EDITORIAL
Pituitary Involvement in Granulomatosis With Polyangiitis Tuck Yean Yong, FRACP,*Þ and Jordan Yuanzhi Li, FRACPÞþ
G
ranulomatosis with polyangiitis (GPA), formerly Wegener granulomatosis, is an antiYneutrophil cytoplasmic antibody (ANCA)Yassociated systemic necrotizing granulomatous small-vessel vasculitis. It typically affects the upper respiratory tract, lungs, and kidneys but can involve virtually any organ including the pituitary. Pituitary involvement in GPA is rare. In this issue, Al-Fakhouri and colleagues1 have reported 2 cases, and a total of 35 cases have been reported in the English medical literature between 1966 and August 2013. There were only 23 cases when the last major review of pituitary involvement in GPA was published in 2008.2 Although GPA affects males and females equally, the majority of patients with pituitary involvement are female. The increasing number of reported cases highlights that clinicians need to be aware of GPA as a cause of pituitary insufficiency, and pituitary function needs to be assessed in GPA patients with clinical features. The pathophysiology of the hypothalamus-pituitary involvement in GPA includes granulomatous lesions by contiguous invasion from nasal or paranasal granuloma, in situ granuloma formation, vasculitis of anterior and/or posterior pituitary blood vessels, or a combination of these mechanisms. However, the reason for the pituitary to be involved in a small number of patients with GPA and yet others are spared is unknown. Pituitary involvement in GPA usually occurs in the course of the disease with other organ involvement. There is only 1 reported case with isolated pituitary involvement at the time of presentation.3 Granulomatosis with polyangiitis can affect partial or global pituitary endocrine function to varying degrees.2 Central diabetes insipidus has been more commonly observed with or without concurrent anterior pituitary insufficiency due to a preponderance of posterior pituitary involvement. The diagnosis of GPA remains challenging with pituitary involvement because initial clinical symptoms can be nonspecific, often resulting in delayed recognition. The presence of symptoms of pituitary insufficiency in conjunction with epistaxis and/or sinusitis should heighten the clinician’s suspicion of GPA as a potential etiology. In the case series of GPA with pituitary involvement, the majority of patients except for 1 case have all been ANCA positive with antiYproteinase 3 specificity observed in many of these cases.2 AntiYneutrophil cytoplasmic antibody levels do not typically correlate with severity of disease.4 With the current limitations of noninvasive tests, tissue biopsy is still necessary for diagnostic confirmation because of the potentially toxic nature of treatment of GPA. In cases of GPA with pituitary involvement, most patients have other organ involvement, which allow tissue biopsies to be performed, whereas biopsy of the pituitary is only rarely required. Magnetic resonance imaging (MRI) of the pituitary is useful in diagnosis. The classic MRI findings in GPA are pituitary enlargement, diffuse or focal infundibular thickening, and the absence of the normal high-intensity signal in the posterior pituitary lobe, seen on T1-weighted images. However, patients may have a predominantly small vessel vasculitis, and only minimal changes would be visible on MRI. These MRI abnormalities may vary with disease activity. The treatment of GPA with pituitary involvement involves 2 components. First, it involves treatment of relevant endocrine insufficiency, which includes corticosteroid, thyroid hormone, testosterone, vasopressin replacement, or combinations of these therapies as clinically indicated, and second, treatment of the underlying GPA. Treatment for the underlying GPA has been diverse. In the past, some patients have undergone surgical treatment of the pituitary lesion, which would usually lead to varying degrees of permanent pituitary insufficiency.3,5 Although this practice has largely been avoided, a case report was recently published about a patient with difficult-to-manage GPA involving the pituitary who underwent surgical intervention for local disease control.6 Conventional therapy for GPA with pituitary involvement uses the combination of high-dose corticosteroid and cyclophosphamide (oral or intravenous) for induction therapy. In case series, this combination therapy induced remission in all patients, but
From the *Department of General Medicine, Flinders Medical Centre; †School of Medicine, Flinders University; and ‡Department of Renal Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia. The authors declare no conflict of interest. Correspondence: Tuck Yean Yong, FRACP, Department of General Medicine, Flinders Medical Centre, Flinders Dr, Bedford Park, South Australia, Australia 5042. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608/14/2003Y0123 DOI: 10.1097/RHU.0000000000000092
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Editorial
TABLE 1. Areas for Future Research in GPA With Pituitary Involvement Epidemiological data on pituitary involvement in GPA The reason for different organs to be affected by GPA and not others in individual patients Treatment of pituitary GPA that prevents long-term pituitary insufficiency The best strategy for preventing GPA relapses Establishing the role of biological agents in the management of GPA 2
about a quarter of patients had a relapse within 10 months. In maintenance treatment, oral cyclophosphamide or azathioprine with or without corticosteroid was commonly prescribed.2 Treatment of GPA can be challenging because of corticosteroid and cyclophosphamide toxic adverse effects and the development of refractory and relapsing disease in some patients. This has led to the use of biological agents, rituximab, an anti-CD20 monoclonal antibody, which depletes B lymphocytes. Rituximab was first demonstrated to be beneficial in the induction of remission in patients with severe ANCA-associated vasculitis in 2 landmark trials in 2010.7,8 Over 20 case series and cohort studies using rituximab in systemic GPA has further supported its use as the preferred agent for patients with chronically relapsing, refractory disease with less cytotoxic effects.9 However, our knowledge of the utility of this agent in treating pituitary GPA is still limited with 3 cases reported.6,10 In the majority of patients with GPA and pituitary involvement, the pituitary functions do not recover even after the GPA is in remission. The long-term outcome of these patients is unknown as no systematic follow-up study has been undertaken. Further studies are required to determine if earlier recognition and treatment can preserve pituitary function. It is uncertain if pituitary GPA affects long-term survival and predisposition to relapses. With the increasing frequency of pituitary involvement in GPA, it is time to review vasculitis or GPA registries to de-
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termine its prevalence (Table 1). Consideration should also be given to setting up an international registry of patients with pituitary GPA to gather more information about the clinical course and long-term outcomes. There are currently still gaps in early diagnosis and the treatment of choice to minimize relapses especially with the introduction of biological agents. REFERENCES 1. Al-Fakhouri A, Mamadan A, Gan J, et al. Central diabetes insipidus as the presenting symptom of granulomatosis with polyangiitis. J Clin Rheumatol. J Clin Rheum 2014;20:151Y154. 2. Yong TY, Li JY, Amato L, et al. Pituitary involvement in Wegener’s granulomatosis. Pituitary. 2008;11:77Y84. 3. Katzman GL, Langford CA, Sneller MC, et al. Pituitary involvement by Wegener’s granulomatosis: a report of two cases. AJNR Am J Neuroradiol. 1999;20:519Y523. 4. Soukiasian SH, Foster CS, Niles JL, et al. Diagnostic value of anti-neutrophil cytoplasmic antibodies in scleritis associated with Wegener’s granulomatosis. Ophthalmology. 1992;99:125Y132. 5. Bertken RD, Cooper VR. Wegener granulomatosis causing sellar mass, hydrocephalus, and global pituitary failure. West J Med. 1997;167:44Y47. 6. Hughes J, Barkhoudarian G, Ciarlini P, et al. Refractory pituitary granulomatosis with polyangiitis (Wegener’s) treated with rituximab. Endocr Pract. 2013;19:e1Ye7. 7. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221Y232. 8. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363:211Y220. 9. Cartin-Ceba R, Fervenza FC, Specks U. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr Opin Rheumatol. 2012;24:15Y23. 10. Cunnington JR, Jois R, Zammit I, et al. Diabetes insipidus as a complication of Wegener’s granulomatosis and its treatment with biologic agents. Int J Rheumatol. 2009;2009:346136.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pituitary Involvement in Granulomatosis With Polyangiitis Tuck Yean Yong, FRACP,*Þ and Jordan Yuanzhi Li, FRACPÞþ
G
ranulomatosis with polyangiitis (GPA), formerly Wegener granulomatosis, is an antiYneutrophil cytoplasmic antibody (ANCA)Yassociated systemic necrotizing granulomatous small-vessel vasculitis. It typically affects the upper respiratory tract, lungs, and kidneys but can involve virtually any organ including the pituitary. Pituitary involvement in GPA is rare. In this issue, Al-Fakhouri and colleagues1 have reported 2 cases, and a total of 35 cases have been reported in the English medical literature between 1966 and August 2013. There were only 23 cases when the last major review of pituitary involvement in GPA was published in 2008.2 Although GPA affects males and females equally, the majority of patients with pituitary involvement are female. The increasing number of reported cases highlights that clinicians need to be aware of GPA as a cause of pituitary insufficiency, and pituitary function needs to be assessed in GPA patients with clinical features. The pathophysiology of the hypothalamus-pituitary involvement in GPA includes granulomatous lesions by contiguous invasion from nasal or paranasal granuloma, in situ granuloma formation, vasculitis of anterior and/or posterior pituitary blood vessels, or a combination of these mechanisms. However, the reason for the pituitary to be involved in a small number of patients with GPA and yet others are spared is unknown. Pituitary involvement in GPA usually occurs in the course of the disease with other organ involvement. There is only 1 reported case with isolated pituitary involvement at the time of presentation.3 Granulomatosis with polyangiitis can affect partial or global pituitary endocrine function to varying degrees.2 Central diabetes insipidus has been more commonly observed with or without concurrent anterior pituitary insufficiency due to a preponderance of posterior pituitary involvement. The diagnosis of GPA remains challenging with pituitary involvement because initial clinical symptoms can be nonspecific, often resulting in delayed recognition. The presence of symptoms of pituitary insufficiency in conjunction with epistaxis and/or sinusitis should heighten the clinician’s suspicion of GPA as a potential etiology. In the case series of GPA with pituitary involvement, the majority of patients except for 1 case have all been ANCA positive with antiYproteinase 3 specificity observed in many of these cases.2 AntiYneutrophil cytoplasmic antibody levels do not typically correlate with severity of disease.4 With the current limitations of noninvasive tests, tissue biopsy is still necessary for diagnostic confirmation because of the potentially toxic nature of treatment of GPA. In cases of GPA with pituitary involvement, most patients have other organ involvement, which allow tissue biopsies to be performed, whereas biopsy of the pituitary is only rarely required. Magnetic resonance imaging (MRI) of the pituitary is useful in diagnosis. The classic MRI findings in GPA are pituitary enlargement, diffuse or focal infundibular thickening, and the absence of the normal high-intensity signal in the posterior pituitary lobe, seen on T1-weighted images. However, patients may have a predominantly small vessel vasculitis, and only minimal changes would be visible on MRI. These MRI abnormalities may vary with disease activity. The treatment of GPA with pituitary involvement involves 2 components. First, it involves treatment of relevant endocrine insufficiency, which includes corticosteroid, thyroid hormone, testosterone, vasopressin replacement, or combinations of these therapies as clinically indicated, and second, treatment of the underlying GPA. Treatment for the underlying GPA has been diverse. In the past, some patients have undergone surgical treatment of the pituitary lesion, which would usually lead to varying degrees of permanent pituitary insufficiency.3,5 Although this practice has largely been avoided, a case report was recently published about a patient with difficult-to-manage GPA involving the pituitary who underwent surgical intervention for local disease control.6 Conventional therapy for GPA with pituitary involvement uses the combination of high-dose corticosteroid and cyclophosphamide (oral or intravenous) for induction therapy. In case series, this combination therapy induced remission in all patients, but
From the *Department of General Medicine, Flinders Medical Centre; †School of Medicine, Flinders University; and ‡Department of Renal Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia. The authors declare no conflict of interest. Correspondence: Tuck Yean Yong, FRACP, Department of General Medicine, Flinders Medical Centre, Flinders Dr, Bedford Park, South Australia, Australia 5042. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608/14/2003Y0123 DOI: 10.1097/RHU.0000000000000092
JCR: Journal of Clinical Rheumatology
&
Volume 20, Number 3, April 2014
www.jclinrheum.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
123
JCR: Journal of Clinical Rheumatology
Editorial
TABLE 1. Areas for Future Research in GPA With Pituitary Involvement Epidemiological data on pituitary involvement in GPA The reason for different organs to be affected by GPA and not others in individual patients Treatment of pituitary GPA that prevents long-term pituitary insufficiency The best strategy for preventing GPA relapses Establishing the role of biological agents in the management of GPA 2
about a quarter of patients had a relapse within 10 months. In maintenance treatment, oral cyclophosphamide or azathioprine with or without corticosteroid was commonly prescribed.2 Treatment of GPA can be challenging because of corticosteroid and cyclophosphamide toxic adverse effects and the development of refractory and relapsing disease in some patients. This has led to the use of biological agents, rituximab, an anti-CD20 monoclonal antibody, which depletes B lymphocytes. Rituximab was first demonstrated to be beneficial in the induction of remission in patients with severe ANCA-associated vasculitis in 2 landmark trials in 2010.7,8 Over 20 case series and cohort studies using rituximab in systemic GPA has further supported its use as the preferred agent for patients with chronically relapsing, refractory disease with less cytotoxic effects.9 However, our knowledge of the utility of this agent in treating pituitary GPA is still limited with 3 cases reported.6,10 In the majority of patients with GPA and pituitary involvement, the pituitary functions do not recover even after the GPA is in remission. The long-term outcome of these patients is unknown as no systematic follow-up study has been undertaken. Further studies are required to determine if earlier recognition and treatment can preserve pituitary function. It is uncertain if pituitary GPA affects long-term survival and predisposition to relapses. With the increasing frequency of pituitary involvement in GPA, it is time to review vasculitis or GPA registries to de-
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termine its prevalence (Table 1). Consideration should also be given to setting up an international registry of patients with pituitary GPA to gather more information about the clinical course and long-term outcomes. There are currently still gaps in early diagnosis and the treatment of choice to minimize relapses especially with the introduction of biological agents. REFERENCES 1. Al-Fakhouri A, Mamadan A, Gan J, et al. Central diabetes insipidus as the presenting symptom of granulomatosis with polyangiitis. J Clin Rheumatol. J Clin Rheum 2014;20:151Y154. 2. Yong TY, Li JY, Amato L, et al. Pituitary involvement in Wegener’s granulomatosis. Pituitary. 2008;11:77Y84. 3. Katzman GL, Langford CA, Sneller MC, et al. Pituitary involvement by Wegener’s granulomatosis: a report of two cases. AJNR Am J Neuroradiol. 1999;20:519Y523. 4. Soukiasian SH, Foster CS, Niles JL, et al. Diagnostic value of anti-neutrophil cytoplasmic antibodies in scleritis associated with Wegener’s granulomatosis. Ophthalmology. 1992;99:125Y132. 5. Bertken RD, Cooper VR. Wegener granulomatosis causing sellar mass, hydrocephalus, and global pituitary failure. West J Med. 1997;167:44Y47. 6. Hughes J, Barkhoudarian G, Ciarlini P, et al. Refractory pituitary granulomatosis with polyangiitis (Wegener’s) treated with rituximab. Endocr Pract. 2013;19:e1Ye7. 7. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221Y232. 8. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363:211Y220. 9. Cartin-Ceba R, Fervenza FC, Specks U. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr Opin Rheumatol. 2012;24:15Y23. 10. Cunnington JR, Jois R, Zammit I, et al. Diabetes insipidus as a complication of Wegener’s granulomatosis and its treatment with biologic agents. Int J Rheumatol. 2009;2009:346136.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
