Anushka Soni

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis

Objective To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA). Methods The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed. Results The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue. Conclusions A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

Background and objectives Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. Methods We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. Results The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4). Conclusions We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

The natural history of radiographic knee osteoarthritis: a fourteen-year population-based cohort study.

OBJECTIVE To establish the natural history of radiographic knee osteoarthritis (OA) over 14 years in a community-based cohort. METHODS We examined women from the Chingford Womens Study, a community-based cohort followed up for more than 14 years. We selected women for whom bilateral radiographs of the knees (with the legs in full extension) were obtained at approximately 5-year intervals. Radiographs were scored for OA in a blinded manner, using Kellgren/Lawrence (K/L) grades. Descriptive statistics and odds ratios (ORs) were used to compare the incidence, worsening, and progression of radiographic knee OA. RESULTS A complete radiography series was available for 561 of the original 1,003 subjects enrolled in the study. The median age of these subjects at baseline was 53 years (interquartile range 48-58 years). At baseline, 13.7% of the subjects had radiographic knee OA (K/L grade≥2) in at least one knee, and the prevalence increased to 47.8% by year 15. The annual cumulative incidence of radiographic knee OA was 2.3% between baseline and year 15. The annual rates of disease progression and worsening between baseline and year 15 were 2.8% and 3.0%, respectively. Subjects with a K/L grade of 1 at baseline were more likely to experience worsening by year 15 compared with subjects with a baseline grade of 0 (OR 4.5, 95% confidence interval 2.7-7.4). CONCLUSION This is the longest natural history study of radiographic knee OA to date. The results showed relatively low rates for the incidence and progression of radiographic knee OA; more than half of all subjects had no radiographic evidence of knee OA over a 15-year period of time. Subjects with a baseline K/L grade of 1 were more likely than subjects with other baseline K/L grades to experience worsening of knee OA.

Neuropathic Features of Joint Pain: A Community-Based Study

OBJECTIVE Quantitative sensory testing (QST) and questionnaire-based assessments have been used to demonstrate features of neuropathic pain in subjects with musculoskeletal pain. However, their direct relationship has not been investigated in the community. The purpose of this study was to conduct an observational study to describe the characteristics of joint pain and to examine the relationship between QST measures and the PainDETECT Questionnaire (PD-Q). METHODS Warm detection, heat pain, and mechanical pain thresholds as well as mechanical pain sensitivity over the sternum were determined and the PD-Q scores were calculated in a cross-sectional study of 462 participants in the Chingford Study. Comparisons were made between subjects with and those without joint pain. Logistic regression modeling was used to describe the association between neuropathic pain features, as determined by the PD-Q score, and each of the QST measures individually, adjusting for age, body mass index, and use of pain-modifying medications. RESULTS A total of 66.2% of the subjects reported recent joint pain, with a median average pain severity of 5 of 10. There was increased sensitivity to painful stimuli in the group with pain as compared to the pain-free group, and this persisted after stratification by pain-modifying medication use. While only 6.7% of subjects had possible neuropathic pain features and 1.9% likely neuropathic pain features according to the standard PD-Q thresholds, features of neuropathic pain were common and were present in >50% of those reporting pain of at least moderate severity. Heat pain thresholds and mechanical pain sensitivity were significantly associated with features of neuropathic pain identified using the PD-Q, with an odds ratio (OR) of 0.88 (95% confidence interval [95% CI] 0.79-0.97; P = 0.011) and an OR of 1.24 (95% CI 1.04-1.48; P = 0.018), respectively. CONCLUSION QST measures and the PD-Q identified features of neuropathic pain in subjects in this community-based study, with significant overlap between the findings of the two techniques.

Prevalence of reported knee pain over twelve years in a community-based cohort

OBJECTIVE To describe the temporal patterns of knee pain in a community-based cohort over 12 years. METHODS Data on self-reported knee pain at 4 time points over 12 years were analyzed in participants from the Chingford Womens Study of osteoarthritis (OA) and osteoporosis. Pain status was defined as any pain in the preceding month and pain on most days in the preceding month. This status was used to classify participants according to pain patterns of asymptomatic, persistent, incident, or intermittent pain. Multinomial logistic regression was used to identify baseline predictors for each pain pattern. RESULTS Among the 489 women with complete followup data, the median age at baseline was 52 years (interquartile range [IQR] 48-58 years), the median body mass index (BMI) was 24.39 kg/m(2) (IQR 22.46-27.20), and 11.7% of the women had a Kellgren/Lawrence radiographic OA severity grade of ≥2 in at least one knee. Among subjects reporting any pain in the preceding month versus those reporting pain on most days in the preceding month, 9% versus 2% had persistent pain, 24% versus 16% had incident pain, and 29% versus 18% had intermittent pain. A higher BMI was predictive of persistent pain (odds ratio [OR] 1.14, 95% confidence interval [95% CI] 1.04-1.25) and incident pain (OR 1.10, 95% CI 1.02-1.18). The presence of radiographic knee OA was predictive of persistent pain (OR 3.70, 95% CI 1.34-10.28; P = 0.012), and reported knee injury was predictive of both persistent pain (OR 4.13, 95% CI 1.34-12.66; P = 0.013) and intermittent pain (OR 4.25, 95% CI 1.81-9.98; P = 0.001). CONCLUSION Significant variability in the temporal fluctuation of self-reported knee pain was seen in this community-based prospective study over a period of 12 years, with few women consistently reporting knee pain at each time point. Distinct baseline predictors for each pain pattern were identified and may explain the observed heterogeneity of self-reported knee pain when pain status is measured at only one time point.

Does obesity predict knee pain over fourteen years in women, independently of radiographic changes?

To examine longitudinal patterns in body mass index (BMI) over 14 years and its association with knee pain in the Chingford Study.

Supervised exercise plus acupuncture for moderate to severe knee osteoarthritis: a small randomised controlled trial

Objectives Although total knee replacement (TKR) is cost effective and successful in most cases, patient-reported outcome measures demonstrate 20% of people remain unsatisfied at 1 year after a technically successful procedure. Our group has previously shown that patients with severe knee osteoarthritis (OA) awaiting surgery can achieve a short-term reduction in symptom severity when treated with acupuncture, and that a trend towards improved walking distance, as a measure of function, is achieved with preoperative supervised exercise. The aim of this study was to evaluate the effect of combined acupuncture and physiotherapy on preoperative and postoperative pain and function. Methods A total of 56 patients awaiting TKR surgery were randomised to receive either combined physiotherapy and acupuncture or a standardised exercise and advice leaflet. Pain and function were measured primarily using the Oxford Knee Score (OKS), with assessments at baseline prior to intervention, 6 and 12 weeks after intervention and at 3 months postoperatively. Results Due to the introduction of the 18-week waiting times target during this study, the required sample size was not achieved. There were no significant differences demonstrated between the control and treatment groups for OKS. Seven patients withdrew from surgery because of symptomatic improvement in their knees: six from the treatment group and one from the control group (OR 7.64, 95% CI 0.86 to 68.20). Conclusions This study demonstrated that the use of combined acupuncture and physiotherapy in the treatment of patients with moderate to severe knee OA preoperatively did not improve patient outcome postoperatively. As the study was underpowered, a larger trial is required to examine this result further.

Contribution of the COMT Val158Met variant to symptomatic knee osteoarthritis

There is extensive literature reporting discordance between the presence and severity of symptoms and the degree of radiographic structural osteoarthritis (OA).1–⇓⇓⇓5 Genetic differences may account for some of this discordance. Indeed, certain genetic variants implicated in pain sensitivity have been shown to be significantly different between asymptomatic radiographic cases of OA and symptomatic cases.6–9 The catechol-O-methyltransferase, encoded by the COMT gene, is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters.10 Genetic variation at the COMT gene has been shown to result in differential pain sensitivity.10–12 Carriers of the Val158Met COMT variant have been reported to have a higher risk (OR=2.9, 95% CI 1.2 to 6.1) of hip pain as compared with carriers of the Val/Val genotype among those with hip OA.9 This result has not been replicated in independent cohorts, nor for OA in other joints. We assessed whether the Met allele in the COMT gene is involved in increased risk of symptomatic knee OA in seven cohorts: five cohorts from the UK, …

Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene

Substance P (SP) is a pain‐ and inflammation‐related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK1). SP and NK1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA.

Tropical rheumatology in a UK District General Hospital: a case report of leprosy presenting as acute vasculitis

tocilizumab, serum CRP and SAA levels became normal and morning stiffness and shoulder pain improved. By March 2009, a total of five infusions of tocilizumab had been administered without any exacerbation of symptoms or any elevation of serum CRP or SAA levels. MMP3 reduced from 508-727 to 334 ng/ml. Ga-citrate scintigraphy also showed a marked reduction of uptake in the bilateral shoulders and hands, and in the left ankle joint (Fig. 1B). However, just before the sixth administration, cholecystitis occurred and tocilizumab treatment had to be stopped. At 3 months after the cessation, the disease activity flared up with shoulder pain and morning stiffness, leading to an increase in the methylprednisolone dose from 6 mg/day to 8 mg/day. In this report, we demonstrated the ameliorative effect of tocilizumab on symptoms caused by RS3PE. To the best of our knowledge, this is the first report to evince the efficacy of tocilizumab for RS3PE. A response to low-dose corticosteroids and absence of relapse after 2 years of treatment are characteristics of RS3PE [5] but our patient was refractory to corticosteroids and then the present case was thought to be a rare one. Increased serum concentration of IL-6 has been observed in patients with RS3PE [2, 3], and therefore IL-6 inhibition with tocilizumab might constitute a novel strategy for treatment of RS3PE. Indeed, reported here, tocilizumab treatment resulted in a remarkable suppression of clinical symptoms, accompanied by a reduction in MMP3 levels as well as in Ga-citrate uptake in joints. Although tocilizumab treatment had to be discontinued due to the complication of cholecystitis in the patient, tocilizumab can be considered a viable option for treatment of refractory RS3PE.