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Overlap of IgG4-Related disease with autoimmune rheumatic diseases: Report of 2 cases and review of literature

1 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission26-Nov-2021
Date of Acceptance10-Feb-2022
Date of Web Publication01-Jun-2022

Correspondence Address:
John Mathew,
Department of Clinical Immunology and Rheumatology, Christian Medical College Vellore, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_265_21


Immunoglobulin G4-related disease (IgG4-RD) is a systemic autoimmune disorder with a variety of manifestations. Association with other systemic autoimmune diseases is uncommonly reported in the literature. Hence, we intended to understand better the uniqueness of the overlapping associations of IgG4RD with other systemic autoimmune diseases. Retrospective electronic medical records-based review of IgG4RD occurring as an overlap with other systemic autoimmune diseases seen in the rheumatology department was done. We present two cases of IgG4 disease overlapping with systemic rheumatic diseases with a brief review of the literature. The first case was an overlap IgG4RD with lupus and the second interesting case had IgG4RD overlapping with 2 autoimmune diseases (lupus and rheumatoid arthritis) in the same patient. Both patients were treated with high-dose steroids and mycophenolate mofetil with good response, however, the second patient needed to be additionally treated with rituximab for better control of arthritis. Although uncommon, here, we report the first case series of 2 patients with IgG4 disease overlapping with other systemic autoimmune diseases. In our case series, the presence of the overlap did not impact the immediate clinical outcome or treatment response of IgG4RD or the co-existent systemic autoimmune disease.

Keywords: Immunoglobulin G4-related disease, retroperitoneal fibrosis, systemic lupus erythematosus

How to cite this URL:
Padiyar S, Manwatkar A, Ganapati A, Roy S, Mathew J. Overlap of IgG4-Related disease with autoimmune rheumatic diseases: Report of 2 cases and review of literature. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 1]. Available from:

  Introduction Top

Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition in which IgG4-positive plasma cell infiltration and fibrosis cause organ swelling and the development of nodular lesions. IgG4-RD was first recognized in the setting of autoimmune sclerosing pancreatitis.[1] Subsequently, other entities have been reported such as Kuttner tumor, Reidel thyroiditis, retroperitoneal fibrosis, sclerosing aortitis, and inflammatory abdominal aortitis, orbital pseudotumor, and other inflammatory pseudotumors (including kidney, brain, lung, breast, and lymph nodes).[2] It can be seen in isolation or it can occur in association with other autoimmune diseases.

Here, we present two cases of IgG4 RD overlapping with other autoimmune disorders.

  Case Reports Top

Case 1

A 23-year-old lady presented with a 1-year history of inflammatory polyarthritis, photosensitive skin rash, and alopecia. Over the past 3 months, she had developed multiple painless progressive swellings on the right side of her neck. She had no history of fever, weight loss, or loss of appetite. She also had pedal edema for a month associated with periorbital puffiness in the morning hours. On examination, she had a resolving malar rash with significant and right cervical (level 3) lymphadenopathy (1 cm × 1 cm, firm, nonmatted), and bilateral axillary lymphadenopathy (2 cm × 1 cm, firm, nonmatted). She was diagnosed with systemic lupus erythematosus (SLE), and she fulfilled Systemic Lupus International Collaborating Clinics criteria 2012 (Clinical symptoms, ANA positivity, low complements, and proteinuria).[3] She had already received pulse methylprednisolone (1 g for 3 days) and one dose of cyclophosphamide (15 mg/kg) before being referred to us for further management. Her detailed laboratory investigations are tabulated in [Table 1]. She had anemia (hemoglobin 8 g/dl) with low albumin (2.5 g/dl) levels. Urine examination showed subnephrotic range proteinuria (24 h protein-2.9 g/day). ANA done by indirect immunofluorescence was 2 + speckled pattern, with elevated anti-dsDNA (270 IU/ml) and low serum complements (C3-54 mg/dl, C4-8.25 mg/dl). Renal biopsy slides done outside were reviewed here which showed Class III lupus nephritis (LN) [Figure 1] as per the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS)[4] classification with the presence of wire loop lesions, endocapillary hypercellularity, and focal capillary tuft fibrinoid necrosis. Interstitial fibrosis and tubular atrophy were 5%. In view of generalized significant lymphadenopathy, a lymph node biopsy was done to exclude lymphoma or infection. Lymph node excision biopsy showed extensive storiform fibrosis and lymphoplasmacytic infiltrate with a predominance of plasma cells. IgG4 immunohistochemistry (IHC) [Figure 1] showed positive staining of numerous plasma cells (50–80 per HPF). By IHC evaluation, the IgG4:IgG ratio was between 42 and 67 in foci. Serum IgG4 level was found to be normal (<584 mg/l). A computerized tomogram (CT) of the thorax and abdomen was negative for generalized lymphadenopathy and organomegaly. The patient was diagnosed as an overlap of lupus with IgG4-RD, however, as per classification criteria of IgG4-RD, she qualifies as probable IgG4-RD.[5] She was initiated on 1 mg per/kg/day of steroids along with mycophenolate mofetil (MMF) 2 g/day as the immunosuppressive agent. She responded well to treatment in terms of resolution of proteinuria and regression of lymph nodes following 3 months of therapy.
Table 1: Laboratory investigations of two cases

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Figure 1: Lymph node and renal biopsy of patient 1. Lymph node excision biopsy (a&b), (a) Light microscopy demonstrating diffuse storiform fibrosis and complete disruption of lymph node tissue architecture. Insert: Dense infiltrate of plasma cells is noted within areas of fibrosis. (b) Immunohistochemical staining for IgG4 in the lymph node shows presence of numerous cells with positive staining; Light microscopy of kidney biopsy (c&d): (c) Glomeruli depicting segmental endocapillary hypercellularity(arrow) and segmental thickening of capillary walls(arrow head); (d) Glomeruli with pronounced segmental 'wire loop' thickening of capillary walls with fuschinophilic deposit(arrow head), Haematoxylin and Eosin stain (A&C) and Masson's trichome stain (d), original magnifications X200 (a&b) and X400 (c&d). original magnifications X200(a&b) and X400 (c&d)

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Case 2'

48-year-old Asian Indian woman, a known case of discoid lupus erythematosus, presented with a 2-year history of inflammatory polyarthritis. She had associated photosensitive skin rash, alopecia, and recurrent painless oral ulcers. For the past 2 months, she had developed painful erythematous skin lesions over both legs associated with low-grade fever and pedal edema. Clinical examination revealed pallor and bilateral pitting pedal edema with palpable coalescent purpuric lesions over the lower limbs. She had tenderness and swelling of both elbow joints with fixed flexion deformities.

She had anemia (hemoglobin 7 g/dl) with low albumin (2.6 g/dl) levels with subnephrotic range proteinuria (24 h protein-1.4 g/day). ANA done by indirect Immunofluorescence was 2+ speckled and nucleolar pattern with elevated anti-dsDNA (684 IU/ml) and low serum complements (C3-119 mg/dl, C4-6.9 mg/dl). Renal biopsy revealed membranous LN (ISN/RPS class V), with immunofluorescence staining showing IgG 2+, IgM2+, IgA 1+, C3 + AND C1q+ [Figure 2].
Figure 2: (a-c): Histopathology of presacral mass and renal biopsy of patient 2. Histopathology of the Pre sacral mass (a&b), (a) Core biopsy displaying dense stromal and storiform fibrosis. Insert: Dense infiltrate of plasma cells is noted within areas of fibrosis. (b) Immunohistochemical staining for IgG4 in the core biopsy shows presence of numerous cells with positive staining; (c) Light microscopy of kidney biopsy displaying glomerulus displaying mild mesangial expansion and global, uniform mild capillary wall thickening, Haematoxylin and Eosin stain (a) and Periodic Schiff stain (c), original magnifications X200 (a) and X400 (b&c)

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Routine prerenal biopsy ultrasound abdomen showed an incidental presacral mass that was further characterized on CT abdomen as a soft tissue thickening extending to the level of the aortic bifurcation. CT-guided biopsy of the same lesion showed fibro-collagenous tissue with extensive fibrosis, including focal areas demonstrating storiform fibrosis. The stroma showed a dense infiltrate of plasma cells, accompanied by foamy macrophages and focal aggregates of histiocytes and lymphocytes. On IHC for IgG4 and IgG, there were >50 IgG4 positive plasma cells/HPF. IgG4:IgG ratio of positive cells was >40% [Figure 2]. Serum IgG4 level was minimally elevated, 1369 mg/l (normal <1350 mg/l). In view of erosive arthritis of wrist on X-ray hands. Anticitrullinated cyclic peptide antibody was done which was elevated (139 IU/ml). Hence, a diagnosis of rhupus and definite IgG4 RD was made.

She was started on 1 mg/kg/day of oral steroid and MMF 2 g/day. On follow-up, her repeat urine studies on treatment showed no proteinuria and improvement in creatinine to 0.97 mg/dl in 1 month. Her repeat CT abdomen after 7 months of treatment showed a significant decrease in size of presacral mass [Figure 3] and a reduction of IgG4 level to 551 mg/l. Although she continued to do well, with respect to lupus and IgG4 RD, she had to be initiated on rituximab, 2 doses of 1 g each 15 days apart, followed by maintenance of rituximab every 6 months, in view of active RA.
Figure 3: (a-c) Imaging of Patient 2 (a) PA view of the bilateral hand and wrist in patient of case 2 showing juxtaarticular osteopenia and joint space narrowing. (b and c) CT abdomen and pelvis before treatment showing pre-sacral mass(b) which has reduced after treatment (c)

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  Discussion Top

The above two cases highlight the overlapping associations of IgG4 disease and SLE. Our first patient was classified as SLE with IgG4-RD presenting with lymphadenopathy as the sole manifestation, with normal serum levels of IgG4. Around one-third of patients with IgG4 disease demonstrate normal serum IgG4 levels.[6] Lymphadenopathy is common in IgG4-RD being present in approximately 40 percent of patients.[7] Lymphadenopathy may present as the first manifestation of the disease or as the sole manifestation.[8] The lymph nodes are nontender, with sizes ranging from 1 to 3 cm, and can involve cervical, supraclavicular, mediastinal, hilar, intra-abdominal, axillary, and inguinal nodes.[9] Cheuk and Chan described the five patterns in IgG4-related lymphadenopathy, namely Multicentric Castleman disease like, Follicular hyperplasia, Interfollicular expansion, Progressive transformation of germinal centers, Inflammatory pseudotumor like.[8] Storiform fibrosis and obliterative phlebitis are not prominently seen in lymph nodes.[10] Lymphomas can arise in association with IgG4-RD or may express IgG4, however, the lymphocytes will be predominant T cells, rather than B cells.[11] Our patient did not have features of lymphoma, and on initiation of 1 mg/kg steroids and MMF, there was resolution of the lymph nodes and decrease in proteinuria at the end of 3 months. MMF was chosen as the agent of choice based on our previous experience with this drug[12] and evidence from a recent randomized controlled trial.[13]

Our second patient responded well to a combination of steroid and MMF induction. However, in view of significant arthritis, she required rituximab infusion which led to improvement in arthritis. Apart from the proven role of rituximab in lupus and RA, there have been many case series which has shown its benefit in IgG4 disease, making it an agent of choice in this scenario.[14]

There is no definite explanation available for the association between IgG4 disease and lupus. However, one postulate may be the role of follicular helper T-cells which is relevant in the pathogenesis of both IgG4[15] disease and SLE.[16] Since we have not done the class subtyping of IgG causing ANA positivity, an argument may be that the ANA positivity is all due to IgG4 antibodies. However, general understanding that IgG4 antibodies do not cause hypocomplementemia refutes this argument and suggests that there must be other subtypes of IgG responsible for SLE. In addition, Anti Annexin V antibodies have been detected in IgG4 disease, which also could be a common player between these 2 diseases.[17] However, our patients did not undergo Anti Annexin V testing. These cases highlight the various overlaps with IgG4RD. So far, 5 cases have been reported in the literature which have described an overlap of IgG4RD and SLE,[18],[19],[20],[21],[22] which is detailed in [Table 2]. A genome wide association study conducted for IgG4-RD recently revealed that this condition shares HLA-DRB1 (P = 1.1 ×10−11 for IgG4-RD. odds ratio of 2.4 for SLE) and FCGR2B (P = 2.0 ×10−8 for IgG4-RD, odds ratio of 2.3–2.45 for SLE).[23] Interaction between CD 40 and CD 40 L which is needed for class switching and thus for different subtypes of immunoglobulin production has been well associated with SLE pathogenesis.[24] Our second case had an overlap of RA, SLE, and IgG4-RD disease which is a unique entity, not yet reported in the literature. One possible explanation of Ra co-existing with IgG4-RD is that the CH2 domain of IgG4, after binding with autoantigens, might become a target for rheumatoid factors. This resultant immune complex, which is bigger, and contains RF-IgG4-autoantigens has been shown to strongly induce immune responses and to cause tissue damage in RA.[25]
Table 2: Case reports showing overlap of immunoglobulin G4-related disease with autoimmune rheumatic diseases

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The treatment should mainly focus on giving an agent which covers both conditions. Among the available data from the case reports, corticosteroids have been used consistently. Yamamoto et al. described a patient with LN and IgG4 RD in the kidney who was successfully treated with belimumab, MMF, and corticosteroids.[20] Other agents that have been successfully used in the previous cases are MMF, rituximab, and cyclophosphamide.

  Conclusion Top

We hereby describe two interesting cases of overlap of IgG4 disease with lupus and rhupus. IgG4-RD needs to be always considered and ruled out when autoimmune rheumatic diseases present with atypical manifestations like retroperitoneal fibrosis. The findings presented in this study suggest a common pathology between the diseases. Further studies are needed to explore the pathogenic mechanisms underlying these diseases.


Informed written consent was taken from the patient for publication.

ORCID iD: ShivrajPadiyar https://orcid. org/0000-0002-5369-7062

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


We thank the Department of Radiology for their contributions in these two cases.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Okazaki K, Uchida K, Miyoshi H, Ikeura T, Takaoka M, Nishio A. Recent concepts of autoimmune pancreatitis and IgG4-related disease. Clin Rev Allergy Immunol 2011;41:126-38.  Back to cited text no. 1
Khosroshahi A, Deshpande V, Stone JH. The clinical and pathological features of IgG (4)-related disease. Curr Rheumatol Rep 2011;13:473-81.  Back to cited text no. 2
Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86.  Back to cited text no. 3
Bajema IM, Wilhelmus S, Alpers CE, Bruijn JA, Colvin RB, Cook HT, et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: Clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int 2018;93:789-96.  Back to cited text no. 4
Okazaki K, Umehara H. Are classification criteria for IgG4-RD now possible? The concept of IgG4-related disease and proposal of comprehensive diagnostic criteria in Japan. Int J Rheumatol 2012;2012:357071.  Back to cited text no. 5
Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: Clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol 2015;67:2466-75.  Back to cited text no. 6
Cheuk W, Chan JK. IgG4-related sclerosing disease: A critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol 2010;17:303-32.  Back to cited text no. 7
Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: An underdiagnosed and overdiagnosed entity. Semin Diagn Pathol 2012;29:226-34.  Back to cited text no. 8
Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol 2008;32:671-81.  Back to cited text no. 9
Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92.  Back to cited text no. 10
Sato Y, Takata K, Ichimura K, Tanaka T, Morito T, Tamura M, et al. IgG4-producing marginal zone B-cell lymphoma. Int J Hematol 2008;88:428-33.  Back to cited text no. 11
Gupta N, Mathew J, Mohan H, Chowdhury SD, Kurien RT, Christopher DJ, et al. Addition of second-line steroid sparing immunosuppressants like mycophenolate mofetil improves outcome of Immunoglobulin G4-related disease (IgG4-RD): A series from a tertiary care teaching hospital in South India. Rheumatol Int 2018;38:203-9.  Back to cited text no. 12
Yunyun F, Yu P, Panpan Z, Xia Z, Linyi P, Jiaxin Z, et al. Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: A randomized clinical trial. Rheumatology (Oxford) 2019;58:52-60.  Back to cited text no. 13
Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: Lessons from 10 consecutive patients. Medicine (Baltimore) 2012;91:57-66.  Back to cited text no. 14
Umehara H, Nakajima A, Nakamura T, Kawanami T, Tanaka M, Dong L, et al. IgG4-related disease and its pathogenesis – Cross-talk between innate and acquired immunity. Int Immunol 2014;26:585-95.  Back to cited text no. 15
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Takanashi S, Hanaoka H, Ota Y, Kaneko Y, Takeuchi T. An overlapping case of IgG4-related disease and klinefelter syndrome with lupus-like serological and neurological features: A case report and literature review. Intern Med 2020;59:2601-9.  Back to cited text no. 22
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Murphy G, Isenberg DA. New therapies for systemic lupus erythematosus – Past imperfect, future tense. Nat Rev Rheumatol 2019;15:403-12.  Back to cited text no. 24
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