For postgraduates and consultants in Internal Medicine, Rheumatology and immunology

1. A Spotlight on
IgG4-related disease
BY
Prof. Dr/ AbdelAzeim M Elhefny
Prof. of Internal Medicine, Rheumatology & Immunology
Ain Shams University

2. Chief Complaint
January 2010
 Mr. G H is a 55 year old male who presents with
nonspecific complaints, particularly fatigue, led him to
visit his primary care doctor.
 A serum creatinine of 3.5 mg/dL was identified by
routine laboratory testing.
 This new-onset renal insufficiency was accompanied by
severe proteinuria (urine protein:creatinine ratio of 9).

3. Past Medical History:
 The patient had a medical history of pancreatitis and
type II diabetes mellitus but was otherwise well

4. Additional History
 A renal biopsy revealed interstitial nephritis (see Figure 1).
 It was observed simultaneously that the patient had
symptoms of xerostomia, and physical examination then
confirmed both parotid and submandibular gland
enlargement (see Figure 2).
 The presumptive diagnosis of Sjögren`s syndrome (SS)
complicated by interstitial nephritis was rendered.
 Following a short course of prednisone, the patient’s renal
function returned to normal.
Emine Atac et al., The Rheumatologist, January 2013

5. A: Kidney showing a lymphoplasmacytic
infiltrate in the renal interstitium. There is
also a moderate number of eosinophils
B: Collagen stain (blue) demonstrating fibrosis
within the renal interstitium.
The fibrosis has a storiform pattern.
Figure 1: Tubulointerstitial nephritis

6. Figure 2: Salivary gland enlargement.
Enlargement in the tail of the left
parotid gland
Enlargement of the right
submandibular gland.

7.  The patient developed pruritus and jaundice.
 His serum bilirubin was 7.9 mg/dL (direct 5.1 mg/dL).
 Other liver function tests are shown in Table 1.
 An ERCP showed a mildly dilated distal common bile duct but
otherwise normal intra- and extrahepatic biliary systems.
 A liver biopsy revealed only nonspecific findings.
 The cholestasis was attributed to severe papillary stenosis.
 His cholestasis resolved following papillary sphincterotomy
and the placement of pancreatic stents, which were later
removed.
Six months later, in (July 2010)

8.  The patient was noted to have diffuse lymphadenopathy,
anemia, and an elevated ESR, raising the possibility of a
lymphproliferative disorder.
 However, a biopsy of an enlarged right axillary lymph node
was interpreted as “reactive hyperplasia,” with follicular
hyperplasia and reactive plasmacytosis.
 A bone marrow biopsy showed normal hematopoiesis, and
there was no evidence of lymphomatous infiltration,
myeloma, or intrinsic marrow pathology.
Two months later, in (September 2010)

9. After two years, in January 2012
 The patient suffered from recurrent submandibular
gland enlargement led to an excisional biopsy.
 This revealed a Küttner’s tumor (see Figure 3).

10. Figure 3: Histopathology of the
submandibular gland.
IgG4-positive plasma cells
stain brown.
Lymphoplasmacytic infiltrate
with germinal center.

11. Laboratory Findings

12. Summary of the pt. data
 Our patient had a multiorgan system disease of at least
two years’ duration characterized by:-
 tubulointerstitial nephritis,
 salivary gland enlargement,
 jaundice,
 diffuse lymphadenopathy, and
 an elevated ESR.
 In addition, it is likely that his pancreatitis, which led to
glucose intolerance, was in fact IgG4-related (type 1)
autoimmune pancreatitis.
 He was misdiagnosed with a number of other conditions
before the correct diagnosis of IgG4-RD was recognized.

13. The Diagnostic Test
 The diagnosis was made following a careful review of
the submandibular gland biopsy.
 It revealed a gland largely replaced by a
lymphoplasmacytic infiltrate: reactive lymphoid follicles
surrounded by small lymphocytes and plasma cells (see
Figure 3A).
 In addition, there was striking storiform fibrosis (see
Figure 3B), obliterative phlebitis, and scattered
eosinophils.
 Immunostaining of the tissue for IgG4 and IgG
demonstrated more than 100 IgG4-positive plasma cells
per high-power field and an IgG4:total IgG ratio of 0.92.
 This biopsy was diagnostic of the case.

14. Which diagnosis can explain this
patient’s multisystem condition?
 Immunoglobulin G4–related disease (IgG4-RD).

15. Follow-up
 Because of his glucose intolerance and the extensive
nature of his disease, we treated our patient with
rituximab 1 gram intravenously given on two separate
occasions.
 Within one month of his first dose, his parotid gland
swelling had resolved, and his serum IgG4 concentration
had declined by more than 600 mg/dL.

16.  IgG4-related disease (IgG4-RD) is an under recognized,
multiorgan fibro-inflammatory condition of unknown
aetiology that is defined by its unique histopathological
features, that are fairly similar regardless of the
affected organ.
 Patients with IgG4-RD also share certain clinical
features: a tendency for formation of mass lesion(s),
frequent elevations in their serum IgG4 concentration,
as well as an excellent response to glucocorticoid
treatment.
http://dx.doi.org/10.1016/j.mpdhp.2013.01.004
What Is IgG4-RD?

17. Is This a New Disease?
 No. Scrutiny and reinterpretation of the medical literature
in light of the emerging knowledge of this newly
recognized disorder indicates that IgG4-RD has been
known by other names, generally while being regarded as
an entity isolated to an individual organ system.
 A disorder termed “multisystemic fibrosclerosis” in the
1960s probably represents—in most cases—IgG4-RD.
 The following Table displays a list of previously recognized
conditions known by other names that comprise (or may
comprise) parts of the IgG4-RD spectrum.

18. BRIEF OVERVIEW OF IgG4-RD
 First case described in 1961 – Autoimmune pancreatitis
(Sarles et al.)
 In 2001, Hamano et al demonstrated that the serum level of
IgG4 was significantly elevated in patients with sclerosing
pancreatitis (now called type 1 AIP).
 In 2003, (Kamisawa et al.) reported the presence of
numerous IgG4-positive plasma cell infiltrates in both the
pancreatic and extrapancreatic lesions of type 1 AIP and
proposed a new clinicopathological entity: IgG4-related
systemic disease.

19. The
1

20. The
2

21. Common Clinical Manifestations
 IgG4-RD has now been described in virtually every
organ system: the biliary tree, salivary glands,
periorbital tissues, kidneys, lungs, lymph nodes,
meninges, aorta, breast, prostate, thyroid,
pericardium, and skin.
 A list of the common clinical manifestations in a broad
variety of organ systems is shown in Table 3.
 The histopathologic features of this disease bear
striking similarities across organs, regardless of the site
of involvement.1
 IgG4-RD is therefore analogous to sarcoidosis, another
systemic disease in which diverse organ manifestations
are linked by unique histopathology.

25. Systemic organ involvement in IgG4-related disease
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

26.  Panel A shows bilateral
enlargement of the
submandibular glands in a
45-year-old woman. Her
serum IgG4 concentration
was 240 mg per deciliter
(normal level, <121).

27.  Panel B shows bilateral
enlargement of the parotid gland
in a 54-year-old man, who also had
asthma, marked enlargement of
the extraocular muscles, swelling
of the left fifth cranial nerve, and
abnormal soft tissue extending
from his left orbit through the left
greater palatine foramen into the
pterygomaxillary cistern, causing
proptosis. His serum IgG4
concentration was 1560 mg per
deciliter.

28.  Panel C shows proptosis of the left
eye, caused by enlargement of the
lacrimal gland, in a 62-year-old
man. His serum IgG4 concentration
was 30 mg per deciliter, indicating
that patients can have classic
histopathological and
immunohistochemical features of
IgG4-related disease within tissue
yet have normal serum IgG values.

29.  Panel D shows a computed
tomographic scan of a diffusely
enlarged pancreas and an irregular,
low-attenuation area (arrow) in
the left kidney.
 These radiologic findings
correspond to autoimmune
pancreatitis and tubulointerstitial
nephritis, with histopathological
and immunohistochemical-staining
features of IgG4-related disease.

30. Pathological Features
of IgG4-Related Disease
 Histopathological analysis of biopsy specimens remains the
cornerstone in the diagnosis.
 Elevated concentrations of IgG4 in tissue and serum are
helpful in diagnosing IgG4-RD, but neither one is a specific
diagnostic marker.
 Correlation with specific histopathological findings is
essential, regardless of the serum IgG4 concentration, the
number of IgG4-positive plasma cells in tissue, or the ratio
of IgG4 to IgG in tissue.
J Clin Pathol 2011;64:237-43.
Curr Opin Rheumatol 2011;23:108-13.

31.  The key morphologic features of IgG4-related disease are:
 a dense lymphoplasmacytic infiltrate that is organized in a
storiform (i.e., matted and irregularly whorled) pattern,
 obliterative phlebitis,
 a mild-to-moderate eosinophil infiltrate.
 The inflammatory lesion frequently forms a tumefactive
mass that may destroy the involved organ.
Pathological Features
of IgG4-Related Disease
Zen Y, Nakanuma Y. Am J Surg Pathol 2010;34:1812-9.

32. brisk intra-
pancreatic periductal
inflammation associated
with fibrosis &
thickening of the wall.

33. The pattern is often
likened to a
cartwheel,
The bands of fibrosis
(arrowheads)
emanating from the
center (asterisk)
representing the
spokes of the wheel.

34. Obliterative
phlebitis
(arrows).
a dense
lymphoplasmacytic
infiltrate

35. lymphocytes,
plasma cells (long
arrow),
eosinophils
(arrowhead)
fibroblasts (short
arrow).

36. IgG4-positive
plasma cells
(arrows)

37. Is Elevated Serum IgG4 Concentration
Diagnostic of IgG4-RD?
 No, many other conditions can be associated with
elevations in the serum IgG4 concentration.
 However, the higher the concentration of IgG4 in the
blood, the greater the suspicion for IgG4-RD,
particularly if the patient’s clinical manifestations are
consistent with this disorder.
 Our patient’s serum IgG4 concentration was 2,020
mg/dL (normal<121 mg/dL).
 <20% of those who have not been treated—have normal
serum IgG4 concentrations in the setting of diagnostic
histopathology and immunostaining findings .

38. Are Radiologic Examinations Specific for
IgG4-RD?
 Radiologic findings in IgG4-RD may mimic malignancies
in their presentation as pseudotumors.
 This fact usually makes histopathological confirmation
of the diagnosis essential.
 In the proper clinical setting, the finding of a diffusely
enlarged, “sausage-shaped” pancreas with
peripancreatic stranding is sometimes sufficient for the
diagnosis of type 1 autoimmune (IgG4-related)
pancreatitis.

39. DIAGNOSIS

40. A typical case with IgG4-related disease exemplifying key
diagnostic features
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

41. Diagnostic algorithm for comprehensive diagnostic criteria for IgG4-RD
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

42. Deferential Diagnosis
The disease tends to cause mass-forming lesions that can
mimic cancer, infections, and rheumatic conditions such
as granulomatosis with polyangiitis (Wegener’s) and SS.
 Malignant tumors
 Granulomatous vasculitis
 Sarcoidisis
 Sjogren
 Thyroid diseases
 Pancreatic disorders
 Other causes of retroperitoneal fibrosis

43. What Is the Treatment for IgG4-RD?
 Glucocorticoids are the first-line treatment for IgG4-RD.
 Many cases require aggressive and immediate treatment to
prevent organ dysfunction and failure.
 IgG4-related lymphadenopathy may remain indolent and
relatively asymptomatic for years.
 Therefore, the treatment regimens must be individualized for
each patient.
 Initially prednisolone dose of 0.6 mg/kgm /day for 2-4 weeks
and then to taper the steroids over 3-6 months.
 Agents such as AZA, MMF, and MTX have been employed as
potential glucocorticoid-sparing agents or remission–
maintenance drugs, but their true efficacy in these roles is
unclear. Cheuk W, Yuen HK, Chu SY, et al. Am J Surg Pathol. 2008;32:671-68

44. Rituximab may represent a promising
approach to treatmen
B-cell depletion with rituximab may represent a promising
approach to treatment.
 For patients with IgG4-RD that is refractory to
glucocorticoids,
 Patients that are unable to taper below a desired dose,
 Patients with recurrent IgG4-RD,
 Patients demonstrated prompt clinical and serological
responses, with the ability to taper glucocorticoids rapidly
and a swift decline in serum IgG4 concentrations.
 Leaving the concentrations of IgG1, IgG2, and IgG3
(stable). through interference with the repletion of short-
lived plasma cells that are producing IgG4 .
Khosroshahi A, Carruthers MN, et al. Medicine (Baltimore).2012;

45. Algorithm informing treatment decisions in patients
with IgG4-related disease
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
A

47. Diagnostic guidelines for IgG4-related disease in Japanese populations
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

48. References
 Deshpande, V. et al. Subclassification of Autoimmune pancreatitis: a
histologic classification with clinical significance. Am. J. Surg. Pathol. 35, 26–
35 (2011).
 Zen, Y. & Nakanuma, Y. IgG4-related disease: a cross-sectional study of 114
cases. Am. J. Surg. Pathol. 34, 1812–1819 (2010).
 Chiba, K. et al. Clinical features of 10 patients with IgG4-related
retroperitoneal fibrosis.Intern. Med. 52, 1545–1551 (2013).
 Matsui, S. et al. Immunoglogulin G4-related lung disease: clinicoradiological
and pathological features. Respirology 18, 480–487 (2013).
 Watanabe, T. et al. Clinical features of a new disease concept, IgG4-related
thyroiditis.Scand. J. Rheumatol. 42, 325–330 (2013).

49. REFERENCES
 1. Plaza JA, Garrity JA, Dogan A, Ananthamurthy A, Witzig TE, Salomao DR.Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4
systemic disease. Arch Ophthalmol 2011;129:421-8.
 2. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg
Pathol 2011;35:701-6.
 3. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol 2011;23:95-101.
 4. Lindstrom KM, Cousar JB, Lopes MB. IgG4-related meningeal disease: clinicopathological features and proposal for diagnostic criteria. Acta Neuropathol
2010;120:765-76.
 5. Leporati P, Landek-Salgado MA, Lupi I, Chiovato L, Caturegli P. IgG4-related yypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol
Metab 2011;96:1971-80.
 6. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol
Int 2010;60:247-58.
 7. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic
disease spectrum. Arthritis Care Res (Hoboken) 2010;62:1312-8.
 8. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology 2009;251:260-70.
 9. Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol 2011;23:88-94.
 10. Sah RP, Chari ST, Pannala R, et al. Differences in clinical profile and relapse rate of type 1 versus type 2 autoimmune pancreatitis. Gastroenterology
2010;139:140- 8.
 11. Saeki T, Nishi S, Imai N, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int 2010;78:1016-23.
 12. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J Med 2006;355:2670-6.
 13. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis