cartilage degeneration, and CCR2 inhibition is only effective if used early in post-traumatic OA.14 Each type of OA has a different mechanism, so treatments should be tested in trials according to specific OA types, Dr. Appleton said.
Persistent Pain & Reduced Activity
Although many patients do well after joint injury, a considerable number of people still struggle with their symptoms even years later, said Jeffrey B. Driban, PhD, associate professor of medicine, Tufts University School of Medicine and Tufts Medical Center, Boston.
One-third of patients report they have unacceptable symptoms, such as knee pain, up to two years after an ACL injury and surgical treatment. Further, about 33% of patients develop tibiofemoral OA within 10 years after an ACL tear, with or without surgical repair, he said.15
“You can observe articular cartilage changes in the first two years after an ACL tear injury, including a thinning on the femoral trochlea, but a thickening at the central medial femur,” he said.16 “Composition of the articular cartilage is compromised, and this is more likely to be swelling” rather than a healthy adaptation. Cartilage changes happen consistently over several years after injury. Two years after injury, the posterior lateral meniscus recovers, but with persistent compositional changes in the medial meniscus that relate to articular cartilage changes.17
“After ACL injury, many people will have a bone bruise, and that typically goes away in a few months,” he said. But 34% of patients develop new bone marrow lesions (BMLs) within two years of an ACL injury, “and it’s unclear why.18 But that number—one in three patients—keeps coming up as having a problematic outcome.” According to his group’s research, BMLs tend to predict progression of OA.19 Bone surfaces in the knee joint also change shape shortly after injury, and may increase the risk of OA progression.
“We can detect and measure subtle changes in the first two years after injury,” said Dr. Driban. “But we need to ask ourselves if some of these changes are normal adaptations to new joint loading conditions, and which of these changes represent pathologic changes that either represent early OA or could expose the patient to a greater risk of OA? Once we answer those questions, we can ask: How do we optimize joint health over time in joints with a history of injury?”
Return to activity in this two-year time period may be an unexplored risk factor for OA, and joint tissues may need time to adapt to new loads that are happening. Patients should return to sports and other activities with the fastest, but safest approach, with adequate rest time, he said.
Quadriceps weakness may linger after knee injury, and patients who report good quadriceps strength following post-surgery rehabilitation also tend to report high function.20 “Quadriceps weakness seems to be linked to structural changes, such as worse articular cartilage composition on MRI and tibiofemoral joint space narrowing on X-ray at two years follow-up after injury,” he said.21
Patients experience quadriceps weakness because of a deficit in neural activation in the muscle after injury. During rehabilitation, exercises should be optimized to address these neural changes: Spinal-reflexive excitability can be targeted within two weeks of surgery, and six months after surgery, therapies that improve cortico-motor excitability can be focused on.22 Muscle weakness can alter walking biomechanics, which may predict OA. Quadriceps weakness, pain and fear of re-injury are all reasons why some people never return to their pre-injury levels of activity, he said.
Preventing Post-Traumatic OA After ACL Surgery
Post-traumatic OA is a disease of interplay between biology, such as structural changes, and biomechanics, which are two fundamental controls of articular cartilage health, said Kurt P. Spindler, MD, vice chairman, research, and co-director, Musculoskeletal Research Center at the Cleveland Clinic, Ohio. “In my opinion, the articular cartilage is an innocent bystander: Initially, it is traumatized by injury, and then biological and biomechanical events result in post-traumatic OA.”
Dr. Spindler is involved in the Multicenter Orthopedic Outcomes Network (MOON), and one MOON study looked at patient-reported outcomes, pain scores and failure in patients who underwent ACL reconstruction surgery at two, six and 10 years of follow-up in 1,592 patients.23
A majority of patients in the study maintained good pain and quality of life scores, but “if you look at their activity level over time, it declines. Much of this is caused by social factors: People graduate from high school or college, or other things in their lives become more important” than sports, such as career or marriage, said Dr. Spindler. Numerous risk factors predict worse pain and quality of life scores at 10 years, including higher grade articular lesion, previous meniscus surgery, any type of subsequent surgery, higher body-mass index and smoking. Pain scores tend to stay the same over this period of time. Graft type, sports competition level and meniscus injury type do not predict worse outcomes.
“One of the concerns is that maybe they’re getting post-traumatic OA, but they’re controlling their symptoms by dialing back their activity,” said Dr. Spindler. Despite a 10-year follow-up on 83% of the patients in the cohort, this sample size was insufficient to model the effect of meniscus tears and treatment in articular cartilage chondromalacia within the same compartment. There was no on-site follow-up in the study, such as physical examination or X-ray data. “At 10 years, only a small percentage of patients have pain and symptoms consistent with post-traumatic OA,” although the average age of patients at the beginning of the study was 22.
Is pain a predictive marker for later articular changes? In his group’s study of 1,761 patients after ACL reconstruction, between 9% and 39% of patients had significant pain six years later, said Dr. Spindler.24 “The dominant risk factor for this outcome is any second surgery. If you think the first hemarthrosis is bad for the articular cartilage, what about the surgery? It’s even worse for the cartilage. Add a second surgery, and you keep adding these hits.”
Are there interventions to help prevent post-traumatic OA in these patients? Some pilot studies are looking at the potential benefits of a corticosteroid triamcinolone acetonide injection soon after ACL reconstruction.
“Even if you block all the inflammation at surgery, you have a conundrum. At the time of surgery, you are putting a graft in there that must heal. You can’t just block all inflammation and stop the healing,” said Dr. Spindler. He is involved in a new study of hyaluronic acid or triamcinolone acetonide injections, both administered one week after ACL surgery, compared to no intervention.
MRI is a potentially powerful tool to identify proteoglycan and collagen loss, both possibly meaningful changes seen early after joint injury.
“We have to prevent collagen loss, because that occurs early on. There is a narrow window, but I think we can prevent a lot of the OA afterward,” he concluded. Proteomic analysis may tell us about gene markers that predict who is likely to develop post-traumatic OA after surgery and reveal more clues on why some people resolve their inflammation while others do not.
Susan Bernstein is a freelance medical journalist based in Atlanta.
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- Anderson DD, Van Hofwegen C, Marsh JL, et al. Is elevated contact stress predictive of post-traumatic osteoarthritis for imprecisely reduced tibial plafond fractures? J Orthop Res. 2011 Jan;29(1):31–39.
- Sward P, Frobell R, Englund M, et al. Cartilage and bone markers and inflammatory cytokines are increased in synovial fluid in the acute phase of knee injury (hemarthrosis): A cross-sectional analysis. Osteoarthritis Cartilage. 2012 Nov;20(11):1303–1308.
- Elsaid KA, Fleming BC, Oksendahl HL, et al. Decreased lubricin concentrations and markers of joint inflammation in synovial fluids from patients with anterior cruciate ligament injury. Arthritis Rheum. 2008 Jun;58(6):1707–1715.
- Lewis JS, Hembree WC, Furman BD, et al. Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee. Osteoarthritis Cartilage. 2011 Jul;19(7):864–873.
- Wu P, Holguin N, Silva MJ, et al. Early response of mouse joint tissue to noninvasive knee injury suggests treatment targets. Arthritis Rheumatol. 2014 May;66(5):1256–1265.
- Borsiczky B, Fodor B, Rácz B, et al. Rapid leukocyte activation following intraarticular bleeding. J Orthop Res. 2006 April;24(4):684–689.
- Van Meegeren ME, Roosendahl G, Mastbergen SC, et al. Blood-induced joint damage: The devastating effects of acute joint bleeds versus micro-bleeds. Cartilage. 2013 Oct;4(4):313–320.
- Haslauer CM, Elsaid KA, Fleming BC, et al. Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury. Osteoarthritis Cartilage. 2013 Dec;21(12):1950–1957.
- Fang H, Huang L, Welch I, et al. Early changes of articular cartilage and subchondral bone in the DMM mouse model of osteoarthritis. Sci Rep. 2018 Feb 12;8(1):2855.
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- Wei T, Kulkarni NH, Zeng QQ ,et al. Analysis of early changes in the articular cartilage transcriptisome in the rat meniscal tear model of osteoarthritis: pathway comparisons with the rat anterior cruciate transection model and with human osteoarthritic cartilage. Osteoarthritis Cartilage. 2010 Jul;18(7):992–1000.
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- Longobardi L, Temple JD, Tagliaferro L, et al. Role of the C-C chemokine receptor 2 in a murine model of injury-induced osteoarthritis. Osteoarthritis Cartilage. 2017 Jun;25(6):914–925.
- Harris KP, Driban JB, Sitler MR, et al. Tibiofemoral osteoarthritis after surgical or nonsurgical treatment of anterior cruciate ligament rupture: A systematic review. J Athl Train. 2017 Jun 2;52(6):507–517.
- Frobell RB. Change in cartilage thickness, posttraumatic bone marrow lesions, and joint fluid volumes after acute ACL disruption: A two-year prospective MRI study of sixty-one subjects. J Bone Joint Surg Am. 2011 Jun;93(12):1096–1103.
- Knox J, Pedoia V, Wang A, et al. Longitudinal changes in MR T1p/T2 signal of meniscus and its association with cartilage T1p/T2 in ACL-injured patients. Osteoarthritis Cartilage. 2018 May;26(5):689–696.
- Eckstein F, Collins JE, Nevitt MC, et al. Brief report: Cartilage thickness change as an imaging biomarker of knee osteoarthritis progression: Data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Arthritis Rheumatol. 2015 Dec;67(12):3184–3189.
- Driban JB, Price LL, Lo GH, et al. Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker—longitudinal relationships with pain and structural changes: Data from the Osteoarthritis Initiative. Arthritis Res Ther. 2013;15(5):R112.
- Pietrosimone B, Lepley AS, Harkey MS, et al. Quadriceps strength predicts self-reported function post-ACL reconstruction. Med Sci Sports Exerc. 2016 Sep;48(9):1671–1677.
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- Lepley LK, Wojtys EM, Palmieri-Smith RM. Combination of eccentric exercise and neuromuscular electric stimulation to improve quadriceps function post-ACL reconstruction. Knee. 2015 Jun;22(3):270–277.
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