Summary Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide, largely due to pain, the primary symptom of the disease. The pain experience in knee OA ...in particular is well-recognized as typically transitioning from intermittent weight-bearing pain to a more persistent, chronic pain. Methods to validly assess pain in OA studies have been developed to address the complex nature of the pain experience. The etiology of pain in OA is recognized to be multifactorial, with both intra-articular and extra-articular risk factors. Nonetheless, greater insights are needed into pain mechanisms in OA to enable rational mechanism-based management of pain. Consequences of pain related to OA contribute to a substantial socioeconomic burden.
Summary Objective To identify the independent relation of synovitis with incident radiographic knee osteoarthritis (OA) after adjusting for other structural factors known to cause synovitis. Design ...We examined MRIs from knees that developed incident radiographic OA from the Multicenter Osteoarthritis Study (MOST) and compared these case knees with controls that did not develop OA. We examined baseline MRIs for knees developing OA at any time up to 84 months follow-up. We scored lesions in cartilage, meniscus, bone marrow and synovitis. Synovitis scores were summed (0–9) across three regions, suprapatellar, infrapatellar and intercondylar region, each of which was scored 0–3. After bivariate analyses examining each factor's association with incidence, we carried out multivariable regression analyses adjusting for age, sex, BMI, alignment and cartilage and meniscal damage. Results We studied 239 case and 731 control knees. In bivariate analyses, cartilage lesions, meniscal damage, synovitis and bone marrow lesions were all risk factors for OA. After multivariable analyses, synovitis was associated with incident OA. A higher synovitis score increased the risk of incident OA (adjusted OR per unit increase 1.1; (95% CI 1.0, 1.2, P = .02)), but increased risk was associated only with synovitis scores of ≥3 (adjusted OR 1.6; 95% CI 1.2, 2.1, P = .003). Conclusions Synovitis, especially when there is a substantial volume within the knee, is an independent cause of OA.
This review outlines the most commonly used quantitative sensory tests to identify pain sensitization. We examine cross–sectional associations between quantitative sensory testing (QST) measures and ...OA symptoms and severity, along with longitudinal associations between QST findings and response to surgical and non-surgical treatments for OA.
We conducted a search in PubMed for English language papers including ‘osteoarthritis’ and ‘quantitative sensory testing’ as search terms. Papers that did not pertain specifically to OA or QST were excluded.
Pressure Pain Threshold (PPT), Conditioned Pain Modulation (CPM), and Temporal Summation (TS) are the QST measures used most frequently to identify pain sensitization. Findings indicate that persons with knee OA often exhibit lower PPT thresholds, inefficient CPM, and facilitated TS as compared with controls who do not have OA, supporting the discriminant validity of QST. Pre-treatment QST has shown some success in identifying persons who experience less pain relief from surgical and non-surgical treatments for knee OA. Post-treatment QST has shown that sometimes PPT and CPM can normalize (PPT thresholds increase, and CPM becomes efficient) in patients for whom joint replacement is successful. Recent studies indicate that QST measures are more closely associated with pain severity than OA radiographic severity, suggesting that sensitization may be a trait rather than a state.
QST may have a role in identifying persons who are susceptible to chronic pain and may offer an opportunity for personalized, more effective treatment of OA.
Summary Objective To describe the insights on the epidemiology of pain-structure association and the ramifications of these studies for clinical trials. Design Narrative review summarizing the ...pertinent literature in this area, summarizing some of the methodologic challenges inherent and proposing some research initiatives to further understanding of this complex science. Results The predominant symptom in most patients presenting with osteoarthritis (OA) is pain. Over recent years a number of imaging based studies have narrowed the discord between structural findings on imaging and symptoms. The interpretation of pain in OA is still enigmatic and difficult to deal with both for clinicians and scientists. Conclusions We would envisage that over the next few years many of the pressing questions pertaining to research into the structure pain relationship will continue to be addressed. With this, we can expect clinically appropriate therapeutic advance.
In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on ...the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA.
The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity ...in early disease. This work was undertaken to develop new classification criteria for RA.
A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'.
In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1).
This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.
There is an interest in identifying a metabolic OA phenotype. We therefore assessed the relation of diabetes and cardiovascular disease to prevalent and incident radiographic (ROA) and symptomatic ...knee osteoarthritis (SxOA).
In two large cohort studies of individuals with or at risk for knee OA, the Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), participants self-reported diabetes and cardiovascular disease (CVD) at baseline. We assessed the relation of baseline diabetes and CVD (exposures) to ROA and SxOA cross-sectionally and after 60 (MOST) or 48 (OAI) months of follow-up using logistic regression with GEE to account for 2 knees within an individual, adjusting for potential confounders.
In MOST, 6,020 knees of 3,021 participants (60.1% female, mean ± SD age 62.5 ± 8.1, mean BMI 30.7 ± 6.0, 83.3% Caucasian) were included in the analyses. In OAI, 8,645 knees of 4,339 participants (58.2% female, mean ± SD age 61.1 ± 9.2, mean BMI 28.6 ± 4.8, 80.3% Caucasian) were included. We found no significant associations between prevalent diabetes or CVD and prevalent or incident ROA or SxOA. Effect estimates for prevalent ROA and SxOA ranged from 0.80 (95% CI 0.63–1.03) to 1.17 (0.91–1.51). Effect estimates for incident ROA ranged from 0.80 (0.58–1.11) to 0.88 (0.60–1.29) in MOST and from 0.75 (0.50–1.14) to 1.19 (0.81–1.74) in OAI, and for incident SxOA from 0.93 (0.65–1.31) to 1.22 (0.89–1.67) in MOST and from 0.82 (0.59–1.16) to 1.19 (0.85–1.66) in OAI).
Diabetes and CVD were not associated with prevalent or incident knee OA.
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