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Clinical Updates

Yoshiki Miyachi, MD, PhD

Skin Diseases First Described by Japanese Dermatologists. Part 3: Eosinophilic Pustular Folliculitis

Yoshiki Miyachi

Wednesday, February 08, 2012

Eosinophilic pustular folliculitis (EPF) is a chronic pruritic and non-infectious inflammatory skin disease characterized by massive eosinophilic infiltration involving the pilosebaceous units that was first described by Professor Ofuji of Kyoto University, Japan.1 Although not a common skin disease, dermatologists should consider EPF when encountering patients with inflammatory acne or dermatophyte folliculitis who do not respond to ordinary treatment.

Although most of the classic types of EPF have been reported in Japan, it is important for dermatologists from all over the world to recognize EPF because immunosuppression-associated EPF has now been recognized as an HIV-related skin disease. Recently, we performed a nation-wide survey of EPF in Japan, as well as some basic research to investigate the pathomechanisms of EPF, and therefore in this article, I would like to introduce the latest viewpoints on EPF.

Definition and Epidemiology

EPF was first reported in 1965 by Ofuji as a follicular variant of subcorneal pustular dermatosis; in 1970, it was termed EPF and was deemed to be a novel clinical entity. It is now also referred to as Ofuji disease.2 EPF consists of chronic and recurrent itchy follicular papules and sterile pustules, which extend peripherally and have a central clearing tendency. Histopathologically, it is characterized by the eosinophil infiltrates in the pilosebaceous unit.

The three variations of EPF are:3

  1. Classic EPF
  2. Immunosuppression-associated EPF (mostly HIV-related)
  3. Infancy-associated EPF

Infancy-associated EPF, which is usually found on the scalp of children and has a good clinical response to corticosteroids, may be somewhat different from adult EPF.4 Epidemiological studies reveal that classic EPF occurs in young adults aged 20-30 years old, with a male/female ratio of 4.8/1 in Japan.5 The most commonly affected lesion of classic EPF is located on the face (85%); however, the eruptions can also be seen on the back, the arms and the chest. 

Recently, we have undertaken a national survey of EPF in Japan and collected data on 147 cases of EPF in 2011. Although the exact incidence or prevalence still remains unclear, there seems to be a few hundred EPF patients under treatment during 2011 in Japan, the population of which is approximately 120 million. As shown in Table 1, most of the cases were classic EPF (92.5%) and only 6.8% of cases were HIV associated, which seems to differ from Western countries, in which the overwhelming majority of EPF cases are found in patients with HIV, and classic/infantile EPF cases are much less common.3 Over 91% of EPF patients responded to oral indomethacin, whereas topical steroids, oral antibiotics and oral cyclosporine were effective in only 50-60% of patients. This is why indomethacin is considered to be the first-choice treatment for EPF in Japan.6

Table 1. Results of Our National Survey on 147 EPF Cases in Japan (2011). 
 (Miyachi Y et al: Reported to Ministry of Health, Labour and Welfare, Japan.)

Pathophysiology

As for the mechanism of eosinophilic accumulation in pilosebaceous units, it has been reported that the eosinophilic chemotactic factor was found in skin-surface lipid products.7 This appears to be a reasonable explanation because most EPF lesions are distributed in the seborrheic region of patients with a past history of acne.

Most cases of immunosuppression-associated EPF are seen in patients with AIDS, and show features both common and different to classic EPF. It is reported that eotaxin and T-helper (Th)2 cytokines play a crucial role in eosinophil recruitment and inflammation, leading to the tissue injury of hair follicles.8

We investigated further the exact mechanism of how eosinophils are attracted to pilosebaceous units. We performed immunostaining for prostaglandin (PG) synthases in EPF skin lesions, which were detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD2 is produced in the lesions. In addition, PGD2 increased the expression of eotaxin-3 in sebocytes in a dose-dependent manner. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of EPF lesions.9 These findings indicate that PGD2 induces eotaxin production from sebocytes, which may explain the large number of eosinophils observed around pilosebaceous units in EPF (Figure 1).

Figure 1. Eosinophils are attracted to pilosebaceous units by PGD2-dependent production of eotaxin in sebocytes.

 

Clinical Manifestations and Laboratory Findings

Characteristic features of classic EPF are pruritic follicular papules and sterile pustules that gradually expand, creating a well-demarcated area (Figure 2). There is a central healing tendency, which leaves a slightly scaly pigmentation. On the face, slightly elevated maculoerythematous indurations with scattered papules and pustules are occasionally seen. They subside spontaneously over time; however, they can flare up periodically, resulting in a chronic course. Over half of patients complain of itching.

Figure 2. Typical clinical features of EPF.
 
 

Differential diagnoses of classic EPF include inflammatory acne, rosacea, tinea corporis, pustular psoriasis, subcorneal pustular dermatosis and seborrheic dermatitis. Mild-to-moderate eosinophilia is occasionally observed, with elevated levels of immunoglobulin (Ig)E. As EPF is sometimes accompanied by HIV infections and other immunosuppressive conditions, eg, hematologic malignancies, these complications should be checked carefully.

Histopathology

Immunosuppression- and infancy-associated EPF are indistinguishable histologically from classic EPF, regardless of their different clinical features. The histopathology of typical EPF is characterized by a dense inflammatory infiltrate of mononuclear cells and eosinophils around the hair follicles and sebaceous glands (Figure 3). 

In the early phase of papular eruption, spongiosis of the outer root sheath of the follicles is observed, presumably because of the destruction mediated by eosinophils. In the advanced stage, eosinophilic infiltration extends to the whole hair follicle, leading to a pustular formation.

Figure 3. The histopathology of typical EPF is characterized by a dense inflammatory infiltrate of mononuclear cells and eosinophils around the hair follicles and sebaceous glands (hematoxylin and eosin stain).

 

Treatment

Various treatments have been proposed for EPF; however, the endpoint of treatment should be to control the disease because EPF shows a chronic course with fluctuations. The clinical effect of topical corticosteroids is limited. Among other treatment options - which include phototherapy, systemic steroids, dapsone, metronidazole, minocycline and retinoids (for which there are no good controlled data) - oral indomethacin seems to be the most promising choice of treatment.6 Indeed, our national survey revealed that over 90% of EPF patients responded to oral indomethacin, a success rate that has also been reported by others.

Although the mechanism of action by which indomethacin is beneficial in EPF remains unclear, it may work by inhibiting the production of cyclooxygenase-dependent PGD2, with resultant suppression of eotaxin production and therefore reduced attraction of eosinophilis to the pilosebaceous units. Inhibition of the PGD2 pathway might also be a therapeutic target for other diseases involving eosinophil infiltration.

Conclusions

Classic EPF was first described as a non-infectious inflammatory skin disease characterized by eosinophilic infiltration of pilosebaceous units, and was later revealed as a globally important skin disease when immunosuppression-associated EPF was recognized as an HIV-related skin disease. If you see patients with pruritic follicular papules on the face resembling dermatophyte folliculitis or inflammatory acne, who do not respond to standard treatment, consider EPF. Although biopsy will make an exact diagnosis, it is advisable to try systemic indomethacin to see if this treatment works.

References

  1. Ofuji S, Ogino A, Horio T, Oseko T, Uehara M. Eosinophilic pustular folliculitis. Acta Derm Venereol 1970;50:195-203.
  2. Ofuji S. Eosinophilic pustular folliculitis. Dermatologica.  1987;174:53-56.
  3. Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular folliculitis: A 40 year retrospect. J Am Acad Dermatol.  2009;55:285-289.
  4. Ziemer M, Boer A. Eosinophilic pustular folliculitis in infancy: not a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2005;27:443-455.
  5. Takematsu H, Nakamura K, Igarashi M, Tagami H. Eosinophilic pustular folliculitis. Report of two cases with a review of the Japanese literature. Arch Dermatol. 1985;121:917-920.
  6. Ota T, Hata Y, Tanikawa A, et al. Eosinophilic pustular folliculitis (Ofuji's disease): Indomethacin as a first choice of treatment. Clin Exp Dermatol. 2001;26:179-181.
  7. Takematsu H, Tagami H. Eosinophilic pustular folliculitis. Studies on possible chemotactic factors involved in the formation of pustules. Br J Dermatol. 1986;114:209-215.
  8. Amerio P, Verdolini R, Proietto G, et al. Role of Th2 cytokines, RANTES and eotaxin in AIDS-associated eosinophilic folliculitis. Acta Dermatovenereol. 2001;81:92-95.
  9. Nakahigashi K, Doi H, Otsuka A, et al: PGD2 induces eotaxin-3 via PPARĪ³ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis. J Allergy Clin Immunol. 2011, in press.
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