BOLILE ASOCIATE IgG4

Danulet Ruxandra, medic rezident reumatologie

Coordonator: Dr. Ioana Saulescu
Plan de prezentare:

• Generalitati
• Epidemiologie
• Imunopatogenie
• Manifestari clinice
• Investigatii paraclinice
• Diagnosticul pozitiv
• Diagnosticul diferential
• Tratament
• Concluzii
 Generalitati:

Bolile asociate Ig G4 constau intr-o grupare de afectiuni

unificate sub aceeasi entitate din 2003, adesea nerecunoscuta
si confundata cu o patologie neoplazica, infectioasa sau
inflamatorie.
Boala sistemica cu multiple fatete, cronica, mediata
imun, fibro-inflamatorie, ce poate afecta orice organ, avand un
potential inalt distructiv si uneori putand fi chiar fatala.

PERUGINO, Cory A.; STONE, John H. IgG4-related disease: an update on pathophysiology and implications for clinical care.  Nature Reviews Rheumatology, 2020, 1-13.
 mase tumorale

infiltrat dens predominant cu

+/- nivel Ig G4 seric ↑ plasmocite Ig G4 +, cu grade variabile
de fibroza storiforma si flebita
obliterativa

raspuns prompt la
administrarea de GLC

AL-MUJAINI, Abdullah, et al. Immunoglobulin G4-related disease: an update. Oman medical journal, 2018, 33.2: 97.
Epidemiologie
• Date putin numeroase
• Initial descrisa in Japonia, la barbatii varstnici, insa
acum este recunoscuta si in alte populatii si alte
areale geografice
• Prevalenta 0,8-3,1:100 000
• Varsta medie la diagnostic 60 ani
• B:F = 4:1 (exceptie fenotipul cu localizare cap si gat)
• Posibila susceptibilitate genetica HLA DRB1

FLOREANI, Annarosa, et al. IgG4-related disease: changing epidemiology and new thoughts on a multisystem disease.  Journal of Translational Autoimmunity, 2020, 100074.
 Nomenclatura
Boli pe care in trecut le numeam idiopatice, acum fac parte din
spectrul IgG4-RD.

STONE, John H., et al. IgG4-related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations.  Arthritis and rheumatism, 2012,
64.10: 3061.
STONE, John H., et al. IgG4-related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations.  Arthritis and rheumatism, 2012, 64.10: 3061
Imunopatogenie
• Ig G = clasa dominanta din serul uman
• Exista 4 subtipuri de Ig G 1, 2, 3, 4 (Ig G1>Ig
G2>Ig G3>Ig G4).
• Difera prin numarul de punti disulfidice si
propritetati.
 Ig G4 - rol ANTIINFLAMATOR
• Nu poate activa complementul pe calea
clasica

• Nu interactioneaza cu R Fc gamma de pe
suprafata macrofagelor

• Proprietatea de “Fab-arm exchange”

...si totusi, de ce atat de mult IgG4 ?

IgG4 - un rol central sau doar un epifenomen ?

VAN DER NEUT KOLFSCHOTEN, Marijn, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.  Science, 2007, 317.5844: 1554-1557.
 • Rol central : celule B si
celule T ctx CD4+

• Cel T CD4+ follicular

helper → maturarea
celulelor B in
plasmablasti → switch
catre clasa Ig G4

PERUGINO, Cory A.; STONE, John H. IgG4-related disease: an update on pathophysiology and implications for clinical care.  Nature Reviews Rheumatology, 2020, 1-13.
• Plasmablastii migreaza in
tesutul inflamat si
activeaza Ly T ctx CD 4 +

• Acesta va produce
citokine profibrotice : IL1,
TGFβ, IFNγ si molecule
citolitice : granzima A/B si
perforina →activarea
macrofage, fibroblasti,
apoptoza

MAEHARA, Takashi; MORIYAMA, Masafumi; NAKAMURA, Seiji. Pathogenesis of IgG4-related disease: a critical review. Odontology, 2019, 107.2: 127-132.
• Faza inflamatorie →Faza
fibrotica

MAEHARA, Takashi; MORIYAMA, Masafumi; NAKAMURA, Seiji. Pathogenesis of IgG4-related disease: a critical review. Odontology, 2019, 107.2: 127-132.
 Manifestari
clinice:

CHEN, Luke YC, et al. IgG4-related disease: what a hematologist needs to know. haematologica, 2019, 104.3: 444.
LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
 D
D

1. KAMISAWA, Terumi, et al. IgG4-related disease. The Lancet, 2015, 385.9976: 1460-1471.

2. BALAKRISHNAN, Neelima; MEEL, Rachna; DAS, Deepsekhar. Case of IgG4 orbitopathy’s remarkable response to oral corticosteroid therapy.  BMJ Case Reports, 2020, 13.8.
 Investigatii paraclinice:

• IgG4 seric↑(30% - nivel N)

• Ig A si Ig M pot fi N/usor↑
• Ig E pot fi intens ↑
Hipergamaglobulinemie
Eozinofilie periferica(40%, policlonala; EPS si EPU
usoara) importante petru
excluderea peakului
monoclonal

Ac ANA, FR pot fi slab + LABORATOR

VSH ↑, CRP
N/moderat↑(tipic
Hipocomplementemie
<20mg/L) – in absenta
50%, mai ales cand exista
periaortitei/unei infectii
NTI Lipaza, glicemie, HbA1c,
active
enzime hepatice, TSH,
creatinine, sumar de urina
→ pentru evaluarea
afectarilor de organ
CHEN, Luke YC, et al. IgG4-related disease: what a hematologist needs to know. haematologica, 2019, 104.3: 444.
 CT cu substanta de contrast cap-gat-
torace-abdomen-pelvis

PET CT- scanare

US glande parotida,
completa a leziunilor IMAGISTICA submandibulara
active

ERCP IRM – util mai ales pentru DD (ex. PAI de

cancer pancreatic)

Hochberg, 7th Edition

 A A : aspect CT PAI tip I, aspect D
“sausage-like”
B: aspect RM pseudotumora orbitala

B E

C : ERCP → colangita sclerozanta

D: aspect CT periaortita
E: ultrasonografie glanda
submandibulara
1. TAKAHIRA, Masayuki, et al. Clinical aspects of and diagnosis of IgIgG4-related orbital inflammation in a case series of ocular adnexal lymphoproliferative disorders.  Internationa
journal of rheumatology, 2012, 2012. 2. KAWA, Shigeyuki. Current concepts G4-related pancreatitis (type 1 AIP). In:  Seminars in liver disease. Thieme Medical Publishers, 2016. p
257-273 3. ASAI, Satomi, et al. Sonographic Appearance of the Submandibular Glands in Patients With Immunoglobulin G4 ‐Related Disease.  Journal of Ultrasound in Medicine,
2012, 31.3: 489-493.
 Fibroza storiforma

EXAMEN
HISTOPATOLOGIC

Flebita obliterativa Infiltrat limfoplasmocitar

predominant cu plasmocite
IgG4+, cu raport plasmocite
IgG4/IgG >40%

Hochberg, 7th Edition

A

B: fibroza storiforma in
coloratie hematoxilin-
eozina

A: coloratie C: flebita obliterativa

imunohistochimica pt
evidentirerea
raportului plasmocite
ig g4+ /ig g >40%

KAMISAWA, Terumi, et al. IgG4-related disease. The Lancet, 2015, 385.9976: 1460-1471.

Criteriile de clasificare ACR-EULAR pentru IgG4-RD 2019
 Diagnosticul diferential

- Complex, in functie de fenotipul bolii

- ↑ serica si tisulara de IgG4 nu este

specifica

Adapted from: Brito-Zerón P, Bosch X, Ramos-Casals M, Stone JH. IgG4-related disease: Advances in the diagnosis and treatment. Best Pract Res Clin
Rheumatol 2016; 30:261
 Boala pancreato-hepato-biliar

Cancerul pancreatic (ADK) Colangita primara sclerozanta Colangiocarcinom Carcinom hepato-celular

Fibroza retroperitoneala si/sau aortita, periaortita

Secundar
Aortite infectioase – sifilis
• medicamentoasa:
Arterita Takayasu/Horton
metisergid, metil-dopa,
Boala Behcet
etanercept, infliximab
• Unor neoplazii :limfom,
• Unor infectii: TB,
histoplasmoza
• Post-radioterapie

Boala localizata la nivelul capului si gatului

Alte tumori pseudoorbitale:

Sindromul Sjogren Hiperplazia limfoida orbitala
benigna
MOUTSOPOULOS, Haralampos M., et al. Uptodate, Diagnosis and differential diagnosis of IgG4-related disease.
Cu alte boli sistemice :

- Boli hematologice:
• Limfoame
• Neoplazii plasmocitare
• Boli histiocitare , ex Boala Erdheim Chester
• Boala Castelman
• Sindroamele hipereozinofilice / Leucemia cronica eozinofilica
- Vasculitele ANCA +
- Infectii
- Sarcoidoza

MOUTSOPOULOS, Haralampos M., et al. Uptodate, Diagnosis and differential diagnosis of IgG4-related disease.
Tratament
1. Inducerea remisiunii
• Glucocorticoizi:
Timp de 2-4 S,
Prednison 0,6-1mg/kgc apoi ↓cu 5 mg la
Metilprednisolon 1g/zi, 3 zile→ in caz de afectare craniana 2S pe perioada de
3-6 luni
/nervi spinali
• Imunosupresoare:
CFM : doza mica oral 50-100mg/zi
MFM :1000-1500mg/zi
AZA, MTX, HCQ, tacrolimus : dovezi slabe –studii
retrospective/serii de caz

LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
• Agenti biologici:

 RTX :
2 infuzii a cate 1g fiecare la interval de 15 zile (protocol Reumatologic) sau
1 infuzie saptamanal 375mg/m2 , timp de 4 S(protocol hematologic)

 ABATACEPT : a indus si mentinut remisiunea la un pacient cu Boala Mikulicz si PAI

rezistente la RTX
 INFLIXIMAB: pentru o pseudotumora orbitala refractara la multiple IS
 DUPILUMAB (blocant de R α IL4) :a redus FRP la un pacient cu IgG4RD si
manifestari atopice severe

LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
2. Mentinerea remisiunii

• Glucocorticoizi: doza mica 5-7,5mg/zi pana la 3 ani

• IS: MFM (1-1,5g/zi) /CFM orala(50-100mg/zi) + glc
• RTX :
- 2 infuzii a cate 1g la interval de 15 zile sau
- 1 infuzie saptamanala 375mg/m2, timp de 4 saptamani
- o singura infuzie de 1g la 6 luni – atunci cand exista semne de recadere, nu la
intervale prestabilite

DURATA OPTIMA ? Date insuficiente, de obicei se opreste la 3 ani daca exista

imbunatatire serologica si radiologica.

LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
Posibile tinte terapeutice

• Inebilizumab: Ac
monoclonal anti CD-19
• Anti CD 40-L sau anti
IL-4
• Elotuzumab: Ac
monoclonal anti
SLAMF7
• XmAB5871 : Ac
monoclonal antiCD19
• Abatacept

LANZILLOTTA, Marco; MANCUSO, Gaia; DELLA-TORRE, Emanuel. Advances in the diagnosis and management of IgG4 related disease.  bmj, 2020, 369.
Concluzii
• Boala Ig G4 este o boala imun-mediata, cu multiple fatete, ce poate afecta orice
organ, important de recunoscut dat fiind potentialul distructiv si chiar fatal.
• Nivelurile serice crescute de Ig G4, respectiv de plasmocite Ig G4 trebuie sa
coexiste cu manifestari clinice, imagistica si histopatologie sugestive de IgG4 – RD
pentru a pune diagnosticul de certitudine
• Pana la momentul actual avem un arsenal terapeutic important , fie confirmat,
fie inrolat in studii clinice
• Terapia cortizonica si cea de depletie celulara B sunt foarte eficiente, confirmand
rolul important al ly B in patogenia bolii
Va multumesc pentru atentie!