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Treatment of scleritis

Treatment of scleritis
Literature review current through: Jan 2024.
This topic last updated: May 23, 2023.

INTRODUCTION — Scleritis is a painful, destructive, and potentially blinding disorder that may also involve the cornea, adjacent episclera, and underlying uveal tract. Up to 50 percent of patients with scleritis have an underlying systemic illness, most often a rheumatic disease.

This topic will review the treatment of scleritis. The clinical manifestations and diagnosis of scleritis are presented separately. (See "Clinical manifestations and diagnosis of scleritis".)

TREATMENT — Treatment of noninfectious scleritis always requires systemic therapy with nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, or other immunosuppressive drugs. In one study, 67 percent of patients required either high-dose glucocorticoids or the combination of high-dose glucocorticoids and another immunosuppressive agent to control the disease [1]. In some patients, particularly those with peripheral ulcerative keratitis or scleromalacia perforans, surgical intervention is required to preserve vision or prevent globe rupture.

The discussion in this section is focused on noninfectious scleritis, since this is far more common than infectious scleritis, which is almost invariably preceded by either surgery or other form of trauma. If the development of scleritis follows trauma or surgery, culturing of the lesion followed by systemic and topical antibiotic, directed at the offending microbial agent, is warranted.

General principles — Treatment must be individualized according to the severity of the patient's disease and extent of ocular inflammation. As an example, patients with either necrotizing anterior scleritis or posterior scleritis require more intensive therapy than those who present with non-necrotizing disease of the anterior [2]. The presence of a systemic inflammatory illness may also dictate an intensive course of therapy, even if the particular subtype of scleritis would normally call for a more benign treatment approach. (See "Clinical manifestations and diagnosis of scleritis", section on 'Scleritis subtypes'.)

It is absolutely essential that scleritis be managed by an ophthalmologist expert in the care of these patients and by a rheumatologist experienced in employing and managing the immunosuppressive therapies required to treat ocular inflammation.

In the absence of systemic disease features that dictate the overall approach to therapy, two major principles guide the treatment of scleritis:

The diffuse and nodular subtypes of anterior scleritis (picture 1 and picture 2) have a reasonable likelihood of responding to NSAIDs alone. If the clinician's sense is that a more aggressive approach is required from the outset, or if NSAIDs fail to control the scleral inflammation, most of these patients respond to high-dose prednisone. (See 'Glucocorticoids' below.)

Necrotizing anterior scleritis or posterior scleritis (picture 3 and picture 4) are more likely to be associated with permanent ocular complications and should be treated aggressively. Historically, most patients have generally been treated with cyclophosphamide as well as high-dose glucocorticoids, but concern about the adverse effects of cyclophosphamide and the success of rituximab-based regimens in treating systemic conditions often accompanied by scleritis (eg, rheumatoid arthritis and granulomatosis with polyangiitis) have made rituximab plus glucocorticoids often the initial treatment of choice. The advent and expansion of biologic therapies have tremendously broadened therapeutic options in these patients.

Nonsteroidal antiinflammatory drugs — NSAID therapy is primarily recommended for patients with the diffuse and nodular subtypes of anterior scleritis (picture 1 and picture 2). There are few data on which to base the choice of a specific NSAID for the treatment of scleritis. Investigators in Europe have used flurbiprofen for this purpose (flurbiprofen 100 mg orally two times daily up to maximal dosing of 300 mg daily) [3]. The clinical impression of some investigators is that indomethacin may be more effective than other available NSAIDs [1]. We suggest indomethacin (25 to 75 mg taken orally three times daily).

NSAID treatment should be continued for as long as there is evidence of scleral inflammation. Side effects of NSAIDs and treatment failures may limit the duration of indomethacin use. (See "Nonselective NSAIDs: Overview of adverse effects".)

Glucocorticoids — Patients with the diffuse and nodular subtypes of anterior scleritis who fail initial NSAID therapy and those with necrotizing anterior scleritis or posterior scleritis (picture 3 and picture 4) should be treated with glucocorticoids.

Based upon clinical experience, we suggest initial therapy with prednisone (1 mg/kg per day, up to a maximum daily dose of 80 mg). This regimen is continued for the first four to six weeks of therapy with ongoing assessment of the clinical response. The initial prednisone dose should not be continued beyond six weeks (and usually only four weeks) because of the potential for glucocorticoid-related morbidity. (See "Major adverse effects of systemic glucocorticoids".)

If patients have not demonstrated signs of clinical improvement within four to six weeks, an additional immunosuppressive agent must be considered. (See 'Immunosuppressive medications' below.)

Tapering regimen — There is no standard tapering regimen for scleritis, but regimens similar to the one outlined below are often used. Assuming that a patient begins prednisone at 60 mg/day and remains on this dose for four weeks, the following taper will require a total of 24 weeks to reach a daily dose of 5 mg.

The prednisone dose is tapered by 10 mg each week until a dose of 40 mg/day is reached.

After one week on 40 mg/day, the prednisone dose is tapered by 5 mg each week until the dose reaches 20 mg/day.

After one week on 20 mg/day, the prednisone dose is tapered by 2.5 mg each week until the dose reaches 10 mg/day.

After one week on 10 mg/day, the prednisone dose is tapered by 1 mg every two weeks until the dose reaches 5 mg/day.

The patient should be monitored carefully during the tapering period, watching for signs of recurrent scleritis or the development of inflammatory disease in other organ systems. Sometimes what appears at presentation to be idiopathic scleritis turns out to be the harbinger of a multiorgan system disease.

Continuation of the prednisone taper can be considered if the patient has achieved and maintained good disease control. Tapering off prednisone completely should not proceed faster than 1 mg/day decreases every two weeks. Deviations from this regimen are often necessary if patients develop glucocorticoid myopathy, iatrogenically induced diabetes, or experience disease flares. (See "Glucocorticoid-induced myopathy".)

Pulse glucocorticoid therapy — For patients with severe necrotizing anterior scleritis or posterior scleritis that threatens immediate ocular complications, pulse glucocorticoid therapy may be indicated. No controlled clinical trials of this approach have been performed, but, in extrapolation from other clinical experience in the treatment of severe, organ-threatening inflammation, we suggest methylprednisolone 1000 mg/day intravenously for three consecutive days. Following the completion of the glucocorticoid pulse, treatment with daily prednisone may begin. (See 'Glucocorticoids' above and 'Tapering regimen' above.)

Immunosuppressive medications — Immunosuppressive therapy in addition to glucocorticoids is generally given if:

There is persistent inflammation after two to three weeks of treatment

There is progression of disease to a more severe variant (eg, the evolution of diffuse anterior scleritis into the necrotizing subtype)

There are no randomized trials in scleritis on which to base the choice of the specific immunosuppressive medication. For patients in whom an underlying inflammatory disease is identified, systemic therapies with proven efficacy in the specific disorder should be considered. For the patient with idiopathic scleritis, first-line immunosuppressive therapies are generally antimetabolites (methotrexate, mycophenolate mofetil, azathioprine). In those with necrotizing scleritis or peripheral ulcerative keratitis, patients should be managed with more aggressive immunosuppression with alkylating agents (cyclophosphamide, chlorambucil) or rituximab.

For patients with milder disease in need of a glucocorticoid-sparing therapy options other than rituximab or cyclophosphamide include cyclosporine, mycophenolate mofetil, and methotrexate. Mycophenolate mofetil has primarily been studied as a glucocorticoid-sparing agent, with variable efficacy [4,5], and may also be used as maintenance therapy; methotrexate has been used in a similar fashion [6]. The general approach is antimetabolites as initial therapy and then progression to alternative options based on disease activity, medication intolerance, or toxicities. Similarly, tumor necrosis factor (TNF) alpha inhibitors may be considered after antimetabolites, especially in those with disease states that may be associated with increased TNF alpha (inflammatory bowel disease, psoriasis, rheumatoid arthritis).

Rituximab — The combination of rituximab plus glucocorticoids appears to be as effective as the combination of cyclophosphamide plus glucocorticoids in treating severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [7,8]. Given the frequency of severe scleritis as a manifestation of granulomatosis with polyangiitis and the strong evidence that rituximab is effective in this setting, it is reasonable to extrapolate the efficacy of rituximab to scleritis. Moreover, two rituximab regimens are effective in the treatment of rheumatic conditions, and either of these regimens are acceptable as the first-line approach for the treatment of patients with scleritis refractory to glucocorticoids alone. The administration of 1 g of rituximab twice (with the two doses separated by approximately 15 days) is the regimen approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis. In addition, the use of four 375 mg/m2 doses administered one week apart have been approved by the FDA for the treatment of ANCA-associated vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Patients resistant to induction with cyclophosphamide'.)

In a case series of 12 patients with noninfectious refractory scleritis not limited to granulomatosis with polyangiitis, it was found that rituximab was effective in 75 percent of those treated [9]. Should a patient not respond within four weeks to the rituximab regimen, it would be advisable to try an alternate therapeutic approach, possibly including more conventional treatments such as cyclophosphamide. (See 'Cyclophosphamide' below.)

Cyclophosphamide — For patients with disease refractory to rituximab, we suggest cyclophosphamide (2 mg/kg per day, with dose adjustments for patients with decreased renal function) [10].

With the use of cyclophosphamide, the general approach is to establish disease control as quickly as possible through combination therapy with prednisone and then to discontinue cyclophosphamide after three to six months. Cyclophosphamide is replaced by a medication with a lower risk of toxicity, usually azathioprine or methotrexate.

Cyclosporine — Cyclosporine has been used in place of cyclophosphamide in a small case series of patients with severe scleritis [11,12]. The typical dose ranges from 2 to 3 mg/kg per day in two divided doses.

Maintenance therapy — Because of the toxicity of long-term cyclophosphamide therapy, a number of less toxic drugs have been used for maintenance therapy after disease control has been attained with cyclophosphamide. The use of some of these drugs (azathioprine and methotrexate) is based upon their proven value as maintenance therapy in granulomatosis with polyangiitis. Specific data on maintenance therapy in scleritis are extremely limited. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)

It is not clear that patients treated with rituximab require an agent such as azathioprine or methotrexate following rituximab therapy, unlike patients treated with cyclophosphamide.

Azathioprine – Before beginning azathioprine, patients should be screened for thiopurine methyltransferase (TPMT) deficiencies. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacology and biologic effects'.)

The initial dose of azathioprine is 50 mg/day. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to the range of 1.5 to 3 mg/kg per day. Most clinicians do not prescribe more than 200 mg/day, even for large individuals.

Methotrexate – The initial dose is usually 15 mg/week, with increases in dose every week of 5 mg/week up to 25 mg/week.

Mycophenolate mofetil – The typical dose of mycophenolate mofetil is 1 to 1.5 g orally twice daily.

Duration of therapy — The regimen for tapering and eventually stopping therapy in patients treated with immunosuppressive drugs plus prednisone is not well-defined since there are no studies that address the optimal duration of treatment in this disorder.

We attempt to discontinue all immunosuppressive medications after disease remission has been achieved and a disease-free period of suitable length (eg, 6 to 12 months) has elapsed. For those with necrotizing scleritis, the duration of quiescent disease may be extended (eg, 12 to 24 months). Most patients and clinicians prefer to discontinue glucocorticoids before stopping the other immunosuppressive medicine. A glucocorticoid tapering regimen is described above. (See 'Tapering regimen' above.)

Attempts to gradually taper the glucocorticoid-sparing agent are reasonable in patients who have achieved remission that is sustained after the cessation of glucocorticoids.

A study of factors predicting remission in noninfectious anterior scleritis from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) database reported that 29.1 percent of patients were able to achieve disease remission, which was defined as quiet disease off systemic immunosuppressive therapies [13]. The median time to remission of scleritis was 7.8 years, suggesting that these patients may require more protracted courses of therapy.

Tapering of the immunosuppressive medication should be conducted at monthly intervals after the patient is in clinical remission, with planned cessation of therapy over approximately six months. The patient's clinical status must be closely monitored to permit early detection of disease flares at a time when the severity of the illness does not require the resumption of high-dose glucocorticoids.

Resistant disease

Tumor necrosis factor inhibitors — Case reports and small, uncontrolled case series suggest that the TNF alpha inhibitors infliximab and adalimumab may be effective in the treatment of scleritis that is resistant to treatment with other agents [14-18]. In patients with rheumatoid arthritis-, psoriatic arthritis-, and inflammatory bowel disease-associated scleritis (diseases that are associated with increased TNF alpha), these agents should be considered as second-line therapy after antimetabolites.

Infliximab is an intravenous medication; adalimumab is given subcutaneously. The dosing regimen for infliximab is typically 5 mg/kg given at week 0, 2, and then every 4 to 8 weeks thereafter. Adalimumab is dosed at 40 mg every 1 to 2 weeks depending upon disease activity. Prior to starting one of these agents, patients should be screened for prior exposure to tuberculosis, hepatitis B, and hepatitis C.

The failure of etanercept (another TNF alpha inhibitor) as a remission maintenance agent in a randomized trial in granulomatosis with polyangiitis argues against efficacy in scleritis [19]. Similarly, in a randomized trial involving 12 patients with juvenile idiopathic arthritis-associated uveitis, etanercept also showed a lack of efficacy compared with placebo [20]. Etanercept is a more selective TNF alpha receptor blocker while the other agents mentioned (adalimumab and infliximab) block both the TNF alpha receptor and free circulating TNF alpha. This difference in the mechanism of action may similarly explain the lack of efficacy of etanercept in scleritis and uveitis.

Role of surgery — Surgical procedures may be necessary for diagnosis, repair of scleral or corneal defects, or prevention of globe perforations (picture 5).

COURSE AND PROGNOSIS — A response of scleritis to therapy is evidenced initially by resolution of pain, which can be rapid and dramatic. Even for patients with severe disease who require cyclophosphamide and prednisone, a disease response should be evident within two weeks of starting therapy.

Scleritis has a high potential for causing permanent disease-associated morbidity. Some degree of permanent vision loss occurs in approximately 10 percent of patients with anterior diffuse scleritis, 25 percent with nodular scleritis, and 75 to 85 percent with necrotizing scleritis or posterior scleritis [1,21].

Disease complications — Common disease complications of scleritis include:

Corneal changes — Peripheral ulcerative keratitis and the corneal melt syndrome, which involves the breakdown of the stromal matrix, may lead to significant visual loss in the involved eye. (See "Ocular manifestations of rheumatoid arthritis", section on 'Corneal inflammation and melting'.)

Glaucoma — The advent of effective treatments for scleritis has reduced the incidence of glaucoma as a complication. Glaucoma is most prevalent in association with posterior and nodular scleritis and occurs least often in diffuse scleritis. Elevated intraocular pressure occurs in approximately 15 percent of patients with posterior scleritis and in 20 percent of those with nodular scleritis. Both inflammation and its treatment with glucocorticoids are significant risk factors for this complication.

Cataracts — Cataract formation is related to the severity of the scleritis. It primarily occurs in necrotizing scleritis, affecting approximately 20 percent of these patients. The incidence of cataract formation is much lower (less than 5 percent) with other subtypes of scleritis. Glucocorticoid therapy may be a contributor to cataract formation. Both inflammation and its treatment with glucocorticoids are significant risk factors for this complication.

When necessary, cataract surgery is safe, provided that the scleritis has been in remission for at least several months. (See "Cataract in adults", section on 'Surgical treatment'.)

Posterior segment complications — Most posterior segment complications represent the effects of posterior scleral inflammation on ocular structures adjacent to the sclera, such as the retina and optic nerve. The most serious complication is exudative retinal detachment that involves the macula, thereby resulting in variable but permanent vision loss.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uveitis".)

SUMMARY AND RECOMMENDATIONS

The patient with active scleritis is at significant risk for losing sight. Additionally, scleritis may be a sign of ongoing active inflammation at nonocular sites and a sign that the underlying disease process needs more aggressive management. The treatment of scleritis varies according to disease subtype. (See 'Treatment' above and 'General principles' above.)

Ocular comorbidities are common with scleritis, as are systemic side effects from the treatments. A team approach involving the rheumatologist and the ophthalmologist is often required for optimal management of these patients. Up to 50 percent of patients with scleritis have an underlying systemic illness, usually a rheumatic disease. (See "Clinical manifestations and diagnosis of scleritis", section on 'Systemic disease associations' and 'Treatment' above and 'General principles' above.)

We suggest nonsteroidal antiinflammatory drugs (NSAIDs) as the initial treatment of choice for diffuse and nodular forms of anterior scleritis (Grade 2C), which are less severe forms of the disease. One agent commonly employed in this setting is indomethacin (25 to 75 mg taken orally three times daily). (See 'Nonsteroidal antiinflammatory drugs' above.)

Necrotizing or posterior scleritis are subtypes that are more likely to be associated with permanent ocular complications; thus, we suggest glucocorticoids or the combination of glucocorticoids and another immunosuppressive agent (usually rituximab or cyclophosphamide) from the start of therapy in such patients (Grade 2C).

A common starting dose for prednisone in this setting is 1 mg/kg per day, up to a maximum daily dose of 80 mg. (See 'Glucocorticoids' above.)

Prednisone is usually tapered over a period of not less than six months, often closer to 9 to 12 months.

For patients with severe necrotizing anterior scleritis or posterior scleritis that threatens immediate ocular complications, we suggest methylprednisolone 1000 mg/day intravenously for three days (Grade 2C). (See 'Pulse glucocorticoid therapy' above.)

For patients with aggressive necrotizing disease, persistent inflammation after two to three weeks of high-dose prednisone, or evolution of disease from a mild to severe subtype despite prednisone, we suggest the addition of rituximab (1 g in each of two doses, separated by 15 days). Some patients with particularly aggressive disease may require four rituximab doses (375 mg/m2, administered weekly) (Grade 2C).

For patients with disease refractory to rituximab, we suggest cyclophosphamide (2 mg/kg per day, with dose adjustments for patients with decreased renal function) and prednisone (Grade 2C). (See 'Immunosuppressive medications' above.)

Cyclophosphamide is usually given for a period of three to six months and is then discontinued in favor of a less toxic medication. (See 'Immunosuppressive medications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.

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