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New treatments in osteoarthritis

Presented by
Prof. Tonia Vincent , University of Oxford, United Kingdom
EULAR 2022
Osteoarthritis (OA) pathogenesis is complex. According to novel data, the compressive load repair pathway is beneficial for the cartilage. Therefore, future research should rather focus on cartilage regeneration instead of fighting inflammation.

As Prof. Tonia Vincent (University of Oxford, United Kingdom) pointed out in her talk, “Stop taking painkillers for arthritis” was a depressing headline published a month ago in The Times. It was based on the draft NICE guidelines released in April 2022 [1]. In the guidelines, exercise for OA patients is recommended instead of pain medication, as several control trials stated that any exercise was beneficial compared with no exercise. There is less established data on a dose-dependent relationship between OA and weight loss. The 2 large existing cohort studies are of low to very low quality. In the United Kingdom, it is recommended to commence topical NSAIDs and intra-articular injections but not to offer other pain medications as these are not deemed to be cost-effective.
Drugs used in inflammatory arthritis failed in OA

OA occurs due to both anabolic and catabolic processes. Previously, research targeted the catabolic process, aiming at dampening immune responses or attacking specific proteases in this pathway. Therefore, some drugs used in inflammatory arthritis (i.e., DMARDs, anti-IL1, anti-IL6, anti-TNF, hydroxychloroquine) were repurposed for OA, but unfortunately, all studies in this regard have failed. However, as Prof. Vincent said: “There is still hope for OA patients in the future!”

Over the past 20 years, revolutionary progress has been made in the OA field, particularly in epidemiology and molecular analysis of articular cartilage, as well as tremendous improvements in Omics studies. However, the way forward is hindered by the high costs of setting up a clinical trial, so more attention is now given to experimental outcomes rather than clinical outcomes, where smaller numbers of patients are necessary.
OA: driven by mechanical injury

OA is a disease driven by abnormal mechanical load going through both large and small joints. This is due to 2 mechanisms: increased load on a normal joint, by obesity or malalignment, or, alternatively, normal load on a joint that has lost its mechano-protection due to ageing or an acute joint injury.

The articular cartilage consists of 5–10% of the total tissue volume of the joint and is one of the most quiescent tissues of the human body. Cartilage is exquisitely sensitive to injury. When an injury occurs, almost every signalling pathway in the cartilage is rapidly activated within 30 seconds. Injury response genes, including inflammatory and anti-inflammatory repair genes, are turned on, producing various proteins. “We think this injury response is really important to what happens in OA,” Prof. Vincent said.
Pathogenesis is a balance of 2 counteracting pathways

Further research has shown the existence of 2 principal pathways that drive different responses in the joint (see Figure):

  • The sheer stress pathway, resulting in mechano-inflammation leading finally to matrix degradation and pain;
  • The repair pathway, releasing a whole host of growth factors that collectively drive the repair and regeneration of the cartilage. Therefore, the compressive load might be beneficial for the cartilage.
Figure: The osteoarthritis pathogenesis [1]

FGF2, fibroblast growth factor 2; TGFβ, transforming growth factor β; HDGF, heparin-binding growth factor; TGFβR, transforming growth factor β receptor; FGFR, fibroblast growth factor receptor.

Research shows that all 70–80 genes directly associated with OA biology activate the repair pathways. “Maybe we have been barking up the wrong tree. Maybe we should be focusing our attempts at repairing cartilage rather than suppressing inflammation in OA,” Prof. Vincent said.

The compelling evidence to support the hypothesis that articular cartilage can undergo spontaneous repair and regeneration is 2-fold:

  • In a knee joint distraction procedure, joints were pulled apart using an external fixator kept in situ for 6 weeks, and patients were allowed to walk, meaning there would be modest compressive load on joints but no shear stress, as the joints were not hinged. After 2 years of follow-up, cartilage-like tissue was seen in all 20 patients in T2-weighted MRI, as well as a significant reduction in the eroded joint surface [2].
  • Intraarticular injections of sprifermin, a recombinant human fibroblast growth factor, resulted in a dose-dependent increase in cartilage thickness [3,4]. Although a post-hoc analysis found no improvement in pain in patients who had already progressed in OA, there was a dose-dependent pain suppression in patients at high risk of progression [5].

Some future pro-regenerative therapies are on the horizon. An interesting candidate is LNA043, an angiopoietin-like 3 agonist. After robust preclinical data, this agent is currently being assessed in 2 clinical trials.   The jury is still out regarding GLPG1972, a highly selective aggrecanase inhibitor, and the senolytic UBX0101, but neither agent met the primary endpoint of their respective trials. Phase 3 results on lorecivivint will be presented later this year.
Choose studies wisely in OA

To enhance future success, it is imperative to optimise clinical outcomes. “It is really important not to throw the baby out with the bathwater, because we are choosing the wrong primary and secondary endpoint in these studies,” Prof. Vincent said. Maintaining momentum in OA research is also essential, as many new avenues are opening. Finally, patient stratification in clinical trials is necessary, as more evidence has uncovered that different OA patients respond differently to treatment.

In an exploratory analysis of the CANTOS trial (NCT01327846), a surprisingly significant 50% reduction in joint replacements in patients treated with any dose of the IL-1 inhibitor canakinumab was observed [6]. Although this requires much deeper investigation, hope can be placed for the future. Another study showed that patients with low levels of collagen type II show a kickstart in their anabolic process with sprifermin. However, no anabolism occurs in patients with adequate levels of collagen type II [7]. Therefore, the future looks bright for OA patients.

  1. Vincent T. New Treatments in Osteoarthritis, EULAR 2022 Congress, 1–4 June, Copenhagen, Denmark.
  2. Wiegand K, et al. Osteoarthritis Cartilage. 2013;21:1660–7.
  3. Hochberg MC, et al. JAMA. 2019:322:1360–70.
  4. Eckstein F, et al. Ann Rheum Dis. 2020;79:525–8.
  5. Guehring H, et al. Seminars in Arthritis and Rheumatism. 2021;51:450–6.
  6. Schieker M, et al. Ann Intern Med. 2020;173:509–15.
  7. Bay-Jensen AC, et al. Osteoarthritis Cartilage. 2022;30:92–99.

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