Reflections from the 2021 OARSI clinical trial symposium:Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

OBJECTIVE: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. DESIGN: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. RESULTS: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. CONCLUSIONS: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of “illness vs disease”. There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient

Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis

OBJECTIVE.: The aim of the present study was to assess the therapeutic potential of a P2X purinergic receptor antagonist, namely periodate oxidized ATP (oATP), in collagen-induced arthritis (CIA). METHODS.: Arthritis was induced in male DBA/1J mice by immunization with type II collagen. Animals showing digits inflammation and paw swelling were treated intraperitoneally each day for 10 days with 100 \u3bcl of 3 mM oATP. At the end of treatment animals were sacrificed and paws removed for histological analysis and evaluation of T-cell infiltration. Humoral response to type II collagen was analyzed and specific serum autoantibody levels were correlated to the clinical score observed in the different animal groups. RESULTS: oATP treatment resulted in a sustained reduction of disease activity, which was associated with a significant decrease in CD3+ T-cells infiltration in arthritic lesions and a significant amelioration of cartilage erosion. Peripheral regulatory T cells (Tregs) were significantly increased upon P2X blockade in lymph nodes. Moreover, a marked reduction of circulating autoantibodies directed against mouse collagen type II wasdetected. CONCLUSIONS.: Our findings indicate that P2X receptor antagonism has an important therapeutic potential for chronic inflammatory rheumatic disorders. The therapeutic efficacy was associated with an increase of Tregs in secondary lymphoid organs. Notably, we observed a significant correlation between serum autoantibodies and clinical efficacy exerted by oATP treatment. Together these results underscore the potential value of the P2X receptor signaling pathway as a potential pharmacological target for the modulation of adaptive immunity in CIA

From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers

\ua9 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. Areas covered: We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. Expert opinion: As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA

OA phenotypes, rather than disease stage, drive structural progression – identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA

SummaryBackground/PurposeThe aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren–Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI.MethodsData from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA).ResultsThere was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner.ConclusionThese data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression

Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice

ABSTRACT Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT 3 R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT 3 R antagonists tropisetron and palonosetron on the development of NA-FLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotoninreuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (Ϫ29%), liver inflammation (Ϫ56%), and liver cell necrosis (Ϫ59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-␣ mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation

The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial

Objective To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin. Methods Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40–90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint. Results The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]). Conclusions Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials. Clinical trial registration : NCT01919164

A consensus-based framework for conducting and reporting osteoarthritis phenotype research

Background The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. Methods A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. Results Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. Conclusions This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients

Predicted and actual 2-year structural and pain progression in the IMI-APPROACH knee osteoarthritis cohort

ClinicalTrials.gov, https://clinicaltrials.gov, NCT03883568[Abstract] Objectives: The IMI-APPROACH knee osteoarthritis study used machine learning (ML) to predict structural and/or pain progression, expressed by a structural (S) and pain (P) predicted-progression score, to select patients from existing cohorts. This study evaluates the actual 2-year progression within the IMI-APPROACH, in relation to the predicted-progression scores. Methods: Actual structural progression was measured using minimum joint space width (minJSW). Actual pain (progression) was evaluated using the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain questionnaire. Progression was presented as actual change (Δ) after 2 years, and as progression over 2 years based on a per patient fitted regression line using 0, 0.5, 1 and 2-year values. Differences in predicted-progression scores between actual progressors and non-progressors were evaluated. Receiver operating characteristic (ROC) curves were constructed and corresponding area under the curve (AUC) reported. Using Youden's index, optimal cut-offs were chosen to enable evaluation of both predicted-progression scores to identify actual progressors. Results: Actual structural progressors were initially assigned higher S predicted-progression scores compared with structural non-progressors. Likewise, actual pain progressors were assigned higher P predicted-progression scores compared with pain non-progressors. The AUC-ROC for the S predicted-progression score to identify actual structural progressors was poor (0.612 and 0.599 for Δ and regression minJSW, respectively). The AUC-ROC for the P predicted-progression score to identify actual pain progressors were good (0.817 and 0.830 for Δ and regression KOOS pain, respectively). Conclusion: The S and P predicted-progression scores as provided by the ML models developed and used for the selection of IMI-APPROACH patients were to some degree able to distinguish between actual progressors and non-progressors

Neuropathic Pain in the IMI-APPROACH Knee Osteoarthritis Cohort: Prevalence and Phenotyping

The study is registered under clinicaltrials.gov nr: NCT03883568.[Abstract] Objectives: Osteoarthritis (OA) patients with a neuropathic pain (NP) component may represent a specific phenotype. This study compares joint damage, pain and functional disability between knee OA patients with a likely NP component, and those without a likely NP component. Methods: Baseline data from the Innovative Medicines Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway knee OA cohort study were used. Patients with a painDETECT score ≥19 (with likely NP component, n=24) were matched on a 1:2 ratio to patients with a painDETECT score ≤12 (without likely NP component), and similar knee and general pain (Knee Injury and Osteoarthritis Outcome Score pain and Short Form 36 pain). Pain, physical function and radiographic joint damage of multiple joints were determined and compared between OA patients with and without a likely NP component. Results: OA patients with painDETECT scores ≥19 had statistically significant less radiographic joint damage (p≤0.04 for Knee Images Digital Analysis parameters and Kellgren and Lawrence grade), but an impaired physical function (p<0.003 for all tests) compared with patients with a painDETECT score ≤12. In addition, more severe pain was found in joints other than the index knee (p≤0.001 for hips and hands), while joint damage throughout the body was not different. Conclusions: OA patients with a likely NP component, as determined with the painDETECT questionnaire, may represent a specific OA phenotype, where local and overall joint damage is not the main cause of pain and disability. Patients with this NP component will likely not benefit from general pain medication and/or disease-modifying OA drug (DMOAD) therapy. Reserved inclusion of these patients in DMOAD trials is advised in the quest for successful OA treatments