Adult-onset Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis Syndrome Responsive to Colchicine

Abstract

We herein report a rare case of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome that occurred in an 18-year-old man. He visited our hospital with recurrent episodes of a fever, pharyngitis and adenitis without suggestive findings of infection. These episodes resolved within 5 days and recurred quite regularly, with an interval of about 30 days. As the febrile episodes significantly impaired his quality of life, he was treated with colchicine (0.5 mg) as prophylaxis. This completely prevented the episodes during six months of follow-up. Colchicine may therefore be effective in cases of adult-onset PFAPA syndrome.

Introduction

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most frequent non-hereditary autoinflammatory disorder in children. It usually occurs before the age of five, but the number of reported adult cases has recently been increasing (1). It is characterized by recurrence of episodic fever attacks with oropharyngeal symptoms and cervical lymphadenitis lasting three to six days (2).

Although the precise pathogenesis has not been determined, immune dysregulation is assumed to be involved. Interleukin (IL)-1 production from peripheral blood mononuclear cells is increased during the fever period (3), and inhibition of IL-1 signaling by anti-IL-1 biologics, such as anakinra, improves the clinical course of this disease (4).

It is well known that the administration of corticosteroids during fever attack can dramatically resolve it in a few hours, which is one of the clinical features of this disease (5). However, the frequent use of corticosteroids may cause bothersome side effects. This disease is considered not to cause life-threating complications (1), but fever attacks per se significantly impair the patient's quality of life (QOL). In this context, prophylactic treatment is important for managing patients with PFAPA syndrome.

Colchicine has been reported to be effective for a reduction in fever flare frequency in pediatric patients (1), but its efficacy in adult patients has not been determined because of the rarity of this disease in that population.

We herein report a rare case of adult-onset PFAPA syndrome that was successfully treated with colchicine therapy.

Case Report

An 18-year-old man presented with recurrent episodes of a high fever with pharyngitis and cervical adenitis for 5 months, since 17 years old. The episodes recurred quite regularly with an interval of around 30 days. He repeatedly visited several clinics because of the episodes and was diagnosed with pharyngitis or tonsilitis possibly caused by a bacterial or viral infection each time. He underwent a rapid antigen detection test for group A streptococcus or throat culture several times, but the results were all negative. The symptoms always resolved in about five days, irrespective of treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or antibiotics.

At the sixth episode, he visited an otolaryngology clinic. Given his periodic recurrent episodes, the doctor mentioned the possibility of periodic fever syndrome, and the patient was referred to our hospital. As his fever attack had completely resolved two to three days before the first visit, he was asymptomatic. He had neither a notable medical history nor any family history of recurrent fever flares. On a physical examination, no abnormal findings were observed. Laboratory examinations revealed that transaminases, C-reactive protein (CRP) and serum amyloid A (SAA) levels were slightly elevated, and antinuclear antibody, rheumatoid factor, matrix metalloproteinase-3, anti-cyclic citrullinated peptide antibody and soluble IL-2 receptor were negative. Anti-Epstein-Barr (EB) virus capsid antigen immunoglobulin G and M titer were 1:40 dilution and <1:10 dilution, respectively. Anti-EB virus nuclear antigen titer was 1:40 dilution. Anti-cytomegalovirus antigen IgG and M were <2 AU/mL and 0.16, respectively. One week later, laboratory investigations were performed again, and we confirmed that the transaminase, CRP and SAA levels had returned to normal. He was followed without any medications and instructed to visit our hospital if an episode occurred again.

One month later, he experienced his seventh fever flare accompanied by sore throat, cervical lymphadenopathy and muscle pain and visited us as instructed. His body temperature was 40.2°C, but all other vital signs were within normal limits. He also underwent an otolaryngological examination, and pharyngeal edema, swollen bilateral palatine tonsils with white exudates and aphthous lesions at the base of the tongue were observed. The bilateral cervical lymph nodes were palpable and tender. A laboratory investigation revealed that his CRP level was mildly elevated (3.78 mg/dL), and his SAA level was extremely high (412.7 mg/L). Gram staining of blood cultures was negative.

The patient was diagnosed with PFAPA syndrome based on Padeh's diagnostic criteria (Table) (6), as he satisfied five of the six criteria: a monthly cyclic fever, exudative tonsillitis with negative throat culture, cervical lymphadenitis, aphthous stomatitis and completely asymptomatic during intervals.

Table.

Diagnostic Criteria of PFAPA Syndrome (6).

Monthly fevers-cyclic fever at any age group

Exudative tonsillitis with negative throat culture

Cervical lymphadenitis

Possibly aphthous stomatitis

Completely asymptomatic interval between episodes

Rapid response to a single dose of corticosteroids

He was treated with NSAIDs, and his symptoms completely resolved within five days similar to the previous episodes, as was confirmed at the next visit. We then prescribed colchicine (0.5 mg per day). Two weeks later, he was completely asymptomatic, but mildly elevated transaminase levels were detected. As we could not deny the possibility that this abnormality was due to colchicine administration, the dose of colchicine was reduced to 0.25 mg per day. In addition, prednisolone (30 mg) was prescribed, and he was instructed to use this dose of prednisolone at the time of the next fever attack.

One month later, he experienced his eighth attack, and a single dose of prednisolone aborted his symptoms within a few hours. He visited us, and elevated transaminases disappeared. As this dose of colchicine (0.25 mg) was not considered to be effective for preventing his attack, the dose was returned to 0.5 mg. After this dose of colchicine was introduced, neither recurrence of febrile episodes nor elevated transaminase levels were observed during six months of follow-up.

Discussion

The diagnosis of PFAPA syndrome is based on clinical criteria. Our case met all of the diagnostic criteria for PFAPA syndrome (Table), and other diseases exhibiting the same symptoms were excluded. Thus, the case was thought to be typical PFAPA syndrome with an onset in adulthood.

Familial Mediterranean fever (FMF) is the most frequent autoinflammatory disorder in adults, typically found in those carrying the MEFV gene mutation (7). Furthermore, as our patient exhibited a good response to colchicine, this case might have been considered to be one of FMF. However, FMF is characterized by recurrent episodes of self-limited fever attacks accompanied by serositis, and in general, patients suffer from symptoms such as peritonitis, pleuritis and arthritis (7), features that differed from those in our case. Although colchicine is the gold standard of FMF treatment, a single dose of steroids is not effective for the resolution of a fever attack in cases of FMF (8). Given these findings, we feel that the diagnosis of our case as one of PFAPA is rational.

The first case of adult-onset PFAPA syndrome was reported in 2008 (9), and more than 100 cases have been reported thus far (9-16). However, such cases are still scarce in Japan, and our patient may be tenth such case (14,17-20).

Several reports have shown that colchicine reduced the fever flares in 45-85% of pediatric PFAPA patients (21-24). However, as these studies were small cohort or retrospective studies, there is limited evidence on the effectiveness of this approach. There are no clinical investigations assessing the response rates to colchicine in adult-onset patients, and only a few colchicine-responsive cases have been anecdotally reported (12,15,18).

A high frequency of variants in several genes associated with inflammation was detected in patients with PFAPA syndrome (3,25). Nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NLRP3) inflammasome, which cleaves pro-IL-1β into mature IL-1β by activating caspase 1 (CASP1) protein, was shown to be activated in the patients (25). Furthermore, a high frequency of NLRP3 variants, which can enhance NLRP3 activity, thereby resulting in the increased production of IL-1β, was also reported (3). In addition, a few studies reported an increased frequency of MEFV gene variants in a PFAPA population (26). The MEFV gene encodes pyrin, which regulates IL-1β production by interaction with CASP1 and other inflammasome components. The mutation of pyrin resulting from MEFV gene variants showed a reduced inhibitory effect on CASP1, leading to the increased production of IL-1β (27). Thus, PFAPA syndrome patients may have a polygenic background related to inflammasome-related genes with increased IL-1 signaling, which is involved in clinical manifestations (28-30).

It was previously demonstrated that colchicine suppressed the activity of NLRP3 inflammasome (31). Therefore, it is plausible to think that colchicine inhibits IL-1β production by suppressing the NLRP3 activity to ameliorate the symptoms of PFAPA. It is well known that prednisolone cannot prevent the subsequent fever flare (32), and several reports have shown that using prednisolone shortened the interfebrile period (1). Tonsillectomy is an effective therapeutic option for pediatric PFAPA patients, but it was reported to be less useful in adult patients (28). In this context, colchicine may be a promising candidate for the prophylaxis of PFAPA.

As a limitation associated with the present study, we did not perform genetic testing for MEFV mutations. As PFAPA is diagnosed based on symptoms and physical examination findings, carrying this gene mutation cannot exclude the diagnosis. In this context, we felt there was no benefit to genetic testing for our patient. Although not all results were consistent, a few studies have suggested that the rates of response to colchicine were higher in PFAPA patients carrying MEFV variants than in others (21,24). Genetic data may be utilized for determining the application of colchicine or the duration of treatment for PFAPA patients in the future.

Adult-onset PFAPA syndrome is still rare, and the awareness of this disease seems to be low among physicians. As this disease significantly impairs patients' QOL, every physician should ensure they are aware of this disease in order to make an accurate diagnosis. Prophylactic treatment can improve the QOL, and colchicine may be an effective therapeutic option. Increasing awareness of this disease may increase the number of reported cases of this disease, which will allow us to conduct a large-scale clinical study to determine the effectiveness of colchicine in adult-onset patients.

The authors state that they have no Conflict of Interest (COI).