IgG4 related disorders afmc symposium arnab vardraj & mha khan

IGG4 RELATED DISORDERS

PathobiologySLC Arnab Ghosh

References International Consensus Guidance Statement on the

Management and Treatment of IgG4-Related Disease

Harrison’s Internal medicine 19e

NEJM review article

Best Practice & Research Clinical Rheumatology 26 (2012) 425–438

Uptodate Topic 16155 Version 11.0 (2017)

Other Reviewed literatures 1. Stone JH, Zen Y, Deshpande V et al (2012) IgG4-related disease. N Engl J Med 366:539

2. Zen Y, Nakanuma Y (2010) IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 34:1812–1819

3. Nishimori I, Tamakoshi A, Otsuki M et al (2007) Prevalence of autoimmune pancreatitis in Japan from a nationwide survey in 2002. J Gastroenterol 42(Suppl 18):6–8

4. Aalberse RC, Stapel SO, Schuurman J et al (2009) Immunoglobulin G4: an odd antibody. Clin Exp Allergy 39:469–477

5. Nirula A, Glaser SM, Kalled SL et al (2011) What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol 23:119–124

6. Canfield SM, Morrison SL (1991) The binding affinity of human IgG for its high affinity Fc receptor is determined by multiple amino acids in the CH2 domain and is modulated by the hinge region. J Exp Med 173:1483–1491

7. Huizinga TW, Roos D, von dem Borne AE et al (1990) Neutrophil Fc-gamma receptors: a two-way bridge in the immune system. Blood 75(6):1211–1214

Online Database This link provides all the articles (meta-

analysis, review or case reports with the key word “IgG4 related disorders”

https://www.readbyqxmd.com/keyword/113996/4



The History 1961 –Discovery of IgG4

First identified in the pancreas-called AIP

1991-First histopathological description

2001-AIP related to elevated IgG4 levels in the serum

2003-Concept of IgG4RD causing diseases in extra-pancreatic tissues

2015-International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease released

Case Scenario 1 A 68-year-old female with new onset

of abdominal pains, fever, weight loss and increased inflammation markers. On CT, a retroperitoneal mass was noticed, FNACIgG4-related fibrosis. Started on oral corticosteroidsslight clinical improvement rept CT no improvement in the mass even slightly enlargedMethotrexate or rituximab not beneficialmass became bigger on rpt CT. IgG4-related fibrosis was suggested Abdominal surgery planned. After surgically removal histopathological diagnosis of liposarcoma was established.

Arrow IgG4 + plasma cells. Anti-IgG4 (MRQ-44)

mononuclear inflammation and extensive fibrosis

Case Scenario 2

A 55-year-old hypothyroid male was admitted with subacute thyroiditis has decrease in TSH, elevated ESR & very high antithyroid antibodies. Owing to enlarging goiter and exacerbation in the patient's complaints, he was operated with excision of a fibrotic and enlarged thyroid lobe. Elevated IgG4 plasma levels and high IgG4/IgG plasma cell ratio on immunohistochemistry led to the diagnosis of IgG4-mediated thyroiditis. IgG4-thyroiditis and IgG4-related disease should be considered in all patients with an aggressive form of Hashimoto's thyroiditis.

Excised left lobe of the thyroid gland showing significant enlargement

Histopathology showing heavy plasmacytic infiltrates and a storiform fibrosis typical of IgG4-related disease of the thyroid gland

DefinitionIgG4-related diseases (IgG4-RD) are

Immunemediated Fibroinflammatory condition Affect multiple organs and lead to

tumefactive, tissue destructive lesions and organ failure

Spectrum other than AIP Mikulicz disease Küttner tumour Multifocal fibrosclerosis Inflammatory pseudotumour Riedel's thyroiditis Inflammatory aneurism of the aorta Cutaneous pseudolymphoma Eosinophilic angiocentric fibrosis

Organs Affected

Epidemiology Middle-aged and older Male> Female

-type 1 (IgG4-related) AIP-retroperitoneal fibrosis-IgG4-related tubulointerstitial nephritis

M=F in sialadenitis and IgG4-related ophthalmic disease

Disease extent and severity similar in men and women

Epidemiology contd… Uchida et al estimated the annual incidence

of IgG4-RD at 0.28–1.08/100,000

For the year 2009, a total of 8,000 patients were expected in Japan, which accounted for a prevalence of ~62 patients per million inhabitants

Mean age 50–70 years

Epidemiology cntd… AIP frequently associated with IgG4-

related cholangitis and kidney disease

Sialadenitis often coexists with dacryoadenitis

RPF may rarely coincide with IgG4-related kidney disease

235 Japanese Cohort 60% - pancreatitis 34% - sialadenitis 23% - tubulointerstitial nephritis 23% - dacryoadenitis 20% - periaortitis 58% - multiple organs involved Most frequent solitary manifestation

pancreatitis

IgG4 RD Mimics ANCA associated vasculitides

Granulomatosis with polyangiitis (Wegener’s)

Microscopic polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Adenocarcinoma and squamous cell carcinoma

peritumoral infiltrate Castleman’s disease (multicentric or localized)

Cutaneous plasmacytosis

Erdheim-Chester disease

Inflammatory myofibroblastic tumor

• Inflammatory bowel disease

• Lymphoproliferative diseases

• Extranodal marginal zone lymphomas

• Lymphoplasmacytic lymphomas Follicular lymphomas

• Perforating collagenosis

• Primary sclerosing cholangitis

• Rhinosinusitis Rosai-Dorfman disease

• Sarcoidosis

• Sjogren’s syndrome

• Splenic sclerosing angiomatoid nodular transformation

• Xanthogranuloma

IgG4 – What is it?Unique featureHalf antibody exchange reaction“fragment antigen-binding (Fab)–arm exchange”

Unique in both structure and function<5% of total IgG in healthy persons Least abundant IgG subclassconcentrations in ostensibly healthy people vary, generally stable in individual person

Potential Initiating Mechanisms

Genetic Risk Factors

-DR B1*405 & DRB1*0401-Japanese-DQβ1-57 without Asp acid-Korean-Non-HLA genes with s-NP encoding CTLAA-4, TNF-α & FcRL3 increased Susceptibility or recurrence


Bacterial Infection & molecular mimicry ▪ Hum CA-II vs H pylori α CA homologus segments▪ binding motif of HLA molecule DRB1*0405

Plasminogen binding protein ubiquitin ligase E3 component

n-recognition 2


TLRPBMCIL-10 IgG4 synthesis

Autoimmunity-No specific Ag identified-? CA, lactoferin, tripsin inhibitors, trypsinogens

-13.1kD protein-granular deposit identified in GBM-?part or bystandards

Specific Disease Pathways

Th2 Cells and Regulatory Immune Reaction

-Increased IL4,5,10,13 releaseB cell proliferationIgG4, IgE, Eosinophilia-FOXP3 mRNA Inc Treg(in classic autoimmune ds impaired) ↑ IgG4 ↑ TGF ↑fibrosis

Role of IgG4 antibodies-unclear

T2 cells & Regulatory Imm reaction

Instability and effect of Ag binding

CLINICAL FEATURES

Sqn Ldr G VaradarajModerator: Wg Cdr S Kartik, Rheumatologist

• Typical patient is a middle aged to elderly male

• Swollen but painless organs

• Rarely present with general symptoms such as fever and malaise

• Overall M:F ratio in most organ systems is 3.5 : 1

• Some variability exists in sex distribution from organ to organ. Eg: Head and neck- M:F ratio is closer to 1 : 1

CLINICAL MANIFESTATION

• Involve one or multiple organs

• Sub-acute development of mass or diffuse enlargement

• Multiple organs in 60%-90%

• Lymphadenopathy common

• Asthma and allergy in 40% patients

• Multi-organ disease have significant weight loss

• Mimic autoimmune rheumatic disease and neoplasm



• Almost all cases present with elevated serum levels of IgG4 (≥135 mg/dl)

• Histopathology :

Lymphoplasmacytic infiltrate

Variable degree of fibrosis Storiform fibrosis

• Respond well to Glucocorticoids

COMMONLY AFFECTED UNCOMMON SITES

• Biliary tree• Salivary glands• Periorbital tissues• Kidneys• Lungs• Lymph nodes• Retroperitoneum

• Meninges • Aorta• Prostrate• Thyroid• Pericardium• Skin

RARE SITES• Brain, joints, Bone

marrow, Bowel mucosa


LYMPHADENOPATHY• Asymptomatic, occur in 80% of AIP

• May be the initial or only presentation

• “Storiform fibrosis” seldom seen

• Biopsy other organs involved to establish diagnosis

Int J Rheumatol. 2012;2012:572539.

Five histological patterns- all featureabundant IgG4 positive cells, eosinophilInfiltration

- Type 1: Multicentric castleman disease like- Type 2: Follicular hyperplasia- Type 3: Interfollicular expansion- Type 4: Progressive transformation of germinal centre like- Type 5: Nodular inflammatory pseudotumour like

LYMPHADENOPATHY

IgG4-related lymphadenopathy (type I). (a) The lymph node shows interfollicular expansion with normal to hyperplastic germinal centers. (b) The germinal centers are penetrated by blood vessels.

DIFFERENTIAL DIAGNOSIS• Sarcoidosis• Infection (Tuberculosis)• Lymphoma• Castleman disease

DISTINGUISHING FEATURE• Modest lymph node enlargement• Histologic distinction• Lack of constitutional feature• Clinical response to Glucocorticoids

LYMPHADENOPATHY

AUTOIMMUNE PANCREATITIS

• Prototypical form - Type 1 (IgG4-ralated) AIP

• 2% of chronic pancreatitis

• Presents as Pancreatic mass or painless swelling –

mistaken for pancreatic cancer

• Frequently associated with Diabetes

• Other concomittant IgG4-related condition common

• Radiologic feature – “Sausage shaped” pancreas with

surrounding halo of edema


Okazaki K. et. al. Autoimmunity Reviews 2014;451–8

Diffuse wall thickening of bile duct Nodule is formed in pancreatic head

Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:315–47 Kamisawa T. et. al. Lancet 2015;385:1460-71


IGG4 RELATED SCLEROSING CHOLANGITIS

• Most frequent extrapancreatic manifestation of Type 1 AIP (70%)

• Primary sclerosing cholangitis Vs Cholangiocarcinoma Vs IgG4-related sclerosing cholangitis

• Histology – infiltrates of IgG4+ plasma cells and severe interstitial fibrosis

• Other distinguishing feature: Increased IgG4 serum level, responsiveness to glucocorticoid, extra-biliary organ involvement

SALIVARY AND LACRIMAL GLAND• Parotid and submandibular –

commonly involved

• Mikulicz disease, Kuttner’s tumour, sclerosing sialadenitis – subcategories of Sjogren’s syndrome are now considered as IgG4-related sialadenitis

• 40% association with Type 1 AIP

• Often presents prior to AIP

• Histology – lymphoplasmacytic infiltrate with IgG4-positive cells

• Increased IgG4 and IgE serum levels

• Low complement level seen in asociation with IgG4-related renal involvement

SALIVARY AND LACRIMAL GLAND

Distinguishing feature from SS:

- Mild dryness of eyes and mouth despite marked gland enlargement

- Higher frequency of allergic rhinitis and bronchial asthma

- Higher frequency of AIP and interstitial nephritis

- Low frequency of autoantibodies (RF, ANA, anti-SSA/SSB)

SALIVARY AND LACRIMAL GLAND

RETROPERITONEAL FIBROSIS AND RELATED DISORDERS• IgG4-RD responsible for majority of “idiopathic”

retroperitoneal fibrosis

• Particularly involve infra-renal aorta and iliac arteries

• Regional tissue involvement – Ureters, obstructive uropathy

• Involvement of other organs most commonly pancreas

THYROID GLAND

• Substantial portion of cases of Riedel thyroiditis

• Fibrous variant of Hashimoto

thyroiditis

• IgG4-related thyroiditis is often associated with massive enlargement of thyroid due to lymphocytic infiltration

LUNG AND RESPIRATORY TRACT• Asymptomatic

• May present with cough, hemoptysis, dyspnoea, pleurisy or chest pain

• 4 patterns of lung involvement described:- - Solid nodular- Bronchovascular- Alveolar interstitial- Round-shaped, ground-glass opacties

• Mimic Sarcoidosis

IgG4-RD has a predilection for bronchovascular bundle regions

KIDNEY

• Middle-aged and older male

• Mainly manifests as tubulointerstitial nephritis (TIN), IgG4-related glomerulonephritis rare

• Lymphoplasmacytic

infiltration of renal interstitium and fibrosis

INVESTIGATIONS

• Radiologic studies • Serum IgG4 level • Histopathology

RADIOLOGIC STUDIES • Diagnosis is often suggested

by incidental radiologic findings

• Selection of imaging modality appropriate to assessment of IgG4-RD

• CT images reveal organ enlargement

• FDG-PET detects severe inflammation

SERUM IGG4 • Remain important in evaluation

and longitudinal assessments, but elevated levels are neither necessary nor sufficient for diagnosis of IgG4-RD

• 3 - 30% of patients have normal serum IgG4 level

• Elevated IgG4 concentrations have been observed in a variety of other conditions

• However, degree of serum IgG4 elevation correlates with number of organs involved: the greater the extent of disease, the higher the likelihood of an elevated serum IgG4

SERUM IGG4

Tabata T. et. al. Intern Med 2011;50: 69-75

PLASMABLAST LEVEL

• Recent study indicates IgG4-RD patients have substantial elevations of circulating plasmablasts

• Plasmablast levels correlate with disease activity

• Additional studies of circulating plasmablasts and IgG4+ plasmablasts as biomarkers are required

Mattoo H. et. al. J Allergy Clin Immunol 2014;134:679-87 . Khosroshahi A. et. al. Arthritis Rheumatol 2015 May 3, 2015

HISTOPATHOLOGIC HALLMARKS

Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:315–47

OBLITERATIVE PHLEBITIS

Obliteration of venous channels by extensive lymphoplasmacytic cell infiltration

Kamisawa T. et. al. Lancet 2015;385:1460-71 Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59

IMMUNOSTAINING

Kamisawa T. et. al. Lancet 2015;385:1460-71

IgG4 shows many IgG4-positive plasma cells

STORIFORM FIBROSIS


Pattern is often likened to a cartwheel, with the bands of fibrosis (arrowheads) emanating from the center (asterisk) representing the spokes of the wheel

HISTOPATHOLOGY • Presence of significant IgG4+ plasma cell infiltrates in

biopsy specimens is not specific for IgG4-RD

• Common mimickers of IgG4-RD include:- Malignancy- Granulomatosis with polyangiitis- Eosinophilic granulomatosis with polyangiitis- Multicentric Castleman’s disease

• Findings of storiform fibrosis and obliterative phlebitis heighten diagnostic specificity

PRACTICAL CONSTRAINTS

• Needle biopsies are usually insufficient for diagnosis of IgG4-RD. However, needle biopsy generally use to exclude malignancy with some confidence

• Storiform fibrosis might not be detected; hence use of en-bloc biopsy is recommended

Maj MHA KhanModerator: Wg Cdr S Kartik, Rheumatologist

DIAGNOSIS AND MANAGEMENT

PATIENT EVALUATION

Most accurate assessment of IgG4-RD is based on :

1. a full clinical history 2. physical examination

3. selected laboratory investigations 4. appropriate radiology studies

DIAGNOSIS Japanese comprehensive clinical diagnostic criteria for

IgG4- RD. 1. Clinical examination showing characteristics

diffuse/localised swelling or masses in single or multiple organs

2. Hematological examination shows elevated serum IgG4 concentrations (135 mg/dl)

3. Histopathalogical examination shows : (1) Marked lymphocyte and plasmacyte infiltration

and fibrosis. (2) Infiltration of IgG4 + plasma cells : ratio of IgG4+

/IgG cells > 40% and > 10 IgG4 + plasma cell /HPF

Okazaki K. et. al. Autoimmunity Reviews 2014;451–8

Definite: 1) + 2) + 3) Probable; 1) + 3)Possible: 1) + 2)

DIAGNOSTIC CRITERIA FOR IGG4+ MIKULICZ’S DISEASE 1. Symmetrical swelling of atleast two pairs of

lacrimal, parotid and submandibular glands continuing for more than 03 months; and

2. Elevated serum IgG4(>135 mg/dl) or 3. Histopathological features including lymphocyte

and IgG4+ plasma cell infiltration (IgG4+ plasma cells/IgG+ plasma cells >50%) with typical tissue fibrosis or sclerosis.

Umehara H. et. al. Mod Rheumatol 2012;22:21–30 Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59

DIAGNOSTIC CRITERIA FOR IGG4+ RELATED KIDNEY DISEASE 1. Presence of some kidney damage, as manifested

by abnormal urinalysis or urine marker(s) or decreased kidney function with either elevated serum IgG or IgE or hypocomplementemia

2. Abnormal renal radiologic findings: a. Multiple low –density lesions on enhanced

computed tomography b. Diffuse kidney enlargement c. Hypovascular solitary mass in the kidney d. Hypertrophic lesion of the renal pelvic wall

without irregularities of the renal pelvic surface Umehara H. et. al. Mod

Rheumatol 2012;22:21–30

3. Elevated serum IgG4(>135 mg/dl) 4. Histologic findings in the kidney: a. Dense lymphoplasmacytic infiltration by >10

IgG4+plasma cells/high power field and/or IgG4+/IgG+ plasma cells >40%

b. Characterisic (sclero-) fibrosis surrounding nests of lymphocyte and/or plasma cells

5. Histological findings in extra –renal organ(s): Dense lymphoplasmacytic infiltration by >10

IgG4+ plasma cells/HPF and /or IgG4+ /IgG plasma cells >40%

Definite 1+ 3+ 4 a, b 2+ 3+ 4 a, b 2+3+5 1+ 3+ 4 a + 5 Probable 1+ 4 a, b 2+ 4 a, b 2+5 3+4 a,(b) 1+3

Possible 1+3 2+3 1+4a 2+4a

CLINICAL DIAGNOSTIC CRITERIA FOR AUTOIMMUNE PANCREATITIS 1. Diffuse or segmental narrowing of the main

pancreatic duct with irregular walls and diffuse or localized enlargement of the pancreas on imaging modalities

2. High serum F- globulin, IgG, or IgG4 concentration or the presence of auto antibodies, such as antinuclear antibodies and rheumatic factor

3. Marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells to the periductal area, occasionally accompanied by lymphoid follicles in the pancreas

Umehara H. et. al. Mod Rheumatol 2012;22:21–30 Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59

AIM OF TREATMENT

Prevention of fibrosis Potentially destructive impact on organs

Khosroshahi A. et. al. Arthritis Rheumatol 2015 [Epub ahead of print] access May 3, 2015

INDICATIONS FOR THERAPY

All patients with symptomatic, active IgG4-RD A subset of patients with asymptomatic IgG4-RD


TREATMENT

Not required for all manifestations “Watchful waiting” Spontaneous remissions or temporary remissions without

treatment In few cases disease improve at least temporarily in one

organ, it may re-emerge months or years later at a different site


TREATMENT

Treatment leads to faster and more complete remission with fewer long-term complications of IgG4-RD

Treatment is therefore justified in most cases in which laboratory evidence or radiology studies suggest organ dysfunction


TISSUE CONFIRMATION PRIOR TO TREATMENT Diagnostic confirmation by biopsy is strongly

recommended for exclusion of malignancies and other IgG4-RD mimics


TREATMENT

Systemic glucocorticoid “Steroid-sparing” immunosuppressive drugs Biologic agents Surgical resection of affected tissues But no randomized clinical trials or formal treatment guidelines

exist


Regimen of oral steroid therapy for AIP

Kamisawa T. et. al. J Gastroenterol 2014;49:961–70 Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59

MAINTENANCE THERAPY

In an effort to minimize morbidity, those with organ-threatening IgG4-RD manifestations and patients at elevated risk of relapse likely benefit from maintenance therapy

1. Higher risk for recurrence following remission induction 2. Multi-organ disease 3. Significantly elevated serum IgG4 concentrations 4. Involvement of proximal bile ducts Relapses in IgG4-RD patients are common, even with the use

of glucocorticoid maintenance therapy


USE OF STEROID-SPARING AGENTS No response to steroid Difficulty in bringing down to low dose of steroid Steroid side effects

USE OF STEROID-SPARING AGENTS

Hart PA, et al. Gut 2013;62:1607–15 Khosroshahi A. et. al. Arthritis Rheumatol 2015 [Epub ahead of print] access May 3, 2015

MECHANISM OF ACTION OF RITUXIMAB


MECHANISM OF ACTION OF RITUXIMAB


RITUXIMAB

Rituximab-mediated B cell depletion results in loss of short-lived plasma cells by depleting their CD20+ precursors..

B cell depletion eliminate a major cell type required for antigen presentation to T cells, leading to loss of activated T cells and profibrotic cytokines and a reduction in inflammatory cellular infiltrate.

Asymptomatic or changes only in facial

appearance

Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59

HIGHLY FIBROTIC LESIONS Long-standing, highly fibrotic lesions may respond

poorly

In such patients, risk-benefit balance may not favour repeated courses of treatment

Surgical de-bulking is an option, but suitability of surgical interventions is governed by anatomic regions and adjacent structures involved

PROGNOSIS

Initial prognosis of patients with IgG4-RD is generally good

Relapse ratio after tapering or discontinuing steroids is very high

Patients who relapse present with new lesions in different organs during both short-term and long-term (>10 years) follow-up

TAKE HOME MASSEGE

IgG4-RD represents a chronic inflammatory disorder characterized by various systemic organ dysfunctions

Disease is associated with elevated serum levels of IgG4 and specific histopathological features, including abundant IgG4+ plasmacyte infiltration, storiform fibrosis and obliterative phlebitis

Examination for systemic organ failure and screening for underlying malignancies is important during the diagnosis and follow-up of IgG4-related disease

Glucocorticoids are effective in the treatment of IgG4-related

disease, but the rate of relapse after tapering or discontinuing glucocorticosteroids is high

Health & Medicine

IgG4 related disorders afmc symposium arnab vardraj & mha khan