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IgG4-related disease

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IgG4-related disease

Presented by Amornrat Prasertcharoensuk, MD.

January12, 2018

Published in: Health & Medicine
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IgG4-related disease

  1. 1. IgG4 Related disease Amornrat Prasertcharoensuk , MD.
  2. 2. • Epidemiology • Historical context • Diagnostic criteria • Pathogenesis • Clinical presentation • Treatment Outline
  3. 3. • In Japan, there is an estimated prevalence of 100 cases per 1 million, and an annual incidence of 1 per 100,000 . • The population between 50 and 70 years of age are more susceptible in developing this disease, with men being affected more than women (2.8:1) • The annual incidence rate of AIP patients was estimated as 1.4 per 100,000 people in Japan in 2011 (Kanno et al. 2015). Epidemiology Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
  4. 4. Clinical Presentation
  5. 5. 23% of 113 patients 62% of 21patients 2%of 129 patients 12 out 0f 53 patients 80% of AIPpatients 9% in 33 cases of non infectious aortitis 4 of 10 patients with inflammatory aortic 23(15%)of 153 patients Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
  6. 6. History of IgG4-related disease Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  7. 7. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  8. 8. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  9. 9. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-454
  10. 10. Clinical features Terumi Kamisawa, Yoh Zen, Shiv Pillai, John H Stone , thelancet,Vol 385 April 11, 2015 Dacryoadenitis Submandibular gland enlargement Submandibular gland enlargement Parotid disease, used to be called Mikulicz disease, the triad of parotid, lacrimal, and submandibular gland enlargement thickening of the bronchovascular bundle in the right lung as well as a posterior ground-glass infiltrate
  11. 11. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGYVol. 69, No. 9, September
  12. 12. Organ involvement Arshia Duza Islam, Autoimmunity Reviews 14 (2015) 914–922
  13. 13. Unrelated conditions encompassing a wide range of organs shared two characteristics : 1. elevations in serum IgG4 concentrations . 2. a set of unique histopathological features . Hallmark of histopathological : lymphoplasmacytic inflitrate : storiform fibrosis : obliterative phlebitis IgG4 Related disease Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
  14. 14. The storiform pattern of fibrosis depicted in this image from a patient with IgG4-RD showing dense fibrosis within which lymphocytes, plasma cells, and occasionally eosinophils are embeddedStoriform fibrosis: a histological pattern characterized by irregular, loosely arranged whorls on low-power light microscopy, akin to a straw blanket Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  15. 15. c) Eosinophilic angiocentric fibrosis involving the orbital soft tissue. The concentric perivascular fibrosis is a characteristic feature of this variant of IgG4-RD. (d ) a diffuse and dense lymphoplasmacytic infiltrate with only rare residual air spaces (asterisk). Numerous lymphoid aggregates are present. Note the obliterative phlebitis (arrowheads), which is typical of IgG4-RD Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  16. 16. highlights the B lymphAn immunoperoxidase stain for IgG4 (of the case shown in panel d ) shows a diffuse and marked increase in IgG4+ plasma cells, which is typical of IgG4-RD. ( f ) An elastin stain performed on an obliterated venous channel. ( g) An immunoperoxidase stain for CD3 shows that T cells are more diffusely distributed. (h) An immunoperoxidase stain for CD20 highlights the B lymphoid aggregates. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  17. 17. DIAGNOSTIC CRITERIA
  18. 18. Diagnosis Criteria Definitive Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dL Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cell Ratio of IgG4 +/IgG + plasma cells < 40% and >10 IgG4 + plasma cells per HPF Probable Diffuse or local swelling in single or multiple organs Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cells Ratio of IgG4 +/IgG + plasma cells <40% and >10 IgG4 + plasma cells per HPF Possible Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dl or >Twofold upper limit of normal Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
  19. 19. PATHOGENESIS
  20. 20. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  21. 21. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
  22. 22. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-
  23. 23. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  24. 24. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
  25. 25. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
  26. 26. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
  27. 27. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
  28. 28. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
  29. 29. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
  30. 30. • small subset –japan study in AIP • human leukocyte antigen (HLA) serotypes DRB1*0405 and DQB1*0401 have been shown to increase susceptibility of IgG4-RD in Japanese populations . • There exist additional non-HLA genes in which single-nucleotide polymorphisms (SNPs) are implicated in increased disease susceptibility and recurrence. Genetic Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL,2017
  31. 31. Organ involvement
  32. 32. • The enlargement of the lacrimal and salivary glands (IgG4-related dacryoadenitis and sialadenitis [IgG4-DS]) in this condition was found to be elastic, painless, and persistent (occurring for >3 months) • In contrast, in Sjogren’s syndrome , the enlargement of the parotid gland is predominant. • Complicating diagnosis IgG4 RD also frequently test positive for anti- SSA and/or anti SSB autoantibody . Organ involvement in the head and neck region Salivary glands Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
  33. 33. Lacrimal gland and orbit •22.5% of cases of orbital lymphoproliferative disorders . •involvement include the lacrimal glands, extraocular muscles, and orbital nerves (IgG4-related dacryoadenitis ) • neuroimaging studies difficult to evaluate whether the lesion is benign or malignant only via imaging, histopathological examination is essential , Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
  34. 34. Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
  35. 35. • IgG4-related thyroiditis reportedly includes Riedel’s thyroiditis (RT) ,Hashimoto’s thyroiditis (HT) and IgG4- related thyroiditis. • RT is now firmly considered as an IgG4-RD variant, and has long been known to be associated with systemic fibrosclerosing diseases, many of which are now included within the spectrum of IgG4-RD. • HT shows a partial overlap with IgG4-related thyroiditis . HT higher anti-thyroglobulin levels, anti-thyroid peroxisomal levels, and antibody titers; and diffuse low echogenicity on ultrasonography Thyroid Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
  36. 36. A – Bilateral enlargement of the parotid and submandibular glands Mikulicz’s disease. B- lacrimal gland disease C- Proptosis and exotropia orbital pseudotumor associated with IgG4-RD Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  37. 37. (d) Coronal computed tomographic image of the patient shown in panel c. In addition to his orbitalpseudotumor, he had left maxillary sinusitis (evidentin this image) and proteinuria caused by tubulointerstitial nephritis. For these reasons, he wassuspected to have granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) formany months. (e) IgG4-related thyroid disease, formerly termed Riedel’s thyroiditis. The thyroid gland has a hard, woody feel Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  38. 38. • IgG4-related hypophysitis of the anterior pituitary , Magnetic resona (MRI) findings show sellar enlargement and thickening of the pituitary stalk • IgG4-RD is one of the most common causes of hypertrophic pachymeningitis (HP), mass effect, nerve compression, or vascular compromise • A recent survey study in Japan showed that among 159 patients with HP, antineutrophil cytoplasmic antibody (ANCA)-related HP was the most frequent form (34%), followed by IgG4-related HP (9%) Pituitary gland and dura mater Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
  39. 39. (a) Magnetic resonance imaging study demonstrating a large mass in the left maxillary sinus that enhances with gadolinium. (b) Magnetic resonance imaging study of the brain showing enlargement and enhancement of the pituitary gland and its stalk Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  40. 40. • Lung : inflammatory pseudotumor, central airway disease, localized or diffuse interstitial pneumonia, and pleuritis . • radiologic manifestations, which include: (a) solid nodular lesions, sometimes with spiculations; (b) round-shaped, ground-glass opacities; (c) alveolar interstitial disease, with honeycombing, bronchiectasis, and diffuse ground-glass opacities; and (d ) thickening of the bronchovascular bundle. • Pleura and pericardium :severe, nodular thickening of the visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural effusion CHEST Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  41. 41. (c) bronchovascular bundle lesion in IgG4-RD involving the lung. IgG4-RD has a predilection for the bronchovascular bundle regions within this organ. hard, pearly nodules adjacent to the large airways. (d ) Histopathology of IgG4-RD involving the bronchovascular bundle within the lung Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  42. 42. (E) Computed tomographic angiogram demonstrating a dissection of the aortic arch. Examination of the resected aorta revealed IgG4-related aortitis. (F) Lymphoplasmacytic aortitis. Shown is a section of the resected aorta stained with hematoxylin and eosin and visualized at 25× magnification. Black arrowheads indicate lymphoid aggregates in the adventitia. Yellow arrowheads indicate plasma cell infiltrates in the media. The dashed line indicates the intima–media boundary Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  43. 43. • Pancreas. type 1 (IgG4- related) AIP include mild abdominal pain; weight loss; and acute, obstructive jaundice (known as painless jaundice). • The sensitivity of igG4 levels in diagnosis AIP range from 50-92%. • Required imaging(MRCP,ERCP,CT,MRI) and histopathology for diagnostic . • diffusely enlarged pancreas, the so-called “sausage-shaped pancreas,” or with a focal mass, have a hypodense rim. • The pancreatic duct is characterized by caliber irregularities, followed by a length of narrowing without distal dilation . ABDOMEN Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
  44. 44. • Biliary tract. IgG4-related sclerosing cholangitis considered to have primary sclerosing cholangitis and who respond well to glucocorticoids. • IgG4- SC is characterized on ERCP, MRCP, CT, and/or endoscopic ultrasound (US) with concentric mural thickening and segmental or long ductal narrowing and possible pre stenotic dilation with delayed contrast enhancing uptake • Type 1 Isolated distal stenosis of the common hepatic duct. Type 2 Diffuse stenosis. Type 3 Hilar and distal common hepatic duct stenosis. Type 4 Isolated hilar common hepatic duct stenosis ABDOMEN Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
  45. 45. (g)Type 1 (IgG4-related) autoimmune pancreatitis. Computed tomography scan of the abdomen revealing diffuse pancreatic enlargement, with loss of normal lobularity. (h) Retroperitoneal fibrosis Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
  46. 46. Kidney Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Common :tubulointerstitial nephritis and membranous glomerulonephritis (negative for phospholipase –A2 receptor ) Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017 Delay steroid – result severe fibrosis and atrophy of kidneys
  47. 47. IgG4-related lymphadenopathy Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017 • modestly enlarged non-tender nodes, absence of constitutional symptoms, and distinct histology fndings on biopsy Five characteristic patterns are seen on histology, all of which feature an abundance of IgG4 positive cells with eosinophilic infltration : Type 1 Multi-centric Castleman disease-like. Type 2 Follicular hyperplasia. Type 3 Interfollicular expansion. Type 4 Progressive transformation of germinal centerlike. Type 5 Nodal infammatory pseudotumor-like
  48. 48. Differential Diagnostic
  49. 49. Diagnosis Criteria Definitive Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dL Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cell Ratio of IgG4 +/IgG + plasma cells < 40% and >10 IgG4 + plasma cells per HPF Probable Diffuse or local swelling in single or multiple organs Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cells Ratio of IgG4 +/IgG + plasma cells <40% and >10 IgG4 + plasma cells per HPF Possible Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dl or >Twofold upper limit of normal Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
  50. 50. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 261
  51. 51. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 261 - 278
  52. 52. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 2
  53. 53. Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
  54. 54. Zhang et al, Medicine ,Volume 94, Number 2, January 2015
  55. 55. Zhang et al, Medicine ,Volume 94, Number 2, January 2015
  56. 56. • elevated serum IgG4 levels (to greater than 135 mg/dl) were reported in 84 % (1586/1883) of patients with IgG4-RD, and the mean serum IgG4 level was 769 mg/dl (Stone et al. 2015). • elevation of serum IgG4 levels is not restricted to IgG4-RD and is also seen in other conditions such as autoimmune disease, allergic conditions, carcinoma, and Castleman’s disease. • elevated serum IgG4 levels by themselves have a low specificity (60 %) and a low positive predictive value (34 %) for the diagnosis of IgG4-RD (Carruthers et al. 2015a). IgG4RD cannot be diagnosed solely on the basis of serum IgG4 levels Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  57. 57. Cutoff value of infiltrated IgG4-positive plasma cells is more than 10 cells per HPF, but the cutoff value varies according to the specific tissue. Measurement of the IgG4-positive cell/total IgG-positive cell ratio, in which a minimum ratio of 40 % is usually used, may also be useful, especially in cases in which fibrosis is predominant. Although findings of storiform fibrosis and obliterative phlebitis enhance diagnostic specificity, clinicopathological correlation is always essential (Deshpande et al. 2012) Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  58. 58. L. Vasaitis / European Journal of Internal Medicine 27 (2016) 1–
  59. 59. TREATMENT
  60. 60. STEROID Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
  61. 61. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-45
  62. 62. EMERGING TREATMENT MODELS IN RHEUMATOLOGY , ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
  63. 63. ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 7, July 2015,
  64. 64. ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 7, July 20
  65. 65. PROGNOSIS 115 patients with either AIP or IgG4-SC were evaluated, with 50% of patients experiencing relapse, and 11% of patients developing malignancy. (Hugget et al.) Indeed, the risk is signifcantly elevated for compared to the general population (odds ratio = 2.25, P = 0.02) Cancers among 15 out of 108 patients with IgG4-related AIP (14%), with a relative risk of 4.9 (Shiokawa et al) increased risk of non-Hodgkin’s lymphoma (NHL) for patients with IgG4-RD, with a standardized incidence rate as high as 16 (Takahasi et al ) Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17

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