Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank.

OBJECTIVE: Acute knee injury is associated with post-traumatic OA (PTOA). Very little is known about the genome-wide associations of PTOA when compared with idiopathic OA (iOA). Our objective was to describe the development of knee OA after a knee injury and its genetic associations in UK Biobank (UKB). DESIGN: Clinically significant structural knee injuries in those ≤50 years were identified from electronic health records and self-reported data in 502,409 UKB participants. Time-to-first knee osteoarthritis (OA) code was compared in injured cases and age-/sex-matched non-injured controls using Cox Proportional Hazards models. A time-to-OA genome-wide association study (GWAS) sought evidence for PTOA risk variants 6 months to 20 years following injury. Evidence for associations of two iOA polygenic risk scores (PRS) was sought. RESULTS: Of 4233 knee injury cases, 1896 (44.8%) were female (mean age at injury 34.1 years [SD 10.4]). Over a median of 30.2 (IQR 19.5-45.4) years, 1096 (25.9%) of injured cases developed knee OA. The overall hazards ratio (HR) for knee OA after injury was 1.81 (1.70,1.93), P = 8.9 × 10-74. Female sex and increasing age at injury were associated with knee OA following injury (HR 1.15 [1.02,1.30];1.07 [1,07,1.07] respectively). OA risk was highest in the first 5 years after injury (HR 3.26 [2.67,3.98]), persisting for 40 years. In 3074 knee injury cases included in the time-to-OA GWAS, no variants reached genome-wide significance. iOA PRS was not associated with time-to-OA (HR 0.43 [0.02,8.41]). CONCLUSIONS: Increasing age at injury and female sex appear to be associated with future development of PTOA in UKB, the risk of which was greatest in the 5 years after injury. Further international efforts towards a better-powered meta-analysis will definitively elucidate genetic similarities and differences of PTOA and iOA.

Harmonising knee pain patient-reported outcomes: a systematic literature review and meta-analysis of Patient Acceptable Symptom State (PASS) and individual participant data (IPD).

OBJECTIVE: In order to facilitate data pooling between studies, we explored harmonisation of patient-reported outcome measures (PROMs) in people with knee pain due to osteoarthritis or knee trauma, using the Patient Acceptable Symptom State scores (PASS) as a criterion. METHODS: We undertook a systematic literature review (SLR) of PASS scores, and performed individual participant data (IPD) analysis of score distributions from concurrently completed PROM pairs. Numerical rating scales (NRS), visual analogue scales, KOOS and WOMAC pain questionnaires were standardised to 0 to 100 (worst) scales. Meta-regression explored associations of PASS. Bland Altman plots compared PROM scores within individuals using IPD from WebEx, KICK, MenTOR and NEKO studies. RESULTS: SLR identified 18 studies reporting PASS in people with knee pain. Pooled standardised PASS was 27 (95% CI: 21 to 35; n = 6,339). PASS was statistically similar for each standardised PROM. Lower PASS was associated with lower baseline pain (ß = 0.49, P = 0.01) and longer time from treatment initiation (Q = 6.35, P = 0.04). PASS scores were lowest in ligament rupture (12, 95% CI: 11 to 13), but similar between knee osteoarthritis (31, 95% CI: 26 to 36) and meniscal tear (27, 95% CI: 20 to 35). In IPD, standardised PROMs each revealed similar group mean scores, but scores within individuals diverged between PROMs (LoA between -7 to -38 and +25 to 52). CONCLUSION: Different standardised PROMs give similar PASS thresholds in group data. PASS thresholds may be affected more by patient and treatment characteristics than between PROMs. However, different PROMs give divergent scores within individuals, possibly reflecting different experiences of pain.

The molecular profile of synovial fluid changes upon joint distraction and is associated with clinical response in knee osteoarthritis.

OBJECTIVE: Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. METHOD: 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS4) was collected at baseline, 3, 6 and 12 months. RESULTS: 13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ≥2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFß-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS4 over 6 months showed greater increases in FGF-2 and TGFß-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS4 over 12 months. CONCLUSION: Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.

Tropomyosin-related kinase A (TrkA) inhibition for the treatment of painful knee osteoarthritis: results from a randomized controlled phase 2a trial.

OBJECTIVE: To investigate the TrkA inhibitor, ASP7962, for treatment of painful knee osteoarthritis. DESIGN: Phase 2a, double-blind, placebo- and naproxen-controlled, double-dummy, parallel-group study. Adults with knee osteoarthritis were randomized (2:2:1) to ASP7962 (100 mg), placebo, or naproxen (500 mg) twice daily (BID) for 4 weeks. Primary endpoint: change from baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale score. Secondary endpoints: change from baseline to Weeks 1, 2, and End of Treatment (EoT) in WOMAC pain subscale score; change from baseline to Weeks 1, 2, 4, and EoT in WOMAC physical function and stiffness subscales, walking pain and WOMAC total scores; and change from baseline in daily average pain score. RESULTS: 215 participants were randomized (ASP7962 100 mg BID, n = 85; placebo, n = 87; naproxen 500 mg BID, n = 43). No significant difference was observed between ASP7962 and placebo in change from baseline to Week 4 in WOMAC pain subscale score (-0.14; 90% 2-sided CI: -0.62, 0.34; P = 0.316); a significant difference was observed between naproxen and placebo (-0.67; 80% 2-sided CI: -1.12, -0.23; P = 0.027). No differences were observed between ASP7962 and placebo in change from baseline in any WOMAC subscale score; statistically significant changes were observed between naproxen and placebo (P ≤ 0.01, all time points for all WOMAC endpoints). ASP7962 was safe and well-tolerated. CONCLUSIONS: Four-week treatment with ASP7962 (100 mg BID) did not improve pain or physical function in individuals with painful knee osteoarthritis. ClinicalTrials.gov, NCT02611466; EudraCT Number, 2014-004996-22.

Towards prevention of post-traumatic osteoarthritis: report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury.

OBJECTIVE: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. DESIGN: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. RESULTS: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. CONCLUSIONS: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.

Osteoarthritis biomarkers: year in review.

OBJECTIVE: To summarise important findings from biomarker studies relevant to osteoarthritis (OA), published between April 2016 and March 2017; to consider these findings in the context of new discoveries and technologies, and clinical and scientific need in OA. DESIGN: Studies were selected by PubMed search, conducted between 01/04/2016 and 01/03/2017. MeSH terms [biomarker] AND [OA] were used; the search was restricted to Human, English language and Full Text Available publications, which yielded 50 eligible publications. Any biomarker was considered, including non-proteins and other clinical measurements. RESULTS: Three main areas are overviewed: 1) Studies examining highly validated biomarkers, in the FNIH OA Biomarkers Consortium and elsewhere, particularly their ongoing application and validation. Control reference intervals, work on predictive validity and other longitudinal studies examining prognostic value of biomarkers in large cohorts are reviewed. 2) Novel studies relating to biomarkers of inflammation are discussed, including complement, the performance of markers of so-called 'cold inflammation' and results from clinical trials including biomarkers. 3) Discovery studies, including whole blood RNA, proteomics and metabolomics are reviewed, with an emphasis on new technologies. CONCLUSIONS: Discovery, characterisation and qualification of various biomarkers is ongoing; several novel protein and non-protein candidate biomarkers have been reported this year. Biomarkers provide us with an opportunity to better diagnose and stratify the disease, via established panels or new discovery approaches. Improving quality of sampling and testing, and measuring large numbers of markers simultaneously in large cohorts would seem likely to identify new clinically applicable biomarkers, which are still much needed in this disease.

Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study.

BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic liver disease with autoimmune features but uncertain aetiology. Increased risk of PBC among relatives of patients may reflect common environmental factors, or inherited immunogenetic susceptibility. Associations between PBC and other autoimmune diseases have been reported, but their true extent and pattern is unknown. AIM: To examine the prevalence and association patterns of autoimmune disease in a representative group of PBC patients. DESIGN: Clinical cohort study. METHODS: We clinically assessed members of a geographically-based PBC patient cohort (n = 160) for the presence of additional autoimmune disease, using established specific diagnostic criteria. RESULTS: Some 53% of patients had at least one additional autoimmune condition, and 63% had serum autoantibodies other than AMA or ANA. AMA+ patients had a significantly lower prevalence of additional autoimmunity than AMA- patients (49% vs. 79%; p < 0.01). The greatest relative increase in disease prevalence was for scleroderma (8% of patients). Autoimmune disease was present in 14% of first-degree relatives. DISCUSSION: PBC patients and their families have a wide susceptibility to autoimmunity. This observation supports an autoimmune aetiology and suggests that the genetic basis of PBC is likely to be expressed, at least in part, through factors controlling immune tolerance in general.

Familial primary biliary cirrhosis and autoimmune cholangitis.

AIM: Autoimmune cholangitis has been proposed as a separate disease entity from primary biliary cirrhosis without serum antimitochondrial antibodies. The ultimate answer to the question of whether autoimmune cholangitis and primary biliary cirrhosis are distinct will require detailed comparison of aetiologic factors and pathogenic mechanisms. METHODS AND RESULTS: Two families are described each of which has one member with classical antimitochondrial antibody positive biopsy-proven primary biliary cirrhosis and a first degree relative with antimitochondrial antibody negative but antinuclear antibody positive autoimmune cholangitis (biopsy proven in one case). Study of such families should allow analysis of the contribution of shared genetic risk factors versus varying environmental triggering mechanisms to disease pathogenesis. CONCLUSIONS: We suggest a European registry of families, such as the two described, which are rare within one centre, to facilitate elucidation of pathogenetic factors.

Familial primary biliary cirrhosis reassessed: a geographically-based population study.

BACKGROUND/AIMS: Development of primary biliary cirrhosis in the close relatives of patients with the disease has been reported in several series, suggesting a genetic component to disease susceptibility. In this study we set out to calculate, as accurately as possible, the prevalence of familial primary biliary cirrhosis in a geographically-based population. Using local population prevalence data, we have also calculated the first-degree relative, sibling and offspring relative risks of overt primary biliary cirrhosis development. METHODS: All patients with definite or probable primary biliary cirrhosis in the city of Newcastle-upon-Tyne, England, were identified by an exhaustive case-finding search and were prospectively interviewed by a single investigator. Full details of family pedigree and familial primary biliary cirrhosis history were obtained. RESULTS: One hundred and seventy-three patients were identified, with 160 participating in the study. Thirteen reported a family history of primary biliary cirrhosis. In three cases, both relative pairs were within the study group. The prevalence of a positive family history of primary biliary cirrhosis was therefore 10/157 (6.4% [95% Confidence Interval 2.6-10.2%]), 8/10 cases occurring in first-degree relatives. The patients had a total of 1118 first-degree relatives (live or dead) and 468 siblings. The first-degree relative prevalence of primary biliary cirrhosis was 0.72% [0.2-1.2%] (siblings 0.41% [-0.2-1.0%]). The offspring prevalence was 1.2% [0.04-2.4%], (2.3% [0.1-4.5%] for daughters). The sibling relative risk (lambda(s)) was 10.5. CONCLUSIONS: The overall prevalence of definite or probable primary biliary cirrhosis in the first-degree relatives of existing patients is <1%. The risk of disease is not, however, uniform, the highest prevalence being seen in the daughters of patients. Suspicion of disease should therefore be highest in this relative group. The calculated lambda(s) for primary biliary cirrhosis in this geographically-based study is significantly lower than previous estimates from case-note-derived case series, but similar to values seen in other autoimmune diseases.

Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.

BACKGROUND/AIMS: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-alpha has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-alpha gene, which may play a role in the control of TNF-alpha secretion, as candidate susceptibility loci in PBC. METHODS: The polymorphisms at positions -238 and -308 in the TNF-alpha promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC. RESULTS: The -308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR = 2.2 [1.2-4.0]) or the PBC patients with earlier disease (38/73 (52%), p = 0.001 OR 3.1 [1.6-5.9]). Linkage between TNF -308 and HLA DR8 was not seen. No association was found between PBC and the biallelic -238 TNF-alpha polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup. CONCLUSIONS: Our study provides no evidence for involvement of the TNF-alpha -308 or -238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the -308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/casemix in the design of disease association studies.

No evidence for involvement of the interleukin-10 -592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. Family studies, which have shown a significantly increased incidence of primary biliary cirrhosis in the close relatives of patients, suggest that genetic factors play a significant role in determining disease susceptibility. Several studies have previously identified loci which appear to play a role in determining this susceptibility, including the MHC class II allele HLA DR8, and the class III encoded C4A null allele (C4AQ0). Here, we have studied another candidate susceptibility locus in primary biliary cirrhosis, an apparently functional biallelic polymorphism at position -592 in the promoter region of the gene encoding the immuno-modulatory cytokine interleukin-10. Interleukin-10 plays an important role in the functional control, in vivo, of autoreactive Th-1 type CD4+ T-cells, with experimental manipulation of interleukin-10 leading to significant modulation of disease development in animal models of autoimmunity. METHODS: Interleukin-10 -592 genotypes were studied by polymerase chain reaction in 171 well-characterised, histologically-staged, primary biliary cirrhosis patients and 141 locally matched controls. RESULTS: Of 171 primary biliary cirrhosis patients, 99 were homozygous for the commoner allele (C/C), 68/171 (40%) were heterozygotes (A/C), whilst 4/171 (2%) were homozygous for the rarer allele (A/A). These genotype frequencies were not significantly different from those seen in controls (p=0.49, odds ratio 1.2 [0.8-1.91). CONCLUSIONS: These findings, in the first study of IL-10 as a candidate locus in a human autoimmune disease, suggest that IL-10 -592 is not a susceptibility locus in primary biliary cirrhosis.