Summary Objective To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee ...osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. Methods One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). Results The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (−70 ± 159 vs −31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was −72 ± 122 μm. Conclusions In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).
Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on ...drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field.
The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development.
Signs or symptoms indicative of nociceptive pain occur in 50–70% of OA patients, neuropathic-like pain in 15–30% of patients, and nociplastic pain in 15–50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions.
The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.
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.
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.
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.
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.
Summary Background/Purpose The 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. Methods Data 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). Results There 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. Conclusion These 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.
Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive 3Hsprifermin, a recombinant ...human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection.
In two studies (48–96-h n = 23 and 28-day n = 12), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose 3Hsprifermin (0.24 mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography.
After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24 h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48 h, respectively; intact 3Hsprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days.
After i.a. injection of 3Hsprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.
Summary Objective Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior ...to KR vs non-replaced controls. Methods A nested case–control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence ( T0 ), and at 1–4 years prior to T0 ( T−1 to T−4 ). Cartilage loss between cases and controls was compared using paired t -tests and conditional logistic regression. Results One hundred and eighty-nine knees of 164 OAI participants 55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5 had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls 94 ± 137 vs 55 ± 104 μm; P = 0.0017 (paired t ); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08–1.70). The discrimination was stronger for T−2 → T0 OR 1.61 (1.33–1.95), n = 127 than for T−1 → T0 , and was not statistically significant for intervals prior to T−2 i.e., T−4 → T−2 , OR 0.97 (0.67–1.41), n = 60. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. Conclusions In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined.
PDF
