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IgG4 related disease (IgG4-RD) Characteristics

General

1. Characterized by elevated tissue levels of IgG4-positive plasma cells
2. "newly recognized fibroinflammatory condition" (Stone 2012) first identified in 2003 characterized by:
   1. Tumefactive lesions (most commonly involving the salivary glands and orbit but has been reported in nearly every organ system)
   2. Dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells
   3. Storioform fibrosis
   4. Often, but not always, elevated serum IgG4 concentrations 
3. Can present in almost every organ system
4. Presents subacutely and most are not constitutionally ill
5. Multi-organ involvement can be demonstrated initially or evolve over months to years
6. Analogous to Sarcoidosis: "systemic disease in which diverse organ manifestations are linked by the same histopathological considerations" (Stone 2012)
7. Spectrum of IgG4-related disease with terms replaced by IgG4-RD
   1. Mickulicz's disease
   2. Kuttner's tumor
   3. Riedel's thyroiditis 
8. Epidemiology
   1. Poorly described to date
   2. Unlike other autoimmune disorders, the majority are male and older than 50 years (Frulloni 2009) 

IgG4-related lymphadenopathy

1. Lymph node involvement is frequent in IgG4-RD
2. Require ratio >40% of IgG4-positive to IgG total plasma cells in lymph node  biopsy to help support the diagnosis (Wong and Morton 2016)

Diagnosis

• Requires integration of clinical, serologic, radiological and histopathologic features; none of these findings, in isolation, are sufficient to clinically diagnose IgG4-RD (Wallace 2020)

Differential diagnosis: 

1. Differential diagnosis for salivary gland enlargement: lymphoma, lymphoproliferative disorders, other malignancy, salivary duct obstruction, infection, other immune-mediated conditions including Sjögren's syndrome
2. Differential diagnosis for presence of IgG4-positive plasma cell infiltrates: malignancy, pemphigus vulgaris, thrombocytopenic purpura, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and multicentric Castleman’s disease (Stone 2012; Khosroshahi 2015)

Radiographic imaging 

1. Ultrasound imaging:

• Li et al (Li 2016) Identified value in ultrasonography in the management of IgG4-related sialadenitis not only to characterize the disease process pre-treatment, but also to follow-up with evluation of treatment impact.
  • These investigators identified 42 patients with clinical and pathologic findings supportive of IgG4RD affecting the salivary glands.  35 reported submanidibular enlargement with 8 presenting with parotid enlargement - with no complaints of swelling with eating - and duration of swelling ranging from 3 to 120 months.  
  • 30 patients receiving immunosuppressant treatment (12 deferring due to concerns about side effects). 28 patients received "intravenous methylprednisolone at a dose of 200 mg for three days and 40 mg for 3 d, followed by oral prednison 0.6 mg/kg/d, which was gradually tapered to a mainenance dose of 5 mg/d. Cyclophasphamide was alos administered..." with ultrasonographic follow-up 3 month after treatment
  • The submandibular gland was more commonly affected on pre-treatment ultrasound
  • Five patterns identified - 
    1. superficial hypo-echoic pattern - coarse echotexture in the superficial portion of the gland  - (60.7% of submandibular glands; 1.8% of parotid glands)
    2. normal pattern, fine homogenoeous echo as seen in normal glands (9.8% of submandibular glands; 71.9% of parotid glands)
    3. space-occupying pattern, a crcumscribed area of decreased echogenicity within the gland (1.6% of submandibular glands; 3.5% of parotid glands)
    4. whole-gland heterogeneity, coarse gland texture and decreased echogenicity (4.9% of submandibular glands; 1.8% of parotid glands)
    5. multiple rounded hypo-echoic foci, a reticulated pattern with mulitple rounded hypo-echoic or cystic foci within the gland parenchyma (similar to Sjogrens) (23.0% of submandibular glands; 1.8% of parotid glands)
  • 90.2% of the submandibular glands were abnormal; 26.3% of the parotid glands were abnormal
  • These investigators (Li et al 2016) reported post-treatment follow-up ultrasonography revealed that the volume of the enlarged glands diminished and the superficial hypo-echoic areas and multiple hypo-echoic foci in the submandibular glands resolved. The heterogeneous hypo-echoic areas in the parotid glands were reported to become more homogeneous.
• Wang et al (Wang 2014) reviewed 16 patients with IgG4-related sclerosing sialadenitis determined by clinical presentation of salivary gland swelling (consistently referred to as 'salivary glands' without clear discrimination as to submandibular or parotid other than one case example) and either hisopathologic findings or serology (elevated IgG4) supportive of IgG4RD. Treatment was with prednison 15mg/d for one month, 'then tapered for 3 months, and continued at a dose of 5 to 10 mg/d"
  • Sonography was reported as being performed in all 16 patients
    • 13 patients (81%) showed multiple hypoehoic foci with 'vague contour scattered against a heterogeneous background, which characteristically presented with an irregular netlike or honeycomb appearance'- with 'diffuse involvement of the salivary glands' identified as similar to Sjogrens syndrome.
    • 3 patients (19%) showed a heterogeneous internal echo texture, which indicated chronic sialadenitis or 'lymphnoditis'
    • of the 15 patients who completed treatement with steroids, clinical improvement was noted at 3 months

2. Sialography

Biopsy

1. FNA - may be inconclusive
2. Open biopsy (or core needle): lymphoid infiltrate with plasma cells IgG4+'ve on immunohistostaining.
   • Dense lymphocytic infiltrate with storiform fibrosis may be seen in salivary glands but not usually in lymph nodes
   • Increased TgG4-positive plasma cells can be seen in tissue without qualifying for IgG4-RD include sarcoidosis / Churg-Strauss syndrome / Wegener's granlomatosis / Castleman's disease
   • "Misdiagnoses of IgG4-related can occur with excess emphasis on moderate elevation so serum IgG4 concentration and overreliance on finding IgG-positive plasma cells in tissue (Stone 2012)
3. Lip Biopsy (minor salivary gland sampling)
   • As per Zhang et al (Zhang 2020) "SMG (submandibular gland)  biopsy cannot be replaced by LSG (labial salivary gland) biopsy for diagnosis of IgG4-RS (IgG4 related sialadenitis)."
     • Our practice differs from that of Zhang et al who, under local anesthesia, performed and open incisional biopsy of the submandibular gland. We request an ultrasound guided core needle biopsy to be done rather than performing an open biopsy as they describe.  Zhang et al (Zhang 2020) do identify that: "Further research is warranted to confirm if specimens achieved from core needle biopsy can reveal typical histological and immunohistochemical characteristics of the disease"
   • In contrast, as per Tachibana et al (2020) " In cases of IgG4-RD with salivary gland involvement, lip biopsy might be one of the options for the histological diagnosis of IgG4-RD."

Serum IgG4 concentaration

• May or may not be raised (30% reported with normal serum IgG4 concentrations) (Sah and Chari 2011) 
• Should obtain (according to Wallace (2019) IgG levels (total and subtypes) - consider other to r/o other causes: CBC with differential, ANA, SSA, SSB antibodies with the caveate "the exclusion criteria should not be interpreted as a list of  studies or tests a clinician must obtain on every patient"

Treatment

1. Generally responds favorably to glucocorticoid or immunosuppressants. 
   1. Glucocorticoids are effective but may be accompanied by disease flares
   2. Other drugs used but not employed in clinical trials include azathioprine, mycophenolate mofetil, and methotrexate (Stone 2012); B-cell depetion with rituximab has been used.
2. Not all manifestation of the disease require immediate treatment - indolent IgG4-realted lymphadenopathy has been treated with observation (Sato 2010)

References

Frulloni L, Lunardi C, Simone R, et al: Identification of a novel antibody associated with autoimmune pancreatitis. NEJM 2009;361:2135-2142

Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982-4.

Khosroshahi A, Wallace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol 2015;67:1688-99.

Li W, Xie XY, Su JZ, Hong X, Chen Y, Gao Y, Zhang ZY, Yu GY. Features of Immunoglobulin G4-Related Sialadenitis.Ultrasound Med Biol. 2016 Jan;42(1):167-75. doi: 10.1016/j.ultrasmedbio.2015.09.014. Epub 2015 Oct 27.

Sah RP and Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol 2011;23:108-113

Sato Y, Kojima M, Takata K et al Multicentric Castleman's disease with abundant IgG4-positive cells: a clinical and pathologicsal analysis of six cases. J Clin Pathol 2010;63:1084-1089

Stone JH, Zen Y, and Deshpande V: IgG4-Related Disease NEJM April 26, 2012

Tachibana T, Orita Y, Wani Y, Komatsubara Y, Kuroda K, Naoi Y, Gion Y, Makino T, Nishizaki K, Sato Y. Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulin G4-Related Disease. Ear Nose Throat J. 2022 Sep;101(8):547-551. doi: 10.1177/0145561320971932. Epub 2020 Nov 4. PMID: 33147065.

Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH; American College of Rheumatology/European League Against Rheumatism:  IgG4-Related Disease Classification Criteria Working Group.The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease.Arthritis Rheumatol. 2020 Jan;72(1):7-19. doi:10.1002/art.41120. Epub 2019 Dec 2.PMID:31793250

Wallace Z, Zhang Y, Perugino CA, Naden R, Choi H, Stone J, ACR/EULAR IgG4-RD Classification Criteria Committee:  Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohortsAnn Rheum Dis. 2019 March ; 78(3): 406–412. doi:10.1136/annrheumdis-2018-214603.

Wang ZJ, Zheng LY, Pu YP, Zhou HH, Xie LS, Shi H, Yu CQ.Clinical features and treatment outcomes of immunoglobulin g4-related sclerosing sialadenitis.J Craniofac Surg. 2014 Nov;25(6):2089-93. doi: 10.1097/SCS.0000000000001016.

Wong WK and Morton RP: Immunoglobulin G4-related disease of the orbital cavity, cervical lymph nodes and greater auricular nerve: case report. Am J Otolaryngol 2016 May-Jun;37(3):182-5

Zhang YY, Hong X, Wang Z, Li W, Su JZ, Chen Y, Gao Y, Yu GY. Diagnostic utility of submandibular and labial salivary gland biopsy in IgG4-related sialadenitis. Clin Rheumatol. 2020 Dec;39(12):3715-3721. doi: 10.1007/s10067-020-05097-1. Epub 2020 May 26. PMID: 32458243.

Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH; American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020 Jan;72(1):7-19. doi: 10.1002/art.41120. Epub 2019 Dec 2. PMID: 31793250.

Tachibana T, Orita Y, Wani Y, Komatsubara Y, Kuroda K, Naoi Y, Gion Y, Makino T, Nishizaki K, Sato Y. Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulin G4-Related Disease. Ear Nose Throat J. 2022 Sep;101(8):547-551. doi: 10.1177/0145561320971932. Epub 2020 Nov 4. PMID: 33147065.

Pereira GG, Pontes FSC, Soares CD, de Carvalho MGF, da Silva TA, Calderaro DC, Ferreira GA, Tanure LA, de Souza LL, Rodrigues-Fernandes CI, de Almeida OP, Fonseca FP, Pontes HAR. Oral and maxillofacial manifestations of IgG4-related disease: A clinicopathological study. J Oral Pathol Med. 2022 May;51(5):493-500. doi: 10.1111/jop.13296. Epub 2022 Apr 11. PMID: 35347770.