Indications and Dosages

An open-label clinical trial to evaluate the use of tacrolimus was performed in Japan; 53 patients (most with Behçet’s disease) were treated at varying doses, and about threequarters were thought to have benefited.141 A review of patients with Behçet’s disease alone142 confirmed these initial observations. A daily dose of 0.10–0.15 mg/kg body weight/ day has been suggested to be appropriate. Sloper and co­ workers143 reported their experience with tacrolimus, treating six patients with uveitis refractory to ciclosporin. Five of the six patients had a two-line or more improvement. Kilmartin and colleagues144 reported on seven patients with uveitis treated with tacrolimus, with two being withdrawn from therapy and the other five continuing. An initial dose of 0.05 mg/kg/day has generally been used in the treatment of uveitis, whereas for use in transplant recipients doses of 0.10–0.15 mg/kg/day have been used. Concentrations in the blood need to be monitored.

Secondary Effects

With essentially the same mechanism of action as ciclosporin, one might assume similar secondary effects for tacrolimus. Adverse affects include renal impairment, noted in 28% of patients reported by Mochizuki and colleagues.141 Neurologic symptoms, including tremors, headache, ophthalmoplegia, and meningitis-like symptoms, have been noted. Gastrointestinal symptoms, usually manifested as nausea, loss of appetite, and abdominal pain, can occur. Hyperglycemia was reported by Mochizuki and colleagues141 in 13% of patients. In a report comparing the nephrotoxic effects of tacrolimus and ciclosporin in liver transplant recipients,145 the early development of severe nephrotoxicity was noted only in some patients receiving tacrolimus.

Lx 211 (Voclosporin)

With ciclosporin being the first, efforts have begun to evaluate the next generation of calcineurin inhibitors for uveitis and other ophthalmic indications.146 This molecule has a modification of the functional group on the amino acid residue at position 1 of the parent molecule (Fig. 7-13). This was designed to affect the metabolism of the new molecule. It is felt that this change gives the molecule a more predict-

Figure 7-13.  A, Structure of Lx 211, compared with B ciclosporin. (From Anglade E, et al. Next-generation calcineurin inhibitors for ophthalmic indications. Exp Opin Invest Drugs 2007; 16: 1525–40.)

Nonsurgical therapeutic options

able pharmacokinetic profile, greater biologic activity and less toxicity. 146 Voclosporin’s therapeutic effectiveness has been tested in the EAU model and was found to effectively suppress the expression of EAU; it also inhibited lymphocyte proliferation from these animals.147 At present Lx211 is being evaluated in three phase III trials, with over 500 patients enrolled worldwide. The results should be made known sometime in 2009.

Rapamycin

Mode of Action

Rapamycin (Rapamune, Sirolimus) is a macrolide immunosuppressant purified from isolates of Streptomyces hygroscopicus collected on Rapa Nui (Easter Island).148 It blocks the proliferative signals of transduction in T cells149,150 (Fig. 7-14). This blockage has been shown to prevent the expression of IL-2, IL-4, and IL-6. Of great interest and potential therapeutic importance is the fact that rapamycin’s effect occurs much later in the cell cycle (G1 to S-phase transition) than that of either ciclosporin or tacrolimus. Rapamycin appears not to inhibit the expression of IL-2 receptors and IL-2 production, but may interfere with the cell’s ability to respond to interleukins, such as IL-2 and IL-4.149,151 Rapamycin is bound in the cytoplasm to the same immunophilin as tacrolimus (FKBP), and therefore these two agents will competitively inhibit each other if placed in the same environment.

Indications and Dosages

Rapamycin has been used in a small number of patients with uveitis, as well those undergoing renal transplantation152,153 at a dose of 2 mg/day. Because it is bound by the same cytoplasmic receptor as tacrolimus, the two agents should not be given together. Rapamycin has been shown to be very effective in inhibiting the induction of EAU in Lewis rats154 and in completely inhibiting transfer of EAU155 at a dose of 0.1 mg/kg/day given as a continuous intravenous infusion. Studies have shown that ciclosporin and rapamycin may have a synergistic effect in vitro on T lymphocytes.156 The combination of ciclosporin 2 mg/kg/day (one-fifth the normal dose) plus intravenously administered rapamycin 0.01 mg/kg/day (one-tenth the normal therapeutic dose) will act synergistically to prevent the expression of EAU.157

Figure 7-14.  Structure of rapamycin. (From Schreiber SL, Crabtree GR.

The mechanism of action of ciclosporin A and FK506. Immunol Today 1992; 13: 136.)

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There is great interest in the possible role of rapamycin in inducing peripheral immune tolerance.

Toxicity

At a therapeutic dosage of 0.1 mg/kg/day animals have been reported to lose weight.150 Of concern have been reports of myocardial toxicity in rats.158 However, these have occurred at relatively high doses of the drug. Gastrointestinal vasculitis has been noted in dogs.159 In some patients diarrhea and a pneumonitis have been associated with the administration of the drug. It is hoped that with combined rapamycin and ciclosporin therapy the markedly lowered doses may provide adequate immunosuppression with minimal or no risk of toxicity. Even better, it is theoretically possible that rapamycin combined with a monoclonal antibody such as daclizumab (see below) may induce peripheral tolerance.

Antibodies and monoclonal antibodies

Antibodies and monoclonal antibodies directed against various parts of the immune cascade have been used more and more extensively in the treatment of uveitis in humans.160,161 (Table 7-4). These antibodies have been used for some time in other areas of medicine. Anti-T-cell monoclonal antibodies, such as OKT3, have been recognized as effective immunosuppressive agents,162 and their use to prevent renal graft rejection has become well established.163 Many regimens for the prevention of graft rejection call for OKT3 monoclonal antibody therapy, followed by other immunosuppressive therapy. It was reported that two patients who underwent renal transplantation suffered marked visual loss after OKT3 therapy.164 In the one patient tested the results of the electroretinogram were flat.

More and more antibodies directed against specific receptors to lymphokines on T cells and other players in the immune system have been developed and evaluated. Other biologic agents, alemtuzumab and anakinra, have been used

in limited case reports for ocular inflammatory diseases, although others have been used more extensively. One of the prime targets for such therapy has been the IL-2/IL-2 receptor complex. The 55-kDa Tac subunit is expressed on T and B cells after lymphokine or antigen activation. Monoclonal antibodies directed against the 55-kDa Tac subunit have been developed. These anti-Tac antibodies have been reported to be effective in prolonging allograft survival in monkeys and humans165,166 and in reducing the incidence of graft-versus-host disease in humans.167 Initial problems dealt with immune reactions against a foreign protein (i.e., mouseproduced antibody), but technology now has permitted these antibodies to be ‘humanized’ (Fig. 7-15) so that essentially they are not recognized as ‘foreign.’168 Another area of prime interest is the TNF/TNF receptor complex.

Adhesion molecules (see Chapter 1) are an area of great interest both for the basic researcher and those interested in interventional studies. Injections of anti-Mac-1 antibodies have been shown to inhibit endotoxin-induced uveitis.169 Using several models of ocular inflammation, Rosenbaum and Boney170 demonstrated that the time of administration was important. Whitcup and coworkers171 have shown that monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1) and lymphocyte functionassociated molecule-1 inhibited EAU. Antibodies against ICAM-1 are being used to prevent allograft rejection and to treat rheumatoid arthritis in humans.

Daclizumab

The IL-2 receptor (IL-2R) system is a well-characterized lymphokine receptor system that plays a central role in the induction of immune responses. High-affinity IL-2R complexes are expressed on activated lymphoid cells. They consist of three subunits (α, β, and γ), each capable of binding IL-2. The 70-kDa IL-2R and 64-kDa IL-2R subunits are normally expressed on most resting T, B, natural killer

Monoclonal Antibodies

Mouse sequences

Mouse antibody

Human sequences

Humanized antibody

Chimeric antibody

Figure 7-15.  Monoclonal antibodies are usually derived in mice. Giving such an antibody to humans induces an immune response against it because it is seen as foreign. Some antibodies are chimeras, which reduces the foreign antigen load to some degree. Most antibodies now are ‘humanized’ with very few of the original amino acids left, which permits the necessary conformational integrity of the antibody. (Courtesy Protein Design Laboratories.)

(NK) and lymphokine-activated killer cells, which mediate signaling and receptor internalization. The 55-kDa IL-2 (p55, Tac, or CD25) subunit, on the other hand, is expressed by most T, B, and NK cells only after they have been activated by interaction with an antigen or with IL-2. The Tac subunit associated with the IL-2R β-γ subunits forms the high-affinity IL-2R complex. Thus expression of the Tac subunit marks a critical step in the activation of all T cells that are major contributors to both allograft destruction and autoimmune disorders. Caspi and associates169 demonstrated the presence of high-affinity IL-2 receptors in animal models of uveitis (see Chapter 1). Additionally, IL-2 receptors can be demonstrated on the surface of human cells in patients with uveitis. The humanized anti-Tac monoclonal antibody (daclizumab, Zenapax) is a recombinant monoclonal immunoglobulin of the human immunoglobulin (Ig) G1 isotype. The recombinant genes encoding daclizumab are a composite of human (90%) and murine (10%) antibody sequences. Therefore, the antibody is ‘humanized’ by combining the complementarity-determining regions and other selected residues of the murine anti-Tac antibody with the framework and constant regions of the human IgG1 antibody. It is hoped that daclizumab can suppress the autoreactive T cells, which play a critical role in the development of intraocular inflammation in patients with uveitis. There are no known toxicities specific to daclizumab, although administration of such a foreign protein could cause an allergic or anaphylactic reaction. Some of the reactions that may have been associated with daclizumab in a small number of patients were shortness of breath and low blood pressure.

A trial of daclizumab at the National Eye Institute, which has been going on for several years,172,173 suggests that there is a benefit from daclizumab therapy for the treatment of noninfectious uveitis. This observation is based on outcomes from a small group of patients. In the original study, nine of 10 participants with uveitis treated with daclizumab infu-

Nonsurgical therapeutic options

sions every 4 weeks were successfully tapered off their standard immunosuppressive regimens and subsequently continued to receive daclizumab, with maintenance or improvement of their visual acuity. After 4 years seven of these 10 patients continued to receive the drug. Patients initially received infusions and currently receive a subcutaneous preparation of the medication once a month. Adverse effects possibly but not clearly related to daclizumab recorded in this study included cutaneous lesions, edema, upper extremity neuralgia, upper respiratory tract infections such as colds and bronchitis, and herpes zoster. One patient in this study, after 4 years of monthly daclizumab therapy, was found to have a small, low-grade renal cell carcinoma that was surgically removed. This patient was initially withdrawn from further daclizumab treatments, but subsequently the treatment was restarted. Further studies have included a small multicenter study examining the possibility of treatment with subcutaneously administered daclizumab without an infusion as induction therapy. Preliminary data suggest that de novo subcutaneous daclizumab therapy yields very good serum levels for an extended period, permitting a taper of other immunosuppressive agents. It would appear that this approach is useful in treating disease that is controlled: that is, daclizumab is given when patient’s disease is controlled with ‘standard’ immunosuppression, which then can be tapered, leaving daclizumab as the only agent. Papaliodis and colleagues174 have reported that daclizumab was an effective therapeutic agent for some of their patients. We noted that patients with active intraocular inflammatory disease did not respond as well as those with quiet disease who then were switched to daclizumab therapy. We performed a small study treating patients with active intermediate and posterior uveitis who initially received 8 mg/kg of daclizumab followed 2 weeks later by 4 mg/kg, after which a standard dose of daclizumab was administered monthly. By 4 weeks, four of the five patients showed a two-step decrease in vitreous haze, with the fifth patient meeting that step at week 20. Vision at enrollment was 69.2 ETDRS letters, and following treatment was 78.2 letters (p < 0.12).175

Etanercept

Etanercept (Enbrel) is engineered to contain two identical soluble tumor necrosis factor (TNF) receptors that have been fused with the Fc domain of human IgG1. This molecule binds to and inactivates TNF. In support of the use of this medication in the treatment of human disease is the finding that TNF-α is found during the acute phase of experimental autoimmune uveoretinitis.176 Additionally, TNF-α levels are higher in both the aqueous and the serum of patients with uveitis compared with those of control subjects.177 Interestingly, the serum levels were significantly higher than the aqueous levels and correlated with recurrent uveitis. In the clinical realm etanercept has been used extensively in the treatment of patients with rheumatologic disorders. In one randomized study, patients with persistently active rheumatoid arthritis despite methotrexate therapy did significantly better when etanercept was added to their regimen (25 mg subcutaneously twice weekly).178 In a study treating children with polyarticular juvenile rheumatoid arthritis, patients’ joints responded statistically far better to etanercept (0.4 mg/ kg subcutaneously twice weekly) than to placebo.179 No

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

differences in adverse effects were noted. The effect of this medication and the next (infliximab) seems not to be as clear. Smith and colleagues180 evaluated 16 patients, 14 receiving etanercept and two receiving infliximab for either eye inflammation or joint disease. Eight patients had rheumatoid arthritis, three had juvenile rheumatoid arthritis, and three had uveitis without joint disease. All of the 12 with articular disease saw benefits with either medication; however, only six of 16 (38%) of those with uveitis had any benefit. It was the conclusion of the authors that other TNF inhibitors, particularly Remicade, may be better at controlling associated inflammatory arthritis than uveitis.

The major concern associated with this agent is infection. Patients who have received etanercept have developed serious infections, including sepsis, and several have died from their infections within 2–16 weeks of initiation of therapy. Etanercept should not be used in patients with active infections, whether chronic or acute or localized or generalized, and it should be discontinued if a patient develops a serious infection. Live vaccines should not be given. The most frequent adverse events reported in clinical trials were injection site reactions (37%), infections (35%), and headaches (17%). Malignancies were rare;181 autoantibody development has been reported, although clinical symptoms of a lupus-like syndrome are rare. As with infliximab, there is concern regarding the possible reactivation of tuberculosis. Fonollosa et al.182 reported that a tuberculous uveitis appeared in a patient receiving etanercept for rheumatoid arthritis.

Infliximab (Remicade)

Infliximab is a mouse-derived chimeric monoclonal antibody directed against TNF-α. It interferes with the binding of TNF to the two known receptors – TNFr1, which binds to soluble TNF, and TNFr2, which binds membrane-bound TNF. One group of authors183 reported giving five patients with Behçet’s disease one infliximab infusion, with a marked resolution of disease within 24 hours and ‘complete’ suppression by 7 days (see also the review by Sfikakis184). It is difficult to assess the value of this treatment because the authors reported that ocular inflammatory disease went into remission after 7 days, which is what could occur during the natural course of Behçet’s disease. Here only a comparison of the number of attacks could really help to assess the value of this approach (see Chapter 26). However, more reports have appeared strongly suggesting that these initial observations may be valid. Indeed, criteria for the use of infliximab in Behçet’s disease have been published, suggesting its use if first-line agents are not effective.185 Pipitone et al.186 reported the usefulness of this agent in treating neuro-Behçet’s. Seven patients with HLA-B27-associated anterior uveitis were treated with infliximab (10 mg/kg);187 six of the seven responded, but relapses were seen in four after a median of 5–6.4 months. It has been used for active scleritis with good results.188 There have numerous reports using this medication in childhood uveitis and other types of intermediate and posterior uveitis as well as retinal vasculitis. As with all studies authors claim success (we do that too!). It is clear from the number of articles that there should be a real therapeutic effect. However, the caveat is always that without a controlled trial we just cannot measure its real effect, in either the short or the long term.

As with etanercept, the major concern with infliximab is an increased risk of infection, in particular tuberculosis189 (including its unmasking), with one calculation being a risk of 70 in 147 000 cases. Ten instances of life-threatening Histoplasmosis capsulatum infection have also been reported, nine in patients receiving infliximab and one in a patient receiving etanercept.190 It has been suggested that signaling through the TNF2 receptor may be crucial in host defenses against intracellular pathogens such as tuberculosis. In addition, the use of infliximab may enhance brain lesions associated with multiple sclerosis. These changes were noted on magnetic resonance images.191 However, in one patient with neurosarcoidosis, infliximab therapy was thought to be beneficial.192 An aseptic meningitis and lupus-like syndromes have been reported, as has been a retrobulbar optic neuritis.193 Although methotrexate-associated pneumonitis is seen in 1% of patients, Kramer and associates194 reported pulmonary toxicity in three of 50 patients (6%) receiving a stable dose of methotrexate and infliximab. Malignancies are rare.181

Adalimumab (Humira)

Adilimumab is a fully human anti-TNF-α monoclonal antibody (IgG1) that blocks the interaction of TNF-α with p75 and p55 cell surface receptors. It has been evaluated in a several trials in rheumatoid arthritis, including studies combining it with methotrexate. It has been licensed for use in rheumatoid arthritis and psoriatic arthritis, and has been reported to be useful in the treatment of Behçet’s disease,195,196 VKH (one case),197 and childhood uveitis.198,199 Humanized monoclonal antibodies are theoretically superior to those that are chimeric. However, whether this agent will show equal therapeutic effectiveness to infliximab still remains to be seen. To date no cases of tuberculosis have been reported with this agent, but its use should be avoided in patients with multiple sclerosis.161

Efalizumab (Raptiva)

We and others have seen that adhesion molecules play an important role in the ocular immune response. CD11a and CD 18 are subunits of LFA-1, a T-cell surface molecule important in T-cell activation, T-cell migration into sites of inflammation, and cytotoxic T-cell function. LFA-1 interacts with ICAM-1 on the vascular endothelial cells at targeted sites to regulate cell trafficking and migration. Binding to CD11a on lymphocytes blocks the interaction between LFA-1 and ICAM-1, thereby interrupting lymphocyte migration and inflammation. The blockage is reversible and does not deplete T cells. We have shown that interference with adhesion mole­ cule function, including CD11a, positively altered the course of disease in animals with experimentally induced uveitis.171 Efalizumab is a humanized immunoglobulin (Ig) G1 version of the murine efalizumab monoclonal antibody MHM24, which recognizes human and chimpanzee CD11a. Efalizumab blocks T cell-dependent functions mediated by LFA1, including inhibition of the mixed lymphocyte response to heterologous lymphocytes and adhesion of human T cells to keratinocytes. Efalizumab has been approved by the FDA for the treatment of adults with moderate to severe chronic plague psoriasis,200 which is believed to be a T cell-mediated disease. It is a subcutaneous injection that is given weekly, the usual dose being 0.7 mg/kg initially and then 1 mg/kg. We