IgG lecture ( autoimmune pancreatitis ) (2).pptx

Comprehensive lecture about IgG4 disease

1. 1

2. From AIP to IgG4-Related disease: The story as a whole not through a hole BY PROF DR Abdel Rahman Abdel Hai Moukhtar Internal Medicine @ Mansoura University Consultant Internist @ NWAFH – Tabuk - KSA 2022

3. AGENDA 1- Historical progress . 2- Definition and spectrum of IgG4-Related disease. 3- Pathogenesis. 4- Clinical picture & epidemiologic features. 5- Diagnostic Criteria and guidelines. 6- Principles of treatment. 3

4. The establishment of IgG4-RD was based on the culmination of specific discoveries 4

5. 5 Definition (IgG4-RD) is an increasingly recognized Immune-mediated * chronic relapsing–remitting * fibro-inflammatory * infiltrative condition Tumefactive : the inflammatory cells typically results in tumor-like masses in many affected organs, such as salivary and lacrimal glands , the pancreas and the kidneys. The infiltrating cells include : CD4+cytotoxic T lymphocytes **IgG4-secreting plasma cells , ** M2 macrophages , **activated B cells and fibroblasts .

6. 6 Autoimmune pancreatitis The Umbrella of the disease

7. And the list is still growing 7 What is common?

8. 8 Serum IgG4 levels were initially thought to be a key diagnostic feature of IgG4-RD, but recent evidence has de-emphasized the value of elevated serum IgG4 levels . Several major points should be drawn from contrasting studies First , elevated serumIgG4 levels by themselves have a low specificity (60%) and a low positive predictive value (34%) for the diagnosis of IgG4-RD . Second, a large proportion of patients with biopsy-proven , clinically validated IgG4-RDhave normal serum IgG4 levels, even before beginning treatment . Therefore , reliance on serum IgG4 concentration elevation for diagnosis will certainly lead to substantial under diagnosis. Mayo Clin Proc. July 2015;90(7): 927-939 ?

9. 9 Infiltration by IgG4+cells Multiple clinical entities can be associated with elevated numbers of IgG4 positive plasma cells in tissue. Yet, these conditions lack the characteristic histopathological features of IgG4-RD . ?

10. 10

11. 11

12. 12 So, what ever your subspecialty you should be aware , and should keep a high index of suspicion. STORIFORM From the Latin for ‘woven mat ’, الحصيره

13. 13 Pathophysiology The Big Debate

14. IgG4 related diseases ????? Autoimmune disease ?????Allergic disease ???? Infective disease IgG4 antibody is a true cause of IgG4-RD or an epiphenomenon

15. Potential Triggers Specific Disease Pathways Cellular response

16. 16 Potential Triggers

17. 17 Th2-cell responses are predominantly activated at affected sites in contrast to classic autoimmune conditions so , release (IL 4 ,5,10,13, TGFB ). Eosinophilia & high serum IgE levels, both observed in approximately 40% of patients with IgG4-related disease, are also mediated by Th2 Cytokines mimicking allergic disease. Activation of regulatory T ( Treg ) cells. In contrast to classic autoimmune conditions, in which the function of Treg cells is impaired.

18. Plasma cells (IgG4 + ve ) T cells more Tumefactive enlargement of organs or sites It is unclear whether these organ dysfucntion are due to immune complex–mediated tissue damage or are a bystander phenomenon V/S Malignancy: B cell Lymphoma So, not all IgG4 looses specificity

19. Legal Debate about IgG4 IgG4 what’s wrong ?

20. IgG4 what is wrong ?

21. Immunoglobulins ( Ig ) are divided in isotypes : nine in humans (IgG1, IgG2, IgG3, IgG4, IgM , IgA1, IgA2, IgD , IgE ) Each isotype displays distinct structural and effector properties

22. 22 Antibodies of the IgG class exert two major effector functions: activation of complement and opsonisation (i.e. the induction of phagocytosis). These functions, mediated via the (constant) Fc fragment are induced as a result of interaction of the antibody with its antigen via the (variable) Fab moiety Fragment, antigen binding. Fragment, antigen binding

23. (Fragment, antigen binding) Most IgG subclasses are symmetric and contain two identical antigen-binding sites . These antibodies are therefore monospecific (i.e. can bind to one particular epitope). IgG4 once they are secreted they engage in a unique process called : Fab -arm exchange so they become bispecific (Van der Neut Kolfschoten et al, 2007).

24. 24 Fab -arm exchange

25. The Unique IgG4 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 All the 3 criteria confers anti-inflammatory properties

26. 26 Message to the Clinicians

27. Diagnostic Challenge ? 27 1 2 3 4

28. Real case presentation. Insidious course. Constitutional Symptoms. Organ specific symptoms. Complications. 28 Clinical Picture

29. 29 R eal case presentation.

30. 30 Insidious course .

31. Acute, fulminant or highly inflammatory clinical presentations DO NOT occur in IgG4- RD. In contrast to the rapidly progressive glomerulonephritis seen in ( ANCA)- associated vasculitis for example. IgG4- RD evolves insidiously, does not cause fever and seldom leads swiftly to organ failure. Moreover, many features of disease are detected only incidentally by imaging (such as retroperitoneal fibrosis) or by surgical pathology (such as IgG4- related aortitis ). 31

32. The slowly evolving nature of IgG4- RD is one of its characteristic features: The long latency period preceding clinical detection probably accounts for the fact that ~60% of all patients with IgG4- RD have some degree of irreversible organ dysfunction owing to damage at the time of diagnosis . The damage brought by the insidious nature of IgG4- RD is typified by the complications associated with IgG4- related autoimmune pancreatitis, which include diabetes mellitus and exocrine pancreatic insufficiency. The dramatic weight loss that many patients with IgG4- RD experience before their diagnosis is often attributable to exocrine pancreatic insufficiency and the consequent inability to digest and absorb nutrients , rather than to the constitutional effects of systemic inflammation . Pancreatic failure often occurs in these patients before the underlying diagnosis can be established. 32

33. 33 Constitutional Symptoms :

34. 34 X A minority of patients—probably fewer than 10%— have weight loss, fevers, dramatic elevations of acute phase reactants , and other manifestations of systemic inflammation . PM09CH14-Stone ARI 24 September 2013

35. 35 ORGAN specific SYMPTOMS

36. 36

37. 37 Gastroenterologists: Are more likely to encounter patients with jaundice, pruritus , and mild abdominal discomfort followed by or preceded by relatively recent onset diabetes. Ophthalmologists: Are more likely to see lacrimal gland swelling or other orbital lesions . Nephrologists : May see renal dysfunction caused by tubulointerstitial nephritis or, rarely, nephrotic range proteinuria associated with IgG4-related membranous glomerulonephropathy (GN ) , or obstructive uropathy from retroperitoneal fibrosis involving the ureters. Rheumatologists: Are perhaps most likely to encounter patients with major salivary gland enlargement because this disease feature often raises the spectrum of Jorgens syndrome, these specialists may also be consulted in the setting of multiorgan disease . Pulmonologist : Pseudotumours , interstitial lung disease , honey comb lung , mediastinal fibrosis , pleural involvement and LN affection.

38. 38 Complications:

39. 39

40. The prevalence is EXACTLY unknown . 40 Epidemiology

41. Epidemiology 41 In JAPAN : The prevalence of the disease has been reported to be approximately 0.28 to 1.08 per 100,000 of population but this estimate is now dated and almost certainly constitutes a substantial underestimate of the true disease prevalence . Increasing recognition of this entity and development of worldwide accepted criteria for IgG4-RD will enable more precise epidemiologic studies. In USA: According to Dr Jhon Stone from Massaschusetts General Hospital

42. 42

43. EPIDEMIOLOGY 43 S EX distribution : generally have a slight predominance of middle-aged and older men. The predilection for older men is certainly true for conditions such as type 1 (IgG4-related ) autoimmune pancreatitis (AIP), retroperitoneal fibrosis, IgG4-related tubulointerstitial nephritis(TIN), and many other organ manifestations. However , the sex distribution differs some what with regard to patients with involvement of the head and neck. In a prospective study of 403 IgG4-RDpatients, sialadenitis and dacryoadenitis, as well as thyroiditis, were more common in women. AGE distribution : The disease is also increasingly recognized to occur in children. In the IgG4-RD described in the pediatric population, general disease characteristics appear to be similar to those observed in the IgG4-RD of the adults. However , eye manifestations, expressed mainly as orbital mass and , to a lesser extent, as dacryoadenitis . are thought to be more common .

44. 44 DIAGNOSIS

45. Orwah M. Al- Khalili , MD & Alan R. Erickson Missouri Medicine | May/June 2018 Diagnosis

46. 46 Mayo Clin Proc. July 2015;90(7):927-939

47. 47 A diagnosis of IgG4-RD relies on a number of factors taken in combination, including; Clinical presentation Serum IgG4 levels Imaging studies Biopsy evidence Response to treatment, including corticosteroids Clinicians can use one of the following criteria to see if a patient may have a diagnosis of IgG4-RD 1. HISORt Criteria for autoimmune pancreatitis 2. Japanese CDC for systemic disease 3. Boston Histopathological Criteria

48. 48

49. 49

50. 50

51. A DECADE AFTER 51 The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD : The Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD

52. 52 The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease .

53. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. According to the researchers: The objective of this study was to develop and validate an international set of classification criteria for IgG4-RD using data from all 4 domains of evidence . Specificity was a key aim : 53

54. المرحله الأولى مرحلة الاشتباه ( Entery Criteria ) 54 Such involvement can be based on clinical or radiographic assessment, or pathologic evidence of an inflammatory process accompanied by a lympho plasmacytic infiltrate of uncertain etiology in one of these organs.

55. ( Exclusion Criteria) المرحله الثانيه مرحلة الاستبعاد 55 ) If case meets entry criteria and does not meet any exclusion criteria, proceed to step 3.

56. المرحله الثالثه مرحلة الاعتماد (Total Inclusion score ) 56 A case meets the classification criteria for IgG4-RD if the entry criteria are met, no exclusion criteria are present, and the total inclusion points is ≥20.

57. 57 The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD : The Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD

58. 58

59. 59 3

60. The authors added : Although immunostaining of IgG4 and IgG is important for diagnose of IgG4-RD, there are no standard for antibodies or staining procedure for IgG4 immunostaining. Therefore ,it is often difficult to evaluate IgG4-positive and IgG positive cells due to the background staining, especially in minute samples . On the other hand, storiform fibrosis and obliterative phlebitis are reported to be unique and characteristic feature for IgG4-RD in addition to lymphoplasmacytic infiltration . Therefore , storiform fibrosis and obliterative phlebitis observed in hematoxylin and eosin staining are helpful for diagnosis of IgG4-RD, especially in the case with poor IgG and/or IgG4 staining. 60

61. The 2019 classification criteria for IgG4-related disease A Note For the clinician The Classification Criteria were developed only for patients with frequently involved 10 organs (e.g. pancreas, bile ducts, orbits, lacrimal glands, major salivary glands, retroperitoneum , kidney, aorta, pachymeninges , thyroid gland), and excluded organs that were not frequently affected (prostate, meninges and skin, etc .) to maximize the specificity. Exclusion criteria include specific autoantibodies such as anti-dsDNA , anti-SSA/Ro or SSB/La antibody and MPO- or PR3-ANCA . Thereby, patients with some autoantibodies were excluded prior to analysis of IgG4-RD, even though they are not accurate autoimmune diseases. 61 MODERN RHEUMATOLOGY 2021, VOL. 31, NO. 3, 529–533 https://doi.org/10.1080/14397595.2020.1859710

62. The overall purpose of classification criteria is to maximize the specificity of classification, even if sensitivity is not good . However, physicians must diagnose exactly and treat all patients in actual clinical practice . Therefore, it is important to understand the general features of IgG4-RD such as organ involvement, clinical symptoms, radiological abnormalities, laboratory data and pathological characteristics, and to diagnose patients carefully using either of the criteria. In addition, the RCD criteria should be validated for sensitivity and specificity in future study. 62 MODERN RHEUMATOLOGY 2021, VOL. 31, NO. 3, 529–533 https://doi.org/10.1080/14397595.2020.1859710

63. Treatment Lines of treatment Response Index 63

64. 64

65. 65

66. To Conclude : First identi fi ed in the initial years of the 21st century as a uni fi ed disorder , IgG4-related disease (IgG4-RD) is a multiorgan entity that integrates numerous conditions formerly considered unrelated, single-organ diseases . Serum IgG4 levels were initially thought to be a key diagnostic feature of IgG4-RD, but recent evidence has de-emphasized the value of elevated serum IgG4 levels . The key to diagnosis is immunohistochemical demonstration of tissue in fi ltration by IgG4-bearing plasma cells and morphological evidence of lymphoplasmacytic in fi ltrates, storiform fi brosis, and obliterative phlebitis .

67. 67 Although the heterogeneous clinical, laboratory, and histological presentation affecting a wide range of organ systems means that the diagnostic approach may be complex, IgG4-RD should be clinically suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissues . The more clinical, laboratory, imaging, and pathological red fl ags the patient presents, the greater the likelihood of a diagnosis of IgG4-RD . New research suggests a promising role of fl ow cytometry analysis in the diagnosis and longitudinal management of IgG4-RD .

68. 68

69. 69 Thank You