Pyoderma gangrenosum, acne, and suppurative

hidradenitis (PASH)ea new autoinflammatory

syndrome distinct from PAPA syndrome
Markus Braun-Falco, MD,a Oleksandr Kovnerystyy, MD,a Peter Lohse, MD,b and Thomas Ruzicka, MDa
Munich, Germany

Background: PAPA syndrome is a recently identified hereditary autoinflammatory syndrome clinically

characterized by pyogenic arthritis, severe acne, and pyoderma gangrenosum. It is caused by mutations in
the PSTPIP1 gene and may be closely linked to the aseptic abscesses syndrome, which has been shown to
be associated with CCTG repeat amplification in the promoter region of PSTPIP1.

Objective: We describe two unrelated patients with a clinical presentation quite similar to, yet distinct from,
PAPA syndrome.

Results: Both patients had pyoderma gangrenosum and acute or remittent acne conglobata, but, in
contrast to PAPA syndrome, lacked any episodes of pyogenic arthritis. Instead, they had suppurative
hidradenitis. Mutations in PSTPIP1 exons 1 to 15 were excluded. In the promoter region, an increased
repetition of the CCTG microsatellite motif was present on one allele in both patients. Alterations of the
most commonly affected exons of the MEFV, NLRP3, and TNFRSF1A genes also were not detectable. One
patient was treated with the interleukin (IL)-1 receptor antagonist anakinra and responded well, although
without complete remission. This implies that IL-1 may be of pathogenetic importance.

Limitations: Small number of patients, no gene mutation identified, and unclear efficacy of therapy are
limitations.

Conclusions: The clinical triad of pyoderma gangrenosum, acne, and suppurative hidradenitis represents
a new disease entity within the spectrum of autoinflammatory syndromes, similar to PAPA and aseptic
abscesses syndrome. For this disease, we propose the acronym PASH syndrome. PASH syndrome may
respond to IL-1 blockade. ( J Am Acad Dermatol 2012;66:409-15.)

Key words: CD2-binding protein 1/proline-serine-threonine-phosphatase-interactive protein 1; inflam-

matory skin disease; interleukin-1; interleukin-1 receptor antagonist; neutrophilic dermatitis; pyogenic
arthritis.

H ereditary autoinflammatory syndromes are

an emerging group of inflammatory diseases
distinct from infectious, autoimmune, and
allergic disorders along with immunodeficiencies
Abbreviations used:
CAPS:
IL:
PG:
cryopyrin-associated periodic syndrome
interleukin
pyoderma gangrenosum
PSTPIP1: proline-serine-threonine-phosphatase-
interactive protein 1
From the Departments of Dermatology and Allergy,a and Clinical SH: suppurative hidradenitis
Chemistry-Grohadern,b Ludwig-Maximilian-University.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication December 22, 2010.
Reprint requests: Markus Braun-Falco, MD, Department of that attract increasing interest (Table I). The term
Dermatology and Allergy, Ludwig-Maximilian-University, autoinflammatory syndrome was initially intro-
Frauenlobstr 9-11, D-80337 Munich, Germany. E-mail: markus. duced by Daniel Kastner and John OShea in 1999
braun-falco@med.uni-muenchen.de. to describe an autosomal dominant periodic fever
Published online July 11, 2011.
0190-9622/$36.00
caused by mutations in the tumor necrosis factor
2011 by the American Academy of Dermatology, Inc. type 1 receptor.1 Since then, the number of
doi:10.1016/j.jaad.2010.12.025 identified autoinflammatory diseases has increased

409
410 Braun-Falco et al J AM ACAD DERMATOL
MARCH 2012

substantially, to include not only hereditary periodic elbows, and ankles. During puberty, joint disease
fever syndromes, but also acquired common diseases seems to diminish and the dermatologic manifesta-
such as gout or type 2 diabetes mellitus.2 tions become more prominent, with PG often affect-
Subsequently, the gene defects causing at least 10 ing the lower extremities and cystic acne that tends to
mendelian autoinflammatory disorders have been persist into adulthood.
described, and some new syndromes were defined.3 Here, we would like to present two unrelated
One of them is the rare autosomal dominant patients with symptoms similar to, but distinct from,
PAPA syndrome (Mendelian PAPA syndrome who ex-
Inheritance in Man No. hibited a symptom triad of
604416).4 It was first de- CAPSULE SUMMARY PG, acne, and suppurative
scribed in 1997 by Lindor hidradenitis (SH), but lacked
PAPA syndrome, characterized by
et al,5 who coined the acro-
d
arthritis.
pyogenic arthritis, pyoderma
nym PAPA that embraces
gangrenosum, and acne, is a rare
the unusual clinical symptom CASE PRESENTATIONS
autoinflammatory disorder caused by
triad of pyogenic sterile ar- Case 1
mutations in PSTPIP1.
thritis, pyoderma gangreno- A 34-year-old man (172 cm;
sum (PG), and acne first d Two patients are described with a clinical 92 kg) of Russian descent had
recognized in a 3-generation presentation similar to, yet distinct from, severe cystic acne lesions on
family with 10 affected mem- PAPA syndrome. Both had severe his face and back since ado-
bers. To date, 41 patients from pyoderma gangrenosum and acne, but lescence, and from clusters of
8 unrelated families in 6 coun- lacked any flare of arthritis, instead chronic and repeatedly drain-
tries on 4 continents and at displaying suppurative hidradenitis. ing sinuses and abscesses in
least one historical case from There was no mutation in PSTPIP1. both axillae for 7 years (Fig 1,
1975 described as streaking d
The constellation of pyoderma A to D). During the last 6
leukocyte factor have been gangrenosum, acne, and suppurative months, slowly expanding
given the diagnosis of PAPA hidradenitis represents a new and painful ulcerations devel-
syndrome.5-14 In all families autoinflammatory disorder distinct from oped on his arms and lower
except one, a heterozygous PAPA, for which we propose the acronym legs. His medical history was
point mutation could be ver- PASH. otherwise unremarkable in
ified in the PSTPIP1 gene on particular for any kind of ar-
chromosome 15q24-q25.1 thritis, inflammatory bowel
encoding CD2-binding protein 1, also known as disease, or hematologic malignancy; his family history
proline-serine-threonine-phosphatase-interactive also was negative for any chronic skin or other inflam-
protein 1 (PSTPIP1). So far, 4 mutations have been matory disease. He had a 20-pack-year smoking
identified in PSTPIP1 exons 10 and 11, resulting in history. Physical examination revealed large inflamma-
amino acid substitutions p.Ala230Thr, p.Glu250gln, tory, suppurative, and scarring plaques with draining
p.Glu250Lys, and p.Asp266Asn.4 PSTPIP1 has been sinuses and abscesses in both axillary vaults (Fig 1, B).
shown to bind to pyrin, the protein mutated in familial On his chest, back, and lower extremities, several
Mediterranean fever linking both diseases to the same sloughy ulcers and hemorrhagic scarring plaques up
pathway.15 PSTPIP1 and pyrin are coexpressed as part to a size of approximately 10 3 15 cm were seen
of the NLRP3 inflammasome in granulocytes and (Fig 1, A). The face and back displayed multiple
monocytes. It has been hypothesized that the muta- depressed scars resulting from acne conglobata.
tions lead to a hyperphosphorylation of PSTPIP1, thus Laboratory workup revealed a slight increase of
increasing its binding affinity to pyrin. As a result, leukocytes, thrombocytes, C-reactive protein, and
pyrin loses its inhibitory effect on the NALP3 inflam- g-glutamyltransferase. Antidesoxyribonuclease B was
masomeedriven and caspase 1emediated proinflam- minimally elevated at 240 U/mL (normal \ 200
matory signaling pathway that cleaves pro-interleukin U/mL), whereas streptolysin O and antistaphylolysin
(IL)-1 into active IL-1. Clinically, the gain-of- titers were normal. Serum amyloid A was slightly
function mutations predispose to an IL-1-dependent increased at 22.1 mg/L (normal \ 5 mg/L). Serology
inflammatory reaction dominated by granulocytes for hepatitis infections revealed negative findings.
and monocytes. Consistent with this hypothesis, There was no IgM peak detectable on immunoelec-
most patients with PAPA syndrome develop recurrent trophoresis to rule out plasma cell dyscrasias. Bacterial
episodes of nonaxial destructive arthritis with intense cultures from multiple sites showed either no bacterial
neutrophilic inflammation of the synovia, starting in growth or Staphylococcus aureus. Histology from
early childhood. Joints most often involved are knees, lesions on the chest and lower right arm revealed
J AM ACAD DERMATOL Braun-Falco et al 411
VOLUME 66, NUMBER 3

Table I. Examples of autoinflammatory diseases with known and unknown genetic defects
Disease Inheritance Mutation Clinics Reference
PAPA syndrome AD PSTPIP1 Pyogenic sterile arthritis, PG, acne 4-14
Aseptic abscesses ? Increased CCTG Recurrent attacks of fever, multiple abdominal 16
syndrome repeats in PSTPIP1 abscesses, often associated with PG, chronic
promoter inflammatory bowel disease,
relapsing polychondritis
FMF AR MEFV Recurrent flares of fever, peritonitis, fewer 2
pleuritis, arthritis, pericarditis
Tumor necrosis factor AD TNFRSF1A Similar to FMF, in addition with myalgias, 2
receptor 1eassociated colocalizing urticarial rash, unilateral
periodic fever conjunctivitis, and periorbital edema
Cryopyrin-associated AD NLRP3 Depending on severity differentiation 2
fever syndromes into FCAS, Muckle-Wells syndrome,
and NOMID/CINCA
FCAS AD NLRP3 Recurrent episodes of nonitchy urticarial 2
rash with fever, arthralgia, myalgia,
and conjunctivitis.
Muckle-Wells AD NLRP3 And hearing loss, amyloidosis 2
syndrome
NOMID/CINCA AD NLRP3 And early onset, severe fever, 2
syndrome lymphadenopathy, hepatosplenomegaly,
meningitis, progressive visual and hearing
loss, mental retardation
SAPHO ? ? Synovitis, acne, acral pustulosis, 2
hyperostosis, osteitis
CROM ? ? Nonbacterial osteomyelitis affecting 2
metaphyses of long bones with
associated inflammation of skin, eyes,
gastrointestinal tract, and lungs
Majeed syndrome AR LPIN2 Relatively similar to CROM, in addition 2
with congenital dyserythropoietic
anemia and Sweet syndrome
Deficiency of IL-1 AR IL1RN Neonatal onset of sterile multifocal 2
receptor antagonist osteomyelitis, periostitis,
and pustulosis

AD, Autosomal dominant; AR, autosomal recessive; CINCA, chronic infantile neurologic, cutaneous articular; CROM, chronic recurrent
osteomyelitis; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; IL, interleukin; NOMID, neonatal onset
multisystem inflammatory disease; PG, pyoderma gangrenosum.

necrotizing suppurative and focally fibrosing derma-
titis with severe neutrophilic infiltration, consistent
with PG (Fig 1, C). Fungal infection was ruled out by
special stains and mycobacterial infection by tissue
polymerase chain reaction and tuberculin skin test.
Esophagogastroduodenoscopy, coloscopy including
multiple biopsies, and chest x-ray did not reveal any
abnormalities. A bone scan depicted only a slightly
increased activity in the acromioclavicular/sternocla-
vicular and humeroglenoidal joints, consistent with a
degenerative process, but not with pyogenic arthritis.
Sequence analysis of exons 1 to 15 of the PSTPIP1
gene and its promoter region did not reveal any
mutations, nor did screening of MEFV exons 2, 3, and
10; NLRP3 exons 2, 3, and 4; or TNFRSF1A exons 2, 3,
4, and 6. The length of the poly-CCTG region was
increased with 5 repeats on one allele and 8 repeats
on the other, the average length being 5 repeats. He
was initially treated with isotretinoin 40 mg/d during a
3-month period, which slightly diminished the sever-
ity of his acne, but had no impact on PG lesions.
Subsequently, treatment with the IL-1 receptor antag-
onist anakinra (100 mg/d) was started that led to a
substantial, but not complete remission of the inflam-
matory activity. During a 6-month follow-up period,
early inflammatory lesions resolved and changed into
scarred plaques (Fig 1, D), but a few new lesions
developed in particular at the injection sites as a sign
of a pathergy phenomenon. This prompted us to add
cyclosporine (200 mg/d) to his treatment regimen
under which the lesions further regressed, but still did
not resolve completely.
412 Braun-Falco et al J AM ACAD DERMATOL
MARCH 2012

Fig 1. Case 1: 34-year-old man with multilocular pyoderma gangrenosum on various body
sites (A) with overlapping involvement of suppurative hidradenitis in axilla (B). C, Intensive
neutrophilic infiltration in biopsy specimen from border of lesion. D, Marked reduction
of inflammation and scarring healing during interleukin-1 receptor antagonistic therapy.
(C, Hematoxylin-eosin stain; original magnification: 320.)

Case 2 The family history was unremarkable. Routine lab-

A 44-year-old man (202 cm; 138 kg) of German
descent presented with a 22- 3 12-cm large ulcer on
the front, lower aspect of his left leg that was
surrounded by a dusky red, inflammatory, under-
mined edge (Fig 2, A). The ulceration developed a
year earlier after a minor trauma, healed almost
completely after autologous split-skin grafting, but
recurred during the last few months. Skin examina-
tion revealed multiple inflammatory and scarring
plaques with abscesses, fistulae, and keloidal scars
in both axillary vaults (Fig 2, B) and groin and along
the large fold under his overhanging abdomen (Fig
2, C ). His medical history was remarkable only for
severe cystic acne at age 17 to 18 years that left
behind multiple depressed scars on both cheeks. He
denied any episodes of inflammatory arthritis or
joint pain. He had a 20-pack-year smoking history.
oratory tests including anticyclic citrullinated pro-
tein antibodies were within normal limits aside from
increased C-reactive protein with 1.42 mg/dL (nor-
mal \0.5 mg/dL) and slight leukocytosis. Serum
amyloid A was also elevated at 66.2 mg/L. Serology
for hepatitis infections revealed negative findings.
There was no IgM peak detectable on immunoe-
lectrophoresis to rule out plasma cell dyscrasias.
Coloscopy showed a few small diverticula, but
without histologic signs of inflammatory bowel
diseases. Dermatohistopathology of a biopsy spec-
imen from the border of the leg ulcer revealed
neutrophilic inflammation and areas of necrotic or
fibrotic connective tissue. Fungal infection was
ruled out by special stains and mycobacterial infec-
tion by tissue polymerase chain reaction and tuber-
culin skin test. Sequencing of PSTPIP1 exons 1 to
J AM ACAD DERMATOL
VOLUME 66, NUMBER 3
Fig 2. Case 2: 44-year-old male with large pyoderma gangrenosum on his lower leg (A),
draining sinuses and scarring from suppurative hidradenitis in axillary vault (B) and large
abdominal fold (C).
15, and of the promoter region did not show any
mutations, nor did the analysis of MEFV exons 2, 3,
and 10; NLRP3 exons 2, 3, and 4; or TNFRSF1A
exons 2, 3, 4, and 6. The length of the poly-CCTG
region was 5 repeats and 6 repeats per allele.
Immunosuppressive treatment was initiated, starting
with 100 mg/d prednisolone that was slowly ta-
pered to 5 mg/d, azathioprine 100 mg twice daily
reduced to 100 mg once daily after 8 weeks, and
topical tacrolimus ointment twice daily. Under this
regimen, a decrease of the inflammatory intensity
and initial re-epithelialization from the border of the
ulcer was observed. To accelerate wound closure, a
split-skin graft was performed after 10 weeks, but
after an initial take, the epidermal sheet dissolved
completely under a newly occurring episode of
inflammation. Nevertheless, with a combination of
low-dose prednisolone and azathioprine the ulcer-
ations decreased very slowly in size to 1 cm in
diameter during a 1-year follow-up period.
Braun-Falco et al 413
DISCUSSION
PAPA syndrome is clinically characterized by py-
ogenic sterile arthritis, PG, and acne, and has been
defined as an autosomal dominant autoinflammatory
syndrome caused by mutations in the PSTPIP1 gene.
Herein, we present two unrelated patients with a
symptom complex very close to, but clearly distinct
from, PAPA syndrome. They share the dermatologic
signs of PG and acne with PAPA syndrome, but in
distinction to PAPA lack the intensive joint inflam-
mation and instead experience severe SH at large
skin folds. They are also distinct on a genetic basis,
because no mutations could be detected in the 15
exons of the PSTPIP1 gene and within 545 nucleo-
tides 5 of the ATG start codon. In addition, both
patients were screened for the most prevalent muta-
tions of the MEFV, NLRP3, and TNFRSF1A genes,
which are responsible for the vast majority of cases of
familial Mediterranean fever, cryopyrin-associated
periodic syndrome (CAPS), and tumor necrosis
414 Braun-Falco et al
factor receptor 1-associated periodic syndromes,
respectively. Again, no mutation could be detected.
The only abnormality that we were able to find was
an increased number of CCTG microsatellite repeats
in the PSTPIP1 promoter region with heterozygosity
for 6 repeats in one case and heterozygosity for 8
repeats in the other. Such an increase recently has
been found to be associated with the aseptic ab-
scesses syndrome in French patients.16 Aseptic ab-
scesses syndrome is characterized by deep abscesses
with a predilection for the spleen, accompanied by
fever, abdominal pain, and a raised leukocyte count.
In 66% of all cases, aseptic abscesses syndrome is
associated with inflammatory bowel diseases, in
particular Crohns disease, and 20% of the patients
develop skin lesions in the form of cutaneous
abscesses and neutrophilic dermatoses, primarily
PG and Sweet syndrome. Thus, the increase in
number of the CCTG motif in the PSTPIP1 promoter
seems to be associated with a susceptibility to
neutrophilic inflammations. It might be possible
that the location of the mutation within the
PSTPIP1 gene influences the organ predilection.
The amino acid substitutions encoded by exons 10
and 11 would induce particularly pyogenic arthritis,
and the CCTG replications in the promoter region
would favor development of visceral (splenic) ab-
scesses or skin manifestations. The phenomenon
that different mutations in a single gene account for a
spectrum of phenotypic manifestations has already
been shown in CAPS, another hereditary autoin-
flammatory syndrome. CAPS is caused by mutations
in the NLRP3 gene encoding the protein cryopyrin, a
major component of the NALP3 inflammasome,
which controls indirectly the production of IL-
1 by activation of caspase-1.3 CAPS comprises
what has formerly been recognized as 3 distinct
diseases, namely familial cold autoinflammatory
syndrome; Muckle-Wells syndrome; and neonatal
onset multisystem inflammatory disease/chronic in-
fantile neurologic, cutaneous articular syndrome.
However, CCTG replications in the PSTPIP1
promoter region have probably only a mild effect
on the development of this rather distinct cutaneous
inflammation. Which additional factors or genes
could possibly be involved in the pathogenesis
and be the subject of further investigations? In
general, the combination of PG, acne, and SH
occurs in extremely rare instances. Ah-Weng et al17
found only 9 cases of coexisting PG and SH in the
English-language literature and they added 6 cases
themselves. In their series, 3 patients also had severe
acne during adolescence. Their patients developed
PG after SH had been present for a median duration
of 21 years, whereas our patients developed PG
J AM ACAD DERMATOL
MARCH 2012
already 1.5 and 7 years after the onset of SH. PG
itself is commonly associated with other diseases.18
In a study of 86 cases, 78% of the patients had
suffered from a comorbidity, of which 37% had
arthritis, 36% inflammatory bowel disease, 10%
monoclonal gammopathy, 5% SH, and 2% acne
conglobata.19 Another study comprising 22 cases
found PG associated with arthritis in 41% of patients,
inflammatory bowel disease in 41%, and monoclo-
nal gammopathy in 18%.20 SH in combination with
acne conglobata was associated with arthritis in 21
of 44 subjects,21 and 31% of the patients with
chronic inflammatory bowel disease experienced
episodes of SH.22 There seems to be a clinical
association of PG, SH, arthritis, and Crohns disease
that favors a largely uniform pathogenic pathway,
although an initial genetic association study of
alterations of the NOD2/CARD2 gene, the suscepti-
bility locus for Crohns disease, in SH failed to reveal
any association.23 However, neither of our two
patients had experienced episodes of arthritis or
inflammatory bowel disease. With regard to auto-
inflammatory diseases, PG has not only been rec-
ognized as part of the PAPA syndrome, but also,
although rarely, in SAPHO, chronic recurrent oste-
omyelitis, Majeed syndrome, deficiency of IL-1 re-
ceptor antagonist, and others. The genes being
mutated in these diseases such as LPIN2 in Majeed
syndrome or IL-1RN in deficiency of IL-1 receptor
antagonist therefore are candidate genes for further
analyses.
Treatment in our two patients was problematic
and challenging, comparable with the difficult sit-
uation in PAPA syndrome. For local treatment,
tacrolimus ointment was applied in combination
with antiseptic preparations. The patient with the
more severe presentation (case 1) failed to respond
to a 3-month course of isotretinoin. Because of our
previously good experience with the IL-1 receptor
antagonistic therapy in a patient with PAPA syn-
drome,12 we switched the medication to anakinra.
Within a few weeks, the previously highly inflam-
matory, dusky, ulcerating lesions faded, leaving less
inflamed vegetating and cribriform scarring pla-
ques, but complete resolution was not achieved.
In fact, the patient developed small new lesions at
the injection sites as a sign of a pathergy phenom-
enon. Thus, anakinra was of great benefit, but so far
unable to induce complete remission. The addition
of cyclosporine further reduced the pathergy-
induced inflammatory responses.
The second patient was treated with a classic
immunosuppressive regimen (systemic glucocorti-
costeroids and azathioprine) in combination with
split-skin grafting. Whereas the latter failed to heal
J AM ACAD DERMATOL
VOLUME 66, NUMBER 3
PG, the former reduced the inflammation and size of
ulceration successfully during a 1-year period.
Alternate treatment options aside from IL-1 antagonists
would include cyclosporine and infliximab, which has
been shown to be beneficial in same cases.24-26
In summary, the clinical triad of PG, acne, and SH
might represent a new disease entity within the
spectrum of autoinflammatory syndromes similar to
PAPA and aseptic abscesses syndrome. However, in
contrast to these two disorders, it shows a clear
predilection for the skin and lacks arthritis and
visceral involvement. We therefore propose the
acronym PASH syndrome for this disease. It may
be linked to genes involved in the NALP3 inflamma-
some pathway regulating IL-1-induced neutrophil-
rich inflammation. The partial responsiveness to
IL-1 inhibition in one of our patients supports that
hypothesis that IL-1 might be involved in its
pathogenesis.
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