TNF Receptor-Associated Periodic Syndrome (TRAPS) , formerly known as familial Hibernian fever (FHF) [2, 3] is an archetypal hereditary periodic fever syndrome and is an autosomal dominant condition characterised by mutations in the TNFRSF1A gene [4, 5]. Periodicity of fevers is typical of TRAPS with peritonitis, arthritis and fasciitis. It is also well recognised that some patients continue to feel unwell between attacks. That subclincal TRAPS is still ongoing in such circumstances is supported by persistent acute phase response [6, 7]. There are no specific features to localise a site for this persistent inflammatory response and, to date, no studies have been done to investigate this interesting observation.
Whole body magnetic resonance imaging (MRI) has recently been introduced for the assessment of various skeletal pathologies including malignancy, myositis and arthritis [8-12]. MRI in inflammatory disorders has the capacity to show both soft tissue inflammatory changes and osteitis. We hypothesised that patients with TRAPS without obvious clinical manifestations and the absence of fevers have subclincal disease affecting the anatomical territories that are prone to inflammation during acute attacks. Herein, we confirm that some cases of TRAPS do indeed have ongoing soft tissue and joint inflammation between attacks. Given that autoinflammatory disorders, like TRAPS, are diseases of the innate immune system, these findings support the concept of persistent innate immune activation between attacks.
The Galway (Ireland) TRAPS cohort consists of 15 affected family members, 2 of whom have amyloidosis and all having the T50M mutation in the TNFRSF1A gene . A total of 9 members of this family attend the clinic regularly. Persistently raised inflammatory markers were found in 7 of these patients, 2 members did not give consent for MRI due to claustrophobia. A total of 5 members participated in the study, however during the course of the study; one of these patients had normal inflammatory markers in spite of having persistently raised markers before screening. Interview and clinical examination were performed to document symptoms, frequency of flares, inflammatory markers and medications (Table 1).
All cases described classical attacks of fever, sweats, abdominal pain and serositis. They also had symptoms between attacks including prominent myalgia, arthralgia, malaise and fatigue, with persistently elevated inflammatory markers in 4 out of 5 patients confirming ongoing disease activity between attacks. After obtaining informed consent, all 5 cases had whole body scanning on a Siemens 1.5 T MRI (Siemens-AG, Symphony). Images were reviewed on Agfa PACS High resolution workstation by two fellowship trained musculoskeletal radiologists. One patient had a flare during the MRI and was rescanned between flares. MRI results are shown in Table 1.
Bilateral knee and hip effusions and bone oedema of left tibia were found in one patient, who was asymptomatic at the time of his scan and did not have osteoarthritis clinically or radiologically in this knee. Repeat MRI of the left knee was done. It is possible that the knee changes could have been contributed to by ligament injury and joint degeneration that was asymptomatic. Only one MRI of 5 was completely normal with corresponding normal inflammatory markers (Figure 1).
In conclusion, we provide MRI evidence for persistent subclinical tissue inflammation in an identical pattern to that seen during classical attacks of TRAPS. This suggests that the innate immune driven pathology is actually chronic and most likely represents recurrent acute attacks of subclinical tissue inflammation. Unlike some other conditions of chronic innate immune activation including Blau syndrome, the inflammation in TRAPS does not appear to lead to target organ destruction . The utility of whole body MRI for exploring febrile illness with a TRAPS phenotype without TNFRS1A mutations is also worthy of consideration.