Dr .Samar Tharwat represents overview of IgG4 related disease

2.  Introduction
 Definition and Histology
 Pathogenesis
 Clinical Manifestations
 Diagnosis
 Differential Diagnosis
 Treatment
 Prognosis

3.  Immune-mediated condition.
 Tumor-like swelling of involved organs.
 A lymphoplasmacytic infiltrate enriched in
IgG4-positive plasma cells.
 A variable degree of fibrosis.
 Elevated serum concentrations of IgG4
 Responsiveness to glucocorticoids.

4.  IgG4-related disease
 IgG4-related systemic disease
 IgG4-syndrome
 IgG4-associated disease
 IgG4-related sclerosing disease
 IgG4-related systemic sclerosing disease
 IgG4-related autoimmune disease
 IgG4-positive multiorgan lymphoproliferative syndrome
 Hyper-IgG4 disease
 Systemic IgG4-related plasmacytic syndrome
 Systemic IgG4-related sclerosing syndrome
 Multifocal fibrosclerosis
 Multifocal idiopathic fibrosclerosis

6.  ↑Middle-aged and older men.
 Sialadenitis & ophthalmic disease :
Males=females.
 Disease extent and severity are similar in
males & females.
UNDERRECOGNITION

8.  IgG4: The least common (3% to 6%) of the 4
subclasses of IgG.
 IgG4 may have a role in tolerance to
allergens and in responses to certain
infectious agents.
 IgG4 antibodies in this disease are not
pathogenic, but rather represent a down-
regulatory response to another primary
process(es).
 Autoimmune / allergic .

10. Conclusions: An autoimmune mechanism against CA-II
(carbonic anhydrase II )or LF (lactoferrin), and Th1-type
immune response, may be involved in AIP.

11. 2010
no antigens/ nor specific autoantibodies
↑Th2 cytokines, IgE, IgG4,
↑ allergic rhinitis,↑bronchial asthma
? Pathogenesis/? epiphenomenon

13.  Asymptomatic/ Mass effect
 < 2 cm, non tender, rubbery
 Biopsies are problematic
storiform fibrosis↓
IgG4+ plasma cells: not specific

14.  Type I – Multicentric Castleman disease-like
 Type II – Follicular hyperplasia
 Type III – Interfollicular expansion
 Type IV – Progressive transformation of germinal
center-like
 Type V – Nodal inflammatory pseudotumor-like

15.  Sarcoidosis.
 Multicentric Castleman disease
 Infection (eg, tuberculosis).
 Lymphoma.
 Malignancy.

16.  Type 1.
 0.82 / 100,000 persons.
 Lymphoplasmacytic sclerosing pancreatitis.
 Pancreatic mass ( ).
 Painless obstructive jaundice.
 Acute/Recurrent/Chronic pancreatitis.
 Diabetes mellitus.

17.  ↑IgG4-positive plasma cells.
 CT: diffuse enlargement “sausage-shaped”
 Halo of edema surrounding the organ

18.  The most frequent extrapancreatic
manifestation
 DD: primary sclerosing cholangitis

21.  Parotid or submandibular: most common
 Lacrimal + parotid gland:
 Submandibular gland:
 Typical pathology
 DD:SS

22. 2010

23.  Orbital pseudotumors
 Orbital myositis→ proptosis
Dacryoadenitis Orbital pseudotumor

24. Involve infrarenal aorta and affect
the iliac arteries
Ureters → obstructive uropathy

25. Contrast material–enhanced computed tomography of the abdomen and
chest showing paraaortic masses in the retroperitoneum and
mediastinum

27.  Reidel’s thyroiditis.
 Hashimoto’s thyroiditis.
 Subclinical hypothyroidism.

28.  IgG4 thyroiditis (↑ males,↑↑ auto-antibodies)
 Non-IgG4 thyroiditis

29. Neck swelling and dysphagia. ↑ inflammatory parameters
Subclinical hypothyroidism . ↑↑↑thyroid autoantibodies
Thyroidectomy, Biosy: IgG4 RD

31.  ↑Tubulointerstitial nephritis/membranous nephropathy.
 Biopsy: Typical lesions.
 Nodular lesions (?? renal cell carcinoma ).
 Profoundly hypocomplementemic
(??SLE/Cryoglobulinemia).

32.  Skin: pseudolymphoma.
 Liver: autoimmune hepatitis, and hepatic inflammato
pseudotumor.
 Stomach: lymphoplasmacytic gastritis.
 Breast: inflammatory pseudotumors.
 CNS: hypophysitis , pachymeningitis
 Prostate: prostatitis.
 Ovary: IgG4-related disease of the ovary.
 Pericardium: constrictive pericarditis.

33.  Type 1 (IgG4-related) AIP
 Mikulicz disease (IgG4-related dacryoadenitis and sialadenitis)
 Sclerosing sialadenitis (Küttner’s tumor, IgG4-related submandibular gland disease)
 Inflammatory orbital pseudotumor (IgG4-related orbital pseudotumor)
 Chronic sclerosing dacryoadenitis (IgG4-related dacryoadenitis)
 A subset of patients with “idiopathic” retroperitoneal fibrosis (Ormond’s disease) and related
disorders (IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis)
 Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis)
 Riedel’s thyroiditis (IgG4-related thyroid disease)
 IgG4-related hypophysitis
 IgG4-related pachymeningitis

35.  Lymphoplasmacytic tissue infiltration (mainly
IgG4-positive plasma cells)
 Storiform fibrosis
 Obliterative phlebitis
 Eosinophilia

36. >135 mg/dL
Not specific:
 Multicentric Castleman’s disease
 Allergic disorders
 Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss)
 Sarcoidosis

37.  Better
 Not widely available
 Assess response to treatment and relapse.

38. Figure 5 Diagnostic algorithm for comprehensive diagnostic criteria for
IgG4-related disease combined with organ-specific criteria
Yamamoto, M. et al. (2013) Mechanisms and assessment of IgG4-related disease:
lessons for the rheumatologist
Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.183

39.  MRI,CT scan : chest, abdomen,pelvis
 Positron emission tomographic (PET)

40.  Urinalysis :proteinuria.
 Serum complement levels:↓ C3,C4.
 ↑ IgE , eosinophil count

42.  The optimal treatment has not been established.
 All patients with active IgG4-RD require treatment.
 Glucocorticoids are the first-line agent for induction.
 Certain patients benefit from maintenance therapy.
 Retreatment with glucocorticoids in relapse.
 Some but not all patients require the combination of glucocorticoi
and a steroid-sparing immunosuppressive agent from the start of
treatment

43.  40 mg prednisolone→ taper (2 months)
 Rituximab: (1 gram IV every 15 days for
a total of two doses)
 Azathioprine: (2 mg/kg/day)
 MMF:(up to 2.5 g/day)

45.  Not well-defined.
 Improvement without treatment.
 Morbidity and mortality:
• cirrhosis
• portal hypertension
• retroperitoneal fibrosis
• aortic aneurysmal dissection
• biliary obstruction
• diabetes mellitus
 Subacute constitutional symptoms marked by
fatigue and weight loss

46.  Debate ???
 Malignancy is associated with subsequent developm
of IgG4-RD.