Granulomatosis with polyangiitis with isolated orbital involvement in children: a case report successfully treated with Rituximab and review of literature

1. Rheumatology Department. Hospital Sierrallana

2. Rheumatology Department. Hospital Universitario Marqués de Valdecilla

3. Radiology Department. Hospital Universitario Marqués de Valdecilla

4. Maxillofacial Surgery Department. Hospital Universitario Marqués de Valdecilla

5. Pathology Department. Hospital Universitario Marqués de Valdecilla

6. Rheumatology Department. Hospital Universitario Marqués de Valdecilla. IDIVAL. University of Cantabria

tremely rare

_{, and literature about the optimal}

treat-ment is scarce. We present the first case of pediatric

GPA with limited orbital involvement successfully

treat-ed with rituximab (RTX).

CLINICAL CASE

A 15-year-old girl with unremarkable personal and

family history, presented with a one-month history of

non-tender right upper eyelid swelling. Visual acuity

and ocular movements were impaired. Her blood tests

including full blood count and complete chemistry

were normal, and acute phase reactants were between

normal limits. Orbital ultrasonography and magnetic

resonance imaging (MRI) confirmed the diffuse mass

within the orbicular musculature in the outer edge of

the right orbit, slightly hyperintense with moderate

contrast enhancement (Figure 1). A biopsy of the mass

was performed showing lymphocytic infiltration

around and within the wall of medium and small

ves-sels, and necrotizing granulomas (Figure 2). A systemic

evaluation ruled out any other organ affection. ANCA

test was repeatedly negative. With the suspicion of GPA

with isolated orbital involvement, treatment with

pred-nisone (40 mg per day for 3 weeks followed by 5 mg

dose reduction every 10 days until dose of 20 mg per

day, then 2.5 mg dose reduction every week) and

methotrexate (20 mg weekly) was started. After initial

improvement, when tappering prednisone to 15 mg

per day, the upper eyelid swelling recurred. The

clini-cal worsening was confirmed with a new MRI. Then,

treatment with RTX 375 mg/m

_{/week for 4 weeks was}

started and followed by maintenance therapy

consist-ing of 500 mg every 6 months. The patient presented

a good clinical response, with complete resolution of

the lesion in the radiological control one year after

start-ing RTX.

ACTA REUMATOL PORT. 2019;44:258-263

Granulomatosis with polyangiitis with isolated orbital

involvement in children: a case report successfully

treated with rituximab and review of literature

Riancho-Zarrabeitia L

_{, Peiró Callizo E}

_{, Drake-Pérez M}

_{, García Montesinos B}

_{, Terán N}

_{, Martínez-Taboada VM}

ABSTRACT

We report the case of a 15-year old girl who presented

with a non-tender right upper eyelid swelling.

Magnet-ic resonance confirmed the presence of an enlargement

of the orbicular muscle with moderate contrast

en-hancement. Biopsy revealed the presence of necrotizing

granulomatous vasculitis. Further studies ruled out

sys-temic involvement. Thus, she was diagnosed with

iso-lated granulomatosis with polyangiitis (GPA). Treatment

with steroids and methotrexate was started. Due to the

persistence of the lesion, rituximab (RTX) was added

with excellent clinical and radiological response. This is,

to the best of our knowledge, the first case of isolated

or-bital GPA treated with RTX in a pediatric patient.

Keywords: Pediatric; ANCA-associated vasculitis;

Or-bital inflammatory disease.

INTRODUCTION

Granulomatosis with polyangiitis (GPA) is a small and

medium-sized vessel vasculitis associated with the

pres-ence of anti-neutrophil cytoplasmic antibody (ANCA).

The incidence of GPA in European pediatric

popula-tion is less than 0.5 cases per million

_{. It may affect any}

organ system with potential life-threatening

morbidi-ties, thus an early diagnosis and prompt treatment are

needed. Cases with isolated organ affection are

ex-tern. However, up to 40% of cases with single organ

GPA are ANCA negative. The frequency of ocular

in-volvement, according to a recent meta-analysis, is 24%

of cases

_{; nevertheless, orbital involvement is}

infre-quent as initial manifestation and exceptional as a

sin-gle-organ affection

_{. In Table I we summarize}

previ-ously reported cases of paediatric GPA with orbital

affection. Due to the absence of controlled trials in

pae-diatric GPA, adult therapeutic approaches are

recom-mended. Thus, high dose steroids and preferably

cy-DISCUSSION

GPA is a very infrequent vasculitis in childhood, with

a female predominance and a mean age at diagnosis

between 11 to 14 years

_{. Most commonly affected}

or-gans include ear nose and throat, kidney and lungs

_.

Subglottic stenosis or nasal deformities such as saddle

nose deformity are more commonly observed in

chil-dren than in adults. More than 90% of patients are

pos-itive for ANCA

_{, being c-ANCA the most common}

pat-FIGURE 1.Diagnostic MRI with axial T2WI (A), axial T1WI (B), and axial contrast enhanced T1WI (C) shows a poorly defined mass in the external periorbital region, with heterogeneous T2 signal intensity and avid enhancement (arrows). Follow up MRI 1 year after treatment onset with axial T2WI (D), axial T1WI (E), and axial contrast enhanced T1WI (F) shows complete resolution of the mass (arrow heads).

A B

C

E

D

F

FIGURE 2.Histological examination revealed a granulomatous inflammatory process with lymphohistiocytic infiltrate, necrotizing granulomas and small and medium-sized vessels vasculitis. (A) Panoramic view of the diffuse inflammatory infiltrate with a necrotizing granuloma (between the arrows) (PAS). (B) Detail of small-sized vessels with lymphohistiocytic infiltrate and activated endothelium (PAS).

TA B LE I. G P A w IT h O R B IT A L A FF EC TI O N IN P A ED IA TR IC P O P U LA TI O N O cu la r S y st em ic o rg an A u th o r, y ea r A g e S ex sy m p to m s in v o lv em en t A N C A Im ag in g t es t B io p sy T re at m en t M o o rt h y A V, 1 9 7 7 1 0 1 0 F B il at er al 6 m o n th s la te r: H em at u ri a N D N D O rb it : g ra n u lo m at o u s G C + C F M a t k id n ey p ro p to si s an d p ro te in u ri a, r en al v as cu li ti s af fe ct io n in su ff ic ie n cy , si n u si ti s, K id n ey : p ro li fe ra ti v e G N n as al u lc er s P ar el h o ff E S 1 9 8 5 1 1 9 F U n il at er al M ax il la ry s in u si ti s N D C T : in tr ao rb it al O rb it : ly m p h o p la sm o ci ti c G C + C F M a t p ro p to si s, 2 2 m o n th s la te r: h em at u ri a, sw el li n g in fi lt ra te , fo ca l n o d u la r k id n ey a ff ec ti o n p er io rb it ar y p ro te in u ri a, r en al in fl am m at io n a n d K id n ey t ra n sp la n t sw el li n g in su ff ic ie n cy , lu n g n o d u le s, m ac ro p h ag u es w it h se iz u re s fo am y c it o p la sm K id n ey : p ro li fe ra ti v e G N P er ry S R , 1 9 9 7 1 2 5 F E y el id N o N D N D Ó rb it : n ec ro ti zi n g v as cu li ti s G C + C F M sw el li n g W ar d y n K A , 2 0 0 3 1 3 7 F P to si s H em at u ri a, p ro te in u ri a N eg at iv e C T : in tr ao rb it al Ó rb it : fi b ri n o id n ec ro si s R et ro b u lb ar G C P ro p to si s c-A N C A m as se s an d n eu tr o p h il s an d G C + C F M 1 :8 0 m o n o n u cl ea r in fi lt ra ti o n K id n ey : P ro li fe ra ti v e G N Z ia k as N G , 2 0 0 4 1 4 5 F E y el id N o c-A N C A M R I: d if fu se M ix ed g ra n u lo m at o u s G C sw el li n g , 1 :1 6 0 sw el li n g a t th e an d a ct iv e in fl am m at io n . o cu la r P R 3 la cr im al g la n d In fl am m at o ry i n fi lt ra ti o n m o ti li ty , m as s re g io n ar o u n d a n d w it h in t h e o n t h e w al ls o f sm al l v es se ls la cr im al g la n d si te L ev i M , 2 0 0 7 1 5 1 2 M D ac ry o ad en it is O ti ti s m ed ia N o t N D K id n ey G C + M T X C o n ju n ct iv it is B ro n ch it is d o n e Ir it is 1 0 M U p p er e y el id H em at u ri a P o si ti v e N D K id n ey G C ,C F M ,M T X ,I F X ed em a, P ro te in u ri a er y th em a Ir it is co n ti n u es o n t h e n ex t p a ge

TA B LE I. C O N TI N U AT IO N O cu la r S y st em ic o rg an A u th o r, y ea r A g e S ex sy m p to m s in v o lv em en t A N C A Im ag in g t es t B io p sy T re at m en t 9 M E y el id e d em a, N o N o t N D O rb it G C er y th em a d o n e L im it ed m o ti li ty P ro p to si s 1 2 F E y el id e d em a A b d o m in al p ai n ,v o m it in g N eg at iv e N D O rb it a n d k id n ey G C P ro p to si s L im it ed m o ti li ty M ar tí n ez -G u ti er re z 7 F D is p la ce m en t 3 y ea rs a ft er o cu la r N eg at iv e C T a n d M R I: O rb it : n o n -s p ec if ic G C a t d ia g n o si s JD , 2 0 0 8 1 6 o f th e g lo b e sy m p to m s: s u b g lo ti c in fi lt ra ti o n a n d h is ti o cy ti c in fi lt ra te G C + C F M + IF X E y el id s w el li n g st en o si s, l u n g a n d k id n ey en la rg em en t o f w it h p la sm ac y to id , p o st er io rl y af fe ct io n la cr im al g la n d s ly m p h o cy te s an d an d s in u si ti s eo si n o p h il ic c el ls L ac ri m al g la n d : p er iv as cu la r an d p er id u ct al ce ll i n fi lt ra te w it h g ra n u lo m at o u s as p ec t C h ip cz y n sk a B , 7 F E y el id S in u si ti s N eg at iv e C T /M R I: T u m o r O rb it : In fl am m at o ry G C + M T X /C F M 2 0 0 9 1 7 sw el li n g , G N m as se s in t h e p se u d o tu m o r (a ll p at ie n ts ) u n il at er al o rb it R en al b io p sy : n ec ro ti zi n g ex o p h th al m ia (a ll p at ie n ts ) G N 1 1 F (a ll p at ie n ts ) H ea ri n g i m p ai rm en t cA N C A + O rb it : N ec ro ti zi n g v as cu li ti s w it h le u k o cy to cl as ia a n d n ec ro ti zi n g g ra n u lo m as su rr o u n d ed b y h is ti o cy te s an d g ia n t ce ll s 8 M O ti ti s m ed ia cA N C A + O rb it N ec ro ti zi n g v as cu li ti s H ea ri n g i m p ai rm en t w it h l eu k o cy to cl as ia a n d n ec ro ti zi n g g ra n u lo m as su rr o u n d ed b y h is ti o cy te s an d g ia n t ce ll s co n ti n u es o n t h e n ex t p a ge

F : fe m al e; M : m al e; N D : n o d at a; A N C A : an ti -n eu tr o p h il c y to p la sm ic a n ti b o d y ; c-A N C A : cy to p la sm ic a n ti -n eu tr o p h il c y to p la sm ic a n ti b o d y ; p -A N C A : p er in u cl ea r an ti -n eu tr o p h il cy to p la sm ic a n ti b o d y ; P R 3 : p ro te in as e 3 ; IR : in su fi ci en ci a re n al ; G N : g lo m er u lo n ep h ri ti s; C T : co m p u te d t o m o g ra p h y ; M R I: m ag n et ic r es o n an ce i m ag in g ; G C : g lu co co rt ic o id s; M T X : m et h o tr ex at e; C F M : cy cl o p h o sp h am id e; I F X : in fl ix im ab ; R T X : ri tu x im ab TA B LE I. C O N TI N U AT IO N O cu la r S y st em ic o rg an A u th o r, y ea r A g e S ex sy m p to m s in v o lv em en t A N C A Im ag in g t es t B io p sy T re at m en t 9 F E y el id s w el li n g , F ev er s A ty p ic al C T /M R I: T u m o r O rb it : N ec ro ti zi n g G C + M T X /C F M u n il at er al R h eu m at ic p ai n s A N C A m as se s in t h e v as cu li ti s w it h ex o p h th al m ia o rb it le u k o cy to cl as ia D ey M , 2 0 1 1 1 8 9 F E y el id s w el li n g S ad d le -n o se d ef o rm it y, o ti ti s cA N C A C T : so ft t is su e Ó rb it : ch ro n ic G C 1 :2 0 sw el li n g i n in fl am m at io n w it h p A N C A la cr im al g la n d p er iv as cu la r in fi lt ra te s 1 :4 0 U re E , 2 0 1 6 1 9 9 F E y es r ed n es s, G N cA N C A M R I: b il at er al O rb it : th ic k en in g o f th e C F M , R T X ey el id s ed em a, in tr ao rb it al -v es se l w al l, m ic ro th ro m b u s T o p ic al G C p to si s an d -e x tr ac o n al s o ft an d p er iv as cu la r ex o p h ta lm u s ti ss u e le si o n s ly m p h o cy ti c in fi lt ra ti o n in t h e v es se ls l u m en a n d fi b ro si s in t h e la cr im al g la n d K id n ey : cr es ce n ti c g lo m er u lo n ep h ri ti s D ro b y sh ev a A , 1 2 M U n il at er al N o cA N C A M R I: i n fi lt ra ti v e O rb it : fi b ro v as cu la r ti ss u e G C + M T X 2 0 1 8 2 0 ey el id s w el li n g 1 :2 0 le si o n o f th e w it h d en se c o ll ag en o u s + p to si s o rb it fi b ro si s an d m ix ed in fl am m at o ry i n fi lt ra te w it h p la sm a ce ll s

clophosphamide (CYP) are used as induction therapy,

although there is an increase in the use of RTX

_{. In}

our case, due to the absence of systemic symptoms and

the potential gonadal toxicity of CYP, methotrexate and

corticosteroids were prescribed initially. RTX was then

started because of refractoriness as a second line the

-rapy. Some cases of GPA with orbital affection

success-fully treated with RTX have been published in

adult-hood

_{, but no cases with limited orbital involvement}

have been previously reported in children.

In our case, the patient presented with a limited

affection of the orbicular musculature, reasonably ru

-ling out any systemic involvement. Treatment with

steroids and methotrexate was started. RTX was

asso-ciated due to refractoriness, with excellent response

and disappearance of the lesion.

CONCLUSIONS

GPA can exceptionally present as a single-organ

dis-ease in childhood. RTX might be considered as a

po-tential treatment in cases refractory to conventional

im-munosuppressive therapy.

CORRESPONDENCE TO

Víctor Martínez Taboada Rheumatology Department

Hospital Universitario Marqués de Valdecilla Av. Valdecilla, 25

39008 Santander, Cantabria, Espanha E-mail: vmartinezt64@gmail.com

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