Summary Report of the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society’s Symposium on Targets for Osteoarthritis Research: Part 1: Epidemiology, Pathophysiology, and Current Imaging Approaches

Abstract

This first of a 2-part series of articles recounts the key points presented in a collaborative symposium sponsored jointly by the Arthritis Foundation and the American Orthopaedic Foot & Ankle Society with the intent to survey the state of scientific knowledge related to incidence, diagnosis, pathologic mechanisms, and injection treatment options for osteoarthritis (OA) of the foot and ankle. A meeting was held virtually on December 3, 2021. A group of experts were invited to present brief synopses of the current state of knowledge and research in this area. Part 1 overviews areas of epidemiology and pathophysiology, current approaches in imaging, diagnostic and therapeutic injections, and genetics. Opportunities for future research are discussed. The OA scientific community, including funding agencies, academia, industry, and regulatory agencies, must recognize the needs of patients that suffer from arthritis of foot and ankle. The foot and ankle contain a myriad of interrelated joints and tissues that together provide a critical functionality. When this functionality is compromised by OA, significant disability results, yet the foot and ankle are generally understudied by the research community.

Level of Evidence: Level V - Review Article/Expert Opinion.

Introduction

Osteoarthritis (OA) is a serious disease that affects more than 500 million adults, 15% of adults globally, that requires more treatment options to help patients and providers manage the disease.^20,28 Treatments for OA in the foot and ankle have lower satisfaction and less longevity than in other weightbearing joints.⁵⁸ The prevalence of OA in the foot and ankle is significant, but unclear because of lack of research.^52,73 A structured search of PubMed shows that there is at least 10-fold more research activity in knee OA compared with foot and ankle OA. Recognizing this need, the Arthritis Foundation (AF), in partnership with the American Orthopaedic Foot & Ankle Society (AOFAS), convened a virtual meeting of academic thought-leaders to overview the state of science and clinical approaches in OA of the foot and ankle. The goal of the meeting was to highlight the need and encourage further research activity in this area. This article summarizes the workshop presentations and discussions.

Epidemiology and Pathophysiology of Ankle OA

J. Lawrence Marsh, MD

Approximately 1% of adults suffer from ankle OA.^52,75 In the ankle, post-traumatic OA (PTOA) is by far the most common etiology (80%), which is different from the other major lower extremity joints such as knee (10%) and hip (2%).^6,61 PTOA is prevalent and accounts for approximately 12% of symptomatic OA and 5.6 million cases of lower extremity OA in the United States.⁶ The burden of ankle OA is high because of the pain and impairment. PTOA occurs at a younger age (approximately 10 years earlier than primary OA), leading to more disability in the productive years of life and providing more challenges to surgical reconstructive options.^35,41 The physical impairment of ankle OA is very significant, having been found to be comparable to that associated with end-stage kidney disease, congestive heart failure, or end-stage hip OA.^22,62

The most common injuries that lead to ankle OA are sprains, dislocations, and malleolar (rotational) fractures.³² Significant risk factors at the time of injury for subsequent ankle OA include smoking, high body mass index, and age >30 years.^36,47 The normal ankle forms a relatively tight mortise, and even slight widening of the mortise may lead to instability.²³ Similarly more subtle instability, as from posterior malleolar fractures, can lead to rapid ankle failure if left untreated.²⁹ Recurrent injury (such as sprains) and chronic instability of the ankle increase the risk for ankle OA.⁴⁶ For fractures involving the articular surface of the distal tibia, the role of the location of the fracture is important in dictating the risk for progression to OA. For example, the ankle joint takes higher load in the anterior portion of the joint, so anterior impaction fractures of the tibial plafond have a high risk of progressing rapidly to OA and subsequent joint fusion.⁸

The effects of mechanical injury to the articular surface have been studied in ankle injuries, animal models, and in vitro preparations. The energy of injury in tibial pilon fractures can be measured as an indicator of fracture severity based on computed tomography (CT) data, and it has a strong correlation with the risk for ankle OA. In vitro studies show in osteochondral samples that the severity of mechanical impact to cartilage directly correlates with the amount and progression of chondrocyte death.⁷² Malreduction of the fracture can lead to chronic increased joint contact stress, which also increases PTOA risk. Weightbearing CT (WBCT) obtained after the fracture heals can be used to model the increased contact stress and can also assess the joint space width as a measure of early cartilage loss.^3,40

Imaging of Foot and Ankle Arthritis

Carolyn M. Sofka, MD

A number of imaging modalities are used to evaluate, treat, and follow patients with arthritis of the foot and ankle, including rheumatoid arthritis, psoriasis, gout, and especially the highly prevalent OA.⁷⁹ Imaging is used to identify nonuniform joint space narrowing, the presence of osteophytes, sclerosis, proliferative changes, and subchondral cysts.^15,19,33,74 Because of the overwhelmingly frequent posttraumatic nature of OA in the foot and ankle, past trauma must also be considered in imaging evaluation.^24,61 Radiographs, CT, ultrasonography, and magnetic resonance imaging (MRI) are the most frequently used and helpful imaging modalities for OA of the foot and ankle.

Conventional radiography remains the first-line imaging modality being accessible, well-established, reproducible, and inexpensive. The technology can assess bone loss (or erosions), patterns of joint space narrowing, and proliferative changes. Radiographs can also provide some ability to see bone density. There are limitations when imaging complicated anatomy or overlapping structures, a common occurrence when imaging the foot and ankle and particularly the midfoot. Cartilage cannot be directly visualized, and subclinical erosions cannot be evaluated. Standardized radiographic atlases of features of OA of the foot and ankle are available for scoring research purposes.⁴⁵

CT allows for better evaluation of bone anatomy than radiographs, including joint space narrowing, erosions, and osteophytes. Weightbearing CT (WBCT), when available, affords the ability to evaluate alignment of the foot and ankle in a loaded position.^2,18 Dual-energy CT (DECT) uses 2 detector pairs to obtain 2 separate data sets that can be used to detect urate crystals in suspected cases of gout.^9,21,49,54

Ultrasonography (or sonography) is useful for soft tissue pathologies such as synovitis or joint effusions.^1,68,77 Power Doppler, available in most ultrasound systems, often correlates with disease activity by indicating presence or absence of blood flow. The Outcome Measures in Clinical Trials (OMERACT) group has worked to standardize definitions and criteria in ultrasonography for erosions, joint effusion, synovitis, tenosynovitis, and enthesitis.^16,70 The sensitivity for detecting erosions by ultrasound is higher than for conventional radiographs. Ultrasonography can be used to complement therapeutic and diagnostic injections as described in the section below.

MRI is the most useful imaging modality for global evaluation of bone and soft tissue of the foot and ankle.³¹ With specialized pulse sequences, the modality is capable also of imaging synovitis with and without intra-articular contrast administration, subclinical erosions to follow activity of disease, articular cartilage, and other soft tissue abnormalities, such as tendons or bursal collections.⁵⁰ Limitations of MRI include that it is relatively expensive and cannot routinely be acquired with the foot and ankle in a loaded position.

Foot and Ankle Biomechanics and Implications for the Treatment of OA

James W. Brodsky, MD

Patients with ankle OA seek the help of an orthopaedic surgeon when they have trouble with pain, function, or structural deformity. The burden of foot and ankle OA is not purely from the pain caused by synovitis, joint degeneration, or joint damage. Symptoms are distinct to deformity of the structures and alteration of function. The biomechanics of the foot and ankle joints are complex and interrelated, meaning that pain and destruction in some joints are caused by deformities in other joints. Evaluating success in reconstructive surgery of the foot and ankle ideally requires that measures of biomechanical function be collected noninvasively, in real time, in vivo, reproducibly, and objectively.

Gait analysis originated in the 1800s and has significantly advanced because of improvements in technology.⁵³ Today, multicamera motion capture systems and in-floor force plates are routinely used to rigorously analyze gait. Normal human gait has reciprocal and symmetrical phases; each foot is touching the ground 60% of the time during the “stance” phase and is off the ground 40% of the time in the “swing” phase. When patients lose proper function of the joints in the ankle and feet, there is a remarkable ability to biomechanically compensate,⁶⁹ which leads to abnormal gait and increased stress and motion in adjacent joints.

Abnormalities of gait caused by ankle OA can be partially addressed by ankle arthrodesis or arthroplasty.^5,63 However, tibiotalar arthrodesis does not restore normal gait, with persistent alterations in cadence, step length, walking velocity, total support time, and ankle power. After ankle arthroplasty, such functional gait measures do not correlate with patient-reported outcomes such as the visual analog scale (VAS) for pain or the 36-Item Short-Form Health Survey (SF-36) for perceptions of function and improvement. The SF-36 is correlated most with walking speed and ankle push-off power, whereas pain and range of motion are not. When considering arthrodesis or arthroplasty, both are good options that significantly improve pain and function; notably, pain is not caused by the “stiffness” or lack of joint motion, but pain inhibits function. Despite having the joints that move the least in the foot, midfoot OA is a frequent cause of chronic foot pain that deserves further research attention.

Diagnostic and Therapeutic Value of Injections

Daniel M. Cushman, MD

Injections in the foot and ankle serve as a (1) diagnostic tool, to identify the pain generator, or (2) therapeutic, to provide 2-3 months of pain relief. Injections are generally used to augment physical therapy, alleviate milder pain, diagnose the location of pain, and to treat those who are unable to undergo surgical intervention.¹⁷ The most commonly performed injections include corticosteroids (usually with anesthetic), and to lesser degrees the applications of anesthetic only (possibly as a diagnostic), hyaluronic acid, or platelet-rich plasma.

Mixed results have been shown with respect to the predictive nature of pain relief from anesthetic injections in the foot and ankle,^13,43,48,51 which may be related to communication between joint spaces.^7,44 Ward et al⁷⁸ showed use of corticosteroid with anesthetic to improve the Foot and Ankle Outcome Score (FAOS) and predict sustained improvement. The study highlights the heterogeneity of OA, even in the foot and ankle, by observing multiple time points in 36 joints and 18 patients. The field may require further study of the many joints and ligaments to specifically determine the positive predictive value in patients with foot and ankle OA.

Palpation guidance is a standard method to guide injections that is inexpensive, quick, and simple but heavily dependent on the operator.¹⁷ Fluoroscopic guidance is considered the criterion standard because of superior accuracy but is expensive, requires intra-articular contrast, and requires a costly procedure suite.²⁷ The procedure is operator-dependent, but less so because of the feedback of the contrast flow pattern. Ultrasonography has good accuracy, allows visualization of soft tissue structures, is less expensive compared with fluoroscopy, and can be performed in the doctor’s office.⁶⁶ Ultrasonography is also heavily operator-dependent. In several studies, ultrasonographic guidance has been found to be comparable to the criterion standard fluoroscopic guidance.^37,42,66

Platelet-rich plasma (PRP) injections have been considered a promising treatment for ankle (tibiotalar) OA.⁵⁶ The high interest is driven by the strong safety profile of PRP and promising results in the knee.^55,57 A recent randomized controlled trial found that intra-articular PRP injections to patients with ankle OA did not significantly improve symptoms or function over placebo in a 26-week period.⁵⁷

The evidence regarding injections in the foot and ankle consists mostly of case series with very few randomized controlled trials.^12,25 Side effects and risks of corticosteroid injections include pain flare (~1/5 patients),¹⁴ infection (~1/10 000 to 1/50 000 patients, or 1/170 physician-years of practice),¹¹ bruising, nerve injury, and arterial injury. There are many adverse effects of corticosteroids, with main concerns being the disruption of the musculoskeletal, endocrine, and dermatologic systems.²⁶ There is a lack of evidence for using injections in the foot and ankle, particularly the provocative PRP, and necessitates more research, primarily prospective trials.

Deciphering Pathways Governing Susceptibility to First MTP Joint OA

Michael J. Jurynec, PhD

Although OA is a debilitating disease affecting a large portion of the aged population in the United States, there is not a single drug available that is used to alter the course of the disease.⁷⁶ With the exception of surgical intervention such as joint replacement, OA treatment is focused on pain management.³⁰ Lack of drugs that inhibit progression of the disease is a huge unmet need. Poor understanding of the pathways underlying OA is the key limitation to the development of effective therapies.^60,71 We do not understand the pathways that are critical for the normal homeostatic maintenance of the joint and whose perturbation by gene variants, aging, physiology, environment, or trauma, confer susceptibility to disease. Ongoing research is focused directly on the discovery of molecular and cellular pathways whose normal function acts to limit OA development.

OA of the first MTP joint is the most common form of progressive OA in the foot, affecting 35% to 60% of adults aged >65 years,³⁴ yet the joint has been largely ignored in genomic studies^4,65 and there are few genes associated with the disease.^39,64 One proven approach toward identifying pathways and biological processes whose normal functions limit disease has been to identify gene variants responsible for highly penetrant familial forms of the disease. Increasing evidence demonstrates there are few differences between the genes contributing to “monogenic” disease and those contributing to complex disease.^10,67 Studying families with first MTP joint OA is a powerful approach to define the genetic factors that contribute to the disease process. A unique medical genetics resource, the Utah Population Database (UPDB), has been used to identify families that segregate highly penetrant, dominant first MTP joint OA. The UPDB provides person-based interlinked records documenting genealogy, medical records, and vital statistics for more than 11 million individuals from the late 18th century to the present.

To date, genomic analysis has been performed on 16 families enrolled with first MTP joint OA. The analyses indicate that alterations in inflammatory signaling are a major risk factor for development of first MTP joint OA. A rare allele of the Receptor Interacting Protein Kinase 2 (RIPK2) gene (p.Asn104Asp) has been associated with dominant inheritance of early-onset OA of the first MTP joint in a single family.³⁸ The RIPK2 signaling pathway is a component of the innate immunity system involved in clearing bacterial infections and maintaining immune homeostasis.⁵⁹ Analysis of additional first MTP joint OA families identified rare variants affecting other components of the pathway, including the upstream activator, NOD2. Introduction of the RIPK2 disease allele into the mouse genome alters the homeostasis of the joint that previews a definitive OA state and makes the joint more susceptible to injury induced OA.³⁹ These data indicate that modulation of the NOD/RIPK2 pathway is a general risk factor for first MTP joint OA. NOD/RIPK2 pathway activity may be used for detection of early stages of disease and may also have therapeutic potential. Finally, analysis of additional first MTP joint OA families will define other key genes and pathways that contribute to disease susceptibility.

Conclusions

OA is a complex disease of the joint that affects millions of adults in the United States and worldwide. The OA scientific community focuses much of their attention toward understanding and managing the disease in the knee, hip, and hand. Yet, a substantial number of patients are painfully disabled by OA in the joints of the foot and ankle, with fewer treatment options with lower satisfaction and longevity. The future can be brighter for these patients and their providers if the broader OA science community can come together to give this neglected area attention and significant expertise. This esteemed faculty of experts sought to provide an overview of the current state of clinical science in OA of the foot and ankle and shared insights for emphasis areas research:

• • It needs to be recognized that the anatomy of joints in the foot and ankle is complex, biomechanically robust, and unique.

• • Orthobiologics are generally viewed as desirable because of safety and the need to preserve joints in the foot and ankle but have not been found to have consistent benefit.

• • Defining the genes and pathways that are significant risk factors for OA in the foot and ankle may help improve understanding of the mechanisms underlying disease onset and progression, development of therapeutics that could modify the course of OA, development of assays to detect biomarkers of early stages of OA, prediction of additional genes that likely contribute to susceptibility, helping to enrich clinical trial populations, and encouraging education and prevention through personalized medicine.