aSR sustained-release preparation

one systemic NSAID or another; however, one may have to experiment sequentially with two or more NSAIDs before finding the one to which the patient responds. The efficacy of topical cyclosporine A is unclear, and appropriate studies to test this agent as applied topically will be required to answer the question of efficacy.

Three of our 85 patients with episcleritis had rheumatoid arthritis, 3 had ankylosing spondylitis, 1 had psoriatic arthritis, 2 had arthritis and inflammatory bowel disease, 1 had sarcoidosis, 1 had Adamantiades–Behçet’s disease, 1 had juvenile idiopathic arthritis, 1 had granulomatosis with polyangiitis (Wegener), 1 had atopy, 4 had rosacea, 5 had infections, and 62 had idiopathic episcleritis. The three patients with rheumatoid arthritis, one with simple episcleritis and two with nodular episcleritis, did not respond to oral NSAIDs; low-dose methrotrexate once a week was required for the ocular and joint activity. Two of the patients subsequently required the addition of adalimumab. The three patients with ankylosing spondylitis required oral NSAIDs with the addition of low-dose methotrexate weekly in one of them. The patients with psoriatic arthritis, arthritis, and inflammatory bowel disease, Adamantiades–Behçet’s disease, and juvenile idiopathic arthritis responded well to adalimumab. The patient with sarcoidosis required systemic steroids. The patient with granulomatosis with polyangiitis (Wegener) responded well to systemic steroids and mycophenolate mofetil.

The patient with atopy was treated successfully with appropriate environmental controls and systemic antihistamine therapy. The four patients with rosacea responded to oral doxycycline (100–200 mg/day). The five patients with infections were treated with appropriate antivirals or antibiotics. Twenty patients with idiopathic episcleritis required therapy. Each had suffered from recurrent episcleritis for prolonged periods (6–24 months) and each had been treated with topical steroids, with the predictable result: recurrence of episcleritis more severe than prior to steroid therapy after steroids were discontinued. Each of these patients responded well to oral NSAID therapy, with no recurrence of episcleritis after drug withdrawal.

9.2Treatment of Scleritis

9.2.1Medical Treatment

Patients with diffuse or even nodular scleritis rarely require cytotoxic drug therapy for successful control of their inflammation. Systemic NSAID therapy is almost invariably effective, although as mentioned above, sequential trials of several NSAIDs may be required before one that is completely effective is found. We habitually treat our scleritis patients who have responded to an NSAID for a minimum of 1 year before attempting to taper and discontinue the medicine. Patients with an associated disease, such as rosacea, gout, or atopy, will require specific treatment for those diseases as described above. One hundred and forty-one (48%) of our 291 patients with idiopathic diffuse and nodular scleritis responded to oral NSAID therapy. Twenty-eight (10%) patients required the addition of systemic prednisone, 94 (32%) required the addition of an immunosuppressive medication, and 28 (10%) required the addition of a biologic.

The treatment of patients with scleritis associated with connective tissue or collagen vascular diseases requires slightly more consideration in that control of their scleral inflammation often needs more potent therapy, and vigilance for extraocular, “silent” inflammatory foci requires

extra effort. For example, we were once consulted about a patient with limited granulomatosis with polyangiitis (Wegener) scleritis, sinus involvement, and a positive antineutrophil cytoplasmic antibody (ANCA) test whose scleritis responded to systemic NSAID therapy, prompting the patient’s ophthalmologist and rheumatologist to settle for this treatment and to become less vigilant for a transformation of the patient’s limited form of granulomatosis with polyangiitis (Wegener) into the lethal generalized form, despite our advice to treat the patient with cyclophosphamide. The patient died of renal complications of granulomatosis with polyangiitis (Wegener) 2 years later.

We believe, quite strongly, that NSAID therapy alone is unacceptable in the care of an individual with scleritis in whom the diagnosis of granulomatosis with polyangiitis (Wegener) or polyarteritis nodosa has been made. It is our frank view that such therapy represents negligence. The published evidence on this point of appropriate therapy for these two lethal diseases is too abundant and the conclusions are unarguable. Regardless of other therapy these patients might be receiving, the 5-year death rate of patients with polyarteritis nodosa who are not receiving cytotoxic chemotherapy is 87% [3], and the 5-year mortality rate of patients with granulomatosis with polyangiitis (Wegener) who are not receiving cytotoxic chemotherapy is 95% [4]. Furthermore, we would extend this therapeutic attitude to patients with necrotizing scleritis associated with rheumatoid arthritis or with relapsing polychondritis. Multiple studies have now shown that, in the rheumatoid arthritis patient who develops necrotizing scleritis and who is not treated with an immunosuppressive agent, the 5-year mortality rate from extraocular vasculitic lesions is approximately 50% [5–7]. Patients with relapsing polychondritis who develop necrotizing scleritis may also die, either from the tracheal complications of this disease or from the eventual emergence of renal pathology. Therefore, our recommendations for the treatment of patients with the various collagen vascular diseases who develop scleritis are as follow.

9.2.1.1 Rheumatoid Arthritis

We suggest treating rheumatoid arthritis patients who develop diffuse scleritis with an oral NSAID, with or without the concomitant use of topical corticosteroids. If the scleritis does not respond, or if it recurs with attempted discontinuation of the topical corticosteroid, we generally switch to a different NSAID, treat once again with topical corticosteroids, taper the steroids and observe for recurrence. We go through these steps as many as three times, that is, with three different NSAIDs, before concluding that additional systemic medication is required. Our next step, if additional systemic medication is deemed necessary, is to treat the patient with a short course of systemic prednisone. We typically start with 1 mg/kg per day, taper when the scleritis has resolved totally (usually within 7–14 days), and then switch to alternate-day therapy once the dose of the prednisone is down to 20 mg/day. If the patient has had no recurrence of the scleritis with topical steroid discontinuation and tapering of the systemic steroid to 20 mg/day, our next therapeutic step is to switch the systemic prednisone to 40 mg every other day. This dose is continued for 2 weeks, after which it is further tapered to 30 mg ever- other-day for the following 2 weeks. If there is still no relapse of the scleritis, the drug is tapered to 20 mg every other day for an additional 2 weeks, with further tapering on an ever-other- week basis to 15 mg every other day, 10 mg every other day, 7.5 mg every other day, and 5 mg every other day, after which the drug is discontinued. This is the usual withdrawal program we use for systemic prednisone. It is the rare rheumatoid arthritis patient with diffuse scleritis who does not respond to this program and who then requires low-dose methotrexate once a week.

Although the vast majority of rheumatoid arthritis patients with nodular scleritis respond well to the systemic prednisone program described above for diffuse scleritis, some require once-a-week methotrexate therapy. We always go through these steps first with our nodular scleritis patients, but in a small number of cases we have discovered that the scleritis does not respond completely or that it continues to recur

with steroid tapering. We treat these patients with methotrexate, generally beginning with 15 mg given once a week (10 mg once a week for an individual weighing less than 50 kg); the drug dosage is generally advanced, every 6 weeks, if the scleritis does not resolve completely, with a maximum dose in our practice of

35mg/week.

Patients with necrotizing scleritis, we believe,

must be treated with a systemic immunosuppressant. Systemic prednisone is generally appropriate as well, concomitant with the nonsteroidal immunosuppressive medication. If the necrotizing scleritis is unilateral, is not severe, and is not rapidly progressive, our first-choice therapy once again is once-a-week methotrexate, with the usual caveats vis-à-vis liver bone marrow, and appropriate monitoring [8, 9]. The dose used is the same as stated above for nodular scleritis. If the disease is bilateral, severe, or rapidly progressive, or if the patient has not responded to the methotrexate, we generally use azathioprine at a starting dose of 2 mg/kg per day, with dosage adjusted on the basis of clinical response and systemic tolerance. Systemic mycophenolate with or without cyclosporine A is an alternative medication under this circumstance, as is the addition of a TNFa inhibitor, such as infliximab or adalimumab. Recently, three new biological agents, rituximab, abatacept, and tocilizumab, have become available for the treatment of rheumatoid arthritis in patients with active disease, including scleritis, who have not responded to TNF blockade. Rituximab is an anti-CD20 monoclonal antibody, abatacept modulates T-cell activation, and tocilizumab is an interleukin-6 receptor antagonist. Clinical studies with these agents have demonstrated that they are effective in rheumatoid arthritis patients with active disease who have not responded to treatment with at least one TNF inhibitor. Thus far, there is no convincing evidence to show that one of these three new drugs has a superior efficacy over the others. However, the benefit for any of these new biological agents appears to outweigh the risk for a rheumatoid arthritis patient with active disease. Adverse events, including (usually mild) infusion reactions, are common. There is a small increased

risk of serious infections that appears to be similar to that with TNF inhibitors.

Cyclophosphamide is considered, in patients with severe or rapidly progressive necrotizing scleritis, unilateral or bilateral. The dosage employed at MERSI is administered intravenously on alternate weeks, beginning with 1 g per square meter body area and then choosing subsequent doses based upon the total and absolute neutrophil white blood cell counts and platelet count, striving to keep the total white blood cell count in the range of 3,000–4,500, the absolute neutrophil count to 1,000 or above, and the platelet count to 70,000 or above. If one must employ oral cyclophosphamide, the initial dose is 2 mg/ kg per day, restricted to morning and noontime, with high fluid intake in afternoons and evenings. Hematological, urological, and systemic monitoring is as previously described, with the usual caveats. The target cell count goals are the same as those described above for intravenous therapy (see Sect. 9.2.3) [8, 9].

9.2.1.2 Systemic Lupus Erythematosus

Patients with SLE who have diffuse scleritis are treated by us with an oral NSAID as described above for diffuse scleritis associated with rheumatoid arthritis. We typically add hydroxychloroquine (plaquenil; 200–400 mg once daily) if the response to the oral NSAID is not complete. Systemic prednisone is added if these first two steps are inadequate to bring about a complete resolution of the scleritis. The strategy for the use of the systemic steroid is the same as that described above for the care of patients with diffuse or nodular scleritis associated with rheumatoid arthritis, with the exception that SLE patients often respond better to split dosage corticosteroid than to once daily dosing. Our strategy for treating patients with SLE who have nodular scleritis is the same as for treating those with diffuse scleritis, with the additional recommendation that low-dose methotrexate be given once a week for those rare patients that do not adequately respond to oral NSAID, plaquenil, and/or systemic corticosteroids. Mycophenolate mofetil may also be used and seems to be especially effective in patients with SLE. In the extremely rare event

that a patient with SLE develops necrotizing scleritis, our first-choice therapy would be highdose oral corticosteroids and/or intravenous pulse corticosteroid therapy. We would, unlike in every other instance of systemic steroid use in our practice, use a split-dosing regimen for the SLE patients, as is generally used in the care of patients with serious systemic manifestations of SLE. We might give, for example, 20 mg of prednisone four times daily to a 60to 80-kg woman, with one to three intravenous pulse doses of 1,000 mg of methylprednisolone to bring about a rapid resolution of the destructive inflammation. Azathioprine (2 mg/kg per day) could be added for those patients who do not completely respond, although oral or intravenous pulse cyclophosphamide would probably be a better choice, at least if one extrapolates from the experience in treating lupus nephritis [10].

9.2.1.3 Polyarteritis Nodosa

Patients with scleritis associated with polyarteritis nodosa must be treated with systemic cyclophosphamide and prednisone. This is true regardless of the form of scleritis the patient has. Not to treat the patient in this way, in our view, represents frank negligence, given the mortality data associated with alternative therapies [3]. If the patient is intolerant to cyclophosphamide, other immunosuppressants should be used in an effort to save not only the patient’s eye but the patient’s life as well. Such alternatives include azathioprine, methotrexate, rituximab, mycophenolate mofetil, and cyclosporine A.

9.2.1.4 Granulomatosis with Polyangiitis (Wegener)

The comments just made about polyarteritis nodosa can be repeated verbatim regarding scleritis associated with granulomatosis with polyangiitis (Wegener).

9.2.1.5 Relapsing Polychondritis

Some of the manifestations of relapsing polychondritis are responsive to dapsone. For this reason, we recommend that the relapsing polychondritis patient who is not sulfa sensitive or

glucose-6-phosphate dehydrogenase deficient be given dapsone, along with an oral NSAID for diffuse or nodular scleritis. Because most patients receiving dapsone will experience low-grade hemolysis, which is typically compensated by reticulocytosis, we generally start with low-dose dapsone therapy, that is, 25 mg twice daily. Monitoring of liver enzymes and peripheral hemograms then allows us to judge whether a slow escalation in the dose is acceptable. We advance, as clinically needed and systemically tolerated, to as high as 150 mg/day with dapsone. For the patient with relapsing polychondritis who is not responding to a combination of oral NSAID and dapsone, we add systemic corticosteroid therapy, using the same kind of dosing technique as described above for rheumatoid arthritis. If the scleritis does not respond to the combination oral NSAID plus dapsone plus systemic corticosteroid, we add low-dose methotrexate (15 mg/week) or daily azathioprine (2 mg/kg per day), or mycophenolate mofetil (2 g a day). This approach is used for both diffuse and nodular scleritis in the relapsing polychondritis patient.

The relapsing polychondritis patient who develops necrotizing scleritis, however, represents one of the most difficult therapeutic challengesthattheophthalmologistandchemotherapist ever encounter. Indeed, the authors and Mr. Watson have independently concluded that, of all the potential etiologies for necrotizing scleritis, necrotizing scleritis associated with relapsing polychondritis is the most intransigent and most difficult to place into full, permanent remission (unpublished observations and personal communication). Combination high-dose systemic corticosteroid and cyclophosphamide therapy is the strategy we most commonly use, as described for polyarteritis nodosa. In some patients, we have resorted to once-a-week pulse cyclophosphamide therapy. We use 1 g/m2 body surface area, intravenous in 250 cc of normal saline, piggybacked onto 1 L of 0.5% dextrose in water, infused over a period of 2 h, for intravenous pulse therapy. These infusions are repeated every 1–3 weeks, depending on the nadir of the leukocyte count and the rate of recovery.