Updates in Osteoarthritis: Research Provides Insights into Molecular Pathogenesis of OA

ACR Convergence 2021—The session Updates in OA: Distinguishing OA Subtypes & Illuminating Future Therapies at ACR Convergence 2021 featured two presenters. Carla R. Scanzello, MD, PhD, associate professor, Division of Rheumatology, University of Pennsylvania Perelman School of Medicine and rheumatology section chief, Corporal Michael J. Crescenz VA Medical Center, both in Philadelphia, gave a talk titled Understand the Diagnostic Landscape of Osteoarthritis & Defining OA Phenotypes.

Dr. Scanzello was followed by Tonia Vincent, MD, PhD, FRCP, professor of musculoskeletal biology at the Kennedy Institute of Rheumatology, University of Oxford, United Kingdom, whose talk was called OA: New Horizons for Therapy.

Phenotypes & Endotypes

Dr. Carla Scanzello

Dr. Scanzello began with noting that consideration of both phenotypes and endotypes is important for the design of clinical trials and for therapeutic development for osteoarthritis (OA).

She reviewed some of the clinical heterogeneity that has led to efforts to define phenotypes of OA. For example, joint involvement can be a single joint or multiple joints. Symptoms can manifest early or late, and progression can happen slowly or rapidly. Bone pathology seen on radiography can be described as atrophic, hypertrophic or erosive.

As researchers try to find associations between these variable phenotypes of OA and prognosis, Gullo et al. found that patients with multi-joint OA had a poorer perception of their health and poorer physical function.¹ Others have identified characteristics of knee OA patients with more rapid progression of both pathology and pain.^2.3   

Dr. Scanzello also presented research on erosive hand OA to further examine phenotypes. Erosive hand OA is associated with more clinical inflammation, and genetic associations and biomarkers for erosive hand OA may differ from those for non-erosive hand OA. A study from Vanhaverbeke et al. found that erosive changes and clinical swelling were predictive of radiographic progression of hand OA over 10 years, suggesting that this is a more aggressive form of hand OA, Dr. Scanzello said.⁴

Limitations in OA Research

Dr. Scanzello also shared some of the challenges associated with conducting OA research.

Established criteria used to include patients in OA clinical trials have important limitations, Dr. Scanzello noted. For example, most studies require a grade of 2 on the Kellgren-Lawrence radiographic scale to be included in clinical studies.⁵ However, recent studies show that those with a grade of 1 also have progression of disease. “The tools that we use to include people in trials are limited in the ability to detect early OA, when patients may be more amenable to treatment,” she said.

Another challenge with early (pre-radiographic) OA is identifying it in the clinic. Along with joint line tenderness on physical exam, symptoms, such as episodic pain, crepitus and a feeling of the joint “giving way,” are already common early in disease. The person with early OA may have physical function limitations, but they typically are associated with leisure activities. In the clinic, health providers will want to be sure to rule out inflammatory arthritis, bursitis and tendinitis in these patients.

When deciding whether OA is a continuum of a disease or one with distinct phenotypes and subsets, Dr. Scanzello believes it is a little of both. More research is needed to examine the interplay of risk factors that can influence prognosis, as patients often develop more risk factors over the course of their disease, she said.

Another important question is how the clinical variables might reflect underlying disease mechanisms. This requires investigating endotypes—subtypes defined by distinct causes or biological mechanisms—that are reflected in many animal models of OA, and close collaboration between those working with these models and those working with human patients. “Defining these mechanisms and understanding the timelines (of pathology and pain) are leading us to a better understanding of when to target and how,” Dr. Scanzello said.

Examining New Targets for OA Therapy

Dr. Tonia Vincent

By tapping both translational and clinical research, rheumatologists are more likely to find real targets to treat OA, said Dr. Vincent in the second part of the session.

The past 20 years have provided huge insights into the molecular pathogenesis of OA. Some of these have arisen from genome-wide studies, she said.

“In that time, we’ve discovered that it is unhelpful to make assumptions about OA. We shouldn’t assume it’s like the arthritides we’ve dealt with before,” Dr. Vincent noted.

“Although research can provide insights into OA, it is also essential to check that the biology in the preclinical models is really relevant to the patient,” Dr. Vincent advised. Rheumatologists should also consider the debate over whether OA has distinct endotypes or whether it’s a single disease.

Dr. Vincent presented work to support two major mechanically driven processes that impact the pathogenesis of OA, with one side induced by compressive load that releases a number of growth factors from the tissue, and another activated by shear stress or friction of the joint surface, which drives mechanoflammation and activates inflammatory genes.^6,7 The former pathway, which is strongly supported by genome-wide association studies, drives joint protection in patients with OA, Dr. Vincent said.

“This has turned pathogenesis on its head and suggests it’s a disease primarily due to failed repair rather than driven by mechano-inflammatory pathways,” she explained.

Having said this, Dr. Vincent also shared findings related to retinoic acid—specifically, that retinoic acid is maintained at high levels in healthy chondrocytes but drops rapidly upon cartilage injury.⁸ Using talarozole, a drug that boosts retinoic acid levels in the cell, mechanoflammation could be suppressed in vitro through a peroxisome proliferator-activated receptor gamma-dependent manner, and was able to suppress OA in mice.

Talarozole has been tested in phase 2 clinical trials in other diseases and has an acceptable safety profile, so these results raise the possibility that this drug could be tested in OA patients, Dr. Vincent concluded.⁹

Vanessa Caceres is a medical writer in Bradenton, Fla.

References

1. Gullo TR, Golightly YM, Cleveland RJ, et al. Defining multiple joint osteoarthritis, its frequency and impact in a community-based cohort. Semin Arthritis Rheum. 2019 Jun;48(6):950–957.
2. Driban JB, Harkey MS, Barbe MF, et al. Risk factors and the natural history of accelerated knee osteoarthritis: A narrative review. BMC Musculoskelet Disord. 2020 May 29;21(1):332.
3. Carlesso LC, Neogi T. Identifying pain susceptibility phenotypes in knee osteoarthritis. Clin Exp Rheumatol. Sep-Oct 2019;37 Suppl 120(5):96–99.
4. Vanhaverbeke T, Pardaens L, Wittoek R. Natural disease progression in finger osteoarthritis: Results from a 10-year follow-up cohort. Scand J Rheumatol. 2020 Nov;49(6):498–504.
5. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec;16(4):494–502.
6. Keppie SJ, Mansfield JC, Tang X, et al. Matrix-bound growth factors are released upon cartilage-compression by an aggrecan-dependent sodicum flux that is lost in osteoarthritis. Function (Oxf). 2021 Aug 2;2(5):zqab037.
7. Vincent TL. Mechanoflammation in osteoarthritis pathogenesis. Semin Arthritis Rheum. 2019 Dec;49(3S):S36–S38.
8. Zhu L, Ismail H, Chanalaris A, et al. OP0261. Retinoic acid is regulated by cartilage injury and is anti-inflammatory in hand osteoarthritis. Ann Rheum Dis. 2018 Jun;77(suppl 2):179–180.
9. Geria AN, Scheinfeld NS. Talarozole, a selective inhibitor of P450-mediated all-trans retinoic acid for the treatment of psoriasis and acne. Curr Opin Investig Drugs. 2008 Nov;9(11):1228–1237.