Summary for the Clinician

■ IOIS is classically exquisitely sensitive to corticosteroids. Patients who do not quickly respond

3to adequate steroid therapy are considered “atypical.”

■Corticosteroid therapy should be considered a failure only if adequately dosed and tapered. Relapse is common if steroid therapy is tapered too quickly.

■Atypical cases of suspected IOIS either at presentation or after failed corticosteroid therapy should undergo further workup, including tissue biopsy.

3.2.3 The Question of Biopsy

The role of orbital biopsy in the diagnosis of IOIS is controversial and has been debated extensively in the literature. Briefly, some experts posit that an orbital biopsy should be attempted in all patients prior to the initiation of steroid treatment of IOIS, provided the tissue in question is easily accessible, arguing that “inflammation” is not a diagnosis but may be a sign of a potentially dangerous underlying tissue process [49] (Fig. 3.9). Others counter that orbital exploration may expose the typical IOIS patient to unnecessary surgical risk (Fig. 3.11). In one study of IOIS in pediatric patients, those who underwent orbital biopsy were more likely to experience “serious residua from their disease,” such as decreased visual

Fig. 3.11 Levator injury after orbital biopsy. Note the significant right eyelid ptosis with poor levator function in this patient who underwent orbitotomy for biopsy of the levator–superior rectus complex. Biopsy was consistent with IOIS. Eyelid function did not improve, and final correction required two additional surgeries

acuity, persistent proptosis, and EOM pareses and restriction [36]. These clinicians concluded that orbital biopsy should be reserved for patients with an atypical presentation, those who do not experience an immediate and sustained response to corticosteroids, and those whose symptoms recur.

Close inspection of the arguments from both camps, however, reveals that in clinical practice the chasm between them may be quite narrow and possibly nonexistent. For example, both agree that in the case of orbital myositis or an inflammatory lesion located at the orbital apex, the benefits of histopathologic confirmation should be carefully weighed against the possibility of iatrogenic damage [46]. In a similar vein, while the advocates for biopsy may argue that there is an unacceptably high incidence of malignancy in cases of lacrimal gland masses [47, 53], in many cases IOIS and lacrimal gland tumors can be distinguished by the history (tempo of onset, associated symptoms, etc.), clinical exam, and results of radiologic studies. In cases that may be uncertain, few would argue with the legitimacy of biopsy. In addition, any atypical variable (e.g., a subacute or smoldering onset, lack of associated pain, bony destruction on imaging), recurrent episodes of inflammation, or a history of local or distant malignancy should prompt a biopsy in most cases.

Summary for the Clinician

■Some experts believe that an orbital biopsy should be attempted in all patients prior to the initiation of steroid treatment of IOIS.

■Others recommend an orbital biopsy only in select patients who (1) present in a manner atypical for IOIS; (2) fail to respond to corticosteroid therapy; or (3) experience recurrent disease.

■Proposed algorithms for the management of typical and atypical IOIS cases are listed in Figs. 3.12 and 3.13, respectively.

3.3 Treatment

The inflammation in IOIS results from the escalation of a series of cascading enzymatic processes that occurs in target tissues as a result of some unknown inciting factor. Localized cellular damage can lead to the activation of phospholipases, which mediate the release of arachidonic acid and perpetuate the cascade of inflammatory mediators in an explosive fashion. While an in-depth discussion of inflammation is beyond the scope of this text,

some knowledge of this inflammatory cascade is necessary to understand the treatment options available for patients with IOIS.

3.3.1Corticosteroids

Corticosteroids inhibit the cascade of inflammation and the immune response at virtually every level via the

suppression of proinflammatory cytokines. The effect is a nonspecific and global immune suppression. Herein lies the argument against the use of corticosteroids as part of thediagnosticalgorithmforIOIS,asdiscussed.Nevertheless, in clinical practice, corticosteroids remain the mainstay of treatment for IOIS at present [18, 33, 34, 36, 46, 60].

The most common route of administration of corticosteroids in the treatment of IOIS is oral, at a starting dosage of 1.0–1.5 mg/kg/day. Parenteral steroids may also

be employed, usually in cases of IOIS-related optic neuropathy. The initial dose is tapered over the course of weeks to months, as dictated by the patient’s symptoms. While too rapid a taper may predispose the patient to

3rebound inflammation, a prolonged steroid taper will expose the patient to some of the more serious treatmentrelated side effects. Weight gain, gastritis, cushingoid facies, and mood swings are commonly cited effects. Corticosteroid treatment can also exacerbate or induce diabetes, hypertension, glaucoma, and cataract in susceptible patients. In light of the significant side effects of systemic therapy, some authors advocate local intraorbital injection of triamcinolone acetonide in cases of inflammatory masses or dacryoadenitis [15]. It should be noted that this is an off-label use of the medication, and it carries with it the inherent risk of retinal vasculature embolization of particulate matter.

A review of the literature reveals numerous examples of “steroid-resistant” IOIS as well as outright steroid failures. Direct comparison of published studies is difficult, however, as inclusion criteria and treatment protocols are inconsistent at best. For example, Mombaerts et al reported a low cure rate (37%) and a high recurrence rate (52%) of IOIS treated with corticosteroids; however, patients with myositis and lacrimal gland involvement were excluded from analysis [34]. In a separate study looking only at patients with idiopathic inflammatory myositis, the authors reported that all patients responded well to corticosteroid therapy, but symptoms recurred in 50% with prolonged follow-up [33]. In Yuen and Rubin’s study [60], 69% of patients were managed with corticosteroids alone and a further 9% with the addition of a nonsteroidal anti-inflammatory drug (NSAID) to manage residual symptoms, for a total of 78%. An incomplete resolution of symptoms was noted in approximately 30%, and these patients were designated steroid failures.

3.3.2Radiation

Radiotherapy is effective treatment for IOIS, especially in patients who are steroid responsive but intolerant of ste- roid-related side effects. The studies demonstrating efficacy of radiation therapy are somewhat dated and, as is the problem with many studies concerning IOIS, are difficult to compare due to different inclusion criteria and treatment measures. For example, Sergott et al [51] showed a response in 15 of 21 patients (72%) with a dose of 1,000– 2,000 cGy over 10–15 days. Orcutt et al [40], on the other hand, showed a 75% treatment effect at doses of 2,500 cGy over 15 days. Gunalp et al [17] reported successful results

of radiation treatment in 9 of 14 (64%) of patients who failed to respond to corticosteroid therapy.

Fortunately, the side effects of low-dose orbital radiation in the range of 1,000–2,500 cGy are rare. The eyelids tolerate approximately 5,000–6,000 cGy before exhibiting significant signs of radiation dermatitis and eyelid scarring. Similar doses induce lacrimal gland atrophy, radiation retinopathy, and optic neuropathy. At the lower end, punctate keratopathy and conjunctivitis are noted with dosages of between 3,000 and 4,000 cGy. A radiation cataract may develop at 2,000 cGy [1]. However, these radiation dosage associations are averages; certain patients, such as those with vasculopathic risk factors (hypertension, diabetes mellitus, etc.), may be more at risk for adverse events related to radiation therapy.

3.3.3 Other Agents

Following a lead from rheumatologists and dermatologists, there has been a growing interest among orbital specialists in the use of immunomodulating agents in the treatment of IOIS. Although corticosteroids remain a first-line treatment, immunosuppressive agents, including antimetabolites (e.g., methotrexate [MTX], azathioprine); alkylating agents (e.g., cyclophosphamide, chlorambucil); T-cell inhibitors (e.g., cyclosporine, tacrolimus); and biologics (e.g., infliximab, etanercep) it are increasingly used as steroid-sparing alternatives.

Methotrexate is an antimetabolite that interferes with intracellular folic acid metabolism during DNA and RNA synthesis. It is a cytotoxic agent that is used in combination with other chemotherapeutic agents in the treatment of many types of cancers. Lower doses of MTX have been shown to be very effective for the management of rheumatoid arthritis, Crohn disease, and psoriasis [24]. Several small studies have addressed the usefulness of MTX in the treatment of orbital inflammatory disease. Both Shah et al [52] and Smith and Rosenbaum [55] showed that MXT (7.5–25 mg/week) had some benefit in patients with noninfectious orbital inflammatory disease, including IOIS, who had failed to respond to systemic corticosteroids or orbital irradiation. Azithroprine is also an antimetabolite that works by inhibiting purine synthesis. Like MTX, it has been used in the treatment of various rheumatologic and dermatologic conditions (i.e., rheumatoid arthritis, inflammatory bowel disease, pemphigus, systemic lupus erythematosis), but its efficacy in terms of orbital disease is limited to a small number of case reports [9].

Alkylating agents slow or stop cell growth by forming cross-links between DNA strands, inducing apoptosis. Examples include cyclophosphamide (Cytoxan), a mainstay

in the treatment of systemic lupus erythematosus (SLE), and chlorambucil, used only in very refractive cases of rheumatoid arthritis. There are limited data on the use of these agents for IOIS, and the results are at times conflicting. Leone and Lloyd [29] successfully treated two patients with cytoxan(200mg/daypluscorticosteroids),whileMombaerts et al [34] found that two patients with steroid-resistant IOIS demonstratednoresponsetoasimilarregimen.Chorambucil has proven useful as an alternative to radiotherapy in the treatment of orbital and adnexal lymphoma [3], but there is little information in the peer-reviewed literature addressing its use in the treatment of IOIS.

Cyclosporine and mycophenolate mofetil (CellCept) are T-cell inhibitors. These agents prevent the transcription of interleukin 2 and inhibit lymphokine production, reducing the function of effector T cells. Cyclosporine is available in systemic formulations as well as topical preparations, well known to ophthalmologists by the brand name Restasis®. Similar to the previously mentioned agents, use of these T-cell inhibitors by the rheumatologic and dermatologic communities (e.g., for rheumatoid arthritis, inflammatory bowel disease, polymyositis) has pioneered their use in orbital disease. There are several case reports that suggested that cyclosporine may have a role in the treatment of steroid-resistant IOIS. Diaz-Llopis and Menezo [10] controlled the symptoms of one patient with low-dose cyclosporine (starting dose 5 mg/kg, maintenance dose 2 mg/kg) for 10 months prior to a recurrence. Sanchez-Roman et al [50] successfully treated one patient with recurrent myositis who became intolerant of steroid-related side effects with low-dose cyclosporine. With similar success, Bielory and Frohman [4] reviewed a small series of four patients with granulomatous optic neuropathy and orbitopathy and noted stabilization in two and improvement in the other two with low-dose cyclosporine therapy. Hatton et al [19] reported on the successful use of mycophenolate mofetil in four patients with refractory IOIS and in one patient with brittle diabetes for whom corticosteroids were contraindicated.

Finally, biologic agents are the newest addition to the armamentarium of drugs available to treat the various rheumatologic diseases. The development of these agents grew out of a more complete understanding of the immune response and its dysregulation. As opposed to the global immune suppression achieved by some of the previously discussed agents, biologics target specific cell surface and soluble molecules to intercept the immune cascade at a specific point with fewer side effects than traditional immunomodulatory agents. Examples of such targets include tumor necrosis factor alpha (TNF-a), interleukin 2, and T-cell surface markers that supply costimulatory signals.

Anti-TNF-a agents such as etanercept and infliximab have shown considerable efficacy in treating a diverse group of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. There are a number of factors that suggest that TNF-a may play an important role in the treatment of orbital inflammation [25]: It is found in orbital connective tissue of patients with TED but not in normal controls. Furthermore, the levels of TNF-a messenger RNA (mRNA) seem to correlate with the size of EOMs in patients with TED. Paridaens et al [41] reported an improvement in soft tissue changes such as conjunctival chemosis and redness in ten consecutive patients with active TED treated prospectively with entercept studied the effects of etanercept. These medications have also been used with some success in the treatment of ocular inflammatory diseases such as uveitis and scleritis [37]. Promising results have also been observed in patients with IOIS. Garrity et al [13] reviewed data from three centers where infliximab was used to treat patients with IOIS who failed conventional treatments such as steroids, radiation, and other anti-inflam- matory agents. Symptomatic improvement was reported in six of seven patients, and three experienced complete resolution. More recently, several small case series have confirmed these earlier successes [32, 44].

Summary for the Clinician

■Treatment of IOIS involves interrupting the inflammatory cascade.

■Corticosteroids remain the mainstay of treatment for IOIS. They are often started at a dose of 1 mg/kg/day and tapered over the course of weeks to months, according to a patient’s symptoms. NSAIDs may be useful adjuncts during the tail end of the corticosteroid taper.

■Patients who do not respond to corticosteroid therapy are often considered “atypical,” and biopsy of the affected tissue should be attempted, if accessible.

■Low-dose 1500-2000 cGy orbital radiation has shown efficacy in the treatment of steroidresistant IOIS.

■Immunomodulating agents have demonstrated efficacy in the treatment of rheumatologic, dermatologic, and uveitic inflammation. The results of a small number of case series and case reports suggest that these agents may be useful in select patients with IOIS.