Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, University of Siena, Italy.
Int J Immunopathol Pharmacol. 2011 Jul-Sep;24(3):695-702. doi: 10.1177/039463201102400315.
Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFV and TNFRSF1A and, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFV and TNFRSF1A genes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<0.001), thoracic pain (OR 3.17, p<0.001), abdominal pain (OR 3.80, p<0.001) and skin rash (OR 1.58, p=0.103). The diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic multivariate model (cut-off equals to 0.24) revealing good sensitivity (0.778) and good specificity (0.718). In conclusion, our score may serve in the diagnostic evaluation of adult patients presenting with recurrent fever episodes suspected of having an autoinflammatory disorder, helping identify the few subjects among them who may be carriers of mutations in MEFV and TNFRSF1A genes.
大多数自身炎症性疾病通常在儿科人群中出现，尽管少数患者可能在成年后发病。迄今为止，仅在家族性地中海热中描述了迟发性疾病发作，这是由 MEFV 基因突变引起的，在肿瘤坏死因子受体相关周期性综合征中，这是由 TNFRSF1A 基因突变引起的。由于成年发病的自身炎症性疾病相对罕见，且缺乏相关信息，因此在这些病例中发现基因突变的可能性更小。为了提高对疑似自身炎症性疾病的成年患者的基因诊断，我们最近确定了一组与 MEFV 和 TNFRSF1A 基因检测基因突变概率相关的变量，并在此基础上提出了一种诊断评分，用于识别这些基因携带突变的高危患者。在本研究中，我们对更多患者进行了初步评分的敏感性和特异性评估，以验证该模型的拟合优度。对 219 例有周期性发热发作临床病史的患者进行 MEFV 和 TNFRSF1A 基因突变筛查；还收集了详细的家族/个人病史和临床表现信息。为了验证评分，我们考虑了用于构建初步诊断评分的 110 例患者的数据，以及本研究中另外纳入的 219 例患者的数据，总计 329 例患者。年龄较小、反复发热家族史、胸痛、腹痛和皮疹，这些变量先前被证明与阳性基因检测结果显著相关（12），用于验证。单因素分析显示与阳性基因检测相关的因素有：发病年龄（比值比 [OR] 0.43，p=0.003）、反复发热家族史（OR 5.81，p<0.001）、胸痛（OR 3.17，p<0.001）、腹痛（OR 3.80，p<0.001）和皮疹（OR 1.58，p=0.103）。诊断评分是使用逻辑多元模型的估计系数的线性组合计算得出的（截点等于 0.24），显示出良好的敏感性（0.778）和特异性（0.718）。总之，我们的评分可用于评估有反复发热发作且疑似自身炎症性疾病的成年患者，有助于识别其中少数可能为 MEFV 和 TNFRSF1A 基因突变携带者的患者。
