A 61-Year-Old Woman Presenting with Low Back Pain Diagnosed with IgG4-Related Disease Affecting the Thoracoabdominal Aorta and Retroperitoneum

Background

Immunoglobulin G4-related disease (IgG4-RD), comprising disease entities of systemic immune-mediated fibro-inflammatory disorders [1–3], was proposed in 2003 [4], defined in 2010 [5], and unified in 2012 [6]. Classification criteria were developed in 2019 [1,2]. IgG4-RD presents inflammation with dense lymphocytes, infiltration with IgG4-positive plasma cells, and marked fibrosis [1–3,7–9]. Clinical manifestations of IgG4-RD vary, depending on the affected multiple organs [6]. The diagnosis of IgG4-RD is challenging because of multiorgan involvement and heterogeneity, thus requiring thorough comprehensive whole-body evaluation [10] and differentiation from malignancies and other immune-related fibro-inflammatory disorders [3,11]. Although IgG4-RD shows a favorable response to glucocorticoid (GC) treatment, relapse or refractoriness to treatment are critical concerns of clinicians [3,9,12,13].

Here, we present the case of a 61-year-old woman with low back pain who was diagnosed with IgG4-RD with rare involvement of the thoracoabdominal aorta and retroperitoneum diagnosed based on histopathological and radiological studies according to the 2019 classification criteria. The role of imaging studies for diagnosis and treatment response monitoring has been increasing, and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (F-18-FDG-PET/CT) is a useful tool for the diagnosis and clinical outcomes of IgG4-RD [14]. We report impressive F-18-FDG-PET/CT imaging findings that simultaneously involved invasion of the thoracoabdominal aorta and retroperitoneum by IgG4-RD, and we provide a brief literature review of IgG4-RD.

Case Report

A 61-year-old woman presented with a 1-month history of persistent low back pain that radiated to the right hip area and was aggravated by walking. She had persistent back pain despite nerve block therapy on the lumbar spine, and poorly demarcated retroperitoneal lesions were identified on lumbar spine magnetic resonance imaging (MRI). She had been referred to a university hospital in South Korea in January 2020. She used to be a light smoker (0.5 packs/day for 15 years) but had quit smoking 10 years earlier. She had right breast cancer, for which she had undergone breast-conserving surgery and adjuvant radiotherapy 6 years previously. She had been using tamoxifen 20 mg/day and required regular follow-up.

Physical examination findings were unremarkable. The abnormal results of blood laboratory test results included anemia (9.2 g/dL hemoglobin [reference range: 12–16], 29.3% hematocrit [reference range: 36–46]) and increased inflammatory markers (21.34×103/μL white blood cells [WBC; reference range: 4.0–10.0×103] with 80% neutrophils [reference range: 40–80%], 0.2% eosinophils [reference range: 1–7%], and 12.96 mg/dL Creactive protein [CRP; reference range: less than 0.3]). Despite constantly increased WBC and CRP levels, the body temperature was within the normal range and no other findings suggestive of an infection were observed. The serum IgG4 concentration was estimated at 418.0 mg/L (reference range: 30–2000). Chest and abdominopelvic CT demonstrated diffuse circumferential infiltrative soft tissue lesions with contrast enhancement from the ascending aorta, aortic arch, descending aorta to the bilateral common iliac artery bifurcation, right internal iliac artery, and retroperitoneum. There was deep vein thrombosis on the right common iliac vein. Multiple lymph nodes were enlarged in the paraaortic and aortocaval areas (Figure 1A, 1D). There was right obstructive hydronephrosis, despite the values being within the normal range of renal function according to the blood laboratory test results. A dilated renal pelvis with partial urinary obstruction for the right kidney and decreased renal function was observed in a diuretic renal scan using Tc-99m MAG3. There was also diffuse heterogeneous F-18-FDG uptake along the aortic arch (standard uptake value [SUV] max: 13.3) involving the origin of 3 branches, without obstruction and the abdominal aorta from the gastroesophageal junction to both the common and right internal iliac arteries, with a prominent hypermetabolic lesion in the right common and internal iliac arteries (SUV max: 9.2) on F-18-FDG-PET/CT (Figure 1B, 1C, 1E). The patient underwent laparoscopic retroperitoneal biopsy of the fibrotic lesion around the infrarenal aorta and common iliac arteries, and a double-J ureteral stent through cystoscopy was placed under general anesthesia. On histopathological examination and immunohistochemical staining, dense lymphoplasmacytic infiltration with 16 IgG4-positive cells per high-power field and a ratio of IgG4-positive cells to IgG-positive cells of 13% were identified. Phlebitis, with obliterative changes, was observed. There was diffuse marked fibrosis without a conspicuous storiform pattern (Figure 2). The patient met the inclusion criteria, had no findings of exclusion criteria, and had a total of 21 points; therefore, she was diagnosed with IgG4-RD involving the thoracoabdominal aorta, iliac arteries, and retroperitoneum based on the 2019 classification criteria for IgG4-RD [1,2]. She was treated with 30 mg/day GCs for 6 months and an anticoagulant (apixaban 5 mg, twice per day). After the treatment was completed, it was considered that there was an objective GC response given the improvement of the back pain, reduction of the serum IgG4 level (145.0 mg/L), and decrease of the extent of the fibro-inflammatory lesion on CT. However, she had radiating pain to the right lower extremity as well as claudication (Stage IIB in the Fontaine classification and Category 3 in the Rutherford classification) [15]. Lack of arterial pulsation and near total occlusion of the right common and internal iliac arteries on CT (Type D in the Trans-Atlantic Inter-Society Consensus Document classification) was identified (Figure 3A) [15]. The patient underwent femoral-to-femoral bypass graft surgery for revascularization of the arterial blood flow in the lower extremities (Figure 3B). Approximately 1 month after surgery, the low back pain and urinary frequency relapsed and the levels of IgG4 (321 mg/L) and inflammatory markers (3.36 mg/dL CRP) became elevated. Moreover, the extent of retroperitoneal fibrosis was found to be increased on CT; this was considered the first IgG4-RD relapse. The axial CT images and values of serum IgG4 according to the patient’s clinical course are presented in Figure 4A–4C. GC treatment was restarted (30 mg/day) for 4 weeks. The clinical symptoms improved, and the level of serum IgG4 decreased (107 mg/dL). When the GC dose was tapered (15 mg/day), the pain worsened; this was regarded as a failure of GC tapering, and the patient was classified as being at high risk of relapse. The symptoms improved through treatment with an immunosuppressant (methotrexate; MTX 7.5 mg per week) added to the GC regimen of 15 mg/day; it was subsequently possible to gradually taper the GCs to 2.5 mg/day.

The IgG4-RD responder index presented in 2019 is designed to assess therapeutic efficacy in a consistent way, scoring the therapeutic response rate at 0–3 depending on the corresponding organ/site [16]. In our patient, the diameter of the descending aorta decreased during treatment, but after stopping treatment, the diameter increased and obstruction of the right common and internal iliac arteries persisted. Bypass surgery was eventually performed because of the claudication symptoms. Therefore, the organ/site score of aorta/large blood vessels was “2”; symptomatic, “yes”; urgent, “yes”; and damage, “yes.” For the retroperitoneal fibrosis, hydronephrosis was caused by obstruction of the right ureter, and a double-J ureteral stent was placed, leading to improvement. Symptoms improved with high-dose GCs and immunosuppressants, without decrease in renal function or permanent complications. Therefore, the organ/site score was considered to correspond to “2”; symptomatic, “yes”; urgent, “yes”; and damage, “no.” The patient is currently being followed up and has been showing a good response to the combination therapy (GC 2.5 mg/day and MTX 7.5 mg per week).

Discussion

The diagnosis of IgG4-RD is challenging because of the condition’s rarity, heterogeneity, and non-specific symptoms. In this patient, the ascending aorta, aortic arch, thoracic descending aorta, abdominal aorta, iliac vessels, and retroperitoneum were simultaneously affected, which is rare [17, 18]. Presenting the advantages and usefulness of F-18-FDG-PET/CT in a case of multiple and systemic IgG4-RD involvement is meaningful.

IgG4-RD is characterized by immune-mediated chronic inflammation with dense lymphoplasmacytes, IgG4-positive plasma cell infiltration, and marked fibrosis, and IgG4-RD is known to involve almost all organs, including the salivary glands, thyroid, meninges, orbits, lacrimal glands, lungs, pancreas, biliary tracts, kidneys, aorta extending to the main branches, mediastinum, and retroperitoneum, simultaneously or sequentially [17–22]. The aorta is a rarely involved organ in IgG4-RD [17,18]. Based on the distribution of aorta involvement in IgG4-RD, Inoue et al reported that among 17 patients, the thoracic aorta was involved in only 4 patients; however, neither side of the thoracic and abdominal aorta was involved [23]. Yabusaki et al reported that, of 15 patients, involvement of both the thoracic and abdominal aorta was observed in 3 and there was no case of only thoracic aorta involvement [24]. Simultaneous invasion of the thoracic and abdominal aorta is rare, and the frequency of invasion is lower for the thoracic aorta than for the abdominal aorta. However, Perugino et al reported that the thoracic aorta was involved in 8 of 13 patients, whereas 5 patients primarily had involvement of the abdominal aorta and iliac artery [25]. It is not clear whether the difference in the results compared with the previous 2 studies is attributable to the small sample size or differences in ethnicity. Large vessels affected by IgG4-RD can develop aneurysmal dilatation extending to aortic dissection and various vascular complications [12,26–28]. If appropriate diagnosis and treatment are not performed, the disease can progress and result in irreversible fatal complications [28,29].

Although the function of IgG4 is controversial, the pathophysiology of IgG4-RD has been elucidated. Plasmablasts present antigens to CD4+ SLAMF7+ cytotoxic T cells along with the B cell lineage. These cells produce important mediators such as interleukin-1, transforming growth factor beta, and interferon-gamma, which is a major cause of fibrosis or tissue damage [19,30]. B cell-depleting agents such as rituximab (RTX) reduce the blood levels of CD4+ SLAMF7+ T cells, and effective treatment can restore fibrosis to some extent [19,30]. A humanized anti-CD19 antibody with an Fc portion designed to increase affinity for Fc-gamma-RIIb by hundreds of times is known to inhibit B lineage cells [19,30].

The laboratory findings are mostly consistent with those of inflammatory disorders. The values of acute-phase reactants (CRP) can reflect inflammatory activity and the extent of systemic involvement and are roughly correlated with the treatment response [7]. Increased serum levels of IgG4 support the diagnosis of IgG4-RD. However, the serum IgG4 concentration alone cannot be used to diagnose or exclude IgG4-RD and does not help in the differential diagnosis because more than 30% of patients with IgG4-RD have normal serum IgG4 levels and 5% of the general population has elevation of IgG4 levels associated with other causes [8,9]. Continuous monitoring of the serum IgG4 concentration can be helpful for predicting the extent of organ involvement, treatment response, and relapse [7–9,21,31,32]. In our patient, diagnosis, treatment response, and development of relapse were correlated with the serum IgG4 and inflammatory marker levels.

Radiological studies such as ultrasonography, CT, MRI, and F-18-FDG-PET/CT play an important role in IgG4-RD. CT and MRI depict the involved organs; extent, location, compression, or obstruction of vascular structures; obstructive uropathy; and associated lymphadenopathy [7,13,32]. The degree of enhancement roughly correlates with the inflammatory activity in the lesions [7,13,32]. F-18-FDG-PET/CT is a useful functional imaging modality for diagnosis, providing whole-body imaging for evaluation of systemic multifocal diseases and for the full extent of vessel involvement, being more sensitive in detecting organ involvement than other techniques [7,13,33–37]. The values of F-18-FDG uptake on the F-18-FDG-PET/CT are considered useful for evaluating IgG4-RD activity and for detecting appropriate biopsy sites [9,33–35]. Regular clinical follow-ups with periodic radiological evaluations are necessary to exclude malignant diseases and to detect relapse, which is an important clinical issue in IgG4-RD [13,26].

Fibro-inflammatory lesions have idiopathic and secondary etiologies, including malignancy, drug use, infection, radiotherapy, and surgery [13,36,37]. Differential diagnosis between idiopathic and malignant fibro-inflammatory lesions is critical and difficult [21,34,36]. The diagnosis is confirmed by exclusion of mimicking diseases and malignancies. The results of radiologic studies are helpful, but not sufficient, for differential diagnosis [9,36,37]. Histopathological confirmation is important and strongly recommended [1–3,9]. It has been reported that only approximately one-third of patients were diagnosed based on histopathology [38]. The characteristic histopathological findings include dense lymphoplasmacytic infiltration, irregularly whorled fibrosis known as storiform fibrosis, and obliterative phlebitis [39]. These characteristic histopathological findings are weakened in marked fibrotic lesions, complicating the diagnosis [8].

Treatment should be started as soon as possible, with the goal of relieving symptoms and complications, aiming at remission and preventing relapse [9]. Medical treatments should be preferentially considered and should aim at modulating the immune system through GC monotherapy or combined with immunosuppressive agents such as B cell-depleting agents [38,40,41]. If there is no response to initial GC treatment, the diagnosis needs to be reviewed [9]. With GC, the recommended first-line agent, induction therapy (0.6 mg/kg/day) is performed for 4 weeks, and then follow-up evaluations are recommended for assessing disease activity and treatment responses [1,2,9]. The GC tapering dose and duration should be tailored depending on the treatment response [1,2,9]. Immunosuppressive agents (azathioprine, cyclophosphamide, MTX, and mycophenolate mofetil) are used as representative steroid-sparing agents for patients with GC refractoriness, GC treatment failure, or relapse [8,13]. RTX acts as a B cell-depleting agent and anti-CD20 antibody to reduce metabolic and fibrotic activity [7–9,13,19]. RTX can also be effective as a steroid-sparing agent to allow early GC tapering or as monotherapy [7–9,12,42–44]. After induction GC therapy, maintenance therapy helps reduce the risk of relapse and minimize morbidity in patients at high risk of relapse. Maintenance therapy is performed with low-dose GC (2.5–5 mg/day) or RTX monotherapy [7–9,38]. However, the optimal dose or treatment duration of maintenance therapy remains uncertain [7–9,38]. As the pathogenesis is revealed, new drugs that act by various mechanisms have been developed and are in clinical trials, such as abatacept, belimumab dupilumab, elotuzumab, inebilizumab, obexelimab, rilzabrutinib, and zanubrutinib [45].

Revascularization procedures, including percutaneous intravascular stenting, endovascular stent insertion, and endovascular bypass graft, have been used to treat vessel obstruction; however, their long-term effectiveness is questionable because of restenosis [27,46]. If vascular complications aggravate in the advanced stage or are refractory to medical therapy, appropriate surgical management is required [27]. Our patient had severe claudication caused by total occlusion of the common iliac and internal iliac arteries with lack of arterial pulsation, and femoral-to-femoral bypass graft surgery was performed for revascularization.

Remission is regarded as improvement of the clinical symptoms, normalization of the acute-phase reactants, significant decrease in serum IgG4 concentration, and regression of the lesions on radiological studies [7,13,26,37]. Approximately 30% of patients experience relapse after first-line GC treatment [40,41], and the rate of relapse increases with a longer follow-up period [40,41]. Relapse frequently occurs after tapering or early discontinuation of GC treatment, particularly within 1 year [7,9,35,38].

The etiology of the periaortic fibrosis in the mediastinum, affected by breast cancer, surgery, and radiotherapy, could not be completely excluded through histopathological confirmation. It is known that when breast cancer metastasis occurs in the mediastinum, it is generally expressed as metastatic lymphadenopathy and rarely as mediastinal fibrosis [34]. If breast cancer metastasis develops in the mediastinum and retroperitoneum, it will not respond to GC therapy without treatment for breast cancer [34]. There was no evidence of recurrence more than 6 years after breast cancer surgery. The possibility of fibrosis caused by radiotherapy was excluded because the lesions occurred along the aorta rather than on the field of the radiotherapy and other accompanying complications such as radiation pneumonitis were not observed. After more than 24 months of follow-up, no other malignancy that could cause fibro-inflammatory lesions was observed. An idiopathic fibrotic lesion in the mediastinum could be classified as an isolated lesion or as one associated with other diseases [47]. As the lesions on the aorta were accompanied by a multifocal thoracoabdominal aorta, iliac vessels, and retroperitoneum, we considered them associated with IgG4-RD rather than as isolated lesions.

In addition, there have been many reports that RTX has good therapeutic effects as a steroid-sparing agent [7–9,12,42–44]. Although this patient experienced relapse and failure of GC tapering, RTX treatment was not administered; RTX is considered a good treatment option if additional relapses occur.

Conclusions

The importance of radiological studies is increasing in the diagnosis and treatment response evaluation of IgG4-RD showing systemic multiorgan involvement. The use of F-18-FDG-PET/CT, which is a functional imaging modality of the whole body, is useful for disease activity monitoring, response evaluation, and drug development.