What Is New in Osteoarthritis
What Is New in Osteoarthritis
In the WIN session on osteoarthritis (OA), Prof. Francis Berenbaum (Sorbonne Université, France) presented striking messages about OA, its prevalence, disease burden, severity, and (non)pharmacological interventions .
“The prevalence of OA is dramatically increasing,” said Prof. Berenbaum. Lieberman et al. looked at skeletons during different time periods . The prevalence of knee OA was found to be 16% among the post-industrial sample but only 6% and 8% among the early industrial and prehistoric samples. Increases in longevity and BMI (obesity) do not fully explain the increased prevalence . “Unknown environmental factors play a role,” Prof. Berenbaum added. Also, a recent paper by Sebbag et al. found that the burden of musculoskeletal diseases -including OA- has increased significantly between 2000 and 2015, with these being the second cause of ‘years lived with disability’ worldwide . Prof. Berenbaum referred to steep disability-adjusted life years for OA due to poor health, disability, or premature mortality. “WHO data analysis from over 183 countries shows that rheumatic and musculoskeletal diseases are now in second place in terms of years of disability. The burden of OA is real. It is a public health concern,” emphasised Prof. Berenbaum. Finally, OA is a fatal disease. Numerous studies show that walking disability due to hip/knee OA increases mortality by nearly 50%. “This is a big increase.” A population-based cohort in 1,163 patients ≥35 years old showed that walking disability was independently linked to cardiovascular death in the OA population . “Altogether, due to these findings, the FDA has indicated a guidance for industry on OA structural endpoints for the development of drugs, devices, and biological products for treatment. The FDA recognises that OA is a disease, which is an important observation. OA is a serious health problem for the years ahead and there is a high need for pharmacological treatments,” said Prof. Berenbaum.
There is no established disease-modifying OA therapy, so treatment relies on a combination of (non)pharmacological therapies that can manage the symptoms of OA . Total joint replacement is commonly performed when conservative and pharmacological treatments provide inadequate relief. However, around 20% of total knee replacements lead to long-term chronic pain and potentially increased opioid consumption, which is highly addictive and therefore problematic.
Pharmacologically, acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) are considered as first-and second-line drug treatment respectively. Tramadol and opioids or duloxetine are prescribed in case of refractory symptoms, whereas intra-articular steroids are applied for knee and hip OA only. However, none of these drugs are free of adverse effects. Furthermore, the efficacy of paracetamol on knee/hip OA is low . A safety message pointed out by Prof. Berenbaum is that diclofenac poses a cardiovascular health risk compared with use of other traditional NSAIDs. A series of nationwide cohort studies showed the deleterious effects on heart and vessels, even if given for a short period of time . Tramadol prescription has increased over recent years but research showed that among OA patients ≥50 years old initial prescription of tramadol was linked to a significantly higher rate of mortality over 1 year of follow-up, compared with commonly prescribed NSAIDs, but not compared with codeine. The only way to move forward is to innovate, but this requires a better understanding of the underlying OA pathophysiology. Then, targeted structural therapies can be developed, aimed to inhibit structural catabolism and to increase anabolism and cartilage repair.
One of the targets to inhibit catabolism is lorecivivint, a Wnt pathway inhibitor, administered as a single intra-articular injection, preventing cartilage degeneration and decreasing bone remodeling . A second Wnt pathway inhibitor is Cathepsin K inhibitor MIV-711. Eligible patients (n=244) received this drug orally in doses of 100 mg or 200 mg, or placebo. Results showed reduced loss of cartilage thickness on the medial femur versus placebo, for both MIV-711 doses at week 26. Cartilage loss on medial tibia was not significant . Other targets are being investigated in experimental (human) studies; these are the ADAMTS and other Wnt pathway inhibitors. “Another way to impact catabolism is to impact inflammation. It is well-known that more pro-inflammatory cytokines induce cells to release more proteinases and catabolic factors. Targeting cytokines has not been effective so far. For example lutikizumab, an anti-IL-1alpha/beta cytokine inhibitor, has not been successful [10,11]. “Maybe we did not target the right cytokines. Other targets may affect structure.” said Berenbaum.
Enhancing anabolism and cartilage repair is another approach with promising results. Prof. Berenbaum talked about the 2-year primary data of the 5-year FORWARD phase 2 trial with sprifermin, a recombinant version of fibroblast growth factor 18, injected intra-articular (100 or 30 micrograms sprifermin vs placebo 3 times weekly). “Animal studies show anabolic effects on cartilage and results so far are encouraging. The primary endpoint is a change in total tibiofemoral joint cartilage thickness on MRI from baseline up to 2 years,” said Prof. Berenbaum. Results showed a dose-dependent increase in total tibiofemoral joint cartilage thickness with significant differences to sprifermin 100 microgram at 6 and 12 months, compared with the placebo group (0.03 vs -0.02 mm; P<0.001, and 0.02 vs -0.02; P<0.001, respectively) . The impact on pain, in addition to structural effects, may be known after completion of the trial.
Other target strategies in regenerative therapies are mesenchymal stem cells (MSCs), which may differentiate into chondrocytes. Prof. Berenbaum warned that the interpretation of MSCs effects is at a preliminary stage. There may be an effect not due to regeneration but because of the release of anti-inflammatory chemicals. There is a need for well-designed trials such as ADIPOA-2; a phase 2b, multicentre, prospective, randomised, double-blind study comparing culture-expanded autologous adipose tissue derived MSCs with placebo. Study results are not yet available.
Finally, Prof. Berenbaum focused on targeted therapies for pain, the pathophysiology of pain, and the role of nerve growth factor (NGF) as a target (phase 3 trials). More than 1 type of pain (nociceptive, neuropathic, sensory hypersensitivity pain) may be present in one patient. “Anti-NGF drugs’ mechanism of action is developed for nociceptive pain. By targeting NGF, released after joint destruction, you can expect to decrease the pain. A meta-analysis comparing the efficacy and safety of tanezumab compared with other pain-modifying agents showed patient improvement of tanezumab in the WOMAC pain subscale at 16 weeks. However, there are safety concerns like rapid progressive OA in 1-3% of the patients . Lowering the dosage by injection every 8 weeks and assessing the benefit-risk ratio are now considered . Targeted therapies should also be linked to phenotype and endotype because not all OA patients are the same.
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Top image: @ iStockPhoto: Suze777
The content and interpretation of these conference highlights are the views and comments of the speakers/authors.