Sarah R. Kingsbury

The role of the NLRP3 inflammasome in gout.

Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1β, underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU ‘danger signal’. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1β antibody), and anakinra have all demonstrated treatment efficacy in such patients.

A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis

IntroductionBone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA.MethodsA search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring.ResultsIn total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively.ConclusionSubchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target.Systematic reviewPROSPERO registration number: CRD 42013005009

Toward a Clinical Definition of Early Osteoarthritis: Onset of Patient‐Reported Knee Pain Begins on Stairs. Data From the Osteoarthritis Initiative

Early detection of osteoarthritis (OA) would increase the chances of effective intervention. We aimed to investigate which patient‐reported activity is first associated with knee pain. We hypothesized that pain would occur first during activities requiring weight bearing and knee bending.

Osteoarthritis in Europe: impact on health status, work productivity and use of pharmacotherapies in five European countries

OBJECTIVES The aims of this study were to examine the impact of peripheral joint OA across five large European countries and how people with OA use pharmacotherapies. METHODS People with self-reported peripheral joint OA were selected from the 2011 five European countries (5EU) National Health and Wellness Survey (NHWS), which included 57 512 respondents from France, Germany, Italy, Spain and the UK. Information was recorded on symptoms, health status, health care utilization, work productivity and medication usage. All variables were analysed descriptively for the total population and individual countries. RESULTS A total of 3750 respondents met the inclusion criteria: 1635 (43.6%) UK, 961 (25.6%) France, 570 (15.2%) Germany, 316 (8.4%) Spain and 268 (7.1%) Italy. The majority were ages 55-74 years and most were overweight or obese. Health status [12-item Short Form version 2 (SF12v2)] was similar across all countries, with a mean (s.d.) of 40.53 (10.99); 21.5% self-reported experiencing depression. Most had visited a health care provider in the previous 6 months (n = 3537; 94.3%). One third were employed: 7% reported absenteeism and 24% presenteeism. The use of prescription medication for OA was reported by 46.9% of patients, over-the-counter (OTC) medication by 26.5%, and both by 9.4%. Medication use increased with pain severity. NSAIDs were the most commonly used medication. Opioid use varied from 1.8% in Italy to 54.5% in France. Fifty per cent reported full adherence (4-point Morisky Medication Adherence Scale), but only 30% reported satisfaction with their OA medication. Most used medication for half the days of the month. CONCLUSION Despite some wide variations in pharmacotherapy for OA treatment, the impact of OA on health status and work productivity is substantial and looks largely similar across major European countries.

How do people with knee osteoarthritis use osteoarthritis pain medications and does this change over time? Data from the Osteoarthritis Initiative.

IntroductionThe aim of this analysis was to describe comprehensively the cross-sectional and longitudinal patterns of analgesic and nutraceutical medication use for knee osteoarthritis (OA) in a contemporary US cohort and to investigate associated demographic and clinical factors.MethodsBaseline, 12, 24 and 36 month data were obtained retrospectively from the National Institutes of Health Osteoarthritis Initiative. Participants had symptomatic radiographic knee OA. Multiple binary logistic regression models identified characteristics independently associated with the use of analgesics or nutraceuticals.ResultsWe included 987 subjects (55.9% female, mean age 61.5 years, 71.0% white). At baseline, 68.2% reported frequent use of a conventional analgesic or nutraceutical for joint pain (for more than half of the previous month). Non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently reported medications (26.8%), even in those more than 75-years old. Multiple conventional analgesics were used by 11.9%. Frequent analgesic use was more likely in women (odds ratio (OR) 1.8 (95% confidence interval (CI) 1.3 to 2.3)) and people with more pain (moderate 1.7 (1.2 to 2.4); severe 3.1 (2.1 to 4.7)); nutraceutical use was less likely in non-whites (0.4 (0.3 to 0.6)), those more than 74-years old (0.6 (0.3 to 0.9)) and those with comorbidities (0.6 (0.5 to 0.9)) and more likely in people with Kellgren-Lawrence (KL) grade 4 (2.2 (1.5 to 3.3)). Overall there was no change in the proportion of participants frequently using prescription or over the counter (OTC) analgesics at 36 months, although most people had changed medication type; of those using a traditional analgesic at baseline approximately one third were still using the same type at 36 months (ranging from 26.2% of baseline prescription NSAID users to 40.6% of baseline acetaminophen users). All participants reporting baseline analgesic use also reported 36 month analgesic use. Female participants (OR 95% CI 1.2 to 3.2, P = 0.009), those with high body mass index (1.2 to 4.8, P = 0.010) and those with moderate (1.6 to 2.6, P = 0.090) or severe (1.8 to 12.0, P = 0.002) baseline pain were more likely to use pain medication during the 36 month follow-up period; participants more than 75-years old were less likely (0.2 to 1.0, P = 0.053).ConclusionsMost people with knee OA used pharmacological therapies frequently, and use appeared to be according to American College of Rheumatology recommendations. Change in medication type used was common. Persistent non-prescription NSAID use in older people is an area of concern.

Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial.

BackgroundOsteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain.Methods/designHERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.DiscussionThe HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a new treatment for OA, which could be of particular use in the primary care setting.Trial registrationISRCTN91859104.

Is caspase 1 central to activation of interleukin-1?

Joint Bone Spine - In Press.Proof corrected by the author Available online since dimanche 3 avril 2011

Does sports participation (including level of performance and previous injury) increase risk of osteoarthritis? A systematic review and meta-analysis

Background To assess the relationship between sport and osteoarthritis (OA), and specifically to determine whether previous participation, in terms of level (elite or non-elite), type of sport, intensity or previous injury, was associated with OA. Methods This systematic review was developed using PRISMA guidelines. Databases were searched (to May 2016). Narrative review and meta-analysis (with risk ratio (RR) and 95% CIs) approaches were undertaken where appropriate. Study quality was assessed using GRADE. Results 46 studies were included. Narratively, 31 studies reported an increased risk of OA, with 19 demonstrating an increased risk in elite athletes. There was an increased risk after sports exposure (irrespective of type; RR 1.37; 95% CI 1.14 to 1.64; 21 studies). It remained uncertain whether there was a difference in risk of OA between elite and non-elite athletes (RR 1.37; 95% CI 0.84 to 2.22; 17 studies). The risk was higher in soccer (RR 1.42; 95% CI 1.14 to 1.77; 15 studies) but lower in runners (RR 0.86; 95% CI 0.53 to 1.41; 12 studies). 9 studies showed an association with the intensity of sport undertaken and OA. 5 studies demonstrated a higher prevalence of OA following meniscectomies and anterior cruciate ligament tears. Overall, the evidence was of GRADE ‘very low’ quality. Conclusions There was very low-quality evidence to support an increased relationship between sports participation and OA in elite participants. It is unclear whether there is a difference in risk between elite and non-elite participants with further prospective studies needed to evaluate this. Pooled findings suggested that significant injuries were associated with OA in soccer players.

The relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the Osteoarthritis Initiative

Summary Background Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB). Methods Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. ‘OA-attributable’ tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression. Results In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB. Conclusion Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures.

The relationship between three-dimensional knee MRI bone shape and total knee replacement—a case control study: data from the Osteoarthritis Initiative

Objective. There is growing understanding of the importance of bone in OA. Our aim was to determine the relationship between 3D MRI bone shape and total knee replacement (TKR). Methods. A nested case-control study within the Osteoarthritis Initiative cohort identified case knees with confirmed TKR for OA and controls that were matched using propensity scores. Active appearance modelling quantification of the bone shape of all knee bones identified vectors between knees having or not having OA. Vectors were scaled such that −1 and +1 represented the mean non-OA and mean OA shapes. Results. Compared to controls (n = 310), TKR cases (n = 310) had a more positive mean baseline 3D bone shape vector, indicating more advanced structural OA, for the femur [mean 0.98 vs −0.11; difference (95% CI) 1.10 (0.88, 1.31)], tibia [mean 0.86 vs −0.07; difference (95% CI) 0.94 (0.72, 1.16)] and patella [mean 0.95 vs 0.03; difference (95% CI) 0.92 (0.65, 1.20)]. Odds ratios (95% CI) for TKR per normalized unit of 3D bone shape vector for the femur, tibia and patella were: 1.85 (1.59, 2.16), 1.64 (1.42, 1.89) and 1.36 (1.22, 1.50), respectively, all P < 0.001. After including Kellgren–Lawrence grade in a multivariable analysis, only the femur 3D shape vector remained significantly associated with TKR [odds ratio 1.24 (1.02, 1.51)]. Conclusion. 3D bone shape was associated with the endpoint of this study, TKR, with femoral shape being most associated. This study contributes to the validation of quantitative MRI bone biomarkers for OA structure-modification trials.