A Case Series of Patients with Isolated IgG4-related Hypophysitis Treated with Rituximab

Abstract

Context: The acute presentation of immunoglobulin G4 (IgG4)-related hypophysitis can be indistinguishable from other forms of acute hypophysitis, and histology remains the diagnostic gold standard. The high recurrence rate necessitates long-term immunosuppressive therapy. Rituximab (RTX) has been shown to be effective in systemic IgG4-related disease (IgG4-RD), but experience with isolated pituitary involvement remains limited.

Case description: We report 3 female patients with MRI findings suggestive of hypophysitis. All patients underwent transsphenoidal biopsy and fulfilled diagnostic criteria for IgG4-related hypophysitis. Treatment with glucocorticoids (GCs) resulted in good therapeutic response in Patients 1 and 2, but the disease recurred on tapering doses of GCs. GC treatment led to emotional lability in Patient 3, necessitating a dose reduction. All 3 patients received RTX and Patients 2 and 3 received further courses of treatment when symptoms returned and B-cells repopulated. Patient 3 did not receive RTX until 12 months from the onset of symptoms. Patient 1 was not able to have further RTX treatments due to an allergic reaction when receiving the second dose. Rituximab treatment resulted in sustained remission and full recovery of anterior pituitary function in Patients 1 and 2, with complete resolution of pituitary enlargement. By contrast, Patient 3 only showed a symptomatic response following RTX treatment, but pituitary enlargement and hypofunction persisted.

Conclusion: Rituximab treatment for IgG4-related hypophysitis resulted in sustained remission in 2 patients treated early in the disease process but only achieved partial response in a patient with chronic disease, suggesting that early therapeutic intervention may be crucial in order to avoid irreversible changes.

Keywords: IgG-4 related hypophysitis; IgG4-related disease; Rituximab; pituitary.

Figure 1.

Histopathological features of the pituitary biopsies from Patients 1–3. Hematoxylin and eosin staining (upper panel) and anti-IgG4 immunohistochemical staining (lower panel). A: Patient 1, adenohypophysis with lymphoplasmacytic inflammatory infiltrates and focal granulomatous formation. The inflammatory infiltrate (D) contains numerous IgG4-positive plasma cells (> 10/HPF). B: Patient 2, extensive lymphoplasmacytic inflammatory infiltration of the anterior pituitary. Many IgG4-positive plasma cells (> 10/HPF) are present (E). C: Patient 3, adenohypophysis with lymphocytoplasmacytic inflammatory infiltrates and xanthogranulomatous changes. The inflammatory infiltrate contains abundant (10–30/HPF) IgG4-positive plasma cells (F).

Figure 2.

Sagittal postcontrast T1W MR images of the pituitary. A: Pretreatment scan showing an enlarged and diffusely enhancing pituitary gland extending into the suprasellar cistern (long white arrow) with adjacent dural enhancement (short white arrow). B: Image following GC and RTX treatment showing the initial response to treatment with significant reduction in the size of the pituitary mass. C: Image following further RTX treatment showing substantial reduction in the size of the pituitary mass. D: Image following treatment with Ofatumumab, demonstrating full normalization of the pituitary gland.

Figure 3.

Sagittal postcontrast T1W MR images of the pituitary. A: Pretreatment scan showing a pituitary mass (long white arrow) elevating and compressing the optic chiasm (short white arrow). B: Image following remission induction with GC treatment, demonstrating mild reduction in the size of the pituitary mass. C: Image following the first cycle of RTX treatment showing significant reduction in the size of the pituitary mass. D: Image 6 months after RTX showing substantial reduction in the volume of the pituitary gland.

Figure 4.

Patient 2. Correlation of symptoms, total B lymphocyte count (y-axis, cells/ul) and RTX treatments. Total B lymphocyte count, normal reference range 100 to 500 cells/ul. Rituximab treatment consisted of 1 gram of RTX given twice, 2 weeks apart. Grey arrows denote the onset of headaches and other systemic symptoms.

Figure 5.

Coronal postcontrast T1W MR images of the pituitary. A: Image at presentation showing a sellar and suprasellar mass lesion involving the pituitary stalk and compressing the optic chiasm and involving the left optic nerve. B: Image following a short period of GC treatment and the first cycle of RTX. C: Image following the second cycle of RTX. D: Image following the third cycle of rituximab. Serial images demonstrate gradual reduction of the left-sided suprasellar component and some decompression of the left optic nerve (white arrows). There is been no significant overall reduction in the size of the pituitary mass lesion.