Dermatology for Pediatric and Adolesce

nt Gynecology

Periodic Fever with Aphthous Stomatitis, Pharyngitis, and AdenitisResponsive to Oral Corticosteroids and Dapsone

Brendan Pillemer MD, Joseph C. English III MD, Robin P. Gehris MD *University of Pittsburgh, Department of Dermatology, Pittsburgh, PA

Key Words: Periodic fever, PFAPA syndrome, Aphthous ulcers, Aphthous stomatitis

Clinical Case

A 12-year-old white female presented to the emergencyroom after several weeks of recurrent high fevers associatedwith painful oral lesions and a sore throat. She denied anygenital involvement. She was previously healthy, took nomedications, and had no prior history of oral lesions or coldsores. Therewas no family history of aphthous ulcers or coldsores. On examination, the patient was uncomfortable-appearing with cervical lymphadenopathy, pharyngitis,and multiple oral aphthous ulcers (Fig. 1). Lab testingincluded negative/normal results of a complete metabolicpanel, complete blood count, rapid strep, tuberculin skintest, parvovirus IgM, cytomegalovirus IgM, erythrocytesedimentation rate (ESR), influenza A/B, urinalysis, throatculture, blood culture, and viral culture of the oral lesions. Adermatology consultation was ordered for evaluation ofmucous membrane findings.

Dermatology Consultation

Acute fever is a common complaint, especially in pedi-atric patients, but chronic recurrent fever is much lesscommon, with a large differential diagnosis, includinginfectious, malignant, genetic, and immunologic/inflam-matory causes. Periodic fever syndromes such as familialMediterranean fever (FMF), tumor necrosis factor alphareceptor 1 associated syndrome, hyperimmunoglobulin Dsyndrome (HIDS), Muckle-Wells syndrome, familial coldautoinflammatory syndrome, chronic infantile neurologiccutaneous articular syndrome or neonatal-onset multi-system inflammatory disease, pyogenic sterile arthritis,pyoderma gangrenosum, acne (PAPA), and periodic feverwith aphthous stomatitis, pharyngitis, and cervical adenitis(PFAPA) are relatively uncommon conditions that can causechronic recurrent fevers and are also sometimes associatedwith mucocutaneous findings.

PFAPA syndrome is a non-inherited, rare disorder due toan unknown etiology, initially described in 12 children in

The authors indicate no conflicts of interest.* Address correspondence to: Robin P. Gehris, MD, Children’s Dermatology

Services, Pine Center, Suite 108, 11279 Perry Highway, Wexford, PA 15090; Phone:(724) 933-9190; fax: (724) 933-9194

E-mail address: gehrrp@upmc.edu (R.P. Gehris).

1083-3188/$ - see front matter � 2013 North American Society for Pediatric and Adoleshttp://dx.doi.org/10.1016/j.jpag.2012.10.002

1987.1 It most commonly affects young children, but isincreasingly being recognized in adults.2 Affected patientsdevelop recurrent feversO39�C frequently lasting 3e6 dayswith recurrence usually every 3e8 weeks, but with widevariability.3e5 This is associated with at least one of thefollowing 3 signs: aphthous stomatitis 38%, pharyngitis 85%,and cervical lymphadenopathy 62%. Other common com-plaints include abdominal pain 41%, nausea/vomiting 27%,and headache 44%.5

Since there are no specific confirmatory laboratorytests, PFAPA is principally a clinical diagnosis of exclusion.However, some cases will demonstrate elevated ESR,C-reactive protein, and fibrinogen as well as leukocytosiswith a left shift.5 Recent research has suggested that severalcytokines and chemokines taken together may serve asbiomarkers to confirm this uncommon diagnosis in thefuture, including IL-1, GM-CSF, MIG, and IP-10.4

Fortunately, many cases will resolve spontaneously with-out long-term sequelae. However, PFAPA can last for monthsto years and sometimes even longer, and therapeutic optionsfor children with PFAPA are limited. Current treatmentsinclude cimetidine, which is effective only in roughly 30% ofpatients, oral corticosteroids, which are associated with flaresfollowing taper, and tonsillectomy which is controversial buthas been proven to be as effective as corticosteroids ina recent meta-analysis.3e6 New research has also demon-strated improvement in a series of 5 patients who weretreated with the interleukin 1 receptor (IL-1R) antagonistanakinra.4 However, until more research is conducted tosupport the use of anakinra, this is unlikely to be widely useddue to cost and the difficulty of subcutaneous administrationin children.

Patient Management

Based on the normal laboratory workup and the con-stellation of findings, we diagnosed our patient with PFAPAsyndrome. Other important items on the differentialinclude complex aphthosis, Behcet’s, herpes simplexinfection, and other periodic fever syndromes. The first 3items on the differential can all present with recurrent oraland genital ulcerations but typically patients are afebrile. Inthe case of Behcet’s, patients will usually have genital andocular involvement.7 The last item on the differentialincludes multiple entities with recurrent fevers, but oral

cent Gynecology. Published by Elsevier Inc.

Fig. 1. Aphthous ulcers and hemorrhagic crusting of the lips on presentation.Ă

B. Pillemer et al. / J Pediatr Adolesc Gynecol 26 (2013) 193e195194

aphthous ulcers are not typically found except in HIDS.However, HIDS usually presents within the first year of lifeand patients have gastrointestinal symptoms which ourpatient lacked.

Our patient was started on cimetidine and topical as wellas oral corticosteroids with rapid defervescence and almostcomplete resolution of oral aphthous ulcers in less than 24hours (Fig. 2). However, the patient flared upon completionof her oral corticosteroid taper.

Many autoinflammatory and periodic fever syndromesdemonstrate upregulated IL-1.8 As mentioned above,recent work has demonstrated that PFAPA patients haveincreased IL-1, IP-10, MIG, and GM-CSF. These cytokinesand chemokines are involved in upregulation of theinnate immune response, particularly neutrophils andmacrophages.4

Colchicine is an oral medication used to block micro-tubule assembly leading to reduced neutrophil motility,chemotaxis, adhesiveness, and lysosome degranulation.9

Colchicine has shown efficacy in the treatment of FMF aswell as Behcet’s disease which causes aphthous andgenital ulcerations.9 Thus, after our patient relapsedfollowing her corticosteroid taper, we initiated therapy

Fig. 2. Almost complete resolution of aphthous ulcers after 24 hours of systemic and topic

with colchicine. Unfortunately, she was unable to tolerateit due to diarrhea.

Dapsone is an anti-lepromatous antibiotic that alsoinhibits myeloperoxidase, neutrophil chemotaxis, dihy-dropteroate synthetase (in the folic acid pathway), andleukotriene generation and binding.9 It is frequently used indermatology to treat neutrophilic dermatoses and diseaseswith aphthous ulcers such as Behcet’s disease and complexaphthosis due to its inhibitory effects on neutrophils,9 andas noted above, PFAPA is associated with upregulation ofcytokines involved in neutrophil upregulation. Althoughuse of dapsone to treat PFAPA is off-label, it is generally safeand well tolerated. Dapsone requires monitoring includingconfirmation that the patient has normal glucose 6 phos-phate dehydrogenase, complete blood count, and liverfunction testing, and after starting dapsone, regular labo-ratory testing of complete blood count and liver functiontesting as well as clinical monitoring for fatigue, which canbe caused by methemoglobinemia on rare occasions. Ourpatient weighed 40 kg and was started on dapsone 50 mgdaily with complete control of symptoms, but had difficultytolerating this dose due to fatigue. She is currently doingwell on maintenance dapsone 25 mg daily without

al corticosteroids.Ă

B. Pillemer et al. / J Pediatr Adolesc Gynecol 26 (2013) 193e195 195

significant side effects. We feel strongly that oral dapsonehas an advantage over other treatments in that it is widelyavailable, easy to administer in children, and generally well-tolerated.

References

1. Marshall GS, Edwards KM, Butler J, et al: Syndrome of periodic fever, pharyngitis,and aphthous stomatitis. J Pediatr 1987; 110:43

2. Cavuoto M, Bonagura VR: Adult-onset periodic fever, aphthous stomatitis,pharyngitis, and adenitis. Ann Allergy Asthma Immunol 2008; 100:170

3. Lee WI, Yang MH, Lee KF, et al: PFAPA syndrome (Periodic Fever, Aphthousstomatitis, Pharyngitis, Adenitis). Clin Rheumatol 1999; 18:207

4. Stojanov S, Lapidus S, Chitkara P, et al: Periodic fever, aphthous stomatitis,pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A 2011; 108:7148

5. Feder HM, Salazar JC: A clinical review of 105 patients with PFAPA (a periodicfever syndrome). Acta Paediatr 2010; 99:178

6. Peridis S, Pilgrim G, Koudoumnakis E, et al: PFAPA syndrome in children: Ameta-analysis on surgical versus medical treatment. Int J Pediatr Otorhinolaryngol2010; 74:1203

7. Keogan MT: Clinical Immunology Review Series: An approach to the patient withrecurrent orogenital ulceration, including Behcet’s syndrome. Clin Exp Immunol2009; 156:1

8. Savic S, Dickie LJ, Battellino M, et al: Familial Mediterranean fever and relatedperiodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol2012; 24:103

9. Wolverton SE: Comprehensive Dermatologic Drug Therapy, (2nd ed.). Philadelphia,W.B. Saunders, 2007