Role of antimetabolites in recalcitrant idiopathic orbital inflammatory syndrome

Authors: Yamini Priya, Suneetha Nithyanandam, Manjoo S. Reddy

Abstract

Background:

High-dose systemic steroids are the primary modality of treatment for idiopathic orbital inflammatory syndrome (IOIS). Occasionally patients experience a relapse of symptoms on tapering steroids or require large doses of steroid, predisposing them to the adverse effects of steroids.

Aim:

We present our experience with the management of three patients with recalcitrant IOIS, with immunosuppressive therapy, using antimetabolites.

Materials and Methods:

A retrospective review of the medical records of the patients being reported. Results: Two patients were treated with Methotrexate and one with Azathioprine for a duration of 6-24 months. Two patients were symptom-free three years after stopping the medication. One was doing well clinically with methotrexate therapy alone, when he was lost to follow-up after six months. No adverse effects of immunosuppressive therapy were encountered.

Conclusion:

High-dose systemic steroid therapy is the first-line treatment for IOIS, but in refractory or steroid-dependent cases, immunosuppressive therapy with antimetabolites is a safe and effective treatment alternative to steroids. However, treatment with antimetabolites warrants close monitoring for complications like bone marrow suppression and liver dysfunction, especially because long-term treatment is required.

Introduction

Idiopathic orbital inflammatory syndrome (IOIS) also known as the pseudotumor orbit is a benign, non-infective, clinical syndrome, characterized by non-specific inflammation of the orbital tissues. It has a highly variable clinical presentation, depending on the orbital tissue involved in the inflammatory process.[1] The disease can be diffuse or focal. In the focal form, the specific orbital tissue is involved, which includes the lacrimal gland and extraocular muscles.[23] The onset is usually acute with an abrupt onset of signs and symptoms. However, subacute and chronic forms of the disease are known.

Idiopathic orbital inflammatory syndrome is a diagnosis of exclusion [Table 1].[45] High-dose systemic steroid with a slow taper over a period of eight to ten weeks is the mainstay of the treatment.[136] Rebound of symptoms during steroid taper, resistance to steroids, and adverse systemic response to steroids are common causes for treatment failure.[347] Various retrospective studies report a low-cure rate (37%) and a high recurrence rate (57%), with steroid therapy.[17] Other modalities of treatment include local radiation and immunosuppressive therapy. There are a few reports in literature of the use of antimetabolites in recalcitrant IOIS.[348–10] We report our experience with the use of antimetabolites in IOIS.

Materials and Methods

This study is a retrospective review of three patients with the diagnosis of IOIS, who were treated at the Department of Ophthalmology, St.John's Medical College Hospital. The study protocol was approved by the institutional review board. The data extracted included age, gender, signs and symptoms, radiological features, histopathological features, clinical course, treatment regimen, and outcome. The follow-up information collected included monitoring for drug side-effects and the response to treatment.

All the patients underwent a complete ophthalmological examination including best corrected visual acuity (BCVA), slit-lamp examination, Fundoscopy, and refraction. The diagnosis of IOIS was made based on the clinical a benign, non-infective, inflammatory condition of the orbit without identifiable local or systemic causes. A Computed Tomography (CT) Scan of the orbit with and without contrast was done in all three patients. Fine needle aspiration cytology in one and open biopsy in two were also performed, to confirm the clinical diagnosis.

Initial investigations included a thorough physical examination, complete blood count, blood sugars, and X-ray chest, prior to starting high-dose steroid therapy.

All the three patients were initially treated with high-dose oral steroids (60 – 80 mg/day) for one to two weeks, with a gradual taper during the next six to eight weeks. In the event of a rebound of symptoms during the steroid taper or recurrence of symptoms after a period of quiescence, the high-dose steroid was reinstituted. As all the three patients developed steroid-related complications following three to four courses of oral steroids, they were started on immunosuppressive therapy, with methotrexate in two and azathioprine in one, along with oral steroids (40 – 60 mg/day). The oral steroids were tapered off over four to six weeks and then stopped, with continuation of antimetabolites (6 – 24 months). For all the patients, baseline full blood count and liver function tests were done and these were monitored every month during the entire follow-up period. The objective criteria for clinical benefit included relief of pain and diplopia, reduction of proptosis and lid edema, improved ocular motility, and chemosis.

Results

Case 1

A 45-year-old male presented with painful right proptosis and cheek swelling, of one-month duration. On examination the BCVA was 20/20 OU, with a normal left eye. Right eccentric proptosis with the eye pushed up was noted. Elevation was restricted and a palpable orbital mass was present. A CT scan showed a mass following the contour of the globe inferiorly without indenting it, and extending over the inferior orbital rim. The mass showed diffuse enhancement with contrast [Figure 1]. Tissue biopsy from the orbital floor showed non-specific chronic inflammation. The patient was treated with 80 mg/day oral prednisolone, which was tapered over eight weeks. Recurrence of symptoms on tapering steroids necessitated reinstitution of steroid therapy four times. The patient developed hypertension, which required antihypertensive medication. Oral Azathioprine 50 mg TID along with systemic steroids 40 – 60 mg/day was started, with standard laboratory monitoring of full blood counts and liver function tests. On regression of signs and symptoms, the steroids were tapered off over four to six weeks and stopped. Azathioprine 50 mg/day was continued for a year and stopped. There was no recurrence of disease at the three-year follow-up. His BCVA was maintained at 20/20 OU.

Case 2

A 50-year-old female presented to the primary treating ophthalmologist with right eye proptosis and pain of six months′ duration. A CT scan of the orbit showed a diffuse intraconal mass involving all the recti muscles [Figure 2], suggesting a diagnosis of IOIS. The patient had received four courses of oral steroid, each lasting for four to six weeks.

Recurrence of the disease on steroid taper necessitated repeat steroid therapy. This caused hypertension and steroid-induced diabetes, which required medical management. The patient was referred to us for further treatment. Methotrexate 15 mg/week along with folic acid 10 mg/week was started and continued for nine months. Stopping methotrexate abruptly resulted in the recurrence of signs and symptoms. Methotrexate was restarted with concomitant oral steroids. The steroids were tapered (40 – 60 mg, over four to six weeks) once improvement was seen and methotrexate was continued for a year, with regular monitoring for likely toxicity. After a year methotrexate was tapered by 5 mg every two months and stopped completely after six months. A repeat CT scan showed resolution of the inflammatory mass [Figure 3]. The patient was symptom-free at the three-year follow-up. Her BCVA was 20/30 throughout the course of follow-up.

Case 3

A 33-year-old male sought treatment for right eye proptosis associated with low grade pain of two months duration. There was eccentric proptosis with an ‘s’-shaped swelling of the lids and painful restriction of abduction and dextro-elevation. A CT scan showed contrast enhancing diffuse enlargement of the lacrimal gland. Histopathology from the lacrimal gland was not very conclusive. Oral prednisolone 60 mg/day was started, with clinical improvement. The high dose was reinstituted on three occasions when symptoms recurred on steroid taper. Oral methotrexate 15 mg/week along with oral steroids was started and resulted in the resolution of the disease during the next three to four weeks. Only methotrexate was continued for six months without recurrence of symptoms. During this period standard laboratory tests to check for drug toxicity were done. The patient was lost to follow-up after six months.

Discussion

Idiopathic orbital inflammatory syndrome (IOIS), also known as pseudotumor of the orbit is defined as a benign, non-infective clinical syndrome, characterized by features of nonspecific inflammatory conditions of the orbit, without identifiable local or systemic causes.[17]

Radiological imaging (CT scan) allows tissue characterization and localization without surgical intervention, and is therefore, an invaluable diagnostic tool. The histopathology of IOIS is typically non-diagnostic and widely diverse, ranging from the typical diffuse polymorphous infiltrate, characterized by a mixed inflammatory infiltrate composed of lymphocytes, plasma cells, polymorphonuclear leukocytes interspersed with varying amounts of fibrosis to the atypical types, with granulomatous inflammation tissue eosinophilia, and infiltrative sclerosis.[13] The sclerosing form tends to be more aggressive than the non-sclerosing forms and appears to have a poor therapeutic outcome.[17]

The pathogenesis of idiopathic orbital inflammatory syndrome is poorly understood. Evidence at hand points to an immune-mediated process, with no specific cause being detected.[17] Hence treatment is empiric and is targeted at suppressing inflammation. IOIS, typically responds favorably to systemic corticosteroid therapy.[3]

Systemic corticosteroid therapy (1.5-2 mg/kg/day dose and tapered slowly over eight to ten weeks following resolution of signs and symptoms) is the mainstay of the treatment of IOIS, with the exception of a sclerotic variant.[1247] However, treatment failure with steroid therapy is common and is reported to occur in the range of 33 to 52%.[9] Recurrence of disease on steroid taper and adverse effects of steroids are the common causes of treatment failure. The spectrum of adjuvant treatment in IOIS is broad and the options surgery (diagnostic and therapeutic), alternative corticosteroid delivery (pulsed intravenous and periorbital injections), radiation therapy, nonsteroidal anti-inflammatory drugs, cytotoxic agents (chlorambucil, cyclophosphamide), corticosteroid sparing immunosuppressants (methotrexate, azathioprine, cyclosporine), intravenous immunoglobulin, plasmapheresis, and the newer class of drugs like the biological agents, which include the antitumor necrosis factor alpha (TNFAlpha).[11] Surgical debulking may be considered if the lesion is easily approachable or in patients with a severely progressive and disabling clinical course (as in the orbital apex syndrome with optic nerve compression).

Response to local radiation is variable with treatment failure being common and is more effective in non-fibrosing lesions.[712] In literature, there are reports of the use of immunosuppressive agents like cyclophosphamide, cyclosporine, azathioprine, and methotrexate.[3489] They are mainly used as steroid-sparing agents and never as the primary treatment modality. Concurrent low-dose steroid therapy is often administered. Although cyclophosphamide is frequently effective in combating inflammation in steroid- and radiation-resistant IOIS, it has serious adverse effects, including profound bone marrow suppression and the risk of opportunistic infections, sterility, and secondary malignancy. Antimetabolites, methotrexate, and azathioprine carry less risk to the patient than do cyclophosphamide or long-term steroid therapy.

Antimetabolites are specially indicated in these patients as they are cost-effective and have a lower level of toxicity when compared to other immunosuppressive drugs like cyclosporine. The most serious side-effects of methotrexate and azathioprine are hepatotoxicity and reversible bone marrow suppression. However, these are unlikely in our context as the duration of therapy in IOIS is relatively short. All the patients were monitored according to the American College of Rheumatology guidelines, with pretreatment liver function tests and full blood counts, with tests repeated four to eight weeks thereafter.[8] Use of other, more potent immunosuppressive agents, mandates closer monitoring of the hematological, liver, and renal functions, increasing the financial burden on the patient, although antimetabolites also need basic laboratory monitoring.

In our patients both methotrexate and azathioprine were effective in controlling orbital inflammation, without concurrent steroid use, once the initial inflammation was controlled. None of known adverse effects of these drugs occurred in our patients.

Although we managed these patients with our past experience of using antimetabolites in uveitis and scleritis, monitoring in consultation with a Rheumatologist is advised.

In conclusion high-dose systemic steroid therapy is the first-line treatment for IOIS, but refractory cases account for a significant proportion of treatment failures. In such recalcitrant cases, immunosuppressive therapy with antimetabolites (methotrexate and azathioprine) is a safe and effective treatment alternative to steroids. However, treatment with antimetabolites warrants close monitoring for complications like bone marrow suppression and liver dysfunction, especially as long-term treatment is required.