Development and Preliminary Validation of a Diagnostic Score for Identifying Patients Affected with Adult-Onset Autoinflammatory Disorders

Abstract

To date, the rate of detection of autoinflammatory gene mutations in patients suspected of having an autoinflammatory disorder is very low. However, most of these data refer to pediatric populations. 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. Our aim was to develop and validate a set of variables for predicting the risk that a given adult patient presenting with recurrent fever episodes carries mutations in the MEFV or TNFRSF1A genes, in order to increase the probability of obtaining positive results on genetic testing. One hundred and ten consecutive patients with a clinical history of periodic fever attacks were screened for mutations in the TNFRSF1A and the MEFV genes. The mean age at disease onset was 27.85 years. Detailed information about each patient?s family history, personal history, and clinical manifestations were retrospectively collected. A diagnostic score was constructed based on univariate and multivariate analysis in a randomly-selected dataset (training set; n=40). The score was validated on an independent set of the remaining patients (validation set; n=70). Age at onset (odds ratio 0.958, P =0.050), positive family history of recurrent fever episodes (OR 5.738, P = 0.006 ), thoracic pain (OR 7.390, P = 0.002), abdominal pain (OR 2.853, P = 0.038) and skin involvement (OR 8.241, P = 0.003) were independently correlated with a positive genetic test result. A diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic model (cut off equal to 0.24) revealing high sensitivity (0.94), high specificity (0.94) and high accuracy (0.94). We have identified variables that appear to be strongly related to the probability of detecting gene mutations in MEF and TNFRSF1A in adults, thus improving the evaluation of patients with suspected autoinflammatory disorders.

Validation of a Diagnostic Score for the Diagnosis of Autoinflammatory Diseases in Adults

“…The predictive potential of the model is demonstrated by the high levels of sensitivity (77.8%) and specificity (71.8%) obtained by ROC analysis, which underlines the high level of predictiveness of the score. The cut-off obtained through a combination of predicted probability of sensitivity and specificity is equal to the optimal cut-off previously estimated (12).…”

“…For the validation ofthe 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 lOR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<O.OOI), thoracic pain (OR 3.17, p<O.OOI),abdominal pain (OR 3.80,p<0.001) and skin rash (OR 1.58,p=0.103).…”

“…In addition, patients with adult-onset TRAPS may present atypical clinical manifestations mimicking autoimmune disorders (13)(14)(15)(16). 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 TNFRSFIA and, in addition, we also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes (12).…”

Autoimmunity and autoinflammation as the yin and yang of idiopathic recurrent acute pericarditis

“…Although pediatric onset is considered the norm, the presence of low-penetrance mutations in the MEFV and TNFRSF1A genes may be identified in adulthood [69][70][71][72] as adult subjects carrying low-penetrance alleles and characterized by a late disease onset display as a less aggressive phenotype [73]. Nonetheless, FMF is the most common recessive and TRAPS the most common dominant autosomally inherited autoinflammatory disorder.…”

Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases

“…SAID conditions have a heterogeneous genetics characterised by monogenic, and at a lesser extent, multifactorial inheritance, with causative genes involved in the innate branch of the immune response 5. Manifestations usually start in early infancy or neonatal period,6 7 but rare adult onset has also been described 8 9. SAID clinical picture is extremely wide, ranging from recurrent and self-limiting fever episodes associated with arthralgia and myalgia, rash, chest and abdominal pain (periodic fevers) to chronic and persistent inflammatory disease course with skin rash, arthritis and possible severe neurological inflammation (cryopyrinopathies).…”