Orbit, 2014; 33(5): 388–391 ! Informa Healthcare USA, Inc. ISSN: 0167-6830 print / 1744-5108 online DOI: 10.3109/01676830.2014.904380

C ASE REPORT

Biopsy-Proven Recurrence of Unilateral IgG4-Related Orbital Inflammation after 20 years Pegah Heidari1,2, Robert M. Verdijk3, W. A. van den Bosch1, and Dion Paridaens1,4 1

2

The Rotterdam Eye Hospital, Oculoplastic & Orbital Service, Rotterdam, the Netherlands, Department of Ophthalmology, Asklepios Clinic Barmbek, Hamburg, Germany, 3Department of Pathology, Erasmus MC University, Rotterdam, the Netherlands, and 4Department of Ophthalmology, Geneva General Hospitals, Geneva, Switzerland

ABSTRACT A 38-year-old female patient presented with a painful swelling in the lateral part of the upper eyelid, a diffuse scleritis and slight hypoglobus of the right eye. An orbital biopsy showed a fibrotic idiopathic orbital inflammation (IOI) with, on immunohistochemical staining, an increased number of IgG4-positive plasma cells scored as 4200 per high-power field, with IgG4/IgG ratio 40.50, indicating orbital IgG4 related autoimmune disease. On treatment with oral prednisone and azathioprine the symptoms resolved within 6 months. Twenty years prior, the patient had been diagnosed with an IOI of at the same side, for which at that time a biopsy had been taken similarly. Reclassification of the previous biopsy specimen with immunohistological staining also showed evidence of orbital IgG4 related disease. To our knowledge this is the first report of a biopsy-proven unilateral IgG4-related orbitopathy that recurred after 20 years. Keywords: Idiopathic orbital inflammation, IgG4, orbitopathy, recurrence

work-up, it is important to differentiate IgG4-related orbitopathy from idiopathic orbital inflammation (IOI) as well as from ocular adnexal marginal zone B-cell lymphoma.2 Idiopathic orbital inflammation is a heterogeneous group of non-specific, noninfectious orbital inflammatory disease without an underlying specific systemic or local cause. It is a diagnosis of exclusion after evaluating other causes of orbital disease. The clinical presentation can vary depending on the involved orbital structures. Idiopathic orbital inflammation may present as dacryoadenitis, myositis, perineuritis and scleritis. Although steroid therapy is generally effective in reducing the size of the lesion in orbital IgG4-related disease, recurrences frequently occur after cessation of steroids. Here we present a case of biopsy-proven unilateral IgG4-related orbital disease, which, in

IgG4-related disease is an inflammatory process of unknown etiology that may occur, in a variety of organs throughout the body, including the pancreas, bile duct, lacrimal gland, salivary gland, thyroid, lung, liver, gastrointestinal tract, kidney, prostate, arteries, lymph nodes, skin, breast, central nervous system and retroperitoneum.1 Such systemic disease is characterized by a raised serum immunoglobulin G4 and/or an increased number of IgG4 positive plasma cells in affected tissues (100 cells/ high power field (HPF) and an IgG4/IgG cell ratio 440%). Some patients show involvement of only a single organ like in isolated orbital IgG4-related disease with an increased number of IgG4 positive plasma cells in inflamed ocular adnexal tissues. Signs of IgG4-related orbitopathy may consist of chronic non-infectious lid swelling and proptosis. For treatment as well as for

Received 13 November 2013; Revised 5 March 2014; Accepted 10 March 2014; Published online 5 June 2014 Correspondence: Dr. Dion Paridaens, Oculoplastic & Orbital Service, the Rotterdam Eye Hospital, Rotterdam, Schiedamsevest 180, 3011 BH, the Netherlands. E-mail: [email protected]

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FIGURE 1. In the upper pictures you can see the Patient before any systemic therapy. After oral prednisolone therapy the symptoms improved slightly. The pictures in the middle show the patient after 4 weeks with redness of conjunctiva and episclera. An additional treatment with azathioprine 225 mg and NSAID eye drops 3 per day improved her symptoms. In the pictures below 6 months later there is no sign of inflammation anymore.

retrospect, had already occurred with similar signs and symptoms 20 years prior to the current manifestation, at which time this condition had not yet been described.

CASE REPORT In 2012, a 38-year-old female patient presented with redness, swelling of the right upper eyelid and pain in her right eye since 4 weeks. She also reported pain on eye movement. On examination, there was a palpebral swelling in the lateral part of the upper eyelid. The superior sclera and conjunctiva were hyperemic and the right eye showed mild hypoglobus (Figure 1). The exophthalmometry value was 18 mm on the right side and 15 mm on the left. Intraocular pressure was 23 mmHg on the right side and 16 mmHg on the left. Visual acuity was 0.9 in the right eye and 1.2 in the left. The patient reported pain on digital pressure over the lateral part of the right upper eyelid. There were no restrictions of eye movement. Echography !

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of the right eye showed a thickened choroid and sclera superiorly. Computed tomography showed an orbital tumor under the orbital roof, involving the lacrimal gland, without bony changes (Figure 2). Laboratory values, including erythrocyte sedimentation rate, C-reactive protein and angiotensin converting enzyme were normal. We had already evaluated this patient 20 years before, in 1992, suffering from similar symptoms. At that time also an orbital biopsy had been taken from the lacrimal gland region. Pathological examination had shown the picture of idiopathic orbital inflammation, without evidence of sarcoidosis, lymphoma or Wegener’s disease. She had been treated with oral prednisolone, starting with 60 mg daily, slowly tapering. The symptoms had resolved after 2 months. However, 8 months later, she had suffered from inflammation of the right eye with the clinical picture of scleritis. She had again been treated with oral prednisolone, starting with 30 mg daily, slowly tapering. After 4 weeks, her symptoms had disappeared. At that time, her ACE-level (angiotensin-converting

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FIGURE 2. Coronal and axial CT-scans show an orbital tumor under the orbital roof involving the lacrimal gland enlargement of the right lacrimal glandon the right side. The right Bulbus is pushed down by the tumoe and the lacrimal gland, Hypoglobus.

FIGURE 3. The left panels show the histological results of the biopsy in 1992 with mixed lymphoplasmocellular inflammatory cells, mild fibrosis, phlebitis and increased numbers of IgG4-positive plasma cells. The middle panels show the results of 2012 with clearly increased fibrosis. The right panels show kappa (bottom) and lambda staining, indicating a skewed light chain usage.

enzyme) had been elevated, but a chest X-ray had not shown hilar lymphadenopathy or any other changes suggestive of sarcoidosis. Between 1993 and 2012, she had not suffered from any orbital or systemic disease. At third presentation, in 2012, we decided again to take a biopsy from the orbital tumor. Now histopathology showed a fibrotic IOI with, on immunhistochemical staining, an increased number of IgG4-positive plasma cells scored as 4200 per high-power field, with IgG4/IgG ratio 40.50,

indicating orbital IgG4 related autoimmune disease (Figure 2, middle panels). Because of this, we performed immunohistological staining and re-examined the specimen from the first orbital biopsy. This also showed an elevated number of IgG4-positive plasma cells, fitting, in retrospect, the diagnosis of IgG4 related orbital inflammatory disease (Figure 3, left panels). At current presentation, she was again treated with oral prednisolone, starting with 80 mg daily, slowly tapering. At first, the symptoms improved slightly, Orbit

IgG4-Related Orbital Inflammation 391 but after 4 weeks, with a prednisone dosage of 45 mg, she suffered from increased pain. Examination revealed redness of the superior conjunctiva and sclera, suggestive of scleritis. Therefore, we added azathioprin 125 mg daily orally and continued steroid treatment, slowly tapering. The symptoms gradually improved over the next 2 months. After 6 months of treatment, the patient reported only a mild pressure feeling in the right orbit, but no pain. On examination there was a slight residual hypoglobus with an exophthalmometry value of 17 mm on the right side (Figure 1).

COMMENT To our knowledge, this is the first report of a biopsyproven unilateral IgG4-related orbital inflammatory disease that recurred after 20 years. While orbital IgG4-related diseases may resolve after systemic steroid therapy, relapse is often observed shortly after discontinuation of steroid use. Our patient developed a recurrent orbital inflammation years after the first clinical presentation. During tapering of the steroids the patient suffered from a relapse. As suggested by Yamamoto et al.3 we added azathioprine to the steroid treatment and the symptoms resolved. Previous reports on ocular adnexal IgG4-related disease mention isolated involvement of the lacrimal gland a frequent feature.4 But rarely, as in our case, the sclera is involved as well.5,6 This implicates that the clinical picture of orbital IgG4-related disease may vary. In conclusion, in IOI, immunohistochemical examination of the material regarding IgG4-mediated

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disease should be performed. This case shows that, in case of recurrent disease, it may be of interest to re-examine previous biopsy regarding this diagnosis. It also shows that orbital IgG4-related disease may in some cases remain dormant for many years and may then re-occur with a very similar clinical presentation.

DECLARATION OF INTEREST The authors have no financial conflict of interest with the subject matter or materials discussed in this manuscript. The authors alone are responsible for the content and writing of the paper.

REFERENCES 1. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): General concept and details. Mod Rheumatol 2012;22:1–14. 2. Kubota T, Moritani S. Orbital IgG4-Related Disease: Clinical Features and Diagnosis, ISRN Rheumatology, Vol. 2012, Article ID 412896, 5 pages, 2012. doi:10.5402/ 2012/412896. 3. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol 2006;16(6):335–340. 4. Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int 2008;58(8):465–470. 5. Ohno K, Sato Y, Ohshima KI, et al. IgG4-related disease involving the sclera. Mod Rheumatol 2014 Jan;24(1): 195–198. 6. Paulus YM, Cockerham KP, Cockerham GC, Gratzinger D. IgG4-positive sclerosing orbital inflammation involving the conjunctiva: A case report. Ocul Immunol Inflamm 2012; 20(5):375–377.

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Biopsy-proven recurrence of unilateral IgG4-related orbital inflammation after 20 years.

A 38-year-old female patient presented with a painful swelling in the lateral part of the upper eyelid, a diffuse scleritis and slight hypoglobus of t...
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