Antithymocyte Globulin Treatment ofOrbital Wegener Granulomatosis: AFollow-up StudyJ. Kool, MD, PhD, R. J. W. de Keizer, MD, PhD,and C. E. H. Siegert, MD, PhD

PURPOSE: To describe the follow-up of patients withorbital Wegener granulomatosis after antithymocyteglobulin treatment.METHODS: Patients with ocular/orbital Wegener granulo-matosis refractory to standard treatment were selectedfor immunotherapy with rabbit antithymocyte globulinintravenously. The specific ocular/orbital symptoms weremonitored in patients with a vision-threatening form ofWegener granulomatosis or a life-threatening form withocular symptoms.RESULTS: One patient had a complete remission, twopatients had remissions but still needed additional treat-ment, and one patient remained refractory.CONCLUSIONS: In selected patients, antithymocyte glob-ulin immunotherapy may present an alternative whenvision or life is threatened by orbital Wegener granulo-matosis. (Am J Ophthalmol 1999;127:738–739.© 1999 by Elsevier Science Inc. All rights reserved.)

WEGENER GRANULOMATOSIS IS A POTENTIALLY FA-

tal systemic disease affecting mainly the kidneysand respiratory tract. Ocular/orbital manifestations occurin 55% of patients, and in 10%, vision is threatened.Therapy consists of cyclophosphamide and corticosteroidsor, in refractory patients, cyclosporine A, azathioprine,co-trimoxazole, and plasmapheresis. In some patients un-responsiveness or serious side effects necessitate cessationof therapy. Apart from c-ANCA (antineutrophil cytoplas-mic antibodies), there is also evidence for a role of Tlymphocytes in the pathogenesis of Wegener granuloma-tosis. In systemic vasculitis the possible benefit of therapiesdirected at the T lymphocyte has been demonstrated,1,2

and antithymocyte globulin has been used successfully invasculitic autoimmune diseases.3

In a previous report,4 we described the systemic effectand side effects of antithymocyte globulin treatment in fivepatients with Wegener granulomatosis who were refractoryto standard and alternative treatment modalities. We nowdescribe the ocular/orbital features and the follow-up ofone of these patients. Data on three other patients arepresented in the Table.

● CASE 1: A 73-year-old man presented in 1989 withchronic recurrent maxillary sinusitis and epistaxis based onWegener granulomatosis (nose biopsy, c-ANCA titer1:128). He was treated with daily cyclophosphamide, 100mg, and prednisone, 60 mg. During the next year, healmost completely lost vision in the left eye because of agranulomatous mass in the maxillary sinus extending intothe left orbit and involving the optic nerve. The processwas ultimately controlled by daily prednisone, 60 mg,co-trimoxazole, 960 mg, and azathioprine, 150 mg (cyclo-phosphamide had to be stopped because of thrombocyto-penia, and plasmaphereses had no effect). Except forco-trimoxazole, all drugs were gradually tapered.

In 1992 the visual acuity of the right eye decreased to20/67 and the visual field of the right eye showed a centralrelative scotoma. Proptosis increased to Hertel 17-23/114(originally 15-18/110). Computed tomography and ultra-sonography showed an increase in the retrobulbar mass inthe left orbit, as well as a new tumor medially in the rightorbit (Figure). c-ANCA titers were 1:512. Daily pred-nisone, 40 mg, and azathioprine, 100 mg, were restarted,but thrombocytopenia necessitated discontinuation of theazathioprine.

Treatment with antithymocyte globulin was institutedin November 1992 as described previously.4 In short,rabbit antihuman antithymocyte globulin was adminis-tered intravenously with prednisolone acetate. The dosewas adjusted based on peripheral blood lymphocyte counts.With this therapy, visual acuity and the visual field of theright eye improved and the visual acuity of the left eyeremained stable (counting fingers at 1 meter). The prop-tosis of both eyes gradually decreased to Hertel 15-18/105in September 1993, and c-ANCA titers became negative.The prednisone was ultimately stopped. After cataract

Accepted for publication Nov 13, 1998.From the Departments of Ophthalmology (J.K., R.J.W.d.K.) and

Nephrology (C.E.H.S.), Leiden University Medical Centre, Leiden, TheNetherlands.

Inquiries to R. J. W. de Keizer, MD, Department of Ophthalmology,Leiden University Medical Centre, J3-P, P.O. Box 9600, 2300 RCLeiden, The Netherlands; fax: 131-71-524-8222; e-mail: ophthalm@div3.azl.nl

FIGURE. Case 1. Computed tomography showing an extensiveretrobulbar granulomatous tumor, with flattening of the left eyeand tumor medially in the right orbit (arrow).

AMERICAN JOURNAL OF OPHTHALMOLOGY738 JUNE 1999

extraction and Nd:YAG laser photodisruption of a poste-rior capsule opacification, the visual acuity of the right eyerecovered to a best-corrected visual acuity of 20/25 (stableuntil January 1998). The visual field of the right eye hasnormalized. As of March 1994, no treatment for Wegenergranulomatosis has been needed. No systemic manifesta-tion of Wegener granulomatosis has developed.

The results of three other patients with ocular Wegenergranulomatosis are presented in the Table. Patient 2 had aremission after therapy with methotrexate. In Patient 3,the left eye was enucleated. No new episodes of scleritisoccurred in Patient 4 after antithymocyte globulin treat-ment, as of the last visit in April 1998.

The side effects of treatment with antithymocyte glob-ulin in our patients have been described4 and consistedmainly of chills during infusion of antithymocyte globulin,herpes simplex infection, and serum sickness, all of whichwere treatable. In another study with antithymocyte glob-ulin, chills and fever occurred in 60% of patients, andserum sickness was reported in 10%.5

Our study shows that in cases of Wegener granuloma-tosis refractory to standard and known alternative thera-pies, treatment with antithymocyte globulin may induceocular and orbital remissions. The exact mechanism onwhich this therapy is based is not completely understood

and may involve depletion of autoimmune T lymphocytes.Antithymocyte globulin treatment should be considered inpatients with orbital vision or life-threatening Wegenergranulomatosis who are resistant to or intolerant of con-ventional therapies.

ACKNOWLEDGMENT

We would like to thank Dr E. C. Hagen for reading themanuscript and for helpful discussion.

REFERENCES

1. Mathieson PW, Cobbold SP, Hale G, et al. Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990;323:250–253.

2. Lockwood CM, Thiru S, Isaacs JD, Hale G, Waldmann H.Long-term remission of intractable systemic vasculitis withmonoclonal antibody therapy. Lancet 1993;341:1620–1622.

3. Tarkowski A, Andersson Gare B, Aurell M. Use of anti-thymocyte globulin in the management of refractory systemicautoimmune diseases. Scand J Rheumatol 1993;22:261–266.

4. Hagen EC, de Keizer RJW, Andrassay K, et al. Compassionatetreatment of Wegener’s granulomatosis with rabbit anti-thymocyte globulin. Clin Nephrol 1995;43:351–359.

5. Hoitsma AJ, van Lier HJJ, Reekers P, Koene RAP. Improvedpatient and graft survival after treatment of acute rejections ofcadaveric renal allografts with rabbit antithymocyte globulin.Transplant 1985;39:274–279.

TABLE. Characteristics of Four Patients With Wegener Granulomatosis Treated With Antithymocyte Globulin

Case, Sex,

Age (yrs)* Organs Involved Biopsy† c-ANCA‡ Previous Therapies Indication for ATG Effect of ATG

1, M, 73 Sinuses, orbits Nose 1:128

1:512

Cyclospor, predn, plasmaph,

co-trim, azath

Bilateral orbital masses

with threatened

vision

Complete

remission

2, F, 39 Oropharynx, nose, sinuses,

conjunctiva, sclera, orbit,

lacrimal gland, parotid

gland, skin

Nose,

sinus

NA

1:64

Predn, cyclophos, azath,

cyclospor, co-trim

Left-sided orbital mass

and systemic lesions

Ocular remission,

systemic

relapses

3, M, 21 Nose, sinuses, orbit, lungs,

kidneys

Nose 1:160

30 U/ml§Predn, cyclophos, azath,

cyclospor, irrad, co-trim

Left-sided orbital mass

with threatened

vision

Unresponsive

4, F, 52 Kidneys, lungs, upper

respiratory tract, skin,

sclera, cornea

Kidney 1:128

1:256

Predn, cyclophos, azath Multiple systemic

lesions and scleritis

Ocular remission,

systemic

unresponsive

ATG 5 antithymocyte globulin; azath 5 azathioprine; co-trim 5 co-trimoxazole; cyclophos 5 cyclophosphamide; cyclospor 5 cyclosporine

A; irrad 5 irradiation; plasmaph 5 plasmapheresis; predn 5 prednisone.

*Age at onset of Wegener granulomatosis.†Organ biopsy on which diagnosis of Wegener granulomatosis was based.

‡ANCA: c-ANCA titer at onset of Wegener granulomatosis (upper field) and before start of antithymocyte globulin treatment (lower field).§ANCA was negative, but 30 U/ml antiprotein 3 antibodies were present.

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