Orbital inflammatory disease management

ABSTRACT

Introduction: Orbital inflammatory disease (OID) represents a spectrum of conditions that can be placed into two groups, specific orbital inflammatory disease (SOIS) and nonspecific orbital inflammatory disease (NSOIS). This manuscript aims to systematically review the therapies for the different types of OID.

Areas covered: The therapy for OID has evolved significantly with the advent of biologic medications, although certain mainstays are still widely used. The authors conducted a review of literature published in the last 20 years with the use of PubMed. This article is organized according to disease syndrome. Specific diseases and their associated treatments are addressed.

Expert commentary: Although corticosteroids are still the mainstay of treatment in most OID, a focus on disease specificity combined with increasing understanding of inflammatory pathways has allowed utilization of inflammatory modulatory medications. Investigating these therapeutics in prospective trials will likely be the vital link to improving patient care in orbital inflammatory disease.

KEYWORDS:

• Orbital inflammation
• orbital inflammatory disease
• orbital inflammatory disease treatment
• orbital inflammation treatment review
• orbital inflammatory disease treatment review
• granulomatosis with polyangiitis orbit
• sclerosing orbital inflammation
• idiopathic orbital inflammation treatment
• orbital myositis
• Castleman’s disease orbit treatment

1. Introduction

Orbital inflammatory disease (OID) represents an etiologically diverse spectrum of conditions unified in their association with abnormal inflammation in the periorbital region. These conditions can be roughly grouped into two categories, specific orbital inflammatory disease (SOIS) and nonspecific orbital inflammatory disease (NSOIS). As the language suggests, SOIS describes those inflammations in the orbit that fit within a distinct clinical and/or pathologic category while the remainder of inflammatory disease that has yet to be classified is discussed under the umbrella of nonspecific inflammation.

Over the past decade, the therapeutic options in OID have evolved significantly, along with inflammatory disease management more generally. Targeted immunotherapy with biologic medications has become increasingly important, although certain therapeutic mainstays, such as prednisone and cyclophosphamide, are still widely used. This discussion aims to provide a contemporary review of therapeutic modalities utilized in treating OID. Given the already significant research base surrounding therapeutic approaches for thyroid eye disease, it will not be addressed in the current review, nor will infectious etiologies associated with OID.

This review has been organized according to disease syndrome and includes nonspecific orbital inflammation, xanthogranulomatous inflammation, inflammatory vasculitides, rheumatoid and autoimmune disease-associated inflammation, and rare diseases. Within each disease category, specific diseases and their associated therapies have been addressed.

2. Idiopathic orbital inflammation

2.1. Orbital myositis

Orbital myositis is a subgroup within idiopathic OID in which single or multiple extraocular muscles are the specific target of inflammation. Orbital myositis typically presents with pain upon eye movement and diplopia, with or without orbital inflammatory signs such as erythema and edema. The disease can be grouped into two forms: limited oligosymptomatic ocular myositis (minimal associated signs and symptoms) and severe exophthalmic ocular myositis (additional ptosis, proptosis, chemosis). Corticosteroids are classically the mainstay of treatment for orbital myositis [1,2].

Corticosteroid dosing usually consists of oral prednisone 1 mg/kg/day for 1–2 weeks followed by a 6–12-week taper. Induction therapy with intravenous (IV) methylprednisone 1000 mg/day has also been utilized to good effect [1,2]. Some advocate for lower doses (20 mg oral prednisone per day) in cases with single muscle involvement [3].

Up to 80% of patients treated with steroids alone eventually experience relapse of myositis during steroid taper and thus steroid-sparing medications are often necessary [4,5]. This rate is lower in patients presenting with single muscle disease [6]. Immunosuppressive agents including methotrexate, cyclosporine, cyclophosphamide, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin (IVIG) have shown efficacy in steroid tapering and/or symptom relief [2]. Among biologic agents, infliximab, daclizumab, rituximab, and adalimumab have all shown efficacy in isolated cases of orbital myositis [7–11]. Radiation therapy has also been utilized in treating orbital myositis, and although a good initial response was noted, long-term control of recurrences was noted to be suboptimal [4]. Treatment failures and chronic relapsing disease may warrant a biopsy [6].

2.2. Dacryoadenitis

Dacryoadenitis is a NSOIS subtype that involves isolated inflammation of one or both lacrimal glands. Dacryoadenitis comprises up to 50% of idiopathic orbital inflammation [12–14]. Risk factors for poor prognosis and limited response to therapy include chronicity, involvement back to the orbital apex, and sclerosing histology [12,14].

Similar to other idiopathic orbital inflammation, corticosteroids have historically been the mainstay of therapy, with 0.6–1 mg/kg/day of oral prednisone being the usual induction dose followed by a 6–10-week taper [15]. However, treatment with corticosteroids alone has been associated with incomplete initial response in over 50% of patients and recurrence rates between 40% and 80% have been reported [16,17].

Surgery has also been proposed for dacryoadenitis. In a recent study by Mombaerts et al., 80% of patients undergoing excisional biopsy with debulking of the orbital lobe of the lacrimal gland had complete relief of symptoms, and only 8% recurrence following surgery. Additionally, surgical failure was associated with corticosteroid therapy prior to surgery, and thus debulking surgery instead of corticosteroids was recommended as first-line treatment. Surgical failures in this study were treated with additional modalities, including radiation therapy, rituximab, methotrexate, and intralesional steroids [18]. Azathioprine has also been used as an adjunctive therapy to surgery [15].

Mohammad et al. recently reported on long-term follow-up in 27 patients receiving intralesional betamethasome (2–4 ml) and per os (PO) indomethacin for idiopathic dacryoadenitis. All patients experienced a good response within 1 week and no recurrences were noted (follow-up ranged from 7 to 96 months), although mean follow-up time and response grading criteria were not elucidated. Other studies have also noted favorable results with intralesional corticosteroids [15,18,19].

2.3. IgG4-related disease

IgG4-related disease (RD) is an idiopathic inflammatory spectrum, often with systemic involvement characterized by tissue infiltration with IgG4-bearing plasma cells and fibrosis [20]. The disease can affect multiple tissues in the orbit, including the lacrimal gland, extraocular muscles, and soft tissue [21–24]. IgG4-RD is a relatively new entity, and although controversial, it may account or a sizeable proportion of what was previously thought to be idiopathic orbital inflammation. Multiple sets of criteria have been established for the diagnosis of IgG4-RD, and a single criterion has yet to be universally adopted.

Regarding treatment, corticosteroids are again typically the first line for IgG4-RD, similar to other idiopathic OIDs. In a review of 174 cases of IgG4-realted disease, Wu et al. noted that 95% of patients treated with corticosteroids improved following treatment; however, 72% of patients later experienced relapse of their disease [25].

Methotrexate, cyclosporine, and azathioprine have been utilized as steroid sparing agents, unfortunately demonstrating little activity against the disease [26]. Rituximab is a promising therapy for IgG4-RD. Wallace et al. in their small trial of rituximab for IgG4-RD noted that 6/16 patients experienced disease resolution and 8/16 patients experienced improved symptoms [26]. Other studies have also noted efficacy for rituximab [27,28]. In cases of vision-threatening disease secondary to mass effect, surgical decompression may be able to prevent further vision loss, if only temporarily [26].

3. Sclerosing orbital inflammation

Sclerosing orbital inflammation (SOI) comprises roughly 5–8% of OID [29]. The disease is typically characterized by the gradual onset of dull pain, proptosis, and double vision. In SOI, orbital structures are gradually replaced by fibrosis leading to functional disability. Histopathologic analysis demonstrates dense collagen deposits with sparse inflammatory reaction comprising lymphocytes, plasma cells, histiocytes, eosinophils, and neutrophils [29,30].

Given the rare presentation of SOI, treatment recommendations are based mostly on small case series and reports. The current mainstays for treatment of SOI include corticosteroids and surgical debulking. Corticosteroid administration is the most common initial treatment for SOI [29,31–33]. The use of steroids alone has produced varying results in the literature. In their systematic review of SOI in 2012, Pemberton and Fay noted a good response (relief of symptoms and signs, without recurrence) to steroids in only 9/21 patients, a partial response (some improvement of signs and symptoms, ±recurrence) in 5/21 patients, and a poor response (no improvement or progression) in 7/21 patients receiving only steroids as treatment for SOI. Steroid dosing ranged from 30 to 150 mg/day and duration of therapy ranged from 1 to 144 months. Follow-up time was not specified, and hence recurrence rate was likely higher than noted [33]. Of note, Hsuan et al. described a trend toward shorter duration of disease prior to presentation being associated with a better response to steroids [32]. Hence, early detection sclerosing inflammation and treatment with steroids may improve outcomes.

The second mainstay of treatment for sclerosing inflammation is debulking surgery. Hsuan et al. noted complete symptom relief in 2/4 patients and partial response in 1/4 patients who underwent surgical debulking and concurrent corticosteroid therapy [32]. Although disease severity was not accounted for, Pemberton and Fay noted good response to surgery and corticosteroids in 3/8 patients, partial response in 5/8, and no response in zero patients [33]. Thus, debulking surgery appears to provide at least partial relief for sclerosing inflammation. To date, surgery is the sole therapy capable of lessening the mass of inflammatory tissue in the orbit.

Various chemotherapeutic and biologic agents, in addition to radiation therapy, have also been used in the treatment of sclerosing inflammation with mixed results. Lee et al. evaluated the effectiveness of radiotherapy for steroid-refractory sclerosing inflammation and noted a complete response in 15/22 patients and partial response in 3/22 patients. Notably, 14 of these patients were progression or recurrence free at a median follow-up of 34 months. It is also noteworthy that in six patients who underwent surgical debulking in addition to radiation therapy, no recurrences were noted [34]. This stands in contrast to several studies that noted partial or no response to radiotherapy in sclerosing inflammation [29,32,33].

Regarding chemotherapeutic and biologic agents, cyclophosphamide, azathioprine, cyclopsporine, methotrexate, infliximab, and rituximab have all been utilized in small case series with varying results [11,33,35,36]. Near complete resolution was noted in one patient who underwent combination therapy with systemic steroids, CyberKnife surgery, and rituximab for sclerosing inflammation [35]. Similarly, Pemberton and Fay noted good responses to treatment in two patients receiving combination therapy with azathioprine and steroids and partial response in one patient [33]. In one case report of sclerosing myositis, infliximab was utilized alongside methotrexate and systemic corticosteroids. Although the patient experienced complete resolution of pain after infliximab treatment, she continued to experience diplopia in primary position and motility deficits [11]. Overall, therapy for sclerosing inflammation is not overwhelmingly effective, likely representing the mixed etiological basis for this clinically unified disease process. Steroid therapy and surgical debulking in combination may represent the best current regimen, although the addition of therapy with radiation or azathioprine also shows some promise.

4. Xanthogranulomatous disease

Xanthogranulomatous disease is diagnosed based on its typical histopathological appearance, demonstrating touton giant cells, foamy histiocytes, fibrosis, and, at times, necrosis. Adult xanthogranulomatous disease can be divided into four syndromes: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim–Chester Disease (ECD) [37]. For the purposes of this review, ECD therapy will be reviewed separately, while AOX, AAPOX, and NBX will be discussed together.

4.1. AOX, adult AAPX, NBX

AOX describes xanthogranulomatous disease affecting the eyelid and orbit without systemic disease and is often self-limited. AAPOX describes a similar periorbital syndrome with systemic involvement in the form of asthma, benign lymphadenopathy, and polyclonal IgG paraproteinemia. NBX syndrome is characterized by ulcerative, necrotic xanthogranulomatous lesions that often affect the conjunctiva, orbit, adnexa, and other vital organs, like the heart, lungs, and kidneys. NBX is also associated with monoclonal gammopathy and hematological malignancy [37,38].

Historically, corticosteroids and excisional surgery have comprised the mainstays of therapy for AOX and AAPOX. Although systemic steroids are typically administered for induction treatment in the form of oral prednisone 1 mg/kg/day, recurrences frequently occur [37,39].

Local therapy has been assessed. Elner et al. noted local control and reduced signs and symptoms associated with AOX in two patients who received 3-monthly injections of triamcinolone. Additionally, no recurrence was noted after a mean follow-up of 38 months [40].

Sivak-Callcott et al. reported that excisional surgery alone was effective in six of eight patients with AAPOX whereas systemic steroids alone were effective in two of two with AAPOX, although the severity of disease was not indicated [37]. Similarly, Karcioglu et al. reported that surgical debulking/excision led to disease regression in at least three of five patients with orbital xanthogranuloma, all with at least 1 year of follow-up. Notably, one of the five patients was lost to follow-up and the other had severe disease that was not responsive to corticosteroids or radiation prior to surgery. No delineation was drawn between AAPOX and AOX in this study [41].

External beam radiation has also been employed in AAPOX and AOX with mixed treatment outcomes [37,41–43].

The mortality rate associated with NBX is significantly higher than that of AOX and AAPOX (10–50% vs. close to 0%, respectively) [40,44], due to its association with multiple myeloma and other hematological malignancies. Hence, in addition to addressing treatment of orbital NBX manifestations, patients in whom NBX has been diagnosed or suspected should undergo investigation up to rule out hematological malignancies. Similar to AOX and AAPOX, NBX has also been treated with systemic and intralesional steroids in the literature, often with recurrence following taper [37,40,45]. Cyclosporine, chlorambucil, and melphalan have also each successfully been used anecdotally in treatment of NBX [45–47]. Regarding surgical excision of NBX lesions, Ugurlu et al. reported that lesions recurred in 42% of patients following surgery and hence recommended against it [44]. Triamcinolone may be less effective in NBX than AOX or APOX as reported by Elner et al., where only minimal sustained and partial improvement was noted [40]. Radiation therapy has also demonstrated mixed results for the treatment of NBX [37,47]. Overall surgery and steroids may be effective for AOX and AAPOX, although there is a risk of recurrence. For NBX, no therapy has proven to be adequately effective in mainlining long-term control. Despite promise of other immunosuppressive agents, the rarity of these diseases makes definitive outcome information difficult to obtain at this time.

4.2. Erdheim chester disease (ECD)

ECD is a rare, non-Langerhan cell histiocytosis associated with aggressive fibrosclerosis of multiple organ systems, including the heart, lungs, retroperitoneum, and bones. Within the orbit and adnexa, ECD is associated with orbital fibrosclerosis and xanthomatous lesions of the eyelids [37,48,49]. Until recently, the 3-year mortality for patients with ECD was close to 40% [50], and the 15-year mortality rate was at least 66%, regardless of therapy [37].

Historically, corticosteroids, chemotherapeutic, and immunosuppressive agents, such as cyclophosphamide, cyclosporine, cladribine, and vinblastine, have been used to treat ECD, usually with minimal effect on long-term disease progression and mortality [37,51,52]. Autologous hematopoietic stem cell transplantation has also shown little effect on disease progression [53]. Surgical debulking of the orbital lesions in ECD may be beneficial in temporarily relieving optic nerve compression, although it likely has minimal effect on long-term survival.

Currently, the first-line therapy for ECD is interferon alpha (IFN-alpha). Several studies have described treatment with IFN-alpha to have a sustained treatment response [54,55], and in one case, improvement in overall survival when compared with other therapies [56]. Dosing of at least 3 million units, 3 times per week, is required in most cases [55,56], with severe cases involving the CNS and cardiovascular systems requiring doses of 9 million units, 3 times per week [57]. Of note, pegylated IFN-alpha appears to be better tolerated than regular IFN-alpha, which has significant side effects, including constitutional symptoms, GI upset, alopecia, myelosuppression, and depression [48].

With regard to biologic therapies, a single case series showed positive results with infliximab treatment in four patients with cardiovascular ECD that was refractory to treatment with IFN-alpha [58].

Another potentially promising therapy for ECD is vemurafenib, a BRAF inhibitor. Approximately half of ECD patients have BRAFV600E mutations in their histiocytes [59]. Haroche et al. noted promising preliminary results associated with vemurafenib administration for patients with BRAFV600E-positive multisystem ECD. All patients in this series experienced at least partial improvement [60]. With respect to the orbit and ocular adnexa, vemurafenib has been associated with improvement in orbital inflammation and/or significant reduction in xanthomatous skin lesions in at least three patients [60,61]. Of note, all patients treated with vemurafenib experienced severe adverse skin reactions, and one patient developed cutaneous squamous cell carcinoma. Thus, the authors of the aforementioned study recommended vemurafenib as a second-line therapy in patients with refractory ECD.

5. Orbital inflammation associated with inflammatory vasculitides

5.1. Granulomatosis with polyangitis

Granulomatosis with polyangitis (GPA; formerly known as Wegener’s granuolmatosis) is a rare, progressive systemic vasculitis affecting primarily small-to-medium-sized blood vessels. Around 90% of patients with generalized GPA have serology positive for C-ANCA (cytoplasmic-antineutrophil cytoplasm antibodies) [62,63], although this percentage is often much lower in patients with disease localized to the orbit, perhaps closer to 50% [64]. Within the orbit, GPA presents typically as a diffuse mass or with lacrimal involvement [64,65].

Prior to the advent of cytotoxic drugs in the late 1960s and 1970s, GPA was almost always fatal, with a mean 1-year mortality of 82% [66]. With corticosteroid therapy alone, mean survival was still only 12.5 months [67]. Although not suitable as monotherapy for GPA, glucocorticoids, including prednisone and methylprednisone, are a valuable adjunct during induction treatment [65,68,69]. With the advent of cyclophosphamide for GPA induction treatment in 1971, survival rates increased significantly to 80–90% at 20 years [70,71]. The combination of cyclophosphamide and corticosteroids is still commonly used for induction therapy of orbital GPA. Although not specifically evaluated for orbital GPA, methotrexate, azathtioprine, mycophenolate mofetil, and 15-deoxyspergualin (an immunomodulatory synthetic analog of bacteria-derived spergualin) have also been shown to assist in inducing remission [72–76].

Biologic therapies may also have a role in the treatment of GPA. Of note, the percentage of activated B cells in peripheral blood correlates with disease activity in GPA [77], and in a randomized controlled study, rituximab, an anti-CD20 monoclonal antibody that depletes B lymphocytes, was shown not to be inferior to cyclophosphamide for the induction of remission in patients with severe, relapsing, ANCA-positive, systemic GPA [78]. These results could be applicable to the orbit although no specific trials have been performed. In initial reports, orbital mass disease associated with GPA was noted to have minimal improvement following rituximab therapy [79,80]. However Taylor et al. found that rituximab induced remission in seven of seven patients with refractory, orbital GPA [81]. Of note, rituximab dosing in this study consisted of two IV doses of 1 g rituximab given 2 weeks apart, whereas the dosing used in the aforementioned studies with minimal improvement consisted of 375 mg/sq. m given every fourth week. Martinez del Pero et al. also demonstrated positive response with 1 g dosing in four of five patients with retro-orbital GPA, although two of four responders experienced recurrence after 6 months and required alternative therapy [82]. Similarly, in a recent study evaluating maintenance therapy for systemic GPA, more patients experienced sustained remission with rituximab than azathioprine after induction therapy with corticosteroids and cyclophosphamide [83]. Thus, although fewer reports describe specifically orbital GPA therapy, findings from systemic disease and the few case series available support a possible role for rituximab in both induction and maintenance therapy.

With regard to other biologic therapies, infliximab has been shown to induce remission in GPA [84] but is now rarely used [69]. In contrast, etanercept showed no significant difference from placebo in induction of remission in patients with systemic GPA in a randomized, placebo-controlled study [85].

Although no case reports or series have been reported yet, the BAFF (B-cell activating factor or the tumor necrosis factor family) inhibitor belimumab may also have a role in GPA therapy [86]. Recent studies have shown elevated BAFF levels in GPA patients [87,88], with levels being further elevated following rituximab treatment [89]. In the event that elevated BAFF leads to selection of autoreactive B cells in recurrent GPA following rituximab therapy, belimumab may be a useful adjunct [86,90].

In uncontrolled, infiltrative orbital GPA, enucleation and exenteration may also be necessary. In patients with nasolacrimal duct obstruction secondary to GPA, dacryocystorhinostomy has been successful for patients with inactive disease [91,92].

5.2. Polyarteritis nodosa

Polyarteritis nodosa (PAN) is a systemic, necrotizing vasculitis involving small- and medium-sized vessels. This entity affects the eye and orbit in roughly 10% of patients. The disease usually affects adults between 40 and 60 years old but can also occur in children [93,94]. Diagnosis of PAN is based on the presence of clinical criteria organized by the American College of Rheumatology [95]. Less than 10 cases having orbital PAN have been reported in the literature [96–99]. In these reports, PAN-associated orbititis was associated with diffuse orbital inflammation leading to exophthalmos, restriction of extraocular movements, and other signs and symptoms secondary to mass effect.

Similar to systemic PAN, corticosteroids and cyclophosphamide are the mainstay of induction therapy for orbital PAN, although some isolated case reports have shown good response of orbital PAN to steroids alone [93,97,98]. In PAN not confined to the orbits, induction treatment has also been successfully carried out with rituximab [100,101] and infliximab [102] in separate, isolated case reports. With regard to maintenance therapy, azathioprine, methotrexate, and mycophenolate mofetil have been successfully utilized in smaller, non-blinded case series [94,103].

5.3. Churg–Strauss syndrome

Churg–Strauss syndrome (CSS) is a small-to-medium-sized vessel vasculitis characterized by granulomatous infiltration. The American College of Rheumatology disease criteria include presence of four of six manifestations including: hypereosinophilia, asthma, mono- or polyneuropathy, non-fixed pulmonary infiltrates, paranasal sinus abnormalities, and extravascular eosinophilic infiltrate on biopsy [104]. A positive p-ANCA test is present in up to 70% of patients with CSS. Although it rarely affects the orbit and periorbital area, CSS can present as diffuse orbital inflammation, panniculitis, myositis, and dacryoadenitis [93,105–108].

Corticosteroids are the classic treatment for orbital vasculitis secondary to CSS, with some cases responding well to oral corticosteroids alone [108,109]. IVIG, methotrexate, and cyclophosphamide have also been utilized in addition to corticosteroids to induce remission with good results in isolated studies [93,105,106,110]. Two case reports have described success with methotrexate as maintenance therapy [105,107]. Various biologic therapies have also been used with good effect in isolated cases of refractory, systemic CSS, including etanercept, infliximab, rituximab, and omalizumab [93,111]. Although these cases did not specifically address orbital disease, the aforementioned biologics may also be useful in refractory orbital CSS.

5.4. Bechet’s disease

Bechet’s disease, named after Turkish dermatologist Hulusi Bechet, is a rare, multisystem small-vessel vasculitis that commonly affects the oral mucosa, skin, eyes, and GI tract, and it is associated with the HLA-B51 serotype [112]. With regard to the visual system, Bechet’s disease is classically associated with retinal vasculitis and uveitis, but several case reports have noted an association with orbital inflammation and myositis [112–116].

In all cases, the associated orbital inflammation and myositis responded well to IV corticosteroids followed by an oral taper [113–116]. Of note, one patient was initially treated with oral steroids with minimal effect, and then experienced complete remission following IV steroids [113]. Hence, initial therapy with pulse dose IV steroids is recommended in patients with Bechet’s who experience new onset orbital inflammation or myositis. With regard to maintenance therapy of orbital Bechet’s, there is a paucity literature; however, good long-term control has been noted with anti-TNF agents, like infliximab [117–120], and more recently with interleukin(IL)-1 inhibitors, like Anakinra [121,122], in patients with systemic disease.

5.5. Large-vessel vasculitides

With regard to large-vessel vasculitides, both Takayasu arteritis and giant cell arteritis have been associated with orbital inflammation in rare case reports. In a single case report of Takayasu’s arteritis presenting with proptosis and diplopia and later shown to have inflammatory orbital inflammation, initial treatment with IV prednisone (60 mg/day) and cyclophosphamide (0.8 g/2 weeks, followed by infusions every 3 weeks for 3–6 pulses) yielded gradual improvement of symptoms, and stable long-term disease on low-dose steroid and monthly IV cyclophosphamide [123]. With regard to Giant cell arteritis, in patients presenting with enhancement of retrobulbar fat on MRI consistent with orbital inflammation, resolution of orbital inflammation was noted with corticosteroids, with one patient receiving bolus IV solumedrol (1 gm/day for 3 days) followed by an oral prednisone taper [124], and the other receiving oral prednisone (100 mg/day for 14 days) [125].

6. Orbital inflammation associated with rheumatoid and autoimmune disease

6.1. Rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with a wide array of systemic manifestations. Although exceedingly rare, orbital manifestations, including myositis [126,127] and diffuse orbital inflammatory disease (OID) [128], have been reported in patients with RA.

In two reported cases of myositis, the patients’ RA had been well controlled on maintenance dose corticosteroids and immunosuppressants prior to development of myositis. Both cases responded well to a temporary increased dose of oral prednisone [126,127]. In another case of RA-associated OID, disease had been well controlled on regular adalimumab when the patient developed orbital involvement. This patient’s OID was successfully treated with pulse dose methylprednisone, methotrexate, and two rituximab infusions [128].

6.2. Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an idiopathic, systemic autoimmune disease characterized by the deposition of autoantibodies and immune complexes leading to subsequent inflammation and tissue damage. Within the orbit and periorbital region, SLE can have different presentations including panniculitis, diffuse orbital inflammation, eyelid edema, trochleitis, and myositis [129–141].

Corticosteroids are the most commonly utilized treatment for SLE-associated myositis and diffuse orbital inflammation. In most cases, the patient were know to have SLE prior to orbital involvement and hence were undergoing systemic immunosuppressant therapy at the time of orbital presentation. Nonetheless, corticosteroids have been shown to effectively manage orbital and periorbital manifestations of SLE with minimal recurrence [129–131,133–136,138–141].

In one case of bilateral trochleitis as the initial presentation of SLE, the patient was initially treated with local injections of dexamethasone and lidocaine, which provided temporary symptomatic relief, but it was not until the patient began systemic corticosteroids and plaquenil that the trochleitis resolved [132]. Mycophenolate mofetil has also been used in periorbital panniculitis with questionable efficacy, although this may have been secondary to poor patient compliance [137].

6.3. Scleroderma

Scleroderma is a chronic and often progressive connective tissue disease of unknown etiology. Scleroderma can be localized to the skin or occur in a systemic form affecting the viscera. Localized scleroderma can take three forms: generalized, morphea, and linear (also known as ‘en coup de sabre’), which is characterized by localized fibrosis of the skin, cutaneous vessels, and subcutaneous fat [142,143]. Although scleroderma rarely leads to orbital symptomatology, it has been most associated with linear form in the literature. Reported orbital manifestations of scleroderma include enophthalmos, orbital mass, myositis, trochleitis/acquired Brown’s syndrome, and ptosis [144–150].

Given the rarity with which scleroderma affects the orbit and periorbital area, records of treatment are limited to case reports. In cases with isolated symptoms and involvement, such as ptosis in a patient with scleroderma and dystrophic calcification of the orbital rim in a CREST patient, surgical management has been successful (external levator resection and excision of dystrophic nodules, respectively) [150,151]. An 11-year-old female with bilateral Brown’s syndrome associated with scleroderma experienced recurrence of Brown’s syndrome after initial therapy with oral prednisone but experienced symptom resolution following local prednisolone injection in the trochlear region [146]. A combination of radiotherapy and corticosteroids also been reported to induce disease resolution in a patient with progressive linear scleroderma and extraocular muscle involvement [149].

6.4. Dermatomyositis

Dermatomyositis (DM) is an inflammatory myopathy that occurs secondary to destruction of the vascular endothelium by the complement system. The disease occurs in both children and adults, and its diagnosis can be confirmed by elevated creatine kinase levels and definitively with tissue biopsy [93]. DM is often associated with systemic malignancies in older patients, and hence underlying malignancy must be ruled out in any patient diagnosed with DM. With regard to the orbit, DM often manifests as periorbital edema or myositis [152–157].

Corticosteroids are often the first-line treatment for orbital DM [93,158]. In two cases of orbital myositis associated with DM, methotrexate was used concurrently with prednisone to good result [152,154], and in another case of DM-associated orbital myositis, methylprednisolone and IVIG led to resolution [153].

In the three reported cases of DM presenting with marked periorbital edema, patients were treated to good response with systemic corticosteroids alone [155] or a combination of systemic corticosteroids and IVIG [156,157]. Minimal literature exists on the treatment of strictly orbital DM with other biologics and immunosuppressants. A recent review of the treatment of systemic DM noted good treatment responses in patients who received abetacept and rituximab and varied responses in patients who received infliximab and etanercept [158].

6.5. Sarcoid

Sarcoidosis is an idiopathic, multisystem inflammatory disorder characterized by the presence of noncaseating granulomas in affected tissues [159]. Ophthalmic sarcoidosis occurs frequently, and about 10% of these cases involve the orbit and ocular adnexa [160], with the lacrimal gland and orbit being the most frequently involved [161].

Systemic corticosteroids are the mainstay of treatment for orbital and adnexal sarcoid. In larger case series, Mavrikakis et al., Demirci et al., and Prabhakaran et al. reported partial or complete response to systemic corticosteroids in at least 95% of their patients with orbital and adnexal sarcoid [161–163], and recurrence rates were noted to be less than 10% [161,163].

Other immunosuppresants, such as cyclosporine, azathioprine, hydroxychloroquine, and methotrexate have also been used successfully in cases of orbital sarcoid presenting with concurrent systemic involvement, and steroid-refractory disease. They have also been utilized as steroid-sparing agents [161,162,164].

Local strategies have also been reportedly effective in controlling isolated disease of the orbit. Authors have discussed periocular steroid injections [161–163] and debulking surgery with concurrent systemic steroid therapy and found both to be effective for local control [161]. Minimal literature exists on the use of biologic and antibody therapy in sarcoid confined to the orbit.

6.6. Psoriatic arthritis

Psoriatic arthritis is an inflammatory arthritis associated with the HLA-B27 serotype. In two case reports, psoriatic arthritis has been associated with orbital myositis. One pediatric patient experienced a relapsing-type myositis that, along with small joint involvement and dermatologic manifestations of psoriasis, was initially treated with cyclosporine. Upon discontinuation of cyclosporine, the patient’s myositis returned. At this time, she was treated with an NSAID that led to resolution of her myositis [165]. Another adult patient, also with a relapsing course, initially failed treatment with an NSAID and then required oral steroids, which could not be tapered below 5 mg without recurrence [166]. Minimal literature exists on the usage of biologic agents on psoriatic arthritis with orbital involvement.

6.7. Inflammatory bowel disease

Crohn’s disease (CrD) and ulcerative colitis (UC) are the foremost types of inflammatory bowel disease (IBD), which comprises autoimmune diseases that attack the digestive system. A population-based study has shown that ocular involvement occurs in 1–2% of patients with IBD [167], with the prevalence of orbital manifestations being presumably lower. Less than 25 cases of IBD associated with orbital inflammation and/or orbital myositis have been reported in the literature [9,168–185].

With regard to treatment, corticosteroids are the mainstay for induction, with some reports employing initial IV pulse dosing (usually 1 mg/kg/day) followed by oral taper and other reports employing only oral dosing, both of which had mixed results [168–170,172,174–178,180–185]. Recently, infliximab has been utilized in several patients with refractory IBD-associated orbital inflammation and led to good long-term control [173,179]. With that said, the use of infliximab should not be taken lightly as several case reports have noted the subsequent development of optic neuropathy in both CaD [186–188] and UC [189,190] in the months after initiation of infliximab. Lastly, long-standing, refractory cases may benefit from orbital decompression or debulking, especially if the optic nerve is compromised secondary to compressive phenomenon [191].

7. Orbital inflammation associated with rare diseases

7.1. Castleman’s disease

Castleman’s disease (CaD), also known as angiofollicular lymphnode hyperplasia, is rare lymphoproliferative disease of unknown etiology that is histologically classified into three types: hyaline-vascular, plasma cell, and mixed/transitional type [192–194]. CaD can also be divided into unicentric disease, which usually presents with a solitary mass, and multicentric disease, which can present with generalized lymphadenopathy and multi-organ involvement and is associated with a poorer prognosis [195]. Within the orbit, CaD can present with diffuse orbital inflammation, lacrimal gland involvement, and eyelid edema [196], although less than 20 cases of CaD involving the orbit have been reported.

The treatment of CaD is best organized according to disease centricity. Unicentric CaD confined to the orbits has been successfully treated with surgical excision in multiple cases [195–199]. Algorithms for the treatment of multicentric CaD have not been established. Similar to other OIDs, corticosteroids are often used during treatment induction, although they often lead to incomplete treatment response or recurrence when used alone [200]. Historically, chemotherapeutic regimens including CHOP and CVAD have been employed, also with mixed results [193,200]. Lasting remission has additionally been noted in two patients with multicentric CaD who received IFN-alpha [201,202].

Radiation therapy has been successfully utilized in both multicentric and unicentric CaD. A review by Chronowski et al. demonstrated partial or complete response in 72% of patients [203]. An additional case report of multicentric CaD involving the orbit described sustained remission when radiation therapy was used as an adjunct alongside prednisone and azathioprine [204].

Aside from corticosteroids, rituximab is the most commonly used therapy for multicentric CaD [205] and has been utilized successfully in multiple case reports [200]. As CaD has been associated with elevated IL-6 levels, another promising new monoclonal antibody is the IL-6 inhibitor siltuximab, which gained US FDA approval for treatment of multicentric CaD in April 2014 and has yet to be utilized for orbital disease [206].

7.2. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia

Although once thought to describe different stages in the progression of the same disease, Kimura’s disease (KD) and angiolymphoid hyperplasia with eosinophilia (ALHE) are now thought to be two separate disease entities [207,208]. KD is rare and characterized by subcutaneous swellings and lymphadenopathy involving head and neck soft tissue, and it is commonly seen in young Asian males [209]. Both KD and ALHE present similarly and are primarily benign in nature. The two conditions are distinguished based on histopathological appearance, with KD demonstrating capillary proliferation rather than proliferation of arterioles, venules, and capillaries (ALHE), and fewer follicles but more fibrosis than ALHE [207]. Within the orbit and adnexa, KD and ALHE present similarly, often with diffuse orbital mass, lacrimal gland involvement, and eyelid edema [208,210–221].

Treatment for ALHE and KD consists primarily of surgical excision and debulking, which is usually curative with low rates of recurrence [211,212,214,215,218,220,221], even in patients with disease refractory to medical treatment [217]. However, in cases of incomplete excision, recurrence is more common.

Spontaneous regression has been noted in cases of ALHE, thus observation may also be suitable in some cases [207]. Radiation therapy with or without concurrent steroid treatment has also been used successfully in refractory cases of KD [208,216,219] and ALHE [217]. In one case of ALHE not amenable to surgery due to location and infiltrative features, concurrent dosing of methotrexate and prednisone appeared to induce remission [210].

7.3. Melkersson–Rosenthal syndrome

Melkersson–Rosenthal syndrome (MRS) is a rare, noncaseating granulomatous disease composed of the triad of lower motoneuron facial paralysis, recurrent non-pitting facial edema, and a fissured dorsal tongue [222,223]. Within the orbit and adnexa, MRS usually presents with upper and lower eyelid edema [224–229].

Treatment for MRS leading to eyelid edema typically involves corticosteroids, and resolution of edema has been reported with both intralesional and systemic administration [225–229], although improvement is often short-lived given the relapsing and remitting nature of the disease.

In a recent case series by Sabet-Peyman et al., patients with orofacial granulomatosis, a disease closely related to MRS, found that local injections of triamcinolone and 5-fluorouracil improved eyelid edema and allowed for steroid tapering in some patients [228]. In MRS patients with recurrent or progressive paralysis of the facial nerve, facial nerve decompression via a transmastoid approach has been shown to improve paralysis [230].

7.4. Rosai–Dorfman disease

Rosai–Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, nonmalignant, proliferative histiocytic disorder that usually affects the head and neck. Rosai–Dorfman disease is characterized by massive, bilateral painless cervical lymphadenopathy. It has been estimated to affect the eyelid and orbit in approximately 8.5% of cases, often as the initial presentation of the disease [231–233]. Within the orbit, RDD usually manifests as a painless soft tissue mass with proptosis, and it can also affect the lacrimal gland [231,232].

The treatment of choice for RDD confined to the orbit is surgical excision, which, in most cases, leads to disease resolution or stability [233–237]. Regarding nonsurgical treatment, remission has been induced with combinations of systemic steroids and rituximab [238]. Steroids and cyclosporine are also useful adjunctive therapies in patients who have undergone surgery [239–242]. Lastly, low-dose radiation therapy and chemotherapy may play a role in progressive, refractory RDD of the orbit [239,243].

8. Expert commentary

Much has changed in the field of OID over the past 20 years. As we learn more about the molecular and biologic basis of inflammatory disease, we become better able to characterize distinct entities. The moniker ‘pseudotumor’ has slowly but surely become less common as the community moves toward more specific syndromic and biologic diagnostic categorization.

This reorganization of thought has aided in better understanding the efficacy of treatment paradigms, as larger groups of nonspecific entities (likely representing a range of biologic processes) are replaced with smaller, more specific diagnoses that behave in a more uniform manner. There is however still much work to do in this area, as the most common disease entities (OID) are still likely representative of wide ranging pathophysiology.

A focus on disease specificity combined with increasing understanding of inflammatory pathways has allowed the community to assess the utility of a continuously expanding group of inflammatory modulatory medications. However, the rarity of OID in general creates multiple challenges to definitively understanding the true efficacy of targeted therapies. There are many financial and practical barriers to the production of high-quality clinical trials, which may be able to guide therapeutic recommendations. The community currently is still heavily dependent on uncontrolled case series and small reports.

That said, inflammatory disease is often systemic and orbital specialists can augment their treatment strategies based on advances made in the rheumatologic community. Recent molecular discoveries may lead to safer and more effective therapies. For instance, BAFF inhibitors in GPA and BRAF inhibitors in ECD may prove to be revolutionary for the treatment of these highly destructive diseases.

Currently, the most common therapy for all of these diseases is corticosteroids. This medication is a powerful tool in the management of inflammatory disease; however, it has well known side effects. In a certain sense, one is exchanging the disease itself for another one, that is of steroid side effects. Thus, in cases that respond quickly and fully to shorter courses and/or lower doses of steroids, this therapy will persist, as there is little motivation to move into other categories. However, the relative prevalence of steroid-refractory disease has pushed clinicians toward the use of other medications. As the list of therapies available has expanded, so has the list of diseases in which they have been tried. Some of these have had promising results, for instance rituximab in GPA, while others have been variable in response.

Overall, the current status of OID is one in which classic therapies with corticosteroids +/− cytotoxic agents still are overwhelmingly utilized. Familiarity and efficacy are the prime motors of this paradigm. In refractory or chronic disease, the literature is increasingly filled with small case series of utilizing a mostly random assortment of repurposed immunomodulatory medications, mostly of the biologic type. For most diseases, corticosteroids remain first line based on the available evidence and there is little information available to determine which of the many second-line agents are best utilized for a specific (or nonspecific) entity. Clinicians are mostly left to make decisions based on availability and convenience.

9. Five-year view

Although orbital inflammatory disease is rare, systemic disease is not. As basic understanding of inflammatory pathways grows, and systems for developing medications improve, the incentives are aligned such that we should continue to see novel medications become available for these conditions. Clinical evidence for efficacy and side-effect profiles will be the main restrictions on widespread adoption.

Of course, orbital specialists will be able to apply clinical knowledge gained in appropriate systemic disease trails to specific orbital inflammatory syndromes. However, for isolated periorbital disease entities and extremely rare conditions, the orbital research community may still be responsible for deriving useful clinical evidence. This may create an environment in which multi-institutional research networks will become increasingly important and hopefully prevalent. Such networks could utilize information technology systems in order to pool data from multiple centers in an efficient way, running multiple protocols simultaneously. These types of networks have led to significant advances in other areas of ophthalmology, particularly retina disease.

It is also entirely plausible that we may see advances in targeted therapeutics for many of these rare conditions. The orphan disease drug industry has been expanding in recent years and the market forces driving it do not appear to be changing. Diseases such as Melkersson–Rosenthal and Rosai–Dorfman may be the next targets of this trend, just as any other disease could be. Advances in these areas could also have fringe benefits related to the building of cooperative research networks, leading to even more clinical information for related conditions. This would be an ideal development.

The progress of biologic understanding and specific therapeutics is ever evolving and many more medicines can be expected to reach the public within the next few years. Clinically investigating these therapeutics in well-performed prospective trials will likely be the most vital link to definitively altering the course of patient care in OID.

Key issues

• Oral or intravenous corticosteroids are still the main stay for induction therapy in most types of orbital inflammation.

• Corticosteroid therapy prior to surgical debulking in dacryoadenitis has been associated with increased likelihood of disease recurrence.

• Overall surgery and steroids may be effective for AOX and AAPOX, although there is a risk of recurrence. For NBX no therapy has proven to be adequately effective in mainlining long-term control. Vemurafenib, a BRAF-inhibitor, has shown positive results in the treatment of ECD in small, preliminary studies.

• In orbital GPA, rituximab may be a good alternative to cyclophosphamide in the induction and maintenance of remission, while also having fewer severe side effects.

• In SOI, steroid therapy and surgical debulking in combination may represent the best current regimen, although the addition of therapy with radiation or azathioprine also shows some promise.

• Focusing on the specific inflammatory pathways associated with orbital inflammatory disease allows for the best utilization newly developed inflammatory modulatory medications.

• Although orbital inflammatory disease is rare, it is often associated with systemic inflammation, which allows for the utilization of advances made in the rheumatology community.

• Clinically investigating these therapeutics in well-designed, prospective trials is likely the most vital link in definitively altering the course of patient care orbital inflammatory disease.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

No funding was received.