RESUMO
Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.
Assuntos
Condrócitos/fisiologia , Condrogênese/genética , Estudo de Associação Genômica Ampla , Metiltransferases/genética , Osteoartrite do Quadril/genética , Fatores Etários , Animais , Cartilagem Articular/patologia , Cartilagem Articular/fisiologia , Linhagem Celular , Condrócitos/citologia , Variação Genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Histona-Lisina N-Metiltransferase , Humanos , Metiltransferases/metabolismo , Camundongos , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Quadril/patologia , Fatores de Risco , Via de Sinalização Wnt/fisiologiaRESUMO
INTRODUCTION: Pain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA. METHODS: In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status. RESULTS: More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health. CONCLUSIONS: Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.
Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/psicologia , Progressão da Doença , Fibromialgia/diagnóstico , Fibromialgia/psicologia , Saúde Mental , Limiar da Dor/psicologia , Idoso , Artrite Reumatoide/epidemiologia , Estudos Transversais , Feminino , Fibromialgia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Medição da Dor/psicologiaRESUMO
OBJECTIVE: Multiple mechanisms are involved in pain associated with osteoarthritis (OA). The painDETECT and Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaires screen for neuropathic pain and may also identify individuals with musculoskeletal pain who exhibit abnormal central pain processing. The aim of this cross-sectional study was to evaluate painDETECT and S-LANSS for classification agreement and fit to the Rasch model, and to explore their relationship to pain severity and pain mechanisms in OA. METHODS: A total of 192 patients with knee OA completed questionnaires covering different aspects of pain. Another group of 77 patients with knee OA completed questionnaires and underwent quantitative sensory testing for pressure-pain thresholds (PPTs). Agreement between painDETECT and S-LANSS was evaluated using kappa coefficients and receiver operator characteristic (ROC) curves. Rasch analysis of both questionnaires was conducted. Relationships between screening questionnaires and measures of pain severity or PPTs were calculated using correlations. RESULTS: PainDETECT and S-LANSS shared a stronger correlation with each other than with measures of pain severity. ROC curves identified optimal cutoff scores for painDETECT and S-LANSS to maximize agreement, but the kappa coefficient was low (κ = 0.33-0.46). Rasch analysis supported the measurement properties of painDETECT but not those of S-LANSS. Higher painDETECT scores were associated with widespread reductions in PPTs. CONCLUSION: The data suggest that painDETECT assesses pain quality associated with augmented central pain processing in patients with OA. Although developed as a screening questionnaire, painDETECT may also function as a measure of characteristics that indicate augmented central pain processing. Agreement between painDETECT and S-LANSS for pain classification was low, and it is currently unknown which tool may best predict treatment outcome.
Assuntos
Inquéritos Epidemiológicos/classificação , Neuralgia/classificação , Osteoartrite do Joelho/classificação , Medição da Dor/classificação , Fenótipo , Autorrelato/classificação , Idoso , Estudos Transversais , Feminino , Inquéritos Epidemiológicos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/diagnóstico , Osteoartrite do Joelho/diagnóstico , Medição da Dor/métodosRESUMO
OBJECTIVE: To survey the use of analgesic medication 4.8 years after total joint replacement (TJR) surgery and assess the determinants of medication usage. PATIENTS AND METHODS: Of 852 patients who had undergone TJR for osteoarthritis were recruited from secondary care. Participants (mean age, 73.7 years) responded to a questionnaire on medication use, physical function and pain (WOMAC, VAS and body pain), pain catastrophizing and illness behaviour (somatization). RESULTS: Only 37% of study participants were not on any pain relief medication, 25.1% were taking opioids, 6.9% were taking prescription NSAIDs and 25.9% were taking only non-prescription analgesics. Use of NSAIDs correlated with presence of back pain, body pain and high illness behaviour. The strongest associations with use of opioids were severe joint pain, high pain catastrophizing, body and back pain. After adjustment for covariates plus presence of pain, catastrophizing remained significantly associated with higher risk of opioid use (OR = 1.66, 95% CI: 1.13-2.43, p < 0.009) and of other prescription medication that can be used to treat pain (anti-depressants, anti-epileptics and hypnotics) (OR = 2.52, 95% CI: 1.61-3.95, p < 0.0005). CONCLUSIONS: Use of opioid medication 4 years post-TJR is very high in our study population. In addition to joint, back and body pain, a major contributor to opioid use is pain catastrophizing. Our data suggest that current opioid and other analgesic prescribing patterns may benefit from considering the catastrophizing characteristics of patients.