Introduction

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder with varying clinical manifestations that often mimic malignant, infectious, or other inflammatory disorders [1]. IgG4-RD has only recently been identified as a distinct condition and is associated with inflammatory and fibrosing lesions that can occur in a multitude of organ sites [2, 3], including the hepatobiliary system, the salivary and lacrimal glands, the kidneys, the lungs, the aorta, and the retroperitoneum [4,5,6]. While much of the etiopathogenesis of IgG4-RD remains unclear, it involves a complex interaction between genetic predisposition and environmental factors leading to a modified Th2-response and resulting in the production of IgG4-antibodies with unique glycosylation patterns and immunological properties [7].

IgG4-RD is typically challenging to diagnose and usually requires a combination of clinical, serological, radiological, and pathological features, after excluding numerous mimicking conditions [8]. Consequently, patients are often evaluated by multiple practitioners, including gastroenterologists, nephrologists, or other specialists, which can result in a delayed diagnosis [9]. To facilitate this diagnostic process, three comprehensive diagnostic criteria for IgG4-RD were first proposed in 2011: typical diffuse/localized swelling or masses in single or multiple organs, elevated serum-IgG4 concentrations (≥ 135 mg/dL) and characteristic histopathologic findings [10]. These characteristic histopathologic features include a dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis [11], in addition to an increased infiltration of IgG4-bearing plasma cells [12]. However, because obtaining a biopsy of an affected site is often challenging, the 2011 diagnostic criteria were later adapted to include several organ-specific criteria [13]. Most recently, the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for IgG4-RD recommend a stepwise approach to diagnosis based on a set of entry, exclusion, and inclusion criteria [14].

However, while the introduction of different sets of diagnostic criteria have certainly contributed to a more accurate categorization of patients in both clinical practice and research, some manifestations of IgG4-RD do not meet these criteria. Furthermore, in some cases of IgG4-RD, the diagnosis is complicated by differences between the existing diagnostic and classification criteria. This is specifically the case with rare clinical manifestations of IgG4-RD, including pericarditis and pericardial effusion. We report a case of IgG4-RD presenting with massive pericarditis as the primary manifestation. The diagnostic process will be described in detail, with a focus on discrepancies with the recent classification criteria. Finally, we will discuss therapeutic options and conclude with a review of the literature dealing with pericarditis as a manifestation of IgG4-RD.

Case presentation

A 76-year-old woman was initially referred for cardiological examination because of bilateral pleural effusion and cardiomegaly on chest X-ray, performed because of a 2-month history of progressive dyspnea and non-productive cough. She had a history of diabetes mellitus, arterial hypertension, hyperlipidemia, and well-controlled chronic obstructive pulmonary disease and was on a steady regimen of oral antidiabetics, antihypertensive drugs, and a statin. Electrocardiogram showed sinus rhythm and an incomplete right bundle branch block. Transthoracic echocardiography was performed and revealed a large pericardial effusion, with a circumferential diameter of 3–4 cm. Left ventricular ejection fraction was within normal range. Because of the imminent cardiac tamponade, the patient was subsequently admitted for further evaluation and therapy. Laboratory tests performed on admission showed an elevated C-reactive protein (170 mg/L) and a borderline increased anti-nuclear antibody (ANA, 1:320) but were otherwise unremarkable. Urgent surgical pericardiocentesis was performed with the evacuation of 1400 mL of clear fluid, along with right-sided pleural drainage and a pericardial biopsy. Analysis of the pericardial fluid and biopsy showed no signs of inflammation, infection or malignancy. A thoracoabdominal contrast-enhanced computed tomography (CT) scan, performed 3 days after the procedure, showed no signs of ascites or tumoral masses. Remarkably though, a recurrence of the pericardial effusion was noted and confirmed by repeat transthoracic echocardiography. Additional cardiac magnetic resonance imaging (MRI) showed no pericardial thickening or intra-cardiac mass (Fig. 1).

Fig. 1
figure 1

Results of cardiac magnetic resonance imaging (MRI). A Cine horizontal long-axis (HLA) image shows extensive pericardial effusion (6.2 cm) (asterisk) with partial right atrial (RA) collapse (arrow) and small bilateral pleural effusion (arrowheads). B Late gadolinium enhancement (LGE) HLA image shows mild pericardial thickening (3 mm). C, D Native T1 (C) and T2 (D) map show high T1 and T2 values of 2826 ms and 204 ms, respectively (asterisk), consistent with pericardial exudate without evidence of hemopericardium

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A diagnosis of incessant pericarditis was made. The patient was empirically started on colchicine and non-steroidal anti-inflammatory drugs (NSAIDs) and subsequently discharged for regular cardiological follow-up. After 3 months of therapy, the pericardial effusion remained refractory on repeated echocardiographic evaluation, despite normalization of biochemical inflammatory markers.

The patient was subsequently referred for rheumatological examination to exclude autoimmune or autoinflammatory causes of persistent pericarditis. Additional blood tests showed increased serum IgG4-levels (179 mg/dL, 1.5 × ULN) and an elevated serum IgG4/IgG ratio (15.7%). Repeated ANA was now negative, as well as other autoantibodies, viral serology, and angiotensin-converting enzyme (ACE). After multidisciplinary discussion involving the treating rheumatologist, cardiologist, and cardiothoracic surgeon, therapeutic thoracoscopic pericardiectomy was performed along with a new pericardial biopsy for IgG4-staining. Histology of the pericardial tissue revealed a lymphoplasmacytic infiltrate (Fig. 2). On immunohistochemistry with staining by IgG4-antibodies, nearly all plasma cells were IgG4-positive (pericardial IgG4/IgG ratio > 80%, 10–50 IgG4 + plasma cells per high power field).

Fig. 2
figure 2

Pathological findings of the pericardium following pericardiectomy. The pericardial tissue is characterized by a lymphoplasmacytic infiltrate with IgG4/IgG ratio > 80% and 10–50 IgG4 + plasma cells per high power field. A Immunostaining for IgG. B Immunostaining for IgG4

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Based on these findings, a diagnosis of IgG4-related pericarditis could be made. Because of a history of dry mouth, a Schirmer-test and unstimulated whole saliva flow test were additionally performed which was strongly suggestive of xerophthalmia (2 mm/5 min) and xerostomia (0.06 mL/min). Consequently, a lip biopsy was taken and revealed a lymphoplasmacytic infiltrate and storiform fibrosis, consistent with IgG4-RD. However, immunohistochemistry of this biopsy showed no presence of IgG4-positive plasma cells. Additional screening, including positron-emission tomography (PET)– CT scan, showed no other sites of inflammation.

Echocardiography following pericardiectomy showed regression of the pericardial effusion. During 8 months of follow-up, the patient remained in remission without the need for glucocorticoids or additional immunosuppressive therapy.

Search strategy

We conducted a review of the literature by searching in MEDLINE and EMBASE from inception to December 2020, using the following search terms: “IgG4-related disease” AND “pericarditis”, “pericardial effusion” or “serositis”. Two authors (MD and SM) independently identified eligible articles, using a coordinated search strategy. Only case reports and case series in English language reporting on IgG4-RD with pericardial involvement and published in peer-reviewed journals were included. Additional reports were hand-picked via a snowballing approach guided by the references of included articles.

Retrieved abstracts were assessed for eligibility. Articles were excluded if they did not report on pericardial involvement of IgG4-RD or if they solely concerned other forms of serositis.

The following clinical and demographic data were extracted from both the cases retrieved through literature search and our case presented below: age, gender, pericardial involvement, pleural disease, other organ involvement, histopathologic features, serum IgG4-levels, initial and maintenance therapy, and evolution after treatment.

Results

We identified 32 published cases of IgG4-RD presenting as or with pericardial involvement (Table 1). In addition to these 32 cases, pericardial involvement was also reported in 1/235 patients in a Japanese observational cohort study [4]. However, since clinical and demographic details of this patient were not available, this case is not included in Table 1.

Table 1 Clinical and demographic characteristics, treatment strategy and evolution of reported cases of IgG4-RD with pericarditis
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Among the 32 cases where clinical and demographic data were reported, the mean age was 64 years (SD 14) and 65.7% of patients (21/32) were male. Pericardial involvement was mostly reported as pericardial thickening (21/32, 66%) and/or effusion (22/32, 69%) and was the only disease manifestation in only 2 cases. IgG4-related pericarditis was most frequently associated with pleural involvement (20/32, 62%), while peritoneal disease was reported in only 2 cases. Other affected organs included the hepatobiliary system, the aorta and retroperitoneum, lymph nodes and salivary glands. In most cases (19/32, 59%), a pericardial biopsy was obtained to support the diagnosis of IgG4-RD. In one case, pericardial fluid was obtained through FNAC. In 28% of cases (9/32), the diagnosis of IgG4-RD was supported by a non-pericardial biopsy, while in 3 cases no histopathologic findings were reported. Serum-IgG4 levels were reported in the majority of cases (29/32, 90%), with a mean concentration of 676 mg/dL (SD 699), and were > 135 mg/dL in many of them (25/29, 86%), in accordance with the 2011 comprehensive diagnostic criteria [10].

Table 1 presents initial treatment and evolution of the reported cases. Most patients were initially treated with glucocorticoids (17/32, 53%), pericardiectomy (5/32, 16%) or a combination of both (5/32, 16%). In glucocorticoid-treated patients, prednisone doses ranged from 0.6 mg/kg/day to 1 mg/kg/day. In one case, initial therapy additionally included cyclophosphamide, while another patient was treated with rituximab in monotherapy. In 24% of patients initially treated with glucocorticoids alone (4/17), treatment escalation to pericardiectomy or additional immunosuppressive therapy was needed because of recurrence or insufficient treatment response. In all 5 reported cases where patients were initially treated with pericardiectomy alone, remission was achieved without a need for maintenance therapy.

Discussion

We reported a case of IgG4-RD presenting with refractory, effusive pericarditis and imminent cardiac tamponade as the main manifestation, successfully treated with therapeutic pericardiectomy.

Although pericarditis remains a rare manifestation of IgG4-RD, a growing number of cases have been reported describing the pericardium as one of the affected sites. In reviewing the literature, we identified a total of 33 published cases of IgG4-RD with pericardial involvement, 32 of which included clinical and demographic data. However, pericardial involvement was the sole manifestation of IgG4-RD in only 2 of those cases. More frequently, pericarditis was associated with other forms of serositis, usually pleuritis, such as in our case. In total, the disease was limited to serositis in 44% (14/32) of the reported cases of IgG4-RD with pericardial involvement. Therefore, in case of refractory idiopathic pericarditis, it seems particularly important to consider a diagnosis of IgG4-RD when pleuritis is also present.

The reported cases also demonstrate several tools that can aid in the diagnostic process. In our case, it was primarily the elevated serum-IgG4 levels that prompted consideration of IgG4-RD. Interestingly, in the majority (86%) of published cases where serum-IgG4 levels were available, IgG4 concentrations were ≥ 135 mg/dL, in accordance with the 2011 comprehensive diagnostic criteria. Therefore, although serum-IgG4 levels are normal in a substantial number of cases of IgG4-RD [15], serum-IgG4 does appear to be a useful diagnostic tool when IgG4-related pericarditis is suspected. Moreover, since most cases of IgG4-RD presenting with pericardial involvement also manifest with pleuritis, assessing serum-IgG4 levels is particularly warranted in those patients who present with multiple refractory or idiopathic forms of serositis.

However, even when serum-IgG4 levels are elevated, a definite diagnosis of IgG4-RD according to the 2011 diagnostic criteria also requires the biopsy of an affected site, with an IgG4/IgG ratio of > 40% and > 10 IgG4-positive cells/HPF. In this regard, a pericardial biopsy was obtained in 59% of reported cases of IgG4-RD with pericardial involvement. It should be noted that, when considering IgG4-related pericarditis as a diagnosis, it is imperative to request specific attention to the pathologic hallmarks of IgG4-RD and to retain a low threshold for IgG4-staining. However, in the case of pericardial involvement, obtaining a biopsy can be challenging and requires an invasive procedure. Moreover, our review of cases suggests a rather favorable prognosis for IgG4-related pericarditis, with most cases responding well to initial treatment with pericardiectomy and/or glucocorticoids. In addition, where follow-up information was available, most patients seemed to sustain remission without a need for intensive maintenance therapy, although additional immunosuppressive therapy (including rituximab, methotrexate, or mycophenolate mofetil) could be warranted in refractory cases. Therefore, the decision to perform a pericardial biopsy should be considered on a case-to-case basis. It could be argued that a pericardial biopsy should be restricted to cases where the benefits of a definite diagnosis outweigh the risks of the procedure, or to cases with a severe clinical presentation that requires surgical intervention. Conversely, in mild cases of pericarditis with a clearly elevated serum-IgG4, corresponding with a possible diagnosis of IgG4-RD according to the 2011 criteria, a trial of glucocorticoids could be considered as an alternative option.

Moreover, when other organ systems are also affected, a more accessible biopsy site can be chosen instead of the pericardium. In our case, a lip biopsy was additionally obtained because of both subjective and objective signs of xerostomia, which suggested salivary gland involvement, or IgG4-related sialadenitis (IgG4-RS). Although IgG4-RS often mimics other autoimmune conditions such as primary Sjögren’s syndrome, there are several key epidemiological, clinical, serological, and histological differences between these entities [16, 17]. In our case, the presence of storiform fibrosis and elevated serum-IgG4 levels, and the absence of anti-Ro(SSA)/La(SSB)-antibodies were most consistent with IgG4-RS. However, since immunohistochemistry of the lip biopsy showed no IgG4-positive plasma cells, a definite diagnosis of IgG4-RD would likely not have been possible without pericardial tissue examination.

This way, our case also sheds new light on the ACR/EULAR classification criteria for IgG4-RD, proposed in 2019 [14]. These criteria are rather complex and require the involvement of a typical organ, such as the pancreas or salivary glands, as an entry criterion, in addition to the absence of exclusion criteria. Furthermore, 20 inclusion points need to be met to classify a patient. Our case meets all 3 of the 2011 comprehensive diagnostic criteria for IgG4-RD, which is compatible with a definite diagnosis [10]. Nevertheless, since pericarditis is not included in the 2019 ACR/EULAR entry criteria as a typical disease manifestation, pericarditis as a solitary presentation can never be classified as IgG4-RD according to these most recent criteria. It should be noted that, according to the authors, the ACR/EULAR criteria were not intended for use in clinical practice to establish the diagnosis of IgG4-RD, but were particularly developed for clinical trials, with high specificity in mind. However, our case does underline the pitfalls criteria can present and illustrates that a diagnosis of IgG4-RD usually requires a combination of clinical, radiological, serological, and histopathological features.

Conclusion

In persistent idiopathic pericarditis, IgG4-RD should be considered as a possible cause, particularly in the presence of other forms of serositis. A serum-IgG4 measurement seems to be a useful first step. When considering a biopsy, specific attention to the pathological hallmarks of IgG4-RD and a low threshold for IgG4-staining are warranted.