Skin Diseases First Described by Japanese Dermatologists. Part 3: Eosinophilic Pustular Folliculitis
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
- Classic EPF
- Immunosuppression-associated EPF (mostly HIV-related)
- 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.)
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
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
Figure 2. Typical clinical features of
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.
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).
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
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.
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
- Ofuji S, Ogino A, Horio T, Oseko T, Uehara M. Eosinophilic
pustular folliculitis. Acta Derm Venereol
- Ofuji S. Eosinophilic pustular folliculitis.
- Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular
folliculitis: A 40 year retrospect. J Am Acad
- Ziemer M, Boer A. Eosinophilic pustular folliculitis in
infancy: not a distinctive inflammatory disease of the skin. Am
J Dermatopathol. 2005;27:443-455.
- Takematsu H, Nakamura K, Igarashi M, Tagami H. Eosinophilic
pustular folliculitis. Report of two cases with a review of the
Japanese literature. Arch Dermatol.
- Ota T, Hata Y, Tanikawa A, et al. Eosinophilic
pustular folliculitis (Ofuji's disease): Indomethacin as a first
choice of treatment. Clin Exp Dermatol.
- Takematsu H, Tagami H. Eosinophilic pustular folliculitis.
Studies on possible chemotactic factors involved in the formation
of pustules. Br J Dermatol.
- Amerio P, Verdolini R, Proietto G, et al. Role of Th2
cytokines, RANTES and eotaxin in AIDS-associated eosinophilic
folliculitis. Acta Dermatovenereol.
- Nakahigashi K, Doi H, Otsuka A, et al: PGD2 induces
eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of
eosinophilic pustular folliculitis. J Allergy Clin
Immunol. 2011, in press.