Synovial changes detected by ultrasound in community-derived people with knee pain

Background: Knee pain, the main symptom of knee osteoarthritis (OA), affects one in 4 people aged over 55 years, of whom 10% have mild to moderate disability. The aetiology of knee pain is heterogeneous and its relationship with structural changes and function is unclear. An important role for synovial pathology in the initiation and progression of knee OA has been emphasised. However, the normal values of synovial changes detected on ultrasound (US) in the general population and their association with knee pain in community-based people with knee pain or OA remain largely unknown. Objectives: [1] to systematically review the literature on synovial changes detected on US in people with knee pain/OA and/or in the general population. [2] to establish the normal ranges for synovial thickness and effusion and determine an optimal cut-off associated with knee pain and radiographic osteoarthritis (ROA) in community-derived men and women over 40 years old. [3] to examine whether community-derived people with early and chronic established knee pain have different risks of having effusion, synovial hypertrophy and Power Doppler signal (PDS), and to explore whether synovial changes detected on US predict/associate with subsequent knee pain worsening. [4] to explore the role of peripheral and central risk factors of knee pain, including the role of synovial changes detected on US in different types of knee pain. Methods: A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. The source population was the Knee Pain and Related Health in the Community (KPIC, n=9506) survey in Nottingham, UK. All participants had bilateral US and radiographic examination. Synovial changes detected on US were measured by two observers (inter-observer concordance correlation was 0.8 (0.6 to 0.9) for effusion and 0.7 (0.5 to 0.9) for synovial hypertrophy). OA structural changes were measured by standardised radiographs (semi-flexed weight-bearing and flexed skyline views) using the Nottingham Line Drawing Atlas (NLDA). A cross-sectional study comprised of 299 randomly selected adults ≥40 years old (147 women, 152 men). The normal range (95% quintile) for effusion and synovial hypertrophy was calculated in the healthy sample (no current knee pain and no ROA, n=163). The optimal cut-off was established using ROC curve analysis. A case-control study compared community-derived participants with early knee pain (n=298), chronic established knee pain (n=100) and no knee pain (n=94) at baseline. 166 early knee pain participants were followed-up at one year for changes in knee pain and synovial changes detected on US. Relationships between changes in synovial changes detected on US and pain severity were examined using correlation analysis. 255 participants with early and established knee pain replied to a one-year follow-up questionnaire. Predictors of knee pain worsening were determined using logistic regression. Central and peripheral risk factors for knee pain were examined using participants from both the cross-sectional and case-control studies (n=736). The contribution of each was presented using ROC curves. Subgroup analysis was undertaken according to the presence/absence of ROA and widespread pain (WSP) for the association between synovial changes detected on US and knee pain. A within-person analysis in participants with unilateral knee pain was also undertaken. Results:Systematic review and meta-analysis: 29 studies (4720 patients) were identified from the literature. The pooled prevalence of US effusion, synovial hypertrophy and PDS in people with knee OA/pain were 51.5% (95%CI 40.2 to 62.8), 41.5% (26.3 to 57.5) and 32.7% (8.34 to 63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8 to 35.3), 14.5% (0 to 58.81), and 15.8% (3.08 to 35.36), respectively). People with knee OA (ACR criteria or ROA) had greater prevalence of synovial changes detected on US than people with knee pain (p=0.037, p=0.010 and p=0.009, respectively). Cross-sectional study: Synovial changes detected on US were different between men and women, therefore, gender-specific reference limits were estimated. In people without KP and structural OA the normal range for effusion was between 0 to 10.3 mm for men and between 0 to 9.8 mm for women and the normal range for synovial hypertrophy was between 0 and 6.8 mm for men and between 0 and 5.4 mm for women. The effusion cut-off able to distinguish a subgroup of people with knee pain and ROA (i.e. “symptomatic OA”) with high specificity was 8.9 mm for men and 7.8 mm for women, and for synovial hypertrophy it was 5.8 mm for men and 4.2 mm for women. Case-control study: At baseline, effusion was associated with early (OR 2.64, 95%CI 1.57 to 4.45) and established KP (OR 5.07, 95%CI 2.74 to 9.38). Synovial hypertrophy was also associated with early (OR 5.43, 95%CI 2.12 to 13.92) and established KP (OR 13.27, 95%CI 4.97 to 35.43). However, the association with effusion diminished when adjusted for ROA. PDS was uncommon (early KP 3%, established KP 2%, controls 0%). Changes in effusion or synovial hypertrophy did not correlate with changes in KP in one year. Effusion and ROA predicted worsening of knee pain at one year (aOR 1.95, 95% CI 1.05 to 3.64, and aOR 3.52 95%CI 1.37 to 9.09, respectively). Central versus peripheral risk factors: A number of central and peripheral risk factors associated with knee pain, including WSP, pain catastrophising, knee injury, ROA, effusion and synovial hypertrophy. Although 25% of knee pain was explained by peripheral risk factors, only 5% was explained by central risk factors. Knee pain was stratified into 4 subgroups according to ROA and WSP. The association between synovial changes detected on US and knee pain varied between subgroups, being strongest in people with isolated ROA (e.g., aOR for hypertrophy 9.99, 95%CI 5.06 to 19.03), moderate in people with ROA plus WSP (aOR 7.24, 95%CI 3.04 to 17.25), weak in people with neither ROA nor WSP (aOR 2.25, 95%CI 1.19 to 4.22) and statistically insignificant in people with isolated WSP (aOR 2.21 95%CI 0.99 to 4.93). This was confirmed by the “one-person two knee” analysis where WSP was fully balanced between painful knees and pain-free knees. The association between synovial changes detected on US and knee pain was stronger when the knees had underlying structure OA changes. Conclusions: Effusion and synovial hypertrophy but not PDS are common in community-derived people with knee pain. These features differ in men and women, requiring different thresholds for abnormality. Synovial changes detected on US are associated knee pain, especially in people with ROA but no WSP. However, changes in effusion and synovial hypertrophy do not correlate with changes in knee pain, and effusion but not synovial hypertrophy predicts pain progression at one year. Further study of the causality between synovial changes detected on US and structural OA, and between peripheral and central risk factors for knee pain is needed

Synovial changes detected by ultrasound in community-derived people with knee pain

Background: Knee pain, the main symptom of knee osteoarthritis (OA), affects one in 4 people aged over 55 years, of whom 10% have mild to moderate disability. The aetiology of knee pain is heterogeneous and its relationship with structural changes and function is unclear. An important role for synovial pathology in the initiation and progression of knee OA has been emphasised. However, the normal values of synovial changes detected on ultrasound (US) in the general population and their association with knee pain in community-based people with knee pain or OA remain largely unknown. Objectives: [1] to systematically review the literature on synovial changes detected on US in people with knee pain/OA and/or in the general population. [2] to establish the normal ranges for synovial thickness and effusion and determine an optimal cut-off associated with knee pain and radiographic osteoarthritis (ROA) in community-derived men and women over 40 years old. [3] to examine whether community-derived people with early and chronic established knee pain have different risks of having effusion, synovial hypertrophy and Power Doppler signal (PDS), and to explore whether synovial changes detected on US predict/associate with subsequent knee pain worsening. [4] to explore the role of peripheral and central risk factors of knee pain, including the role of synovial changes detected on US in different types of knee pain. Methods: A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. The source population was the Knee Pain and Related Health in the Community (KPIC, n=9506) survey in Nottingham, UK. All participants had bilateral US and radiographic examination. Synovial changes detected on US were measured by two observers (inter-observer concordance correlation was 0.8 (0.6 to 0.9) for effusion and 0.7 (0.5 to 0.9) for synovial hypertrophy). OA structural changes were measured by standardised radiographs (semi-flexed weight-bearing and flexed skyline views) using the Nottingham Line Drawing Atlas (NLDA). A cross-sectional study comprised of 299 randomly selected adults ≥40 years old (147 women, 152 men). The normal range (95% quintile) for effusion and synovial hypertrophy was calculated in the healthy sample (no current knee pain and no ROA, n=163). The optimal cut-off was established using ROC curve analysis. A case-control study compared community-derived participants with early knee pain (n=298), chronic established knee pain (n=100) and no knee pain (n=94) at baseline. 166 early knee pain participants were followed-up at one year for changes in knee pain and synovial changes detected on US. Relationships between changes in synovial changes detected on US and pain severity were examined using correlation analysis. 255 participants with early and established knee pain replied to a one-year follow-up questionnaire. Predictors of knee pain worsening were determined using logistic regression. Central and peripheral risk factors for knee pain were examined using participants from both the cross-sectional and case-control studies (n=736). The contribution of each was presented using ROC curves. Subgroup analysis was undertaken according to the presence/absence of ROA and widespread pain (WSP) for the association between synovial changes detected on US and knee pain. A within-person analysis in participants with unilateral knee pain was also undertaken. Results:Systematic review and meta-analysis: 29 studies (4720 patients) were identified from the literature. The pooled prevalence of US effusion, synovial hypertrophy and PDS in people with knee OA/pain were 51.5% (95%CI 40.2 to 62.8), 41.5% (26.3 to 57.5) and 32.7% (8.34 to 63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8 to 35.3), 14.5% (0 to 58.81), and 15.8% (3.08 to 35.36), respectively). People with knee OA (ACR criteria or ROA) had greater prevalence of synovial changes detected on US than people with knee pain (p=0.037, p=0.010 and p=0.009, respectively). Cross-sectional study: Synovial changes detected on US were different between men and women, therefore, gender-specific reference limits were estimated. In people without KP and structural OA the normal range for effusion was between 0 to 10.3 mm for men and between 0 to 9.8 mm for women and the normal range for synovial hypertrophy was between 0 and 6.8 mm for men and between 0 and 5.4 mm for women. The effusion cut-off able to distinguish a subgroup of people with knee pain and ROA (i.e. “symptomatic OA”) with high specificity was 8.9 mm for men and 7.8 mm for women, and for synovial hypertrophy it was 5.8 mm for men and 4.2 mm for women. Case-control study: At baseline, effusion was associated with early (OR 2.64, 95%CI 1.57 to 4.45) and established KP (OR 5.07, 95%CI 2.74 to 9.38). Synovial hypertrophy was also associated with early (OR 5.43, 95%CI 2.12 to 13.92) and established KP (OR 13.27, 95%CI 4.97 to 35.43). However, the association with effusion diminished when adjusted for ROA. PDS was uncommon (early KP 3%, established KP 2%, controls 0%). Changes in effusion or synovial hypertrophy did not correlate with changes in KP in one year. Effusion and ROA predicted worsening of knee pain at one year (aOR 1.95, 95% CI 1.05 to 3.64, and aOR 3.52 95%CI 1.37 to 9.09, respectively). Central versus peripheral risk factors: A number of central and peripheral risk factors associated with knee pain, including WSP, pain catastrophising, knee injury, ROA, effusion and synovial hypertrophy. Although 25% of knee pain was explained by peripheral risk factors, only 5% was explained by central risk factors. Knee pain was stratified into 4 subgroups according to ROA and WSP. The association between synovial changes detected on US and knee pain varied between subgroups, being strongest in people with isolated ROA (e.g., aOR for hypertrophy 9.99, 95%CI 5.06 to 19.03), moderate in people with ROA plus WSP (aOR 7.24, 95%CI 3.04 to 17.25), weak in people with neither ROA nor WSP (aOR 2.25, 95%CI 1.19 to 4.22) and statistically insignificant in people with isolated WSP (aOR 2.21 95%CI 0.99 to 4.93). This was confirmed by the “one-person two knee” analysis where WSP was fully balanced between painful knees and pain-free knees. The association between synovial changes detected on US and knee pain was stronger when the knees had underlying structure OA changes. Conclusions: Effusion and synovial hypertrophy but not PDS are common in community-derived people with knee pain. These features differ in men and women, requiring different thresholds for abnormality. Synovial changes detected on US are associated knee pain, especially in people with ROA but no WSP. However, changes in effusion and synovial hypertrophy do not correlate with changes in knee pain, and effusion but not synovial hypertrophy predicts pain progression at one year. Further study of the causality between synovial changes detected on US and structural OA, and between peripheral and central risk factors for knee pain is needed

Partial undersampling of imbalanced data for cyber threats detection

Real-time detection of cyber threats is a challenging task in cyber security. With the advancement of technology and ease of access to the internet, more and more individuals and organizations are becoming the target for various cyber attacks such as malware, ransomware, spyware. The target of these attacks is to steal money or valuable information from the victims. Signature-based detection methods fail to keep up with the constantly evolving new threats. Machine learning based detection has drawn more attention of researchers due to its capability of detecting new and modified attacks based on previous attack's behaviour. The number of malicious activities in a certain domain is significantly low compared to the number of normal activities. Therefore, cyber threats detection data sets are imbalanced. In this paper, we proposed a partial undersampling method to deal with imbalanced data for detecting cyber threats. © 2020 ACM.E

Trends in incidence and prevalence of osteoarthritis in the United Kingdom:findings from the Clinical Practice Research Datalink (CPRD)

Objective: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. Design: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. Results: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. Conclusion: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes

Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort.

OBJECTIVES: We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain in the Community cohort. METHOD: 1471 participants reported knee pain at baseline and responded to a 1-year follow-up questionnaire, of whom 204 underwent pressure pain detection thresholds (PPTs) and radiographic assessment at baseline. Logistic and linear regression models estimated the relative risks (RRs) and associations (β) between self-report traits, PPTs and pain outcomes. Discriminative performance for each predictor was compared using receiver-operator characteristics (ROC) curves. RESULTS: Baseline Central Mechanisms trait scores predicted pain persistence (Relative Risk, RR = 2.10, P = 0.001) and persistent pain severity (β = 0.47, P < 0.001), even after adjustment for age, sex, BMI, radiographic scores and symptom duration. Baseline joint-line PPTs also associated with pain persistence (RR range = 0.65 to 0.68, P < 0.02), but only in univariate models. Lower baseline medial joint-line PPT was associated with persistent pain severity (β = -0.29, P = 0.013) in a fully adjusted model. The Central Mechanisms trait model showed good discrimination of pain persistence cases from resolved pain cases (Area Under the Curve, AUC = 0.70). The discrimination power of other predictors (PPTs (AUC range = 0.51 to 0.59), radiographic OA (AUC = 0.62), age, sex and BMI (AUC range = 0.51 to 0.64), improved significantly (P < 0.05) when the central mechanisms trait was included in each logistic regression model (AUC range = 0.69 to 0.74). CONCLUSION: A simple summary self-report Central Mechanisms trait score may indicate a contribution of central mechanisms to poor knee pain prognosis

Prediction of persistent knee pain by pressure pain detection thresholds: results from the Knee Pain In the Community cohort (KPIC)

Background: Knee pain results from a combination of nociceptive input from the joint, and processing by the central nervous system. Pressure pain detection thresholds (PPTs) are lower and pain is more severe in people with greater central sensitisation. Objective: We hypothesised that lower PPTs predicted worse pain prognosis in people with knee pain. Methods: KPIC participants were people aged >40 years recruited from Nottingham, UK. Participants were mailed questionnaires at baseline and 1 year. This study reports a sample of responders who attended baseline and 1 year clinical assessment, had self-reported knee pain (within the last 4 weeks) and underwent PPT. PPTs were measured at the knee, anterior tibia and the sternum. Radiographic knee OA was classified using an atlas. Questionnaires measured ICOAP (constant and intermittent knee pain), painDETECT (neuropathic-like) and average knee pain severity over 4 weeks (0-10). The presence of pain at baseline and 1 year (persistent pain), or pain severity were predicted from baseline anterior tibia PPT. Additional analyses adjusted for baseline pain score, age, sex, BMI, or for radiographic knee OA. Pain persistence (Yes/No) was analysed using t tests, odds ratios (OR) and logistic regression. Pain severity was analysed using linear regression. Results: The sample for this study contained n=419 people at baseline, and n=182 people reported knee pain persistent over both time points. The mean (SD) values were age 61 (9) years, BMI 30.1 (5.8) kg m-2, 59% female, and 36% fulfilled radiographic OA criteria at the index knee, for those with persistent knee pain at 1 year. In univariate analysis, persistent knee pain was associated with a lower PPT at baseline (461 vs 424 kPa; OR (95% CI) 0.58 (0.34-0.97) p=0.020). Adjustments for age, sex and BMI removed the significance from the association (adjusted OR (95% CI) 0.64 (0.36-1.13) p=0.120). In those with persistent pain, worse 1 year ICOAP-constant, ICOAP-intermittent, painDETECT and knee pain severity were correlated with lower baseline anterior tibia PPT ( r= -0.28 to -0.24; p<0.004). After adjustment for baseline pain, 1 year ICOAP-constant pain scale was significantly predicted by baseline PPT (B (95% CI), -1.05 (-1.91 to -0.20) p=0.016). Linear regression with adjustments for age, sex and BMI also indicated that baseline PPT predicted worse ICOAP-constant pain (B (95% CI)-0.99 (-1.94 to -0.04) p=0.041). The presence of radiographic OA at baseline was not significantly associated with PPT at baseline. Adjustment for baseline radiographic OA did not remove the association between baseline PPT and ICOAP-constant at 1 year (anterior tibia PPT -1.04 (-1.89 to -0.18) p=0.018). PPT at joint lines or sternum displayed similar patterns of association with 1 year pain as did PPT at the anterior tibia. Conclusions: Pressure pain detection thresholds suggestive of central sensitisation at baseline were associated with knee pain prognosis at 1 year, in particular with constant knee pain. The presence of radiographic OA also predicted 1 year pain prognosis, independent of PPT

Thresholds of ultrasound synovial abnormalities for knee osteoarthritis: a cross sectional study in the general population

ObjectiveTo establish “normal” ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community.Methods147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The “normal” range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls.ResultsEffusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the “normal” ranges between men and women were similar for effusion (0–10.3 mm vs 0–9.8 mm), but different for synovial hypertrophy (0–6.8 mm vs 0–5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively.ConclusionsUS effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials

OBJECTIVES: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials. METHODS: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant. RESULTS: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined. CONCLUSION: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT03146689

Contribution of central and peripheral risk factors to prevalence, incidence and progression of knee pain:a community-based cohort study

AimTo explore risk factors that may influence knee pain (KP) through central or peripheral mechanisms.MethodsA questionnaire-based prospective community cohort study with KP defined as pain in or around a knee on most days for at least a month. Baseline prevalence, and one year incidence and progression (KP worsening) were examined. Central (e.g., Pain Catastrophizing Scale (PCS)) and peripheral (e.g., significant injury) risk factors were examined. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Proportional risk contribution (PRC) was estimated using receiver-operator-characteristic (ROC) analysis.ResultsOf 9506 baseline participants, 4288 (45%) had KP (men 1826; women, 2462). KP incidence was 12% (men 11%, women 13%), and KP progression 19% (men 16%, women 21%) at one year. While both central and peripheral factors contributed to prevalence, central factors contributed more to progression, and peripheral factors more to incidence of KP. For example, although PCS (OR 2.06, 95% CI 1.88–2.25) and injury (5.62, 4.92–6.42) associated with KP prevalence, PCS associated with progression (2.27, 1.83–2.83) but not incidence (1.14, 0.86–1.52), whereas injury more strongly associated with incidence (69.27, 24.15–198.7) than progression (2.52, 1.48–4.30). The PRC of central and peripheral factors were 19% and 23% for prevalence, 14% and 29% for incidence, and 29% and 5% for progression, respectively.ConclusionsBoth central and peripheral risk factors influence KP but relative contributions may differ in terms of development (mainly peripheral) and progression (mainly central). Further study of such relative contributions may inform primary and secondary prevention strategies

Knee pain and related health in the community study (KPIC): a cohort study protocol

Background: The incidence, progression and related risk factors for recent-onset knee pain (KP) remain uncertain. This study aims to examine the natural history of KP including incidence and progression and to identify possible phenotypes and their associated risk factors. Methods: A prospective community-based cohort of men and women aged 40 years or over within the East Midlands region (UK) will be recruited via a postal questionnaire from their general practices. The questionnaire will enquire about: presence and onset of KP; pain severity (0–10 numerical rating scale (NRS)); pain catastrophizing and neuropathic-like pain (NP) using the painDETECT questionnaires (definite NP scores ≥19–38); risk factors for KP and/or osteoarthritis (OA) (age, body mass index, constitutional knee alignment, nodal OA, index: ring finger length (2D4D) ratio); quality of life (SF12); and mental health (Hospital Anxiety and Depression Scale). Clinical assessments will be undertaken in a sample of 400 participants comprising three groups: early KP (≤3 year’s duration), established KP (>3 years) and no KP. Assessments will include knee radiographs (standing semi-flexed and 300 skyline views); knee ultrasound (synovial effusion, hypertrophy, and Doppler activity); quantitative sensory testing; muscle strength (quadriceps, hip abductor, and hand-grip); balance; gait analysis (GAITrite); and biomarker sampling. A repeat questionnaire will be sent to responders at years 1 and 3. The baseline early KP group will undergo repeat assessments at year 1 (apart from radiographs) and year 3 (with radiographs). Any incident KP individuals identified at year 1 or 3 questionnaires will have clinical and radiographic assessments at the respective time points. Discussion: Baseline data will be used to examine risk factors for early onset KP and to identify KP phenotypes. Subsequent prospective data, at least to Year 3, will allow examination of the natural history of KP and risk factors for incidence and progression. Trial registration: The study was registered on the clinicaltrials.gov portal: NCT02098070) on the 14th of March 2014