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521ISSN 1758-427210.2217/IJR.13.43 © 2013 Future Medicine Ltd Int. J. Clin. Rheumatol. (2013) 8(5), 521–529
ReseaRch aRticle Case RepoRt
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in adult-onset Still’s disease: case report and literature review
The classic rash of adult-onset Still’s disease (AOSD) is an evanescent, salmon-colored, macular or maculopapular eruption that tends to occur with a fever. The rash predominantly involves the trunk and extremities, but it can also involve the palms, soles of the feet and, occasionally, the face. The cutaneous histo-pathology in AOSD typically reveals dermal edema and mild perivascular inflammation in the superficial dermis consisting primarily of lymphocytes and histio cytes (Figures 1A & B). Immunofluorescence of the skin biopsy may show slight deposition of C3 in the blood ves-sel walls.
We now present an atypical case of AOSD whose skin presentation manifested as a per-sistent plaque. The reported rates of persis-tent eruptions in AOSD patients varied from 25 to 78% [1–3]. A review of all known cases of persistent plaques associated with AOSD demonstrated that prurigo pigmentosa may be associated with AOSD more commonly than previously thought.
Case presentationA previously healthy 25-year-old Malay-sian woman presented to the hospital with a 2-month history of fevers, chills, night sweats,
diffuse myalgia, lethargy and sore throat. She also had a diffuse scaly, dry and pruritic persistent hyperpigmented rash on her back, chest and distal extremities (Figures 2A & B). The patient was diagnosed with AOSD based on Yamaguchi criteria (Box 1). Our patient met criteria based on fevers, arthralgias, leuko-cytosis, sore throat, abnormal liver function tests, inguinal lymphadenopathy and negative antinuclear antibody and rheumatoid factor. No synovitis was found on examination of her peripheral joints. She had extensive infec-tious workup with negative HIV and respira-tory syncytial virus titers, negative bacterial and fungal cultures, and negative stains for malaria. Her urine initially showed micro-scopic hematuria, but this resolved. Her ferri-tin levels were elevated up to 7372 ng/ml. Her sedimentation rate was up to 120 mm/h. She had extensive rheumatologic workup including anti-Ro, anti-La, dsDNA, complements, RNP and Smith antibodies that were all normal. Her peripheral blood smear showed moderate nor-mocytic anemia. She had an inguinal lymph node biopsy which was unrevealing. She also had a bone marrow biopsy that showed mildly hypercellular bone marrow with trilineage hematopoiesis. Her PET scan was normal.
Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unclear etiology. It is classically characterized by spiking fevers, arthralgias, leukocytosis and a typical rash. Usually most of these clinical findings are not specific to this disease and it is often a diagnosis of exclusion. The exception to this is usually the typical maculopapular nonpruritic salmon-colored eruption, which has been shown to have high sensitivity and specificity for the diagnosis of patients with AOSD. It is important to be aware, however, that some patients also present with an atypical rash. Prurigo pigmentosa is a distinctive inflammatory disease first described in Japan. The patient in our case presentation was diagnosed with AOSD based on Yamaguchi criteria and also had a diffuse pruritic persistent hyperpigmented rash on the back, chest and distal extremities with a biopsy revealing histopathology and clinical findings consistent with the diagnosis of prurigo pigmentosa. This review of literature was carried out to examine all the known cases of persistent plaques associated with AOSD. The findings indicated that the histopathologic and clinical findings were similar to those found in prurigo pigmentosa. AOSD can be a chronic debilitating disease if left untreated and can ultimately lead to death. Prurigo pigmentosa may be an under-recognized atypical skin manifestation of AOSD that rheumatologists need to consider in clinical practice.
keywords: adult-onset still’s disease n persistent plaques n prurigo pigmentosa n pruritic n salmon-colored
Asha S Muthalaly1, Joshua Bradish2, Roy Sampson1, Steven T Hugenberg1, Dennis C Ang1, Simon Warren2,3 & Agith Muthalaly*1
1Indiana University School of Medicine, Department of Medicine, Division of Rheumatology, Indianapolis, IN, USA 2Indiana University School of Medicine, Department of Pathology & Laboratory Medicine, Indianapolis, IN, USA 3Indiana University School of Medicine, Department of Dermatology, Indianapolis, IN, USA *Author for correspondence: amuthala@iuhealth.org
part of
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
Int. J. Clin. Rheumatol. (2013) 8(5)522 future science group
She also had both an endoscopy and colon-oscopy with biopsies that were unremarkable. On physical examination, her rash was atypical of the common Still’s rash. Because of initial unclear etiology of the atypical rash, the skin biopsies were performed twice. Histologically, the first skin biopsy taken from lesional skin revealed confluent parakeratosis, acanthosis and necrotic keratinocytes identified within all levels of the epidermis. Within the super-ficial and mid-dermis, a perivascular mixed infiltrate consisting of lymphocytes, neutro-phils and a few eosinophils was noted. No cytologic atypia was identified within the infil-trate (Figures 3 & 4). A second skin biopsy from lesional tissue was performed 23 days later due to the complexity of the case in the hope that it would help elucidate a cause of the patient’s condition. No treatment was initiated during the interim as the diagnosis was unknown at
the time. Histologically, the second biopsy showed acanthosis and mild spongiosis of the epidermis. There was less parakeratosis and fewer necrotic keratinocytes than in the pre-vious biopsy. A perivascular mixed infiltrate within the superficial dermis similar in appear-ance to the first biopsy was seen. Additionally, melanin pigment incontinence and melano-phages were seen within the superficial dermis (Figures 5 & 6).
Our patient met criteria for the diagnosis of prurigo pigmentosa based on clinical and histo-pathologic findings (Box 2). The first biopsy dem-onstrated several findings seen in fully devel-oped prurigo pigmentosa including: a mixed inflammatory infiltrate, acanthosis with over-lying parakeratosis and necrotic keratinocytes. The second biopsy showed continued evolution into a late lesion, as there was marked mela-nin pigment incontinence and melanophages
Figure 1. specimen taken from a 35-year-old patient with still’s disease. The biopsy revealed superficial dermal edema and a mild superficial perivascular infiltrate consisting predominately of neutrophils and histiocytes, consistent with an evanescent eruption of Still’s disease. (A) This image taken at lower power demonstrates more of the dermal edema (white arrows) while the second image (B) demonstrates the perivascular infiltrate of neutrophils and histiocytes (black arrows).
Figure 2. diffuse scaly, pruritic persistent hyperpigmented rash. Rash on (A) abdomen and (B) lower extremities of our patient.
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
www.futuremedicine.com 523future science group
identified. Our patient was initially treated with naproxen 500 mg orally two-times a day with no improvement. She was then started on low-dose prednisone 15 mg daily and her fevers and arthralgias improved. She was subsequently dis-charged from the hospital and initially started on methotrexate 10 mg orally per week. She developed a recurrent episode 1 month later complicated by infection and was placed on high-dose steroids again at 1 mg/kd/day. She then stabilized and was eventually seen in clinic to start on anakinra.
discussionThe typical salmon-colored evanescent rash is observed in 87% of patients in AOSD with his-topathology showing relatively sparse perivas-cular mixed inflammatory infiltrate containing some neutrophils.
Prurigo pigmentosa is a distinctive inflam-matory disease of unknown etiology that was first described by the Japanese dermatolo-gist Masaji Nagashima in 1971 [4]. Clues to diagnosis include a trunk-centered ‘scratched urticaria’ that usually involves the back, chest and neck, and may also involve proximal extremities and upper extremities. It is rarely diagnosed outside of Japan because of its unfa-miliarity. Various mechanisms proposed have been friction, contact allergy, sensitivity to sunlight, endocrine disorders such as diabe-tes, and metabolic disorders such as ketosis [5]. Prurigo pigmentosa has also been described in association with anorexia nervosia and strict diet, pregnancy, primary biliary cirrhosis and Sjogren’s syndrome.
Histologically, the lesions have a distinct appearance and evolve over time depending on the stage at which a biopsy is obtained (Box 2). In early lesions, neutrophils may infiltrate the
Box 1. yamaguchi criteria.
Four major criteria
� Fever of at least 39°C lasting at least 1 week
� Arthralgias or arthritis lasting 2 weeks or longer
� A nonpruritic macular or maculopapular skin rash that is salmon-colored in appearance and usually found over the trunk or extremities during febrile episodes
� Leukocytosis (10,000 µl or greater) with at least 80% granulocytes
Five minor criteria
� Sore throat
� Lymphadenopathy
� Hepatomegaly or splenomegaly
� Abnormal liver function studies, particularly elevations in aspartate and alanine aminotransferase and lactate dehydrogenase concentrations
� Negative tests for antinuclear antibody and rheumatoid factor
Data taken from [11].
epidermis and subcorneal collections may be seen. Necrotic keratinocytes are identified throughout all levels of the epidermis. The epidermis becomes spongiotic and a mixed infiltrate, including lymphocytes, neutrophils and eosinophils, is seen in the papillary der-mis. As the disease progresses, the epidermis may begin to develop parakeratosis and acan-thosis while the mixed inflammatory infiltrate may appear more lichenoid [5]. There is vari-ability in the amount of vacuolar change one sees in the lesions. Melanin pigment inconti-nence and melanophages may become more prevalent [6]. These late stage lesions are nearly indistinguishable from the postinflammatory hyperpigmentation seen in other diseases. Immunofluorescence studies are invariably
Figure 3. Acanthosis and hyperkeratosis with patchy parakeratosis. Scattered necrotic keratinocytes in all levels of the epidermis were identified.
Figure 4. Mixed superficial perivascular infiltrate composed of neutrophils, eosinophils and lymphocytes.
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
Int. J. Clin. Rheumatol. (2013) 8(5)524 future science group
negative [7,8]. While the cases in TABle 1 appear to be histologically consistent with a diagnosis of prurigo pigmentosa, it is difficult to defini-tively determine without seeing the original slides; however, the histological descriptions as well as the clinical findings found in the papers appear to correlate well with different stages of prurigo pigmentosa.
ConclusionThe recognition of an atypical rash seen in patients with a confusing clinical picture as a possible manifestation of AOSD may aid in the diagnosis. Prurigo pigmentosa may be an under-recognized atypical skin manifestation of AOSD that rheumatologists need to consider in clinical practice. The presence of the aforemen-tioned skin lesions, based on our review of the literature and cases, should alert physicians to the possibility of AOSD. Nonetheless, due to the uncommon nature of prurigo pigmentosa in patients with AOSD, these skin lesions should not be considered diagnostic criteria.
Figure 5. Acanthosis with mild parakeratosis and a superficial perivascular infiltrate.
Figure 6. Mild spongiosis and interface changes with scattered necrotic keratinocytes. A mixed inflammatory infiltrate with melanin pigment incontinence and melanophages within the superficial dermis are noted.
Future perspectiveThere are some similarities in the immunohisto-chemistry of prurigo pigmentosa and AOSD that may help us understand the treatment of both diseases. Over the next 5–10 years this may pro-vide better insight into potential future therapies for treating both conditions. To date, there have been no studies evaluating doxycycline for treat-ment of AOSD; these should be considered in the near future. Using immunohisto chemistry, a study by Lu et al. has shown IL-6 to be more strongly expressed in prurigo pigmentosa skin lesions; the results were statistically significant [9]. Increases in IL-8 were also present. This may explain the potential therapeutic benefits of doxycycline due to its anti-inflammatory action, inhibiting IL-6, Il-8, IL-15, Rantes and IP-10 that normally regulate leukocyte differentiation and tissue inflammation response. Treatment of at least a 2–4 week course of doxycycline at a dose of 200 mg/day has been effective in most cases in initial and recurrent episodes. Other established treatments include minocycline, tet-racycline, dapsone, sulfamethoxazole and mac-rolide antibiotics. In a review article by Mavra-gani et al. it was concluded that many cytokines are involved in the pathogenesis of AOSD including IL-6, IL-8, IL-1, TNF-a, IL-17 and IL-18 [10]. Cytokines involved as potential mark-ers of disease activity include IL-1B and soluble IL-2 receptor. IL-18 has been a marker of disease severity and response to corticosteroids. Atypical skin rash is also linked to more aggressive dis-ease. There are limited data for the treatment of AOSD, however, disease-modifying agents, such as methotrexate, cyclosporine, hydroxychloro-quine, gold, penacillamine and azathioprine, as well as biologics, such as anakinra, rilonacept and anti-TNF, are used in refractory disease.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Informed consent disclosure The authors state that they have obtained verbal and writ-ten informed consent from the patient /patients for the inclusion of their medical and treatment history within this case report.
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
www.futuremedicine.com 525future science group
Box 2. Typical findings of prurigo pigmentosa.
Clinical
� Distribution of lesions:– Symmetrical, especially on the trunk
� Sites of predilection:– Back, chest and neck
� Sites rarely involved:– Proximal extremities (especially the upper extremities) and forehead
� Sites never involved:– Distal extremities, face and mucous membranes
� Individual lesions:– Early lesions: urticarial papules and plaques, often scratched– Fully developed lesions: papules, papulovesicles, rarely papulopustules with frank vesicles
� Arrangement of lesions:– Reticular
� Typical clinical dynamics of the disease process:– Papules erupt in crops and subside within a week; recurrences at the same sites are common,
often lesions of different ages being present together
� Symptoms:– Pruritus of early lesions is often severe, resolving lesions are devoid of symptoms
Histopathologic
� Early lesion:– Superficial perivascular infiltrate of neutrophils and possible microabscess formation– Edematous papillary dermis with extravasated erythrocytes – Spongiosis of epidermis– Few necrotic keratinocytes may be present, even early in the course of this disease
� Fully developed lesion: – Lymphocytes and eosinophils increase in number while neutrophils are found in variable
numbers– Epidermal spongiosis is accompanied by ballooning, acanthosis and parakeratosis begin– A lichenoid infiltrate may be seen with interface changes– Numerous necrotic keratinocytes and necrosis en masse are sometimes seen
� Late lesion: – Predominately lymphocytic infiltrate– Epidermis is slightly acanthotic and parakeratotic– Melanin incontinence and melanophages are seen– Individual necrotic keratinocytes may be present
� Subtle variations: – Features of prurigo simplex may overlay signs diagnostic of prurigo pigmentosa because of
intense pruritis associated with onset
Reproduced with permission from [5].
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
Int. J. Clin. Rheumatol. (2013) 8(5)526 future science group
Tab
le 1
. rev
iew
of
12 a
rtic
les
wit
h p
ersi
sten
t p
apu
les
and
pla
qu
es.
Cas
e(s
)C
linic
al &
la
bo
rato
ry d
ata
Gro
ss fi
nd
ing
s d
isea
se
du
rati
on
Pr
uri
tic
His
tolo
gy
Path
olo
gic
d
iag
no
sis
res
po
nse
to
tre
atm
ent
ref
.
1 (o
ur
pati
ent
from
th
is
arti
cle)
AN
A n
egat
ive,
RF
fact
or n
egat
ive,
el
evat
ed f
erri
tin,
norm
ocy
tic
anem
ia,
and
leuk
ocy
tosi
s
Dif
fuse
per
sist
ent
hyp
erpi
gmen
ted
rash
on
back
, che
st a
nd d
ista
l ex
trem
itie
s
2 m
onth
s Ye
sH
yper
kera
tosi
s, m
ild s
pon
gio
sis,
ac
anth
osi
s, n
ecro
tic
kera
tino
cyte
s,
neu
tro
phili
c an
d ly
mph
ocy
tic
per
ivas
cula
r in
filtr
ate
wit
h m
elan
oph
ages
Prur
igo
pigm
ento
saC
ompl
ete
reso
luti
on o
f ra
sh
and
syst
emic
sym
ptom
s w
ith
pred
niso
ne
20 m
g an
d st
arte
d on
met
hotr
exat
e fo
r m
aint
enan
ce
2 Le
uko
cyto
sis,
ele
vate
d LF
Ts a
nd e
leva
ted
ferr
itin
Pers
iste
nt s
kin
rash
on
upp
er c
hest
an
d ba
ck a
nd e
van
esce
nt s
kin
erup
tion
on
low
er e
xtre
mit
ies
3 w
eeks
N
/A
Dys
kera
tosi
s, m
ild a
cant
hosi
s, s
light
sp
ongi
osi
s, d
ense
infla
mm
ator
y in
filtr
ate
cons
istin
g of
lym
pho
cyte
s,
neu
tro
phils
, mel
ano
phag
es a
nd
eosi
noph
ils
Prur
igo
pigm
ento
saC
ompl
ete
reso
luti
on o
f ra
sh
wit
h pr
edni
son
e 4
0 m
g
[12]
3 Le
uko
cyto
sis,
ele
vate
d LF
Ts, e
leva
ted
ferr
itin
, no
rmo
cyti
c an
emia
, R
F an
d A
NA
neg
ativ
e
Papu
lar
erup
tion
arr
ang
ed in
re
ticu
late
pat
tern
and
dis
trib
uted
on
fac
e, n
eck,
tru
nk a
nd le
gs
10 d
ays
Yes
Peri
vasc
ular
neu
tro
phili
c an
d ly
mph
ocy
tic
infil
trat
e w
ithi
n su
per
ficia
l der
mis
, mild
ed
ema
Prur
igo
pigm
ento
saRe
spon
ded
to
pred
niso
lon
e 1
mg
/kg
/day
and
the
n pr
edni
son
e th
erap
y
[13]
4 Fe
ver,
sore
thr
oat
, ar
thra
lgia
and
itch
ing
skin
eru
ptio
ns, n
eck
lym
phad
eno
path
y,
leuk
ocy
tosi
s, e
leva
ted
AST
/ALT
, and
ele
vate
d fe
rrit
in
Num
erou
s re
ticu
late
d,
eryt
hem
atou
s an
d br
owni
sh
prur
itic
pap
ules
and
pla
ques
on
ches
t, a
bd
omen
and
bac
k.
Evan
esce
nt u
rtic
ated
eru
ptio
ns
occ
urrin
g w
ith
feve
r
2 w
eeks
Yes
Para
kera
tosi
s, m
ild a
cant
hosi
s, s
ome
foci
of
eosi
noph
ilic
spon
gio
sis,
sc
atte
red
dys
kera
toti
c ce
lls in
the
up
per
epi
der
mis
, and
a m
ixed
d
erm
al p
eriv
ascu
lar
infil
trat
e co
mp
ose
d of
lym
pho
cyte
s,
eosi
noph
ils a
nd n
eutr
oph
ils
No
spec
ific
diag
nosi
sRe
spon
ded
to
3-d
ay c
ours
e of
pul
se in
tran
veno
us
met
hylp
redn
iso
lon
e an
d th
en
oral
ste
roid
s. M
aint
enan
ce
ther
apy
wit
h m
etho
trex
ate,
hy
drox
ychl
oro
quin
e an
d pr
edni
solo
ne
[14]
5 El
evat
ed E
SR,
neg
ativ
e A
NA
and
RF,
el
evat
ed f
erri
tin
Papu
lar
erup
tion
tha
t th
en b
ecam
e hy
per
pigm
ente
d pa
pule
s ov
er
thig
hs, p
retib
ial a
reas
and
up
per
ba
ck a
nd f
orea
rms
N/A
Ye
s H
yper
kera
tosi
s, d
yske
rato
sis,
n
ecro
tic
kera
tino
cyte
s, m
ild
per
ivas
cula
r ly
mph
ocy
tic
infil
trat
e w
ith
rare
eo
sino
phils
, der
mal
muc
in
No
spec
ific
diag
nosi
s In
itia
l pre
dnis
one
ther
apy
wit
h no
res
pon
se t
hen
met
hotr
exat
e an
d et
aner
cept
an
d sw
itche
d to
IL-1
rec
epto
r an
tag
onis
t (a
naki
nra)
[15]
6 N
orm
ocy
tic
anem
ia,
elev
ated
LFT
s, a
nd
neg
ativ
e A
NA
and
RF
Mig
rato
ry p
laqu
e-lik
e ra
sh o
n lo
wer
le
gs t
hen
bec
ame
fixe
d an
d sp
read
sy
mm
etric
ally
on
arm
s, d
orsa
l ha
nds,
upp
er c
hest
and
bac
k
8 m
onth
s Ye
s M
ild s
pon
gio
sis,
mic
roab
sces
ses,
n
ecro
tic
kera
tino
cyte
s, m
ild d
erm
al
edem
a, ly
mp
ocy
tic
and
eosi
noph
ilic
per
ivas
cula
r in
filtr
ate,
neg
ativ
e IF
No
spec
ific
diag
nosi
s M
ethy
lpre
dnis
olo
ne
for
3 d a
ys w
ith
reso
luti
on o
f ra
sh a
nd t
hen
pred
niso
ne
oral
dai
ly w
ith
met
hotr
exat
e
[16]
7 A
nem
ia, l
euko
cyto
sis,
th
rom
bo
cyto
sis,
el
evat
ed E
SR a
nd C
RP,
el
evat
ed f
erri
tin,
neg
ativ
e A
NA
and
RF
Gen
eral
ized
sal
mon
-pin
k,
mac
ulo
papu
lar
and
urti
caria
l le
sion
s in
arm
s an
d ch
est.
Als
o br
owni
sh, n
onfo
llicu
lar
papu
les
that
co
ales
ced
into
pla
ques
wit
h irr
egul
ar b
ord
ers
and
disc
rete
, but
ad
here
nt s
cale
s on
for
ehea
d, n
eck
and
back
5 w
eeks
N
/A
Para
kera
tosi
s, a
cant
hosi
s, n
ecro
tic
kera
tino
cyte
s, ly
mph
ocy
tic,
n
eutr
oph
ilic
and
hist
iocy
tic
per
ivas
cula
r in
filtr
ate,
neg
ativ
e IF
No
spec
ific
diag
nosi
s R
apid
res
olu
tion
of
all
syst
emic
sym
ptom
s w
ith
the
skin
lesi
ons
fadi
ng w
ithi
n 10
day
s
[17]
A t
otal
of
49 p
atie
nts
wit
h A
OSD
in t
he c
ases
rev
iew
ed. T
hree
of
the
hist
op
atho
log
ic fi
ndin
gs in
clu
din
g o
ur c
ase
wer
e d
iag
nose
d as
pru
rig
o p
igm
ento
sa, w
ith
othe
r ca
ses
rep
ort
ed c
om
mo
nly
foun
d in
dif
fere
nt s
tag
es o
f p
ruri
go
pig
men
tosa
. See
Bo
x 2
fo
r d
etai
ls.
ALT
: Ala
nine
am
inot
rans
fera
se; A
NA
: Ant
inu
clea
r an
tib
od
y; A
OSD
: Adu
lt-o
nset
Sti
ll’s
dis
ease
; AST
: Asp
arta
te a
min
otra
nsfe
rase
; CR
P: C
-rea
ctiv
e p
rote
in; E
SR: E
ryth
rocy
te s
edim
enta
tio
n ra
te; I
F: Im
mun
oflu
ore
scen
ce;
LFT:
Liv
er f
unct
ion
test
; N/A
: Not
ava
ilab
le; R
F: R
heum
ato
id f
acto
r.
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
www.futuremedicine.com 527future science group
Tab
le 1
. rev
iew
of
12 a
rtic
les
wit
h p
ersi
sten
t p
apu
les
and
pla
qu
es (
con
t.).
Cas
e(s
)C
linic
al &
la
bo
rato
ry d
ata
Gro
ss fi
nd
ing
s d
isea
se
du
rati
on
Pr
uri
tic
His
tolo
gy
Path
olo
gic
d
iag
no
sis
res
po
nse
to
tre
atm
ent
ref
.
8–1
9 Fe
ver,
rash
, le
uko
cyto
sis,
ele
vate
d fe
rrit
in, n
egat
ive
AN
A
and
RF,
hep
atom
egal
y an
d sp
leno
meg
aly
Eryt
hem
atou
s, v
iola
ceou
s, d
usky
re
d or
bro
wni
sh, s
caly
or
crus
ted
papu
les
wid
ely
dist
ribut
ed. O
ne
pati
ent
wit
h w
ides
prea
d p
oik
ilod
erm
atou
s an
d lic
heno
id
lesi
ons
mai
nly
on s
un-e
xpo
sed
area
s
N/A
N
/A
Para
kera
tosi
s, a
ppr
oxim
atel
y ha
lf ha
d m
ild a
cant
hosi
s an
d sp
ongi
osi
s,
nec
roti
c ke
ratin
ocy
tes
in a
ll bi
ops
ies,
neu
tro
phili
c an
d ly
mph
ocy
tic
per
ivas
cula
r in
fitra
te
rang
ing
from
spa
rse
to d
ense
, few
bi
ops
ies
wit
h eo
sino
phils
and
mor
e es
tabl
ishe
d le
sion
s co
ntai
ned
m
elan
oph
ages
No
spec
ific
diag
nosi
sN
/A[18]
20
Poly
arth
ralg
ias,
fev
er,
rash
, sor
e th
roat
, le
uko
cyto
sis,
ele
vate
d ES
R, C
RP
and
ferr
itin
Fixe
d, p
ruri
tic,
mild
ly s
caly
, pin
k to
er
ythe
mat
ous,
bla
ncha
ble
plaq
ues
on
low
er b
ack,
po
ster
ior
nec
k/up
per
bac
k an
d up
per
ab
dom
en
N/A
Ye
s H
yper
kera
tosi
s, d
yske
rato
sis,
mild
ac
anth
osi
s, s
pars
e p
eriv
ascu
lar
lym
pho
cyti
c an
d n
eutr
oph
ilic
der
mal
infil
trat
e w
ith
occ
asio
nal
eosi
noph
ils
No
spec
ific
diag
nosi
s Tr
eatm
ent
wit
h an
akin
ra,
met
hotr
exat
e an
d m
ethy
lpre
dnis
olo
ne
resu
lted
in r
eso
luti
on o
f sy
mpt
oms
and
rash
[19]
21So
re t
hro
at, r
ash,
fe
ver,
po
lyar
thra
lgia
, el
evat
ed L
FTs,
el
evat
ed E
SR, C
RP
and
ferr
itin
Fixe
d pa
pule
s an
d pl
aqu
es w
ith
blan
chab
le e
ryth
ema
and
fine
scal
e in
volv
ing
the
prox
imal
ext
rem
itie
s,
back
, ab
dom
en a
nd a
nkle
s
1.5
mon
ths
Yes
Hyp
erke
rato
sis,
dys
kera
tosi
s, m
ild
per
ivas
cula
r ly
mph
ocy
tic
infla
mm
ator
y in
filtr
ate
wit
h o
ccas
iona
l neu
tro
phils
and
rar
e eo
sini
oph
ils
No
spec
ific
diag
nosi
s Tr
eatm
ent
wit
h pr
edni
son
e an
d la
ter
met
hylp
redn
iso
lon
e re
solv
ed t
he p
atie
nt’s
sy
mpt
oms
and
rash
[19]
22
Feve
rs, r
ash,
p
oly
arth
ralg
ia,
leuk
ocy
tosi
s, e
leva
ted
ferr
itin
Cla
ssic
tra
nsie
nt m
orbi
llifo
rm S
till’s
ra
sh a
nd p
ersi
sten
t, e
ryth
emat
ous,
sl
ight
ly s
caly
pap
ules
wit
h so
mew
hat
linea
r co
nfigu
rati
on o
n up
per
bac
k an
d ch
est
N/A
N
/A
Hyp
erke
rato
sis,
dys
kera
tosi
s,
acan
tho
sis,
mild
per
ivas
cula
r ly
mph
ocy
tic
infla
mm
ator
y in
filtr
ate
wit
h sc
atte
red
neu
tro
phils
No
spec
ific
diag
nosi
s Pa
tien
t di
ed p
rior
to
trea
tmen
t fr
om u
nrel
ated
ca
uses
[19]
23–4
9 Fe
ver,
rash
, art
hrit
is,
mya
lgia
s,
hepa
tom
egal
y,
elev
ated
fer
ritin
, ab
norm
al li
ver
test
s an
d le
uko
cyto
sis,
n
egat
ive
RF
and
AN
A
Wid
espr
ead,
pru
riti
c, e
ryth
emat
ous
urti
caria
l or
vio
lace
ous
to b
row
nish
fla
t-to
pp
ed li
chen
oid
pap
ules
ove
r th
e tr
unk,
nec
k, f
ace
and
exte
nsor
si
des
of
the
extr
emit
ies
N/A
Yes
Mou
nds
of h
yper
kera
tosi
s an
d so
litar
y or
clu
ster
nec
roti
c ke
ratin
ocy
tes
in t
he s
uper
ficia
l ep
ider
mis
wit
h in
filtr
atio
n of
ly
mph
ocy
tes
and
neu
tro
phils
in t
he
upp
er a
nd m
id d
erm
is. M
ild
acan
tho
sis
and
spon
gio
sis
wer
e no
ted
in a
ppr
oxim
atel
y ha
lf of
the
sp
ecim
ens
No
spec
ific
diag
nosi
sA
ll pa
tien
ts t
reat
ed w
ith
NSA
IDs
init
ially
and
the
n sy
stem
ic s
tero
ids
wer
e us
ed
in 2
7 pa
tien
ts w
ith
resp
onse
. Tw
o pa
tien
ts h
ad
imm
uno
sup
pres
sion
wit
h m
etho
trex
ate
and
azat
hio
prin
e w
ith
resp
onse
[1]
A t
otal
of
49 p
atie
nts
wit
h A
OSD
in t
he c
ases
rev
iew
ed. T
hree
of
the
hist
op
atho
log
ic fi
ndin
gs in
clu
din
g o
ur c
ase
wer
e d
iag
nose
d as
pru
rig
o p
igm
ento
sa, w
ith
othe
r ca
ses
rep
ort
ed c
om
mo
nly
foun
d in
dif
fere
nt s
tag
es o
f p
ruri
go
pig
men
tosa
. See
Bo
x 2
fo
r d
etai
ls.
ALT
: Ala
nine
am
inot
rans
fera
se; A
NA
: Ant
inu
clea
r an
tib
od
y; A
OSD
: Adu
lt-o
nset
Sti
ll’s
dis
ease
; AST
: Asp
arta
te a
min
otra
nsfe
rase
; CR
P: C
-rea
ctiv
e p
rote
in; E
SR: E
ryth
rocy
te s
edim
enta
tio
n ra
te; I
F: Im
mun
oflu
ore
scen
ce;
LFT:
Liv
er f
unct
ion
test
; N/A
: Not
ava
ilab
le; R
F: R
heum
ato
id f
acto
r.
Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
Int. J. Clin. Rheumatol. (2013) 8(5)528 future science group
executive summary
Adult-onset Still’s disease
� It is difficult to make a diagnosis of adult-onset Still’s disease (AOSD), due to a lack of pathognomonic histopathological and serological findings.
� The Yamaguchi criteria are the most commonly used, with high sensitivity and specificity. However, it is critical to exclude other infections, inflammatory diseases and malignancies before a diagnosis of AOSD is made.
� The typical salmon-colored evanescent rash is observed in 87% of patients in AOSD, with histopathology showing relatively sparse perivascular mixed inflammatory infiltrate containing some neutrophils.
� More evidence has demonstrated that persistent papules and plaques of AOSD have important diagnostic value and could be related to poorer prognosis and more aggressive refractory disease.
� The reported rates of persistent eruptions in AOSD patients varied from 25 to 78%.
� Our patient with AOSD also had a histopathological diagnosis of prurigo pigmentosa.
Prurigo pigmentosa
� Prurigo pigmentosa is a distinctive inflammatory disease of unknown etiology.
� Histologically, the lesions have a distinct appearance and evolve over time depending on the stage at which a biopsy is obtained.
� As the disease progresses, the epidermis may begin to develop parakeratosis and acanthosis, while the mixed inflammatory infiltrate may appear more lichenoid.
� While the cases in our review of literature of atypical persistent plaques appear to be histologically consistent with a diagnosis of prurigo pigmentosa, it is difficult to definitively determine without seeing the original slides; however, the histological descriptions as well as the clinical findings found in the papers appear to correlate well with different stages of prurigo pigmentosa.
Immunohistochemistry
� IL-1, IL-6, IL-18 and TNF-a have been shown to be associated with AOSD and IL-6 has been shown to correlate with disease activity.
� A statistically significant difference in IL-6 expression has been observed in prurigo pigmentosa skin lesions. Increases in IL-8 were also present.
Treatment
� There are limited data for the treatment of AOSD; however, disease-modifying agents, such as methotrexate, cyclosporine, hydroxychloroquine, gold, penacillamine and azathioprine, as well as biologics, such as anakinra, rilonacept and anti-TNF, are used in refractory disease.
� A novel IL-6 antagonist, tocilizumab, has been proved to be a promising treatment for AOSD.
� Treatment of at least a 2–4-week course of doxycycline at a dose of 200 mg/day has been effective in most cases in initial and recurrent episodes of prurigo pigmentosa.
� Other established treatments for prurigo pigmentosa include minocycline, tetracycline, dapsone, sulfamethoxazole and macrolide antibiotics.
Conclusion
� The recognition of this atypical rash seen in patients with a confusing clinical picture as a possible manifestation of AOSD may aid in the diagnosis and help establish prognosis.
� There are many similarities between the immunohistochemistry between prurigo pigmentosa and AOSD, and more studies need to be done to help us understand and broaden the treatment options of both diseases over the next 5–10 years.
� Prurigo pigmentosa may be an under-recognized atypical skin manifestation of AOSD that rheumatologists need to consider in clinical practice.
references1 Lee JY, Hsu CK, Liu MF, Chao SC.
Evanescent and persistent pruritic eruptions of adult-onset Stills disease: a clinical and pathologic study of 36 patients. Semin. Arthritis Rheum. 42(3), 317–326 (2012).
2 Nagai Y, Hasegawa M, Okada E, Hattori T, Tago O, Ishikawa O. Clinical follow-up study of adult-onset Still’s disease. J. Dermatol. 39(11), 898–901 (2012).
3 Lee YY, Yang CC, Hsu ML. Histopathology of persistent papules and plaques in adult-onset Still’s disease. J. Am. Acad. Dermatol. 52(6), 1003–1008 (2005).
4 Böer A, Misago N, Wolter M, Kiryu H, Wang XD, Ackerman AB. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am. J. Dermatopathol. 25, 117–129 (2003).
5 Boer A, Asgari M. Prurigo pigmentosa: an under diagnosed disease? Indian J. Dermatol. Venereol. Leprol. 72(6), 405–409 (2006).
6 Asgari M, Daneshpazhooh M, Davatchi C, Boer A. Prurigo pigmentosa: an underdiagnosed disease in patients of Iranian descent? J. Am. Acad. Dermatol. 55, 131–136 (2006).
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skin. Am. J. Dermatopath. 25(2), 117–129 (2003).
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Prurigo pigmentosa as an atypical persistent plaque-like skin rash in Still’s disease Case RepoRtCase RepoRt Muthalaly, Bradish, Sampson et al.
www.futuremedicine.com 529future science group
11 Yamaguchi M, Ohta A, Tsunematsu T et al. Preliminary criteria for classification of adult Still’s disease. J. Rheumatol. 19(3), 424–430 (1992).
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13 Dowod TAHM, Khalel MESH, Mohammed MAA, El Sharawy MAWM, Al-Ghabandi SJ, Al-Sumait AY. Adult-onset Still’s disease and prurigo pigmentosa: an unusual association and review of literature. Pak. J. Med. Sci. 23(5), 792–797 (2007).
14 Cho YT, Liao YH. Prurigo pigmentosa-like persistent papules and plaques in a patient with adult-onset Still’s disease. Acta Derm. Venereol. doi:10.2340/00015555-1615 (2013) (Epub ahead of print).
15 Wolgamot G, Yoo J, Hurst S, Gardner G, Olerud J, Argenyi Z. Unique histopathologic findings in a patient with adult-onset Still’s disease. Am. J. Dermatopathol. 29(2), 194–196 (2007).
16 Affleck AG, Littlewood SM. Adult-onset Still’s disease with atypical cutaneous features. J. Eur. Acad. Dermatol. Venereol. 19(3), 360–363 (2005).
17 Lübbe J, Hofer M, Chavaz P, Saurat JH, Borradori L. Adult-onset Still’s disease with persistent plaques. Br. J. Dermatol. 141(4), 710–713 (1999).
18 Lee JY, Yang CC, Hsu MM. Histopathology of persistent papules and plaques in adult-onset Still’s disease. J. Am. Acad. Dermatol. 52(6), 1003–1008 (2005).
19 Fortna RR, Gudjonsson JE, Seidel G et al. Persistent pruritic papules and plaques: a characteristic histopathologic presentation seen in a subset of patients with adult-onset and juvenile Still’s disease. J. Cutan. Pathol. 37(9), 932–937 (2010).
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