evaluated the safety and possible effectiveness of efalizumab in treating uveitic macular edema. Six patients received weekly subcutaneous injections for an extended period, during which no serious side effects were noted. Best visual acuity improved by over six letters in the worst eye, together with reductions in macular thickness.201 Recently two cases of progressive multifocal leukoencephalopathy (PML) have been reported in older patients with plaque psoriasis who received efalizumab for many years. Although other medications have been associated with this complication, it is not yet clear how this will affect the further use of this medication for uveitis. One possible approach taken for other medications is to reserve this for short-term use in order to effect a quick therapeutic response. However, as of this writing, sales of Raptiva in the United States have been suspended.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/ human monoclonal IgG1 κ antibody directed against the CD20 antigen. . The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro, leading to B-cell depletion. Rituximab has an approximate molecular weight of 145 kDa. It has been used to treat a number of hematologic processes, including B-cell lymphoma and primary central nervous system lymphoma.202,203 It will certainly be used for the treatment of primary intraocular lymphoma as there are preliminary reports suggesting usefulness. There are also studies reporting its use in ocular adnexal lymphomas.204,205 It has been reported to have a positive therapeutic effect in rheumatoid arthritis and other autoimmune diseases.206 The recommended dose is 375 mg/ m2 as an intravenous infusion, weekly for four to eight doses for non-Hodgkin’s lymphoma and two-1000 mg intravenous infusions separated by 2 weeks for rheumatoid arthritis (for rheumatoid arthritis it was given intravenously at days 0 and 15 and was combined with methotrexate 10–25 mg/ week). Glucocorticoids, administered as methylprednisolone 100 mg intravenously or its equivalent 30 minutes prior to each infusion, are recommended to reduce the incidence and severity of infusion reactions. In rheumatoid arthritis, treatment with rituximab induced depletion of peripheral B lymphocytes, with all patients demonstrating near complete depletion within 2 weeks after receiving the first dose of Rituxan. The majority of patients showed peripheral B-cell depletion for at least 6 months, followed by subsequent gradual recovery after that time. A small proportion of patients (4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment. In RA studies, total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months, with the greatest change observed in IgM. However, mean immunoglobulin levels remained within normal levels over the 24-week period. Small numbers of patients experienced reductions in IgM (7%), IgG (2%), and IgA (1%) levels below the lower limit of normal. The clinical consequences of a reduction in immunoglobulin levels in RA patients treated with rituximab are unclear.

This raises a very interesting question as to mechanism, as anti-T-cell therapy has been the dominant approach in the past. B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through the produc-

Nonsurgical therapeutic options

tion of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production; alternatively, it may be inducing peripheral immune tolerance. It has been used in the treatment of anterior uveitis, Behçet’s disease and Wegener’s granulomatosis.207–209

Anakinra (Kineret)

Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1RA) that binds to interleukin-1 type 1 receptors. In doing so it downregulates the proinflammatory effects of IL-1. It has been shown to effectively treat the clinical expression of experimentally induced uveitis in mice.210 Reports of its use in patients with ocular inflammation have appeared. This includes pediatric uveitis patients with CINCA syndrome (chronic infantile neurologic, cutaneous, and articular 211 and the Blau’s syndrome, a pediatric granulomatous arthritis associated with the NOD2 gene).212

Alemtuzumab (Campath-1H)

This is an anti-CD52 monoclonal antibody that targets T and B lymphocytes. It has been used to treat a variety of hematologic disorders, including myelodysplastic syndrome, aplastic anemia, chronic lymphocytic leukemia, and T-cell leukemias/lymphomas.213–215 Dick et al.216 reported its use for severe ocular inflammation in 10 patients with a variety of ophthalmic inflammatory diagnoses, including Wegener’s granulomatosis, retinal vasculitis, sympathetic ophthalmia and Behçet’s disease. All patients showed an initial improvement, and remission was seen in eight. No serious adverse events were noted during a short follow-up period.216

Abatacept (Orencia)

This medication is a fusion protein that consists of the extracellular domain of the human cytotoxic T-lymphocyte-asso- ciated antigen 4 (CTLA-4) and a modified Fc portion of an immunoglobulin G1 molecule. It binds to the ligand of CTLA-4 and is used in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Its use to date in the treatment of uveitis is very limited, with one paper published so far.217 It can be used alone or in conjunction with diseasemodifying antirheumatic drugs (DMARDs) such as metho­ trexate, but not with a TNF-α inhibitor. Studies showed that patients receiving abatacept and Remicade had considerably higher rates of infection compared to controls. It is also not recommended in patients with chronic obstructive pulmonary disease, again because of the risk of infection. It may increase the risk of lymphoma and possibly lung carcinoma. Just how useful this medication may be in the treatment of uveitis remains to be seen.

Intravenous immunoglobulin therapy

Intravenous immunoglobulin (IVIg) therapy has been used in the treatment of a few patients with ocular inflammatory disease, including ocular cicatrical permphigoid, VKH, and birdshot retinopathy,218–220 and in patients with cancerassociated retinopathy.221 IVIg was initially intended for the treatment of patients with immunodeficiencies. It is a preparation that is almost completely intact IgG, including all IgG subclasses as seen in normal human plasma. It is a pooled

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Part 3 • Medical Therapy and Surgical Intervention Chapter 7 Philosophy, Goals, and Approaches to Medical Therapy

Neutralization of

T-cell superantigens

Figure 7-16.  Effects of IVIg on the immune system. (Reproduced with permission from Immunomodulation of Autoimmune and Inflammatory Diseases with Intravenous Immune Globulin Michel D. Kazatchkine, M.D., and Srini V. Kaveri, D.V.M., Ph.D, New England Medical Journal Vol. 345, No. 10 September 6, 2001. Copyright 2001 Massachusetts Medical Society. All rights reserved.)

material made up from 7–10 000 donors218 and has slowly found a place in the treatment of putative immune-mediated disorders such as Guillain–Barré syndrome, Kawasaki disease, and juvenile dermatomyositis. The mechanism of its action is speculative (Fig. 7-16)222 and several have been suggested, such as a blockage of B-cell responses, inhibition of phagocytosis, and alteration of cytokine production.223 Recently it has been suggested that immunoglobulins may neutralize C3a and C5a of the complement cascade, also known as anaphylotoxins.224 It has been reported to prevent the expression of experimental autoimmune uveitis.225 Rosenbaum and colleagues220 treated 10 patients with IVIg, five of whom appeared to have a clear clinical benefit. Patients received 0.5 g/kg body weight/day (infused over 4 hours) for 3 consecutive days on a monthly basis, ultimately changing to an every- 3-month schedule. Guy and Aptsiauri221 reported using IVIg in three patients with carcinoma-associated retinopathy. One patient had increased visual acuity within 24 hours of the first dose, one had an improvement in visual fields but no increase in vision, and one had no improvement. Some concerns that have been raised include the problem of infection despite surveillance. Hepatitis C infection was ascribed to this form of therapy, and we still are concerned about disorders caused by prions. Uveitis has been described in patients after IVIg infusions for immune-mediated (nonocular disorders),226 and there is a risk of thrombosis, including retinal vein thrombosis. Finally, IVIg should not be given to patients with an isolated IgA deficiency because they develop allergic responses to preparations that contain IgA.

Oral tolerance

Oral tolerance is an approach that has received much clinical interest. A discussion of some of the basic mechanisms leading to the clinical application mentioned here can be

found in Chapter 1. Feeding of antigens has been reported to be effective in the treatment of multiple sclerosis and rheumatoid arthritis.227,228 In a pilot study this approach was applied to two patients with uveitis, one with pars planitis and one with the ocular complications of Behçet’s disease.229 The patients who entered into this study had lymphocytes demonstrating in vitro proliferative responses to the retinal S-antigen. The patient with pars planitis had been treated with prednisone and was able to stop his medication completely once he began the feeding with 30 mg of S-antigen three times a week. Of interest is the fact that because of the maintenance of good visual acuity with the feeding, continued oral dosing of the retinal S-antigen was stopped, in the hope that long-standing tolerance had been achieved. However, the patient had a reactivation of his disease. He was treated with systemic steroids and S-antigen feedings were begun again; he ultimately needed no further medication because his disease abated, and he was left with a visual acuity of 20/20 and 20/25 in each eye. After these observations, a randomized phase I/II masked trial to evaluate the effect and safety of the oral administration of retinal antigens was undertaken.230 Patients with uveitis were randomly assigned to receive either bovine retinal S-antigen alone, a mixture of soluble retinal antigens alone, retinal S-antigen and retinal soluble antigens, or placebo. Although the time to the primary endpoint (time to ocular inflammatory disease) was not statistically significant for any of the groups, the group that received the purified S-antigen alone appeared to be able to be tapered off their immunosuppressive medication more successfully compared with either the placebo group (p = 0.08) or either group receiving multiple soluble antigens. No toxic effects attributable to any treatment were observed (Fig. 7-17).

This approach is beginning to attract attention once again.231 Thurau and Wildner232 used as antigen for uveitis a 14 amino acid sequence of HLA-B antigens that was seen to mimic retinal S-antigen. The underlying logic for this choice is different from using the retinal S-antigen found in the eye. Here it is hypothesized that because of low avidity, T cells that can bind to this antigen sequence escape the normal clearing mechanisms in the thymus and enter into the systemic circulation. Under certain circumstances these cells can enter the eye and are then activated by antigens in the eye that mimic the original antigen, in the eye perhaps S-antigen, thereby producing a auveitis (Fig. 7-18.) Thurau and Wildner would suggest that this could explain the association between HLA class I antigens and uveitis. This approach has been used in a limited number of patients,233 and a larger proof of concept study is planned.

Interferon-α

Interferon-α is used for its antitumor and antiviral actions, but the exact mechanism for either is not known other than it inhibits tumor growth and viral replication. One report has suggested that IFN-α may inhibit inflammatory processes by enhancing IL-10 production, an event that may be negative in a patient with AIDS but very beneficial in one with an excessive sterile inflammatory response.234 It has been used in the treatment of the ocular complications of Behçet’s disease and multiple sclerosis.235 Several reports suggest that treatment with IFN-α will diminish or com-

Time to stopping systemic medications female patients

Figure 7-17.  Results of the oral administration of bovine S-antigen to patients with uveitis tapering off their immunosuppressive agents. The power of this phase I/II study could definitively demonstrate efficacy. Results are shown as Kaplan–Meier curves. A, The time to flare up (i.e., longer is better) was longer in the patients receiving pure S-antigen, whereas those receiving multiple antigens (the retinal mix) did the worst, even when compared with placebo. B, Time to stopping medications. Here shorter is better, and the reverse of A is seen. Those patients receiving the purified S-antigen alone appeared to be tapered off their immunosuppressive medication more successfully than those given placebo (p = 0.08); the retinal mix group did the worst. C, Tapering of medications for the female patients. All of these patients receiving S-antigen were tapered off their standard medication. It is unclear why patients receiving multiple antigens should do so much worse, but other studies have now shown this phenomenon. No toxic effects were attributable to the medication. (Modified from Nussenblatt RB, et al. Treatment of uveitis by oral administration of retinal antigens: results of a phase I/II randomized masked trial. Am J Ophthalmol 1997; 123: 684–7.)

pletely stop all attacks (see Chapter 26). Kötter and colleagues236 used an initial dose of 6 × 106 IU subcutaneously daily and then 3 × 106 IU every day for 1 month, followed by 3 × 106 IU subcutaneously every other day. This group saw an improvement in all seven patients treated. PivettiPezzi and coworkers237 and Wechsler and associates238 used a dose of 3 × 106 IU three times a week. Pivetti-Pezzi and coworkers237 saw a 50% reduction of ocular relapses. There have been numerous reports suggesting the usefulness of this approach, from treating nerve-head neovascularization239 in Behçet’s disease to performing intraocular surgery under IFN-α therapy.240 All patients had a flu-like illness during therapy, and a Behçet’s disease-like retinopathy has been associated with IFN-α. It is interesting that the use of IFN for Behçet’s disease is far more common in Europe than in North America. The FDA further warns that the α interferons cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Controlled trials will be needed to resolve this difference and see whether the potential advantages outweigh the potential risks.

In summary, the general approach to the use of immunosuppressive agents is to choose the smallest amount histori-

cally considered effective for the anatomic area affected (Fig. 7-19). However, it is important to establish control of the disease early with sufficient medication and to taper the medication after the inflammation resolves. Topical steroids for anterior segment disease can be most effective if given frequently. Periocular administration of steroids is often overlooked, but it is effective for the patient with unilateral disease or cystoid macular edema, and for the child in whom one wishes to avoid the secondary effects of systemic corticosteroid administration. The use of intraocular steroid (injection or device) may change our therapeutic paradigm significantly. Systemic corticosteroid administration is still the mainstay of therapy in sight-threatening bilateral intermediate and posterior endogenous uveitis, but a second (and sometimes third) agent needs to be started once it is clear that immunosuppressive therapy needs to be continued for an extended period. Both azathioprine (Imuran) and methotrexate, which are being used more frequently in both children and adults, are reasonable steroidor ciclosporinsparing agents. The role of monoclonal antibody therapy remains to be seen, and just where intraocular steroid or immunosuppressive therapy will fit also needs evaluation. We generally reserve cytotoxic agents for therapeutic failures

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