IgG4-related disease presenting with multiorgan involvement

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a rare fibroinflammatory immune-mediated condition which can affect multiple organ systems and form mass-like lesions. Initial presentation can mimic other diseases such as pancreatic malignancy when there is pancreatic involvement or tuberculosis (TB) when there are pulmonary lesions or hypertrophic pachymeningitis (HP). Here, we report a novel case of IgG4-RD presenting as bilateral subdural haematomas with additional findings. Our patient is a male who presented with headaches and blurred vision. Physical examination showed disconjugate gaze with a fixed pupil. Trauma survey radiologic imaging revealed a pancreatic mass concerning for malignancy. Subsequent workup found hypophysitis with optic chiasm compression and hypopituitarism, mediastinal lymphadenopathy and HP. Laboratory values showed an elevated serum IgG4 level and latent TB. Our case adds to the existing IgG4-RD literature by highlighting a unique presentation. It is important to maintain it on the differential diagnosis especially in multisystemic presentations with competing diagnoses.

Background

Immunoglobulin G4-related disease (IgG4-RD) is a rare entity that can have a variety of presentations. Its prevalence is difficult to ascertain especially considering that it does not yet have its own International Statistical Classification of Diseases and Related Health Problems-10 code. The pancreaticobiliary system is commonly affected with the pancreas being the most frequently involved organ. Other affected systems include salivary glands, kidneys, periorbital tissue, lungs, lymphatic system, aorta, thyroid, pericardium and skin. The definition of IgG4-RD has evolved over time and now encompasses a spectrum of conditions which were previously recognised as standalone. These include plasma cell granuloma, xanthofibroma (brain),¹ Mikulicz’s syndrome (salivary and lacrimal glands), Küttner’s tumour (submandibular glands), Riedel’s thyroiditis, multifocal fibrosclerosis (orbits, thyroid, retroperitoneum, mediastinum), inflammatory pseudotumour and Ormond’s disease (retroperitoneal fibrosis). Regardless of the involved site, the diagnostic hallmarks include lymphoplasmacytic infiltration of predominantly IgG4-positive plasma cells with a varying degree of fibrosis. Serum IgG4 levels may be elevated.²

We report an unusual presentation of IgG4-RD in a patient whose initial findings were bilateral subdural haematomas (SDH). Our case demonstrates the need for a high clinical index of suspicion especially when the initial presentation is deceptive, and many differential diagnoses come forth as the case evolves.

Case presentation

A male in his late 50s, with no medical history presented with 1 week of progressive left frontotemporal headache, left eye blurred vision and abdominal pain. History was notable for a fall from a chair 3 months ago—medical care was not sought at the time as he was asymptomatic.

On admission, he was afebrile, awake and alert with a blood pressure of 157/87 mm Hg, heart rate of 76 beats/min, respiratory rate of 16, and O₂ saturation of 98% on room air. Eye examination was notable for disconjugate gaze with a fixed non-reactive left pupil and lagging movements in all directions (video 1). Auscultation of his chest revealed normal heart sounds and no adventitious breath sounds. His abdominal examination was benign.

Video 1.

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bcr-2022-250637supp001.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2022-250637.video01

Basic laboratory values showed normal electrolytes, renal function, haemoglobin and platelet count. Non-contrast CT head demonstrated bilateral SDH, left greater than right with mass effect but no midline shift (figure 1). Non-contrast CT chest–abdomen–pelvis revealed extensive mediastinal and hilar lymphadenopathy, multifocal pulmonary nodules, and a 5.9 cm pancreatic body/tail mass without evidence for abdominopelvic metastatic disease raising concern for pancreatic neoplasm.

Figure 1.

(Left) Axial non-contrast CT slice above the level of the lateral ventricles shows two subdural parietal convexity collections. The left parietal convexity is hypodense and is consistent with a chronic subdural haematoma. The smaller right parietal collection is isodense to brain parenchyma consistent with subacute subdural haematoma. Both collections result in local sulcal effacement without midline shift. (Right) Coronal non-contrast CT slice of the same collections (arrows) at the level of the pineal gland.

Neurosurgery recommended interval CT imaging to ensure stability of the bilateral SDH and ultimately did not require surgical intervention. Given his ocular findings, MRI brain was pursued and revealed an enlarged infundibulum with mass effect on the optic chiasm. There was note of diffuse pachymeningeal enhancement (figure 2). Despite the absence of pulmonary symptoms, concern for TB was high in the presence of hypertrophic pachymeningitis (HP) and pulmonary nodules. An interferon gamma release assay (IGRA) returned positive. This prompted infectious disease consultation and airborne precautions. The patient recalled receiving the BCG vaccine remotely while in the military in El Salvador but otherwise had no knowledge of TB exposures including incarceration. Lumbar puncture and three induced sputum samples for acid-fast bacilli (AFB) were obtained which were negative. Cerebrospinal fluid was unremarkable including normal opening pressure, seven white blood cells, normal glucose, normal protein, negative cryptococcus antigen and negative cytology.

Figure 2.

(A) Coronal T1-weighted post contrast image shows enhancement of a thickened infundibulum adjacent to the optic chiasm. Diffuse pachymeningeal enhancement is also seen. (B) Sagittal T1-weighted Image at the midline shows infundibular thickening. (C) Axial post contrast 3D FSPGR slice at the level of the optic nerves shows an enlarged enhancing infundibulum contacting the optic chiasm. (D) Sagittal SPGR slice shows thickened hyperintense infundibulum with a normal pituitary.

Other pertinent laboratory values included a negative HIV and normal serum ACE. Carbohydrate antigen-19–9 and carcinoembryonic antigen were normal. Thyroid stimulating hormone (TSH) was normal at 3.467 uIU/mL, free thyroxine-4 (fT4) low at 0.80 ng/dL (reference range 0.89 to 1.78), low follicle-stimulating hormone (FSH) at 1.0 mIU/mL (reference range 1.5–14.3), normal luteinising hormone at 0.4 mIU/mL, low total testosterone 0.8 nmol/L (reference range 10 to 42), high prolactin 26.5 ng/mL (reference range between 0.6 and 19), normal growth hormone, low insulin-like growth factor-1 (IGF-1) at 10 ng/mL (reference range 50–317), normal adrenocorticotropic hormone, and normal cortisol. Lastly, serum IgG4 was markedly elevated at 262.6 mg/dL (reference range 3.9–89).

5.9 cm pancreatic mass on initial CT prompted a contrast-CT pancreas protocol that showed circumferential soft tissue encasing the splenic artery with abutment along the pancreatic body-tail. Soft tissue also encased the distal thoracic and proximal abdominal aorta extending to the level of the proximal coeliac artery (figure 3). Pancreaticobiliary consult team performed an endoscopic ultrasound that identified an irregular, lobular and hyperechoic mass-like area involving the proximal pancreatic body and pancreatic tail (figure 4). The mass had a ‘rim’ encompassing it. Biopsies were obtained.

Figure 3.

(Left) Axial arterial phase CT slice shows a hypodense pancreatic mass involving the posterior pancreatic body and tail with encasement of the contrast filled partially visualised splenic artery without displacement of the artery. (Right) Axial venous phase CT slice shows a posterior pancreatic tail hypodense mass encompassing but not displacing the splenic vein.

Figure 4.

Endoscopic ultrasound images show a hypodense lobular well circumscribed mass that measures 24 mm by 34 mm involving the proximal pancreatic body and pancreatic tail.

This patient’s findings which included pancreatic/peripancreatic-periaortic mass, HP, pulmonary nodules and hypophysitis with cranial nerve palsies and hypopituitarism in conjunction with elevated serum IgG4 levels led to strong consideration of IgG4-RD.

Further investigations

During his extensive workup, the patient underwent endobronchial ultrasound with sampling of his thoracic lymph nodes which were negative for AFB and malignancy. Immunohistochemical stains showed IgG and IgG4 positive plasma cells. Pancreatic body/tail pathology eventually showed fibrosis, chronic inflammation and positive IgG4 cells.

Treatment

Treatment with pulse-dose methylprednisolone and a prolonged prednisone taper was started prior to final pathology. He had improvement in his symptoms.

Outcome and follow-up

The patient completed a 15-week prolonged prednisone taper. While on the prednisone taper, he also received a dose of rituximab 1 day prior to discharge. He was directly admitted 15 days later for a second rituximab infusion. He completed directly observed therapy for latent TB. Five months later, he has continued to follow-up with rheumatology and is doing well. His headache has resolved and visual symptoms have improved.

Discussion

IgG4-RD recognition continues to grow, and its definition has evolved to a current unified systemic disorder of what was once considered unrelated single-organ processes. The exact pathogenesis remains unclear; however, it is known that CD4 +T and B cells, including IgG4-expressing plasma cells, form most of the cellular inflammatory population and drive fibrosis. Regardless of the presentation, the common histological thread is a dense lymphoplasmacytic infiltrate of predominate IgG4-plasma cells, fibrosis, frequent tissue eosinophilia, and frequently elevated serum IgG4 levels.² The latter is only seen in 50%–70% of patients.³

Our patient was found to have bilateral SDH on CT, and to our knowledge, this is the first case of IgG4-RD presenting as bilateral SDH. In review of the literature, there is one case of multifocal fibrosclerosis—which is now reclassified under IgG4-RD—in a 60-year-old man with no history of trauma that presented with unilateral chronic SDH, persistent high-grade fevers and sclerosing cholangitis on biopsy.⁴ In a recently published case, a 25-year-old man presented with seizures and was found to have HP with a right-sided skull lytic lesion mimicking a SDH on CT. Subdural collection pathology showed aggregates of chronic inflammatory cells, plasma cells and lymphocytes.⁵

Neurological presentation in IgG4-RD is a rare entity but will usually present as hypophysitis with HP.⁶ Although HP is a distinguishing clinical finding, it has a broad range of possibilities which include TB, syphilis, trauma, lymphoma, granulomatosis with polyangiitis and sarcoidosis to name a few. If no cause is found, then it is deemed idiopathic HP of which there is one published case presenting as unilateral chronic SDH.⁷ Hypophysitis led to optic chiasm which explains our patient’s left cranial nerve VI palsy with a fixed nonreactive pupil. These findings along with headache are among the most common presentations of the uncommon neurological presentations. In a study of 33 HP cases, 33% presented with cranial nerve palsies and 21% with vision disturbances.⁸

IgG4-related hypophysitis was also established in our patient using Leporati et al. criteria⁹ (table 1). Our patient also had hypopituitarism in the form of a high prolactin (impaired dopaminergic inhibition), low fT4 with an inappropriately normal TSH, low total testosterone, and low IGF-1. In a prevalence study, hypopituitarism was observed in 24 cases (83%) of confirmed IgG4-related hypophysitis.¹⁰

Table 1.

Leporati et al proposed diagnostic criteria for IgG4-related hypophysitis

Criterion 1	Pituitary histopathology Mononuclear infiltration of the pituitary gland, rich in lymphocytes and plasma cells, with more than 10 IgG4-positive lesions per high power field
Criterion 2	Imaging Pituitary MRI sellar mass and/or thickened pituitary stalk
Criterion 3	Biopsy-proven involvement in other organs Association with IgG4-positive lesions in other organs
Criterion 4	Serology Increased serum IgG4
Criterion 5	Response to glucocorticoids Shrinkage of the pituitary mass and symptomatic improvement with steroids

Diagnosis established with any of the following: Criterion 1, Criterion 2 and 3, or Criterion 2, 4, and 5.

Reproduced with permission from Leporati P et al. IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab. 2011 Jul;96(7):1971–80. By permission of Oxford University Press.

Glucocorticoids are first-line treatment—a dramatic response is a hallmark of IgG4-RD. Without treatment, fibrosis can progress to severe organ damage. Treatment protocol is to give 0.5 mg/kg of prednisone (30–40 mg/day) for 2–4 weeks and dose reduce by 5 mg per 1–2 weeks.¹¹ Rituximab is preferred in patients with glucocorticoid-refractory disease, multiorgan involvement, or extremely high serum IgG4 levels. The recommended dosage is 1 g intravenous infusion on day 1 and repeated on day 15.⁷ Our patient received a combination of both with remarkable results.

Learning points.

• Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory process that leads to fibrosis of almost any organ.

• This is a case of IgG4-RD with a unique presentation of bilateral subdural haematomas. Other notable findings include pancreatic-peripancreatic and periaortic mass, pulmonary nodules, mediastinal-hilar lymphadenopathy, diffuse hypertrophic pachymeningitis, hypophysitis, ocular nerve palsies and hypopituitarism.

• Elevated serum IgG4 supports the diagnosis in the appropriate clinical context but final diagnosis requires tissue biopsy.

• Glucocorticoids are first-line treatment and typically provide a dramatic response. Rituximab can be used for refractory or severe disease.

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