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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 2  |  Page : 141-144

Immunoglobulin G4-related disease, constitutional symptoms, human leukocyte antigen b27 positivity, and sacroiliitis

1 Department Rheumatology, ISIC Superspeciality Hospital, New Delhi, India
2 Medanta-The Medicity, Gurugram, Haryana, India

Date of Web Publication29-May-2020

Correspondence Address:
Prof. Anand Narayan Malaviya
Flat 2015, Sector B-2, Vasant Kunj, New Delhi - 110 070
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_1_20

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IgG4-related disease (IgG4-RD) is a relatively new clinical entity with protean manifestations that pose diagnostic difficulties especially so if the clinical features are atypical. Here we present a 55-year-old man with back-buttock pains, a knee and ankle arthritis with moderately severe constitutional symptoms. The acute phase reactants were high, and the test for HLA B27 was positive. Spondyloarthritis (SpA) was suspected but, because of the symptom-onset >45 years of age, infection and malignancy were also considered. Detailed investigations including a whole-body positron-emission tomography (PET) scan that showed hypermetabolic soft tissue thickening in the periaortic recess and at the base of the heart encasing root and ascending aorta. Fluorodeoxyglucose (FDG) uptake was also seen in the peripheral zones of the prostate, bilateral, parotid nodes, and in the right sacroiliac joint. A biopsy of the parotid gland nodule confirmed the diagnosis of IgG4-RD. The presence of features of inflammatory back-buttock pains, lower extremity oligoarthritis, good relief to non-steroidal anti-inflammatory drugs (NSAIDs), presence of HLA B27, and an acute involvement of the right sacroiliac joint were typical of spondyloarthritis. However, the moderately severe constitutional symptoms were not typical of SpA. Thus, this patient had both the IgG4-RD as well as SpA. Was the presence of HLA B27 incidental and the sacroiliitis was due to the infiltration of IgG4 cells or, he had true SpA with sacroiliitis and the IgG4 cell infiltration was incidental? This issue has been discussed in depth.

Keywords: Aortic encasing, aortitis, human leukocyte antigen B27, IgG4-related disease, sacroiliitis, spondyloarthritis

How to cite this article:
Verma S, Khurshid L, Voleti PR, Malaviya AN. Immunoglobulin G4-related disease, constitutional symptoms, human leukocyte antigen b27 positivity, and sacroiliitis. Indian J Rheumatol 2020;15:141-4

How to cite this URL:
Verma S, Khurshid L, Voleti PR, Malaviya AN. Immunoglobulin G4-related disease, constitutional symptoms, human leukocyte antigen b27 positivity, and sacroiliitis. Indian J Rheumatol [serial online] 2020 [cited 2021 Sep 22];15:141-4. Available from:

  Introduction Top

Immunoglobulin G4-related disease (IgG4-RD) has protean manifestations.[1],[2] We present a patient who had inflammatory back pain and pain in some of the peripheral joints and was positive for human leukocyte antigen (HLA) B27 gene associated with moderately severe constitutional symptoms and certain unusual features. On further evaluation, he was found to have an uncommon overlap of IgG-RD and features of spondyloarthritis (SpA).

  Case Report Top

A 55-year-old man presented with complaints of back and buttock pain and pain in the right knee and left ankle joint associated with fever and significant weight loss for a few weeks. Detailed history did not give any clue to diagnosis. Physical examination was also unremarkable but for fever, weight loss, and tenderness in the right knee and the left ankle joint. His acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein) were high (96 mm/h and 26 mg/l, respectively). The clinical picture being strongly suggestive of the involvement of sacroiliac joint (SIJ), a magnetic resonance imaging (MRI) with short tau inversion recovery sequence of the pelvis was carried out. It confirmed right-sided active sacroiliitis [Figure 1]. As the onset of SpA >45 years of age is unusual and the sacroiliitis being unilateral, there was a suspicion of some infectious pathology. Therefore, Mantoux test, QuantiFERON-TB Gold test, and  Brucella More Details serology were carried out, which were all negative. However, the test for HLA B27 was positive. Considering his age, the possibility of malignancy was also considered. A whole-body positron-emission tomography (PET) scan showed hypermetabolic soft-tissue thickening in the periaortic recess and at the base of the heart encasing root and ascending aorta [Figure 2]a. Fluorodeoxyglucose (FDG) uptake was also seen in the peripheral zones of the prostate [Figure 2]b, bilateral parotid nodes [Figure 2]c, and along the right SIJ [Figure 2]d. A biopsy of the parotid gland nodule showed focal periductal chronic inflammation and plasma cells that were positive for IgG as well as for IgG4 [Figure 3]. Serum IgG level was 2024 mg/dl (normal range in adults 700–1600 mg/dL) and serum IgG4 level was 210.7 mg/dl (10 mg/dL to 140 mg/dL, definitely high if >200 mg/dL); the IgG/IgG4 ratio was 9.6. Based on these findings, a diagnosis of IgG4-RD was made. In addition, an overlap with the axial SpA was considered in the presence of lower back pain, a positive HLA B27, and an acute right-sided sacroiliitis demonstrated by MRI. All through these investigations, the patient was given symptomatic treatment with etoricoxib 90 mg daily with a marked relief in pain. After the diagnosis was made, he was advised the following treatment: (1) prednisolone 40 mg daily after breakfast, (2) methotrexate (MTX) 20 mg in the lateral thigh or the abdominal wall subcutaneous injection, (3) folic acid 5 mg tablets three times per week (not to be taken on the day of MTX injection), and (4) naproxen 500 mg at bedtime with weekly follow-up. MTX was chosen for the treatment because of its proven efficacy, decades of experience in its use for systemic immunoinflammatory rheumatic diseases, and proven safety record.[3],[4],[5]
Figure 1: Magnetic resonance imaging-short tau inversion recovery sequence (2 adjacent planes) showing (encircled) right active sacroiliitis with subcortical bone marrow oedema (on the iliac side) and erosions

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Figure 2: (a) A whole-body positron emission tomography-scan showing hyper-metabolic soft tissue thickening in periaortic recess and at the base of the heart encasing root and ascending aorta. (b) Positron emission tomography-scan, fluorodeoxyglucose uptake indicative of involvement of the peripheral zones of the prostate. (c) positron emission tomography-scan, fluorodeoxyglucose uptake indicative of involvement bilateral parotid glands, (d) positron emission tomography-scan, fluorodeoxyglucose uptake along the right sacroiliac joint indicative of active sacroiliitis

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Figure 3: Histopathology of the parotid gland nodule showing focal periductal chronic inflammation and plasma cells that were positive for IgG as well as for IgG4

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At the follow-up visit after 4 months of treatment, the patient described a rapid improvement of the constitutional symptoms, gained weight to his predisease level, and he was able to walk normally without any discomfort. Prednisolone was tapered down to 2.5 mg alternate days and MTX 15 mg per week.

  Discussion Top

Our patient had two distinct clinical features. First, an inflammatory back pain, with unilateral acute sacroiliitis and a positive HLA B27 with a good response to etoricoxib (even before he was initiated on prednisolone), all the features were typical of SpA. Therefore, a clinical diagnosis of SpA was entertained. It is of note that he could not be classified as having SpA according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria because the disease onset was beyond the age of stipulated 45 years.[6] However, these criteria are for classification and not for diagnosis. The second issue was that of the constitutional symptoms including low-grade fever and significant weight loss. Fever and constitutional symptoms are not characteristic of adult SpA. Therefore, infection and malignancy were considered in differential diagnosis. The investigations proved that the patient had IgG4-RD, which could explain most of the symptoms of the patient. Recently, formal ACR/EULAR classification criteria for IgG4-RD have been published.[7] On applying these criteria retrospectively, the patient under discussion fulfilled the “Entry Criteria,” i.e., characteristic clinical/radiological involvement of a typical organ (affected by enlargement or tumor-like mass), in his case the salivary glands and the aorta. Furthermore, there were no features for the exclusion criteria. In addition, high IgG4 levels gave another 4+ points. There was pathological evidence of an inflammatory periductal chronic lymphoplasmacytic infiltrate and plasma cells that were positive for IgG as well as for IgG4. This histopathology could be scored 5+ (on a scale 4–9) by the pathologist. Parotid gland involvement on both the sides added another 14+ points, giving a total of 23+ points. The ACR/EULAR criteria require a score of >+20 points for the classification of IgG4-RD. Thus, our patient with 23+ points could be classified as IgG4-RD.

The next question was whether these features of SpA and IgG4-RD were related or unrelated. A literature search found only two cases of IgG4-RD with sacroiliitis till 2016.[8],[9] The first case was of an elderly woman with lacrimal gland enlargement and sicca features with chronic sinusitis and hearing loss.[8] IgG4-RD was confirmed on the lacrimal gland biopsy. On PET scan for staging the disease, increased uptake of the FDG activity was noted at the SIJs bilaterally in the absence of any clinical features of sacroiliitis. Histopathological examination of the SIJ infiltration showed IgG4 positive cells in significant numbers (>80 IgG4 cells/hpf). HLA B27 was not reported. The second case has been described in detail.[9] In summary, she was a 52-year-old Caucasian woman with retroperitoneal fibrosis, involvement of the right ureter with hydronephrosis. In addition, she had increasing low back pain and joint pains. An ureterectomy and reimplantation operation was carried out. An IgG4 immunostaining on the resected tissue confirmed the presence of numerous plasma cells (>80/high-power field). Serum IgG4 level was 192 mg/dL (normal 11–86 mg/dL), thus confirming the diagnosis of IgG4-RD. For evaluating the buttock pain, an MRI of the pelvis showed acute sacroiliitis (subcortical bone marrow edema right > left). HLA B27 gene test was positive.

In the year 2017, a retrospective series of five patients with IgG4-RD were presented from Egypt at the “9th World Congress and Expo on Immunology, Immunity Inflammation and Immunotherapies” held between November 02 and 03 2017 in Atlanta, USA.[10] These patients had back pain and sacroiliitis on MRI, and three of them were positive for HLA B27. In addition, low Vitamin D levels were found in all the five cases. The authors suggested further studies to elucidate the relationship of sacroiliitis with IgG4-RD cases.

Our patient was more like the second patient (above) and patients in the Egyptian series. He had typical clinical features of SpA including the good response to etoricoxib, even before the initiation of prednisolone. Although the clinical diagnosis of SpA was made, he could not be classified “SpA” according to the EULAR criteria, which are not meant for making a clinical diagnosis.[6] It is of note that elderly-onset SpA is being increasingly recognized.[11] Therefore, the occurrence of IgG4-RD and SpA in the same patient could simply should be coincidental. The second possibility could be that the patient's sacroiliitis was caused by the infiltrating IgG4 plasma cells. The treatment with glucocorticoid (GC) and a GC-sparing drug MTX led to a highly satisfactory clinical improvement. These observations strongly suggest that the patient did not have SpA and the sacroiliitis was due to IgG4-RD. If that was so, then, the presence of HLA B27 would have to be considered “coincidental.” It is to be noted that the prevalence of HLA B27 in Northern parts of India is 6%.[12] Only a histopathological examination of the SIJ tissue could have resolved this dilemma; unfortunately, the patient did not give consent for that.

The recent review of IgG4-RD by Zhang and Stone describes two broad overlapping clionicopathological categories, namely proliferative and fibrotic subset that seem to have therapeutic relevance.[2] The former subset includes lymphadenopathy, dacryoadenitis, sialadenitis, autoimmune pancreatitis, sclerosing cholangitis, lung disease, tubulointerstitial nephritis, paranasal sinusitis, and hypophysitis. These patients usually have high levels of IgG4, IgG1, and IgE; hypocomplementemia; peripheral eosinophilia; and multi-organ disease often accompanied by atopy.[13],[14] In contrast, the fibrotic subset affects certain limited body regions rather than specific organs, for example, retroperitoneal fibrosis, sclerosing mesenteritis, and fibrosing mediastinitis. Occasionally, however, this subset also shows organ limited involvement, for example, Riedel's thyroiditis and hypertrophic pachymeningitis. These two subsets may often overlap. A clinically relevant feature of this classification is the difference in response to treatment. The proliferative subtype is highly responsive to treatment. Thus, the type and distribution of lesions and satisfactory response to treatment favor the proliferative category of IgG4-RD in our patient.

There was another feature in our patient, namely encasing of the aortic root is uncommon.[15],[16],[17] On the other hand, there are reports of the involvement of the aorta in IgG4-RD including aortic insufficiency and aortitis of the ascending aorta.[18] However, none of the reported cases have described the encasing of the aortic root in IgG4-RD, as seen in our patient.

In summary, rheumatologists must be aware of the possibility of a “chameleon” that is IgG4-RD and consider its possibility in any patient where a single rheumatological disease does not explain all the clinical features.

Declaration of patient consent

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

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-51.  Back to cited text no. 1
Zhang W, Stone JH. Management of IgG4-related disease. Lancet Rheumatol 2019;1:e55-65.  Back to cited text no. 2
Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009;68:1086-93.  Back to cited text no. 3
Rovati L, Della-Torre E, Lanzillotta M, Cassione EB, Bozzolo E, Canevari C, et al. Methotrexate as induction of remission therapy for localized manifestations of IGG4-related disease. Rheumatology 2015;54:1934-6.  Back to cited text no. 4
Della-Torre E, Campochiaro C, Bozzolo E PA, Dagna L, Scotti R, Nicoletti R, et al. Methotrexate for maintenance of remission in IgG4-related disease. Rheumatology 2015;54,1934-6.  Back to cited text no. 5
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al. The development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): Validation and final selection. Ann Rheum Dis 2009;68:777-83.  Back to cited text no. 6
Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Jean-Francois D, et al. The 2019 American College of Rheumatology/European League against Rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol 2020;72:7-19.  Back to cited text no. 7
Possemato N, Crescentini F, Pazzola G, Ragazzi M, Salvarani C. IgG4-Related Sacroiliitis. Arthritis Rheumatol 2016;68:774.  Back to cited text no. 8
Paul S, Udayakumar PD. A case report on IgG4 related sacroiliitis. J Orthoped Rheumatol Sports Med 2016;2:112-3.  Back to cited text no. 9
El-Saadany HA. Case series: Presence of sacroiliitis and their associated HLAB27 positivity and Vitamin D deficiency in a cohort of IgG4-RD Egyptian patients. Presented from Egypt at the 9th World Congress and Expo on Immunology, Immunity Inflammation and Immunotherapies. Atlanta, USA.; 02-03 November, 2017.  Back to cited text no. 10
Toussirot É. Diagnosis and management of late-onset spondyloarthritis: Implications of treat-to-target recommendations. Drugs Aging 2015;32:515-24.  Back to cited text no. 11
Malaviya AN, Sawhney S, Mehra NK, Kanga U. Seronegative arthritis in South Asia: An up-to-date review. Curr Rheumatol Rep 2014;16:413.  Back to cited text no. 12
Wang M, Zhang P, Lin W, Fei Y, Chen H, Li J, et al. Differences and similarities between IgG4-related disease with and without dacryoadenitis and sialoadenitis: Clinical manifestations and treatment efficacy. Arthritis Res Ther 2019;21:44.  Back to cited text no. 13
Cortazar FB, Stone JH. IgG4-related disease and the kidney. Nat Rev Nephrol 2015;11:599-609.  Back to cited text no. 14
Stone JR. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr Opin Rheumatol 2011;23:88-94.  Back to cited text no. 15
Stone JH, Khosroshahi A, Deshpande V, Stone JR. IgG4-related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care Res (Hoboken) 2010;62:316-22.  Back to cited text no. 16
Kasashima S, Zen Y, Kawashima A, Endo M, Matsumoto Y, Kasashima F, et al. A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta. J Vasc Surg 2010;52:1587-95.  Back to cited text no. 17
Ozkan Y. Cardiac involvement in ankylosing spondylitis. J Clin Med Res 2016;8:427-30.  Back to cited text no. 18


  [Figure 1], [Figure 2], [Figure 3]


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