Azathioprine and prednisone combination treatment for adult periocular and orbital xanthogranulomatous disease


Ward R. Bijlsma
University Medical Centre Utrecht
Department of Ophthalmology
Heidelberglaan 100
3584 CX Utrecht
The Netherlands.
Tel: +31 88 755 1683
Fax: + 31 88 755 5417


Purpose:  To report the authors’ experience with azathioprine and prednisone combination for adult periocular and orbital xanthogranulomatous disease.

Methods:  We identified 13 adults with histology-proven periocular or orbital xanthogranuloma in two tertiary referral orbital centres from 1984 to 2008. Patient records were reviewed and data collected on orbital localization, immune dysfunction, applied treatment and outcome.

Results:  Five patients with periocular or orbital xanthogranulomatous disease were fully treated with prednisone and azathioprine combination, which resulted in stabilization in two and regression in three. Two other patients had to discontinue azathioprine because of side-effects. Of the non-fully treated prednisone/azathioprine patients, four out of eight progressed.

Conclusion:  In adult periocular and orbital xanthogranuloma, combined treatment with prednisone and azathioprine yields adequate immunosuppression, often for a prolonged period of time.


Orbital xanthogranuloma is a rare disease. The clinical presentation in adults consists of uni- or bilateral orbital mass lesions or periocular yellow-brown infiltrates that may mimic xanthelasmata. These abnormalities tend to progress, causing eyelid disfigurement, eyeball displacement, eyeball motility disturbances and – rarely – optic neuropathy. Periocular and orbital xanthogranulomatous disease is now considered to constitute a spectrum of four entities that comprise adult-onset orbital xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX)(Jakobiec et al. 1993), necrobiotic xanthogranuloma (NBX) (Robertson & Winkelmann 1984; Bullock et al. 1986) and Erdheim–Chester disease (ECD) (Alper et al. 1983).

Various treatments have been applied for periocular and orbital xanthogranulomas including surgical debulking (Schaudig & Al-Samir 2004; Vieira et al. 2005), radiotherapy (Char et al. 1987; Sivak-Callcott et al. 2006), immunosuppression (Myra et al. 2004; Meyer et al. 2005; Ziemer et al. 2005; Elner et al. 2006; Torabian et al. 2006; Goede et al. 2007; Hayden et al. 2007) and observation. Best treatment results are gained with a combination of prednisone and an immunosuppressive (Ugurlu et al. 2000). However, there is no consensus on the best choice of immunosuppressive drug. In this article, the authors report on their good results with combined azathioprine and prednisone treatment in orbtial xanthogranulomatous disease.

Materials and Methods

We analysed the records of 13 consecutive patients of adult periocular and orbital xanthogranulomas: 10 from the Rotterdam Eye Hospital and three from the University Medical Centre Utrecht. Diagnostic features of three patients (patients 1, 2 and 4) have been reported previously (Sivak-Callcott et al. 2006). From the case records we collected data on demographics, presence and extent of orbital involvement, ophthalmic signs, systemic immune function, treatment modalities and outcome in terms of regression of lesions and functional deficit. Patients were categorized to suffer from ECD in the event of systemic involvement of retroperitoneal structures and/or long bones, from NBX in the event of marked necrobiosis on histology specimens, and from AAPOX when adult-onset asthma was present. When lesions were isolated to the periocular structures and/or orbit the patient was categorized as having AOX.

Regression was defined as reduction in orbital and adnexal tissue involvement and resolution of inflammatory signs. Stabilization was defined as persistent structural changes of orbital and adnexal tissues. Progression was defined as an increase in orbital or adnexal tissue involvement. The extent of orbital involvement was determined radiographically.

This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and institutional review board approval was not required.


Patient characteristics are summarized in Table 1. Diagnosis of xanthogranuloma was based on biopsy of orbital tissue in patients 7 and 11, of lacrimal gland in patients 4 and 6 and of eyelid tissue in all others. Six patients suffered from AOX, three from NBX, three from AAPOX and one from ECD. There were eight men and five women. The age at presentation ranged from 30 to 78 years (median 47). The most commonly involved orbital structures were the lacrimal gland, with diffusion into adjacent structures (9/13) and the extraocular muscles (5/13). Superficial eyelid lesions were present in nine patients.

Table 1.   Characteristics of 13 adult periocular and orbital xanthogranuloma patients.
PatientAge at diagnosisSexStructures involvedPeriocular skin findingsOther ocular signs and associations
  1. AOX, orbital xanthogranuloma; NBX, necrobiotic xanthogranuloma; AAPOX, adult-onset asthma and periocular xanthogranuloma; ECD, Erdheim–Chester disease.

1 AOX34MBilateral lacrimal gland regionsBilateral eyelid swellingMotility disturbance
2 AOX40FLeft lacrimal gland region, bilateral extraocular muscles, left fossa temporalisBilateral xanthomatous lesionsMotility disturbance, xanthogranuloma of oral cavity (sublingual)
3 AAPOX75FRight lacrimal gland region and extraocular musclesBilateral eyelid swelling, xanthomatous lesionsPsoriasis, asthma
4 ECD43MBilateral: lacrimal gland regions, extraocular muscles, intraconal, apical, cavernous sinus, hypophysisBilateral xanthomatous lesionsBilateral: motility disturbance, optic neuropathy; retroperitoneal fibrosis,long bones and skull involvement
5 NBX43MPreseptal eyelidXanthomatous lesionsMultiple myeloma, granuloma annulare
6 AAPOX60FBilateral lacrimal gland regions, extraocular musclesXanthomatous lesionsMotility disturbances, asthma, autoimmune thyroiditis
7 AOX30MLacrimal gland region, extraocular muscles, apex, fossa pterygopalatinaMotility disturbance, optic neuropathy, hypesthesia supraorbital nerve
8 AOX62FPreseptal eyelidBrown xanthomatous lesionsMotility disturbance
9 AOX60MPreseptal eyelid and conjunctivaXanthomatous lesions
10 AAPOX78FBilateral lacrimal gland regionsEyelid swellingCheek swelling, asthma
11 AOX44MLacrimal gland regions, extraconal upper temporal quadrantMotility disturbance
12 NBX58MLacrimal gland regionsBilateral xanthomatous lesionsIdiopathic thrombotic thrombocytopenic purpura,lymphadenopathy
13 NBX47MPreseptal eyelidXanthomatous lesionsChronic lymphocytic leukaemia

Table 2 summarizes the applied treatment and outcome. The median follow-up is 2 years (range 0.5 to 17 years). The mainstay of medical treatment consisted of oral prednisone with azathioprine combined (8/13). Of the eight patients with prednison and azathioprine combination, two had to discontinue treatment because of nausea or gastrointestinal upset, and one refused further medical treatment for years. Of the five patients who had been fully treated with combination azathioprine and prednisone, two stabilized and three regressed. Of the patients who discontinued azathioprine because of its side-effects, one progressed slowly under ciclosporin with prednisone and one regressed under cyclophosphamide with prednisone. The patient who refused azathioprine and other medical treatment progressed slowly.

Table 2.   Treatments and outcomes of 13 patients with adult periocular and orbital xanthogranuloma.
PatientTreatmentTreatment complicationsFollow-up (years)Outcome
  1. AOX, orbital xanthogranuloma; NBX, necrobiotic xanthogranuloma; AAPOX, adult-onset asthma and periocular xanthogranuloma; ECD, Erdheim–Chester disease.

1 AOXPrednison, debulking 3 ×Ectropion17Slowly progressive, lost to follow-up
2 AOXBlepharoplasty 7 × 16Slowly progressive, lost to follow-up
3 AOXPrednison, azathioprine, ciclosporinAzathioprine stopped because of nausea11Slowly progressive
4 ECDPrednison, ciclosporin, octreotide, cyclophosphamide, etanercept, gammaglobulin, azathioprine (maintenance), decompression, debulking, radiotherapy 36 Gy, 177Lu-DOTA-Tyr3-octreotateSystemic herpes infection12Stable, mild optic nerve dysfunction, moderate motility disturbances
5 NBXChemotherapy for multiple myeloma, radiotherapy to systemic lesions, bone-marrow transplantationPulmonary fibrosis1Died of pulmonary complications
6 AAPOXPrednison, azathioprine, decompression (diagnosis of Graves’ orbitopathy was presumed), debulking, blepharoplasty 2 × 9Slowly progressive, refused medical treatment for 2 years, regression after restarting prednison
7 AOXPrednison, azathioprine (maintenance)2Regression with persistent hypesthesia and minor optic nerve dysfunction
8 AOXPrednison, azathioprine, debulkingEyelid retraction2Regression
9 AOXPrednison, azathioprine, debulking1Regression
10 AOX0.5Spontaneous resolution
11 AOXPrednison, azathioprine, cyclophosphamideWeight loss and abdominal discomfort resolved after discontinuation azathioprine3Regression
12 NBXPrednison, azathioprine (maintenance)2Stable
13 NBXChemotherapy for leukaemia2Stable

Two patients with lymphoproliferative disease were treated with chemotherapy, of whom one stabilized and one died because of pulmonary complications after bone-marrow transplantation and the development of graft-versus-host disease. One patient was treated with prednisone alone and progressed slowly. Two patients were not treated medically, of whom one progressed slowly and one regressed spontaneously.

Overall, the patients treated fully with combined prednisone and azathioprine seemed to have better outcomes: five of five patients stabilized or regressed, compared with three of the eight patients who were treated differently (p = 0.075, Fisher’s exact test).

The combined prednisone–azathioprine treatment regimen consisted of high-dose prednisone at 0.5–1 mg/kg/day and azathioprine 1–2 mg/kg/day. Upon clinical resolution of inflammatory signs, the prednisone was first tapered to 10 mg/day or less. Secondly, the azathioprine was tapered to the lowest effective dose (patients 4 and 7) or discontinued after an average administration duration of 1 year. Figure 1 shows pre- and post-treatment images of patients treated with both prednisone and azathioprine. Table 3 compares the treatment effects of various therapeutic regimens for orbital and adnexal xanthogranuloma; it demonstrates that corticosteroids combined with other immunosuppressives, particularly azathioprine, are most effective.

Figure 1.

 Results with combined prednisone and azathioprine treatment. (A, B) case 4 Erdheim-Chester Disease. (A) before eyelid lesions appeared. (B) extensive, but stable involvement of retrobulbar spaces left more than right. Stabilization was achieved by maintenance therapy with azathioprine and prednisone. (C, D) case 8 Adult onset Orbital Xanthogranuloma. (C) brown xanthomatous lesions of the lower left eyelid. (D) eyelid lesions disappeared after treatment with azathioprine and prednisone.

Table 3.   Treatment effects of various therapeutic regimens for orbital and adnexal xanthogranuloma.
 Oral corticosteroids: number improved/ treatedLocal corticosteroids: number improved/ treatedCorticosteroids with other immunosuppressives: number improved/treatedExternal beam radiotherapy: number improved/ treatedSurgery: number improved/ treated
  1. MTX, metotrexate; CHL, chlorambucil; MEL, melphalan; AZT, azathioprine.

Cruz et al. 2006 5/6   
Hayden et al. 2007  2/3 MTX  
Karcioglu et al. 20030/3  1/44/6
Ugurlu et al. 2000 2/910/17 CHL or MEL2/5 
present series0/1 5/5 AZT 0/1
Total (%)0/4 (0)7/15 (47)17/25 (68)3/9 (33)4/7 (57)


In this series of 13 patients, good treatment results of combined azathioprine and prednisone are shown in adult periocular and orbital xanthogranulomas. Regression and stabilization of orbital disease occurred in all five patients treated fully with both azathioprine and prednisone. In contrast, progression after cessation of azathioprine treatment occurred in two out of three patients who were treated with azathioprine and prednisone, two of whom had to discontinue azathioprine because of gastrointestinal upset or nausea and one of whom refused medical treatment. Of the patients never treated with azathioprine/prednisone, three showed progression. Interestingly, the patient with Erdheim–Chester disease, a disease known to be a recalcitrant fibrosclerosis of the orbit and internal organs, had been treated with numerous different immunosuppressive agents, but finally stabilized under maintenance treatment with prednisone and azathioprine.

The effectiveness of corticosteroids combined with immunosuppressives in adult periocular and orbital xanthogranulomatous disease is consistent with literature findings, as is shown in Table 3. Of these combined treatments, chlorambucil, melphalan and metotrexate appear to be less effective than azathioprine.

Azathioprine is a purine antagonist belonging to the group of antimetabolites and causes disruption of nucleic acids. Lymphocytes rely on de novo synthesis of purines. Azathioprine is thought to be relatively specific to lymphocytes, i.e. more specific for T-cells than for B-cells (Patel et al. 2006). Azathioprine is a widely used immunsuppressive agent in rheumatic and dermatological diseases (Patel et al. 2006).

The association between orbital xanthogranuloma and other autoimmune diseases is interesting. In our patient series the co-occurrence of asthma, psoriasis, granuloma annulare and idiopathic thrombocytopenic purpura is noted. These conditions are considered to be related to T-cell dysfunction, and to be more specific as a CD4+ T-helper cell derangement. Recent findings suggest orbital xanthogranuloma to be CD8+ cytotocix T-cell-related (Sivak-Callcott et al. 2006). However, there is evidence for a B-cell-related pathogenesis by immunohistochemistry of a necrobiotic xanthogranuloma showing strong CD20 (B-cell-related) (Ho et al. 2007), a monocyte-related pathogenesis, in a patient with ECD (Myra et al. 2004); there is also evidence of a link with Borrelia burgdorferi in six NBX patients (Zelger et al. 2007). In view of these findings, treatment of adult periocular and orbital xanthogranulomatous disease should be directed at T-cells and, preferably, also against B-cells. Azathioprine is one of the immunosuppressive agents that has both T- and B-cell effects.

A substantial number of NBX patients are seen by dermatologists when there is solitary or additional involvement of skin of the trunk or extremities (Finan & Winkelmann 1986; Mehregan & Winkelmann 1992). Dermatologists tend to treat NBX with more aggressive cytotoxic drugs such as cyclophosphamide, chloroambucil and melphalan. Because immunosuppression with the least toxic drug is preferable, azathioprine is proposed as a good alternative (Karcioglu et al. 2003; Meyer et al. 2005; Cruz et al. 2006; Oumeish et al. 2006; Sivak-Callcott et al. 2006; Torabian et al. 2006).

Two of the nine patients treated with azathioprine had to discontinue medication because of side-effects. Among the side-effects of azathioprine, leucopaenia and bone-marrow depression are encountered most frequently, necessitating frequent blood counts. Nausea, gastrointestinal upset and thrombocytopenia occur in about one in 10 patients. When the drug is tolerated, people can often stay on azathioprine for years, as shown by patients 4 and 12. In others, after regression had been observed, the immunsuppressive agents were phased out and discontinued.

This study is limited by its observational nature. To fully demonstrate azathioprine with prednisone treatment to be superior to other treatments in adult periocular and orbital xanthogranulomas, a randomized controlled clinical trial would be necessary. However, because of the low incidence of the disease, this would not be feasible.

In conclusion, because of the good outcome of combined treatment with prednisone and azathioprine in our patients, supported by a positive statistical trend, we recommend this regimen as initial treatment for periocular and orbital xanthogranulomatous disease.


This research was facilitated by a grant from the F. P. Fischer foundation.