The advantages of the present study include nationwide coverage in a country with universal access to medical services of high diagnostic standards. Amyloidosis diagnostics are time-consuming and it has been reported that a small proportion of hereditary amyloidosis is misdiagnosed as the common immunoglobulin light chain amyloidosis . However, FAP is well known in Sweden and, moreover, two thirds of the patients were discharged more than once with the same specific amyloidosis subtype which implies consistent diagnostics. Also, the striking finding showing the precise geographic location of FAP cases and the immigrant dominance of hereditary autoinflammatory disease testify to a high diagnostic accuracy. Based on the similar geographic location, approximately similar age distribution and interchanged diagnosis in many patients of FAP and unspecified heredofamilial amyloidosis, they may be the same disease, with a joint incidence of 2.28 per million, somewhat less than that of hereditary autoinflammatory disease (2.83 per million). These incidence rates refer to inpatients and outpatients for years 2001 to 2008.
Swedish neuropathic heredofamilial amyloidosis (FAP) is caused by any of three identified transthyretin mutations. However, even for the same mutation penetrance and manifestations vary . The mean age of onset has been reported to be 56 years, which is somewhat lower than what we found here (the median age at diagnosis was 67 years for men and 57 years for women). The likely explanation is that symptoms do not immediately lead to hospitalization, but once patients are hospitalized amyloidosis is fulminant. However, considering the variable penetrance of FAP, the present incidence rates underestimate the incidence of FAP. Our data showed that 77% of the Swedish FAP patients were diagnosed in the two northernmost provinces of Sweden (West and North Bothnia), which together account for slightly more than 5% of the Swedish population. The incidence of FAP was over 100-fold higher in West Bothnia than in the rest of the country (excluding North Bothnia), in spite of large population movements within Sweden since the Second World War.
Autoinflammatory diseases are caused by dysfunction of the inflammasome complex of the innate immune system [13, 14]. They include several monogenic diseases such as pyrin-associated FMF, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated periodic syndrome. Many of these diseases are diagnosed by pediatricians and, for example, 80% of FMF cases occur before age 20 years . FMF is, according to a review, almost always restricted to Turks, Armenians, Arabs and non-Ashkenazi Jews or emigrants with these ethnicities and, according to this source, no cases have been described in individuals of Scandinavian origin . Autoinflammatory conditions may give rise to reactive amyloidosis, which may manifest initially as renal problems; the amyloid precursor is serum amyloid A, the normal and not a mutated protein [13–16, 18]. Our first clue that code E85.0 included periodic fever syndromes was the overwhelming proportion of patients who were immigrants from the Eastern Mediterranean area, with the incidence being highest in first-generation Syrian immigrants (109 per million) and their descendants (136 per million). In endemic areas, rates have been estimated to be as high as 1,000 per million . The relatively early age of onset also supported the disease identity of periodic fever syndrome; the highest incidence rates were in the 20 to 29 years age group in second-generation immigrants (median age at diagnosis 14 years). However, it is important to note that the immigrant populations originating from the Eastern Mediterranean area are relative newcomers to Sweden and their oldest descendants are still young adults . Thus, the calculated median ages at hospitalization are likely to be too high in the first generation immigrants who entered Sweden at around age 25 years and who could have the disease already at immigration. The delay between first disease episodes and diagnosis was over 7 years in the Eurofever registry . The calculated median ages may be too low for the young second generation because of the age truncation (still a young population).
An obvious question resulting from the above findings is whether native Swedes have indigenous hereditary autoinflammatory or related diseases. Among the 210 identified patients, 95 were born in Sweden but for only nine (2.3%) had both parents been born in Sweden. However, we were unable to confirm parental ethnicity. Recent data demonstrated that some inflammasome-related conditions appear to have indigenous origins in Sweden. Cryopyrin-associated periodic syndrome cases diagnosed in adulthood have been reported and common inflammasome-related NLRP3 and CARD8 polymorphisms have been described, although without evidence on disease susceptibility [15, 16]. Cases of pediatric periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) have also been described in Sweden, but the disease is apparently not heritable; mevalonate kinase deficiency has not been diagnosed in ethnic Swedes . Taken together, the available data suggest that hereditary autoinflammatory disease, as described in the present study, is a disease of immigrants originating from the Eastern Mediterranean area.