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Case ReportEffective Administration of Rituximab in Anti-MDA5Antibody–Positive Dermatomyositis with Rapidly ProgressiveInterstitial Lung Disease and Refractory Cutaneous Involvement:A Case Report and Literature Review
YukaOgawa,1DaiKishida,1 Yasuhiro Shimojima,1KoichiHayashi,2 andYoshiki Sekijima1
1Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto390-8621, Japan
2Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Correspondence should be addressed to Yasuhiro Shimojima; [email protected]
Received 31 July 2017; Accepted 24 September 2017; Published 31 October 2017
Academic Editor: Gregory J. Tsay
Copyright © 2017 Yuka Ogawa et al. -is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.
We describe the case of a 48-year-old man with dermatomyositis (DM) who demonstrated rapidly progressive interstitial lungdisease (RP-ILD) and refractory cutaneous involvement together with high levels of anti-melanoma di9erentiation-associatedgene 5 antibody (anti-MDA5-Ab). Even after combination immunosuppressive therapy including a corticosteroid, cyclosporineA, and intravenous cyclophosphamide, his respiratory insu;ciency and cutaneous involvement progressively worsened.However, the administration of rituximab (RTX) resulted in clinical remission as well as a visible reduction in anti-MDA5-Ablevels, suggesting that RTX could be a useful remedy in cases refractory to conventional immunosuppressive agents, especiallythose of RP-ILD related to anti-MDA5-Ab–positive DM.
1. Introduction
Dermatomyositis (DM) is an autoimmune in@ammatorymyopathy with characteristic cutaneous involvement such asGottron’s papules, a heliotrope rash, and/or an erythematouseruption around the neck and shoulders [1]. As a subtype ofDM, clinically amyopathic DM (CADM), which is charac-terized by a typical skin lesion of DM with no or subclinicalmuscular manifestations, is substantially di9erentiated fromclassic DM [2]. In both CADM and classic DM, interstitiallung disease (ILD) has been recognized as the complicationimpacting on the prognosis; moreover, numerous studieshave recently described that the development of rapidlyprogressive ILD (RP-ILD) is implicated in the positivity ofanti-melanoma di9erentiation-associated gene 5 antibody(anti-MDA5-Ab), which is more frequently detected in pa-tients with CADM than in those with classic DM [3–6].
Although combination immunosuppressive therapyconsisting of a corticosteroid, calcineurin inhibitor, and
intravenous cyclophosphamide (IVCY) is sometimesselected to prevent patients with DM-related RP-ILDfrom developing fatal disease, such an intensive thera-peutic strategy is not entirely su;cient to ensure a fa-vorable prognosis [7–9]. Rituximab (RTX), a chimericmonoclonal antibody for depleting B cells showing CD20protein, was recently demonstrated to be e9ective forintractable muscular and/or cutaneous involvement inpolymyositis or DM [10, 11]. It was also suggested thatRTX could be useful for severe ILD in antisynthetasesyndrome [12, 13]; meanwhile, there are only a few casereports in which RTX was used in anti-MDA5-Ab–positive DM with ILD [14–18].
Here we describe a case in which RTX amelioratedRP-ILD as well as refractory cutaneous involvement in apatient with anti-MDA5-Ab–positive DM despite the resis-tance to the conventional immunosuppressive therapy. Wealso review the literature for studies of RTX in anti-MDA5-Ab–positive DM with ILD.
HindawiCase Reports in RheumatologyVolume 2017, Article ID 5386797, 6 pageshttps://doi.org/10.1155/2017/5386797
mailto:[email protected]://doi.org/10.1155/2017/5386797
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2. Case Presentation
A 48-year-old man with a 1-month history of fatigue, ap-petite loss, and fever was admitted to our hospital. He re-ported experiencing arthralgia and a dry cough as well as
mild exertional dyspnea prior to admission. A physicalexamination demonstrated a body temperature of 37.7°C,mild muscular weakness of the proximal lower limbs,edematous hands, and cutaneous manifestations includinga heliotrope rash, Gottron’s papules, mechanic’s hands,
(a) (b) (c)
Figure 1: Skin lesions including palmar papules (a) and erythema on the back (b) before the initiation of treatment. A skin biopsy from theback indicates liquefactive degeneration with perivascular in@ammation between the epidermis and dermis (c) (hematoxylin and eosinstaining; scale bar 100 µm).
(a) (b) (c)
(d) (e) (f)
Figure 2: Sequential Lndings of cutaneous lesions on the dorsum of the hand and elbow before the initiation of treatment (a, d), before theaddition of rituximab (RTX) (b, e), and after RTX administration (c, f ).
2 Case Reports in Rheumatology
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palmar papules, and an erythematous rash on his face andback; in particular, ulcerative and erosive erythema wasvisible on his elbows (Figures 1 and 2). -e pathologicalLnding of the biopsied skin from his back demonstratedperivascular inLltration of in@ammatory cells with lique-factive degeneration through the epidermis to the dermis(Figure 1(c)). Laboratory examinations revealed elevatedserum levels of creatine kinase (CK) (278U/L; normal,43–230), C-reactive protein (0.59mg/dL; normal, 150indexes; normal, 150 indexes 44 indexes
Anti-MDA5 antibody
1500
1000
500
0
Cutaneous involvements
Serum ferritin (ng/mL)
Oxygenation support
1L 1.5L 1L
Figure 4: Clinical course of this patient. mPSL, methylprednisolone; PSL, prednisolone; IV-CsA, continuous intravenous infusion ofcyclosporine A; oral-CsA, oral administration of cyclosporine A; IVCY, intravenous infusion of cyclophosphamide; RTX, rituximab.
Case Reports in Rheumatology 3
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Tabl
e1:
Summarized
clinical
proL
lesin
patie
ntsof
anti-MDA5-an
tibod
y–po
sitiveDM
with
ILD
who
weretreatedwith
rituximab.
Ref.
no.
Sex/
age
Precedingman
ifestations
Previous
treatm
ent
Adm
ission/afterR
TX[m
axim
um1 ]
RTX
targeting
lesio
n
Duration
prior
toRT
X2
RTX
dosage
(cycles)
-erap
ydu
ring
orafterR
TXOutcome
Respiratory
(ILD
)Muscular
(CKlevels)
Cutan
eous
Others
Ferritin
(ng/mL)
KL-6
(U/m
L)
[14]
F/68
Cou
gh,u
nusual
dyspne
a
Gen
eralized
weakn
ess
(normal)
Rayn
aud,
erythema
ontheface,b
ack,
limbs,and
hand
s
Fever,
arthralgia,
appetite
loss
mPS
L,PS
L,IV
Ig,IVCY,
MMF,
CsA
,Tac
(top
ical),HCQ
805/n.d.
n.d./n.d.
Cutan
eous
lesio
nAbo
ut2
years
1000
mg,
per1
5da
ys(×2)
n.d.
Improv
ed3
[15]
F/58
n.d.
Weakn
esso
nthedelto
ids
(normal)
Heliotrop
erash,
Gottron
’spa
pules
n.d.
PSL,
Tac,IV
CY
891.7
/n.d.
613/2756
[4185]
ILD
Abo
ut3
mon
ths
500mg,
375mg/m
2 /week(×4)
mPS
L,PS
L,IV
CY,
IVIg,
PMX
Improv
ed
[16]
F/55
Rapidly
prog
ressive
shortnesso
fbreath
Non
e(normal)
Rayn
aud,
helio
trop
erash,
Gottron
’spa
pules,
rash
ontheha
nds
Weigh
tloss
mPS
Ln.d./n.d.
n.d./n.d.
ILD
n.d.
n.d.
CPA
,PE
Died
[17]
F/71
Rapid
deteriorationof
respiratory
status,h
ypox
ia
Non
e(211
U/L)
Heliotrop
erash,
Gottron
’spa
pules,
ulcero
nthe
butto
cks,pa
pules
ontheLn
gersan
delbo
ws
App
etite
loss,fatigue
mPS
L,PS
L,IV
CY,
IVIg,
PMX
1782.8/
253.1
[3149.8]
666/
4ILD
cutane
ous
lesio
n102da
ys525mg,
350mg/m
2 /week(×4)
PSL,
Tac
Improv
ed
[18]
F/71
Dry
coug
h,continuo
usdeteriorationof
respiratory
status
Non
e(n.d.)
Purpuraon
theelbo
ws,
erythemaon
the
anterior
chest
Fever
mPS
L,PS
L,Ta
c,CsA
,IVCY
507/1740
[1740]
991/n.d.
ILD
38da
ys600mg,
375mg/m
2 /week(×2)
mPS
L,PS
L,CsA
,MMF,
Tac
Died
[18]
F/69
Exertio
nal
dyspne
a,respiratory
distresswith
hypo
xia
Non
e(225
U/L)
Gottron
’spa
pules,
rash
onthe
extrem
ities,
hyperkeratosison
thepa
lmer
sideof
Lngers
Arthralgia
mPS
L,PS
L,CsA
219/1930
922/1520
ILD
33da
ys500mg,
375mg/m
2 /week(×2)
mPS
L,PS
L,CsA
,IVCY,
tocilizum
ab,
CHD
Died
-is
case
M/48
Exertio
nal
dyspne
awith
hypo
xia,dry
coug
h
Mild
weakn
esso
nthelower
limbs
(278
U/L)
Heliotrop
erash,
Gottron
’spa
pules,
mecha
nic’sh
ands,
palm
arpa
pules,
erythemao
nthe
face
andback,
ulcer/erosionon
the
elbo
ws
Fatig
ue,
fever,
appetite
loss,
arthralgia
mPS
L,PS
L,CsA
,IVCY
781/186
[1437]
602/638
[1674]
ILD
cutane
ous
lesio
n125da
ys700mg,
375mg/m
2 /week(×4)
PSL,
CsA
Improv
ed
DM,dermatom
yositis;
ILD,interstitiallung
disease;Re
f.,referenc
e;CK,creatinek
inase;n.d.,n
otdescribed;Ra
ynau
d,Ra
ynau
dph
enom
enon
;RTX
,ritu
ximab;m
PSL,
methy
lpredn
isolone
;PSL
,predn
isolone
;IVIg,
intraven
ousimmun
oglobu
lin;IVCY,
intraven
ousc
ycloph
osph
amide;MMF,
mycop
heno
latemofetil;
CsA
,cyclosporineA;T
ac,tacrolim
us;H
CQ,h
ydroxychloroqu
ine;CPA
,cycloph
osph
amide;PM
X,p
olym
yxin
Bhemop
erfusio
ntreatm
ent;PE
,plasm
aexchan
ge;C
HD,con
tinuo
ushemod
iaLltration.
1 Maxim
umvalueifitwas
describedin
therepo
rt.2Durationpriorto
administeringRT
Xsin
ceinitiatingho
spita
lization.
3 Rem
issionof
painfule
rythem
atou
spa
puleson
theha
ndswas
obtained
[14].4Decreaseof
KL-6levelsafterRT
Xad
ministratio
nwas
show
nin
theLg
ureof
thedescribedrepo
rt[17].
4 Case Reports in Rheumatology
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-erefore, IVCY was additionally administered at the dosageof 500mg every 2 weeks for 6 cycles. However, his respiratorystatus was gradually worsening even after additional admin-istration of 750mg of IVCY. Moreover, further exacer-bation of the chest CT Lnding was obviously demonstrated(Figure 3(b)). In addition, ulcerative and erosive eruptionson his hands and elbows also deteriorated (Figures 2(b) and2(e)). On the 125th day since the initiation of the therapy,RTX was administered at the dosage of 700mg (375mg/m2)weekly for total 4 weeks. Consequently, cutaneous involve-ments on his hands and elbows were remarkably improved(Figures 2(c) and 2(f)), and recovery from respiratory in-su;ciency and amelioration of the radiographic Lndingwere also achieved (Figure 3(c)). Furthermore, serum levelsof ferritin and anti-MDA5-Ab decreased to 186 ng/mL and44 indexes, respectively (Figure 4).
3. Discussion
-is patient was found to be in the severe stage of ILDassociated with DM because of having some prognosticfactors including not only hypoxemia with anti-MDA5-Abpositivity but also refractory ulcerative eruptions as well aspalmer papules. In fact, it has been previously described thatexisting cutaneous ulceration and/or palmer papules areassociated with acute progression of ILD in DM [6, 7];furthermore, the positive correlation between severity ofulcerative cutaneous involvement and anti-MDA5-Ab hasbeen demonstrated [6, 19, 20]. In addition, anti-MDA5-Abpositivity is associated with fever and arthritis [19, 20], whichwere also revealed prior to initiating treatment in the presentcase. -erefore, immediate and intensive immunosuppres-sive therapy was required in this patient in order to avoida fatal situation. It has been recognized that the concomitantuse of CsA or tacrolimus with PSL is indispensable toprevent the progression of ILD in DM [21–23]; furthermore,additional administration of IVCY should be required in theacute exacerbation of the disease [7, 9, 23]. However, initialcombination therapy, including PSL, CsA, and IVCY, waseventually insu;cient for healing both cutaneous involvementand ILD. On the other hand, RTX therapy obviously con-tributed to achieving a favorable outcome.
MDA5 plays a crucial role in inducing an innate immuneresponse against viral infection and is also recognized as thespeciLc autoantigen in DM, suggesting that upregulation ofMDA5 in the innate immune system subsequently promotesanti-MDA5-Ab production [24]. -e production of speciLcautoantibodies in autoimmune diseases is attributed toautoreactive B cells; furthermore, RTX is found to succeed indepleting the pathogenic autoreactive B cells which secretea speciLc autoantibody in several autoimmune diseases [25].Even though autoreactive B cells also play the roles in ac-tivating e9ector T cells or producing proin@ammatory cy-tokines, RTX may be indirectly implicated in preventingthese immunological factors from attacking the target organ[25–27]. Interestingly, the recent overviewed study dem-onstrated that favorable therapeutic e;cacy of RTX could beobtained in majority of patients with in@ammatory myositiswho had disease-speciLc autoantibodies [28]. It was described
that high titer of anti-MDA5-Ab is associated with the severityof disease [29, 30]. On the other hand, subsequent reductionof anti-MDA5-Ab after starting the treatment means obvi-ously predicting a successful outcome [20]. Although thispatient initially had a level of anti-MDA5-Ab over the uppermeasurable limit, RTX administration reduced the levels ofanti-MDA5-Ab and serum ferritin, which is also known as theprognostic factor in DM-related RP-ILD [31] (Figure 4),demonstrating that RTX therapy could correspondinglycontribute to the recovery from severe clinical situations andsuppress the production of anti-MDA5-Ab. Given the re-lationship between the therapeutic mechanism of RTX andautoantibodies including anti-MDA5-Ab, RTX therapy maybe a reasonable option for achieving a favorable outcome,especially in RP-ILD related to anti-MDA5-Ab–positive DM.
To our knowledge, six cases treated with RTX in anti-MDA5-Ab–positive DM with ILD have been reported in theEnglish literature to date [14–18] (Table 1). -eir clinicalcharacteristics were CADM or minimal muscular mani-festations, the latter of which is consistent with the presentcase. One patient was also given RTX to treat the refractorycutaneous involvement even after ILD remission inducedby the prior immunosuppressive therapy, whereas othersrequired RTX because the preceding use of other immu-nosuppressive agents was ine9ective in suppressing theexacerbation of ILD with or without cutaneous involvement.However, only half of them recovered from the RP-ILD,suggesting that it may be necessary to initiate e9ectivetherapy within the reversible state of disease even if RTX isa potential remedy in cases that are resistant to the prevalentimmunosuppressive therapies.
Anti-MDA5-Ab–positive DM usually emerges with re-fractory cutaneous involvement and/or RP-ILD as a life-threatening complication. -e present case demonstratedthat RTX could be a useful therapy for achieving a favorableoutcome. On the other hand, further clinical experiencesmust be accumulated to establish the therapeutic strategyusing RTX for this disease.
Conflicts of Interest
-e authors declare no Lnancial or personal con@icts ofinterest.
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6 Case Reports in Rheumatology
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