IgG related diseases

1. BY-DR SHELLY MAJUMDAR

2. IgG4 related disease is a immune mediated fibro-
inflammatory condition characterised by a
tendency to form tumefactive lesions with
lymphoplasmacytic infiltrations in single or
multiple organs.
It can result in organ failure and death if untreated.

3. 1892- mikulicz et al.,1st observed a patient with symmetrical
lacrimal,submandibular and parotid gland swelling with massive
mononuclear cell infiltration(it was called atypical sjogren then)
1961- Sarles et al .,observed a form of idiopathic chronic
pancreatitis with obstructive jaundice and
hypergammaglobulinemia,found to be of autoimmune
nature(Yoshida,1995)
2000-THE CONDITION KNOWN AS LYMPHOPLASMACYTIC
SCLEROSING PANCREATITIS BECAME THE PARADIGM OF IgG 4
RELATED DISEASES
2001-Elevated levels of serum IgG4 concentrations found
NOW TERMED AS AUTOIMMUNE PANCREATITIS TYPE 1
2002-not just serum but abundant plasma cell infiltration in
pancreatic tissue found(Hamano)
2003-Extrapancreatic manifestations found.
2008-It was seen that these other organs involved also exhibiting
abundant IgG4 bearing plasma cell infiltration

4. FINALLY IN 2011
INTERNATIONAL IgG4
RELATED DISEASES
SYMPOSIUM HELD IN BOSTON
THE TERM IgG4 RELATED
DISEASE WAS PROPOSED

5.  Slight predominance of middle aged to elderly male
 This predilection for older men is certainly true for
AIP1,retroperitoneal fibrosis,IGg4RD
tubulointerstitial nephritis.
 But for IgG4 RD involving head and neck,like
orbits,sialdenitis,dacroadenitis–the sex ratio may
be closer to 1
 The disease is also increasing in pediatric
population,however eye manifestations are more
common.

8.  A slowly evolving nature of IgG4 RD is one of it
characteristic features.
 Nearly affects all organs.
 Even patients with multiorgan involvement and
significant disease burden within individual organ can
remain asymptomatic for long periods of time.
 Many features of the disease are detected incidentally by
imaging(retroperitoneal fibrosis )or surgical
pathology(IGg4 related aortitis)
 IRREVERSIBLE ORGAN INJURY CAN OCCUR EVEN BEFORE
THE PATIENT IS AWARE OF HAVING THE DISEASE.

9.  Allergic features like atopy , eczema , asthma, nasal
polyps , sinusitis and modest peripheral eosinophilia
 Pseudotumors in multiple organ systems(PATIENTS MAY
UNDERGO MAJOR SURGERIES BEFORE CORRECT
DIAGNOSIS IS MADE)
Destructive bony lesions in sinuses,head,middle ear
spaces mimicking Granulomatosis with Polyangitis
occassionally.

11.  Acute,fulminantor highly inflammatory clinical
presentations DO NOT occur in IgG4 RD.
 FEVERS ARE DISTINCTLY UNUSUAL and nearly
always implicate another diagnosis.
 However a minority of patients<10% may have
weight loss,fever,dramatic elevation of acute
phase reactants,and other systemic
inflammatory features.

14.  HISTOPATHOLOGICAL HALLMARKS-
 1)Dense lymphoplasmacytic infiltration(ratio of
IgG4/IgG>40% in immunohistochemistry,>10o/o
per HPF)
 2)Fibrosis,usually storiform in character
 3)Obliterative phlebitis and eosinophilic
infiltration.
 Necrotizing features,granulomatous
inflammation,multinucleated giant cell and
neutrophilic inflitrates are highly atypical of the
disease.

18.  Large unclear,however a cross talk between
innate and adaptive immunity is considered.
 Potential triggers-
 1)genetically susceptible individuals (HLA
DRB1*04:05-DQ B1*04:01)
 2)Chronic stimulation by candidate
antigens/autoantigens(Galectin3,annexin
A11,laminin511,prohibitin) /infectious agent/allergic
component
 3)Environmental factors

19.  Abnormal adaptive immune response mediated
by-
 Th2 cells,Treg cells,CD4CTLs,Tfh cells,Tfr
cells,PD1hiCXCR5 peripheral Th cells,B cell
subsets
 Innate immune response involved include-
 complement,macrophages,mast
cells,basophils,pDCs

20.  Th2 Cell and Treg Cell involvement--

23. Memory Bcells increased,while regulatory Bcells
decreased.
Elevated Bcell subsets (plasma cells/plasmablasts)
CD19+CD24-CD 38hi,CD19+,CD20-,CD27+,CD38+ are
increased in active IgG4RD which decrease after
Rituximab mediated Bcell depletion therapy.
Higher levels of serum BAFF and APRIL found.
APRIL forms heterotrimers with BAFF and enhances
BAFFmediated Bcell activation at the level of Ig class
switch and plasma cell generation/survival.
Anti BAFF(Belimumab) therapy already proven in
SLE might be promising in IgG4RD.

28.  Unlike other IgG subclasses IgG4 does not bind to
C1q compared to FcyRI,RII,RIII,yet patients having
hypocomplementemia in IgG4RD have high serum
levels of C1q binding IgG4,an unknown mechanism
suggested.
 IgG with G0 glycan seem to activate alternate and
classical pathway.
 Agalactosylated IgG also seem to activate lectin
pathway
 Serum C5a level is seen to be high in active disease
and low in remission

30.  M2 macrophages(typically 163+)binds to TLR
2+,4+,7+ to produce IL33,Th2 cytokines leading to
class switching and fibrosis and binds to MARCO
scavenger recepter produce IL10 and CCL18
precipitating exagerrated fibrosis
 Mast cells with strong IgE staining is also raised.
 Role of GALECTIN 3 as a negative regulator of
difeerentiation of B cells into plasma cells and Tcell
apoptosis may act as protective factor.

40.  1)Hepatobiliary phenotype-pancreatic
adenocarcinoma,cholangiocarcinoma,primary
sclerosing cholangitis,type 2 autoimmune
pancreatitis
 2)Retroperitoneal/aortic phenotype-idiopathic
retroperitoneal fibrosis,large vessel vasculitidis
 3)Head and neck limited-
autoimmune(GPA,graves,sarcoidosis),malignncy,
histiocytosis
 4)Mikulicz/systemic phenotype-
sjogren,GPA,multicentric castleman disease

42.  Low specificity(60%),low positive predictive value(34%)
 Large proportion of patients with biopsy proven IgG4RD
have normal IgG4 levels
 Hence reliance on IgG4 levels-SUBSTANTIAL
UNDERDIAGNOSIS
 Multiple clinical entities associated with elevated
numbers of IgG4 positive cells in tissue but lack specific
histopathological findings(GPA,allergic
diseases,eosinophilic
granulomatosis,sarcoidosis,multicentric castleman
disease etc)
 Granulomatosis with polyangitis associated with
high levels of IgG4 + plasma cells,but no study
noted with ANCA positivity in IgG4RD.

43. MASQUERADING FEATURES
DIAGNOSTIC CHALLENGES
EXCELLENT STEROID RESPONSE

44.  GOAL OF DISEASE MANAGEMENT-
 1)Reduce inflammation
 2)Maintain disease remission
 3)Preserve organ function whileminimising adverse effects
 ALL PATIENTS WITH ACTIVE SYMPTOMATIC
IgG4RD REQUIRES TREATMENT,some require
urgent treatment
 Asymptomatic patients with disease progression
also require treatment
 Watchful waiting only in few patients with asymptomatic
lymphadenopathy or mild submandibular gland
enlargement.6monthly evaluations in such patients.

45.  Aortitis-Inflammatory aortic aneurysms can enlarge and cause
aortic dissection
 Retroperitoneal fibrosis -irreversible nerve damage and/or
ureteral obstruction/renal failure
 Proximal biliary strictures -superimposed infectious
cholangitis,irreversibl fibrosis and cirrhosis
 Tubulointerstitial nephritis -irreversible chronic kidney
disease
 Pachymeningitis -neurological deficits/seizures
 Pancreatic enlargement -irreversible endocrine and exocrine
failure
 Pericarditis - tamponade/constrictive pericarditis

46.  SUCCESSFUL REMISSION INDUCTION-
 Resolution of symptoms related to active
disease(or substantial improvement) of
most biochemical and radiological
abnormalities.

48.  Initially oral prednisolone is used at high dose
regimen( 0.8-1.0mg/kg/day )or medium dose
regimen(0.5-0.6mg/kg/day),,,30-40mg/day or in
combination with DMARDs
 Starting dose maintained for 2-4 weeks
 Dose is tapered by 5mg per day for 1-2 weeks to
maintenance dose or discontinuation in 2-
3months
 A biological agent especially B cell depleting
medication to be considered where prolonged GC
therapy contraindicated.

51.  MAINTENANCE THERAPY-Oral prednisolone 5-10
mg /day for upto 3years.
 Although this varies across countries.
 OTHER DRUGS IN IgG4RD
 Conventional DMARDs
MMF,cyclophosphamide,MTx,leflunomide,azathiop
rine are commonly used in combination with GC to
reduce toxicity. Few studies show decreased
relapse rate when combination therapy used.

52.  BIOLOGICS
 Rituximab a B cell depleting agent is an excellent 2nd line
therapy(2 doses of 1g iv separated by 15days)
 1)B cell depletion interrupts antigen presentation to CD4
CTLs
 2)decreases tissue fibrosis by reducing number of
infiltrating activated myofibroblasts
 3)reduction of serum IgG4
 Abatacept-CTLA4Ig interferes with Tcell costimulation
 Anti SLAMF7 Mab Elotuzumab used to treat relapsed
multiple myeloma is under development.

54.  Placement of biliary ,ureteral stents,nephrostomy
tubes may be required at the startof medical
therapy,but ideally,the use of these measures is
temporary.
 Removal of stents or tubes at the earliest possible
opportunity is important from the perspective of
patient comfort and avoidance of complications.

55. THANK YOU