Registry
Data from a total of 740 APS patients included in the Piedmont and Aosta Valley Rare Disease Registry was analyzed. Median age at diagnosis was 45 years old (Interquartile Range, IQR 34–57), while the median age of the first clinical manifestation of APS (either thrombotic or pregnancy morbidity) fulfilling the diagnostic criteria of the disease [
1] was 40 years old (IQR 29–52). The mean diagnostic delay was of 4.7 years (S.D. ±8.3), median 1 year (IQR 0–5).
Data was then stratified by time period, as shown in Fig.
1. Interestingly, the diagnostic delay was significantly reduced over time, starting from data collected since 1983 (the year of APS description [
10]), with a mean diagnostic delay of 3.4 years ± 5.2 (median 5 years; IQR 3–10), since 1990 (mean diagnostic delay 3 years ± 4.7; median 5, IQR 3–9), since 2000 (mean diagnostic delay 2.2 years ± 3.2; median 4, IQR 2–7), since 2010 (mean diagnostic delay 1.1 years ± 1.4; median 3, IQR 3, 2-3.75) and since 2015 (mean diagnostic delay 0.8 years ± 0.8; median 2, IQR 2, 2–3).
When comparing the diagnostic delay between patients diagnosed between 1983 and 1999 and patients diagnosed between 2000 and 2015, we found a significant statistical difference (Mann-Whithey U Test; mean rank 1216.6 vs. 1066.9, respectively; p < 0.0001).
Questionnaire
Among the eligible patients, thirty-three patients (66% females; mean age at data collection 46.7 ± 13.2 years old) filled out the anonymous questionnaire via Google Forms. The rate of response to the questionnaire was (33/74, 45%). Seventeen patients (52%) were primary APS, while 16 patients (48%) had secondary APS. Twenty-four patients (73%) had at least one thrombotic event, 6 patients experienced pregnancy morbidity (3 recurrent miscarriages and 3 foetal deaths), and 3 patients fulfilled the criteria for both thrombotic and obstetric APS.
When asked if, in their perception, there has been a delay when diagnosing their autoimmune condition, 20 patients (61%) replied yes, 11 (33%) replied no and 2 (6%) were unsure of the reply. Of the patients that thought there had been indeed a diagnostic delay, the mean delay was of 46.5 months (S.D. ±65; max 240; min 3). When we asked these patients if their clinical manifestations, in light of their current disease knowledge, were suggestive of APS, the majority of case (50%) answer yes, while 30% were unsure and 20% believed that their first clinical manifestations were not linked to APS.
Interestingly, when looking at first clinical manifestations of autoimmune disease, the most common manifestation in patients that believed there had been a diagnostic delay was an autoimmune manifestation not linked to APS, as arthralgia and cutaneous manifestations (45%), followed by “extra criteria” APS manifestations, such as thrombocytopenia, hip osteonecrosis, migraine and livedo reticularis (30%) and by “criteria” manifestations such as thrombotic events (25%). In comparison, the first clinical manifestation of patients that did not believe there had been a diagnostic delay were “criteria” manifestations, such as thrombotic events and pregnancy complications (45.5%), followed by autoimmune manifestation not linked to APS (45.5%), and “extra criteria” APS manifestation (9%).
When we focused on patients with referred diagnostic delay (20/33) and analyzed only those with a diagnostic lag of more than one year (8/20), we noticed that patients that waited the most (namely patient 1 and 2) were those with symptoms that emerged in the nineties, when APS knowledge was growing and sharpening. More in detail, patient 1 manifested first clinical sign in 1990 and was diagnosed in 2015; patient 2 had first clinical sign in 1998 and was diagnosed in 2016. In case 1, the first symptom was a cutaneous rash, that was later classified as systemic lupus erythematosus over time; in case 2 amnesia, migraine and digital petechiae manifested as first clinical signs, all now recognized “extra criteria” manifestations of APS.
When enquiring what was the reason the patients believed the delay was caused by, the majority of patients (16/20, 80%) thought that the doctor that first diagnosed them had been wrong or didn’t recognize the disease proceeding with further investigations. Two patients claimed of being misunderstood by the clinician and of having neglected their health issues contributing to the delay. All the reported answers are listed and resumed in Fig.
2.
When exploring the number of clinicians/centers consulted before diagnosis was established, 26 patients (79%), with and without declared delayed diagnosis, reported of being evaluated by one to three different physicians. Seven patients (21%), nonetheless, consulted more than four different centers/physicians before receiving APS diagnosis. Respondents stated that the first clinician who suspected the disease was a specialized physician, but three subjects indicated their general practitioners as the first clinician to point it out.