Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: Results from two population‐based cohorts

Objective

The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported.

Methods

A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥2 time points; n = 164) compared with pain‐free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0–29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r² > 0.8) single‐nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero‐inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively.

Results

SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01–2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07–2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta‐analysis of the data from the 2 cohorts further strengthened these findings.

Conclusion

The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain.

     

Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies.

PURPOSE: To compare the effect of delayed and early treatment strategies on disease outcome in patients with rheumatoid arthritis. SUBJECTS AND METHODS: Between 1993 and 1995, 109 patients diagnosed with probable or definite rheumatoid arthritis of recent onset were initially treated with analgesics; if they had persistent active disease, they were treated subsequently with the disease-modifying drugs chloroquine or salazopyrine (delayed treatment). Between 1996 and 1998, similar patients (n = 97) were promptly treated with either chloroquine or salazopyrine (early treatment). RESULTS: The median lag to the initiation of disease-modifying treatment was 15 days in the early treatment group and 123 days in the delayed treatment group. There was less radiologic joint damage after 2 years in the early treatment group (median Sharp score, 3.5; 95% confidence interval [CI]: 1 to 7) compared with the delayed treatment group (median Sharp score, 10; 95% CI: 5 to 15; P <0.05). The median area under the curve of the 2-year disease activity score was lower in the early treatment group (64 units; 95% CI: 59 to 69 units) compared with the delayed treatment group (73 units; 95% CI: 69 to 77 units; P = 0.002). CONCLUSION: In this nonrandomized comparison, early introduction of disease-modifying antirheumatic drugs was associated with a better disease outcome after 2 years.     

Work disability among two cohorts of women with recent-onset rheumatoid arthritis: a survival analysis

OBJECTIVE: To analyze factors associated with leaving employment among women with newly diagnosed rheumatoid arthritis (RA). METHODS: Women with RA were recruited from a national sample of rheumatologists in 1987 and 1998. Inclusion criteria were RA diagnosis <18 months earlier, age >or=18 years, and no other disabling health condition. The 1987 and 1998 cohorts comprised 48 and 91 women, respectively. Data were collected by telephone for 4 years. Survival analysis was conducted using Kaplan-Meier curves and a proportional hazards generalized linear model to assess whether the time to stopping work differed between the cohorts and to identify baseline predictors and time-varying covariates of leaving work. RESULTS: Most patients were age <50 years, married, had >12 years of education, and were white. Fifteen patients (31%) in the 1987 cohort and 24 patients (26%) in the 1998 cohort stopped working in the observation periods. Kaplan-Meier survival curves for each cohort were not significantly different. Multivariate analyses demonstrated that married women (P = 0.03) and those with joint deformities (P = 0.00) were more likely to stop working. A significant flares by cohort interaction (P = 0.01) indicated that, in comparison with patients in the 1998 cohort, those in the 1987 cohort with <2 disease flares had the lowest risk of stopping work and those with >or=2 flares had the greatest risk. CONCLUSION: Unexpectedly, the cumulative rate of stopping work among women in the 1998 study did not differ from that among women diagnosed >16 years earlier. However, disease flares greatly affected employment in the 1987 but not the 1998 cohort, possibly indicating that newer medications were effective in maintaining functional status among those with more severe disease activity, measured by number of flares, in the 1998 group.     

Peripheral pain mechanisms in chronic widespread pain

Clinical symptoms of chronic widespread pain (CWP) conditions like fibromyalgia (FM), include pain, stiffness, subjective weakness, and muscle fatigue. Muscle pain in CWP is usually described as fluctuating and often associated with local or generalised tenderness (hyperalgesia and/or allodynia). This tenderness related to muscle pain depends on increased peripheral and/or central nervous system responsiveness to peripheral stimuli, which can be either noxious (hyperalgesia) or non-noxious (allodynia). For example, patients with muscle hyperalgesia will rate painful muscle stimuli higher than normal controls, whereas patients with allodynia may perceive light touch as painful, something that a 'normal' individual will never describe as painful. The pathogenesis of such peripheral and/or central nervous system changes in CWP is unclear, but peripheral soft tissue changes have been implicated. Indirect evidence from interventions that attenuate tonic peripheral nociceptive impulses in patients with CWP syndromes like FM suggest that overall FM pain is dependent on peripheral input. More importantly, allodynia and hyperalgesia can be improved or abolished by removal of peripheral impulse input. Another potential mechanism for CWP pain is central disinhibition. However, this pain mechanism also depends on tonic impulse input, even if only inadequately inhibited. Thus, a promising approach to understanding CWP is to determine whether abnormal activity of receptors in deep tissues is fundamental to the development and maintenance of this chronic pain disorder. CONCLUSIONS: Most CWP patients present with focal tissue abnormalities including myofascial trigger points, ligamentous trigger points or osteoarthritis of the joints and spine. While not predictive for the development of CWP, these changes nevertheless represent important pain generators that may initiate or perpetuate chronic pain. Local chemical mediators, including lactic acid, adenosine triphosphate (ATP) and cytokines, seem to play an important role in sensitising deep tissue nociceptors of CWP patients. Thus, the combination of peripheral impulse input and increased central pain sensitivity may be responsible for widespread chronic pain disorders including FM.     

Comparison of three classification criteria of rheumatoid arthritis in an inception early arthritis cohort

The aim of this study is to compare the three classification criteria for rheumatoid arthritis (RA) in a large cohort of early arthritis patients. Patients who had at least one clinically swollen joint with disease duration no more than 1 year and age more than 18 years were enrolled. The clinical and laboratory parameters were recorded. The patients were diagnosed by two experienced rheumatologists. Undiagnosed patients were followed up every 3 months until 1 year. The sensitivity, specificity, and predictive value were compared among the early RA (ERA) criteria, the 1987 ACR criteria, and the 2010 ACR/EULAR criteria in this inception cohort of early arthritis patients. A total of 417 patients with inflammatory arthritis were recruited. By the end of 1 year follow-up, there were 399 patients (95.7 %) with a definitive diagnosis and 18 (4.3 %) patients remained as undifferentiated arthritis. Among the patients with definitive diagnosis, 202 (50.6 %) patients were diagnosed with RA and 197 (49.4 %) with non-RA. The sensitivity of ERA criteria was equal to 2010 ACR/EULAR criteria (both were 72.3 %), but much higher than 1987 ACR criteria (72.3 vs. 39.1 %, P?<?0.001); the specificity of ERA criteria was comparable to 2010 ACR/EULAR criteria (87.8 vs. 83.2 %) and slightly lower than 1987 ACR criteria (87.8 vs. 92.4 %, P?<?0.001). Unlike the complicated scoring system of 2010 criteria, the ERA criteria were more feasible to use in practice with five criteria only. The ERA criteria have a high sensitivity and more clinically feasibility in daily practice for early RA diagnosis.     

两种类风湿关节炎滑膜侵蚀软骨联合免疫缺陷模型的建立及比较

目的 比较背部皮下与肾包囊内2种不同移植方式所建立的类风湿关节炎(RA)滑膜侵蚀软骨联合免疫缺陷(SCID)模型的病理学及血清学改变,为采用人滑膜和软骨进行RA炎症及软骨损伤机制和治疗的体内研究提供实验系统.方法 15只SCID小鼠随机分为皮下移植组、肾包囊移植组及空白对照组,无菌获取RA患者滑膜及人正常软骨,通过相应的移植方式共同植入各组SCID小鼠体内.分别于术后4、8周取移植组织,进行组织病理学分析;留取血清,用酶联免疫吸附试验(ELISA)检测人类风湿因子(RF)水平.结果 皮下移植组成活率及建模成功率较肾包囊组明显增高,两组滑膜中炎细胞浸润、滑膜增殖、软骨侵蚀评分及血清RF-IgM水平差异均无统计学意义(P>0.05).结论 与肾包囊移植相比,背部皮下移植建立的SCID-HuRAg在炎症及骨侵蚀及血清学改变上差异无统计学意义,且操作简便,成功率高,是进行人RA滑膜对软骨侵蚀机制和治疗体内研究的理想动物模型.     

Clinimetric evaluations of patients with chronic widespread pain

Assessing chronic widespread pain (CWP) and its impact on physical, emotional and social function requires multidimensional qualitative and health-related quality of life (HRQL) instruments. The recommendations of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) concerning outcome measurements for pain trials are useful for making routine assessments, the most significant of which include pain, fatigue, disturbed sleep, physical functioning, emotional functioning, patient global ratings of satisfaction and HRQL. However, despite the growing spread of instruments and theoretical publications devoted to measuring the various aspects of chronic pain, there is little widespread agreement, and no unified approach has yet been devised. There is therefore still considerable scope for the development of consensus around a core set of measures and response criteria, as well as for the development and refinement of the related instruments, standardised assessor training, the cross-cultural adaptation of health status questionnaires, electronic data capture and the introduction of valid, reliable and responsive standardised quantitative measurements into routine clinical care. Clinicians need to be aware of the psychometric properties of the instruments used, including their levels of imprecision and minimum clinically important differences (those indicating a meaningful change in clinical status). This article reviews a selection of the instruments used to assess CWP patients, including validated newly developed and well-established screening instruments, and discusses their advantages and limitations.     

The prevalence of rheumatoid arthritis in Sweden

The aim of this study was to ascertain the prevalence of rheumatoid arthritis (RA) in a Swedish general adult population. A questionnaire about chronic pain was mailed to a total of 3928 subjects who were chosen as a random sample of the population in two communities in the county of Halland. All persons answering affirmatively to questions intended to identify patients with RA were invited to a clinical examination. X-rays of hands and feet, and analyses of rheumatoid factor and C reactive protein were performed provided that the patients fulfilled two or more of the five clinical items of the 1987 ARA criteria. Furthermore, non-participants were searched for in a patient register and in medical records from the local rheumatology unit in an attempt to identify further cases. Using the modified 1987 ARA criteria for population studies the prevalence rate of RA was calculated to 0.51% (95%, CI = 0.31-0.79).     

Work disability among two cohorts of women with recent‐onset rheumatoid arthritis: A survival analysis

Objective

To analyze factors associated with leaving employment among women with newly diagnosed rheumatoid arthritis (RA).

Methods

Women with RA were recruited from a national sample of rheumatologists in 1987 and 1998. Inclusion criteria were RA diagnosis <18 months earlier, age ≥18 years, and no other disabling health condition. The 1987 and 1998 cohorts comprised 48 and 91 women, respectively. Data were collected by telephone for 4 years. Survival analysis was conducted using Kaplan‐Meier curves and a proportional hazards generalized linear model to assess whether the time to stopping work differed between the cohorts and to identify baseline predictors and time‐varying covariates of leaving work.

Results

Most patients were age <50 years, married, had >12 years of education, and were white. Fifteen patients (31%) in the 1987 cohort and 24 patients (26%) in the 1998 cohort stopped working in the observation periods. Kaplan‐Meier survival curves for each cohort were not significantly different. Multivariate analyses demonstrated that married women (P = 0.03) and those with joint deformities (P = 0.00) were more likely to stop working. A significant flares by cohort interaction (P = 0.01) indicated that, in comparison with patients in the 1998 cohort, those in the 1987 cohort with <2 disease flares had the lowest risk of stopping work and those with ≥2 flares had the greatest risk.

Conclusion

Unexpectedly, the cumulative rate of stopping work among women in the 1998 study did not differ from that among women diagnosed >16 years earlier. However, disease flares greatly affected employment in the 1987 but not the 1998 cohort, possibly indicating that newer medications were effective in maintaining functional status among those with more severe disease activity, measured by number of flares, in the 1998 group.     

The prevalence of foot ulceration in patients with rheumatoid arthritis

OBJECTIVE: To establish the prevalence of foot ulceration in patients with rheumatoid arthritis (RA) in secondary care. METHODS: A postal survey of all patients with RA (n = 1,130) under the care of rheumatologists in Bradford, West Yorkshire, UK was performed. The prevalence data were validated through clinical examination, case-note review, and contact with health professionals. The false-negative rate was investigated in a subsample of patients (n = 70) who denied any history of ulceration. RESULTS: The postal survey achieved a 78% response rate. Following validation, the point prevalence of foot ulceration was 3.39% and the overall prevalence was 9.73%. The false-positive rate was initially high at 21.21%, but use of diagrammatic questionnaire data to exclude leg ulceration reduced the rate to 10.76%. The false-negative rate was 11.76%. The most common sites for ulceration were the dorsal aspect of hammer toes, the metatarsal heads, and the metatarsophalangeal joint in patients with hallux abducto valgus, with 33% of patients reporting multiple sites of ulceration. Patients with open-foot and healed-foot ulceration had significantly longer RA disease duration, reported significantly greater use of special footwear, and had a higher prevalence of foot surgery than ulcer-free patients. CONCLUSION: Foot ulceration affects a significant proportion of patients with RA. Further work is needed to establish risk factors for foot ulceration in RA and to target foot health provision more effectively.