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

Indications and Dosages

Several dosage schedules have been suggested, with a weekly oral or intramuscular dose of 7.5–25 mg given until a therapeutic response is noted (see Table 7-2). Patients need to be told to abstain from all alcohol consumption. Cyclitis and sympathetic ophthalmia have been reported to improve with the administration of this agent, but Behçet’s disease and iridocyclitis have not.80 Holz and colleagues81 reported the use of low-dose methotrexate in the treatment of 14 patients with uveitis. Using a regimen of either 40 mg given intravenously once weekly followed by 15 mg/wk given orally, or 15 mg of oral methotrexate only, they found an improvement of visual acuity in 11 of the patients and an improvement in inflammatory disease in all. However, using the low dose of 12.5 mg/week of methotrexate, Shah and colleagues82 found that 16 patients with assorted ocular inflammatory conditions (including intermediate uveitis (nine patients) and retinal vasculitis (three patients)) had a reduction in inflammatory activity and most of those could taper or discontinue their steroid therapy. However, when one looks at the success rate for those patients with chronic uveitis, only five of the nine showed a response, and improvement in visual acuity was not used as the criterion for success. Of the three patients with retinal vasculitis, an improvement from moderate to mild disease was seen in two, and the other one had no improvement. Most practitioners will usually not treat acute uveitis in adults with methotrexate alone. Usually it is used as a steroidor ciclosporin-sparing agent as reported by Dev and coworkers83 in treating sarcoid uveitis. Pascalis and associates84 used all three – corticosteroids, ciclosporin, and methotrexate – with good results in patients with uveitis. Methotrexate is well tolerated in children and is used extensively. Even in a disorder such as rheumatoid arthritis for which methotrexate monotherapy has been shown to be effective, the addition of ciclosporin has been shown to produce significant clinical improvement in some patients.85 One combination to be particularly careful of is methotrexate and leflunomide. Weinblatt and colleagues86 reported serious liver disease in a patient receiving this combination. In a subgroup analysis of the SITE study (see the final conclusions of this chapter below), methotrexate was evaluated in 534 patients with uveitis. Adding methotrexate to an anti-inflammatory regimen was often effective in the management of anterior uveitis, sometimes effective for scleritis, but less often effective for intermediate, posterior or panuveitis.87

Methotrexate has been used periocularly for the treatment of malignant conditions. Rootman and Gudauskas88 used subconjunctival injections of methotrexate, cytarabine, and corticosteroids to successfully treat a leukemic infiltrate into the eye. Methotrexate has been used intravitreally to treat intraocular B-cell lymphoma.89 Good responses have been seen using 400 g/0.1 mL. These injections can be repeated, but care must be taken because reflux at the side of the intravitreal injection can damage limbal stem cells.

Secondary Effects

The secondary effects of methotrexate are legion,29,44 but more recent use of lower doses has given this agent a new therapeutic life. Severe toxic reactions have been reported with this medication, although usually at higher doses.

Marked depression of the white blood cell count and thrombocytopenia can occur. Hepatotoxicity (liver atrophy, cirrhosis, and even necrosis) is one of the most worrisome side effects.90 Up to one-third of those receiving long-term weekly doses of methotrexate will have elevated serum aminotransferase levels.91 Liver enzyme levels twice normal warrant withholding or stopping the medication; the levels usually return to normal rapidly. Zachariae and coworkers92 have reported that cirrhosis developed in 25% of patients with psoriasis who received long-term low-dose methotrexate therapy. The age of the patient and the duration of therapy are both independent predictors of possible toxicity. When to perform a liver biopsy still remains a controversial question. It has been suggested that a liver biopsy should be considered in patients before methotrexate therapy is begun if there is a history of excessive alcohol consumption, abnormal results of liver function tests, or chronic hepatitis. Liver biopsy should also be considered during therapy if elevated liver function test results persist or a decrease in the serum albumin concentration is seen.36

Another concern is an acute pneumonitis that can be accompanied by fever, progressive shortness of breath, and cough in 1–5% of patients treated with methotrexate.93–95 This appears to be due to a drug hypersensitivity reaction, and it can occur early or late in the course of therapy. Because an X-ray film may reveal interstitial and alveolar infiltration, sometimes bronchoalveolar lavage is needed to rule out an infectious process such as Pneumocystis carinii pneumonia. In most patients the reaction disappears with discontinuation of therapy.

Methotrexate may also impair renal function. The agent has been noted in the tears of patients receiving high-dose therapy.96 Methotrexate can have a high rate of toxicity, but this appears to be partly dose related. In the low-dose study of Holz and colleagues,81 slight elevations of transaminase levels were noted in four of 13 patients, partial alopecia in two, and nausea in three. A disturbing report from ZimmerGaller and Lie97 described a patient with rheumatoid arthritis treated with low-dose methotrexate for 16 months who developed blurred vision. This was noted to be due to choroidal nodules, which ultimately were shown to be a large B-cell non-Hodgkin’s lymphoma. It is always difficult to distinguish the underlying propensity of patients with autoimmune disease for developing neoplasms from a real risk from the therapy.

Methotrexate is teratogenic and may foster malformations in children whose fathers are receiving the medication. Therefore it should not be used during pregnancy, and birth control should be used for some time after the medication is stopped.

Ciclosporin

Mode of Action

Ciclosporin is a natural product of several fungi. It was first investigated because of its potential antibiotic qualities, and is indeed antibacterial but with a most limited spectrum. It was the unique immunomodulatory properties first observed by Jean Borel at Sandoz Ltd, Basel, Switzerland, that altered immunotherapy principles and therapeutics in a profound way. Ciclosporin A, now termed ciclosporin (Sandimmune), is a neutral lipophilic cyclic endecapeptide with an unique

Figure 7-8.  Structure of ciclosporin (Sandimmune).

amino acid side chain at the C1 position (Fig. 7-8). It is one of a large family of ciclosporins, some naturally occurring and some synthetically produced. This uncharged molecule, with a molecular weight of 1202 Da, is insoluble in water. The original preparation for human use was an olive oil solution with 12.5% ethanol, which was taken by mouth with either milk or juice. The absorption of this oral preparation was variable, ranging from 4% to 60%, with probably about one-third of the agent usually absorbed.98,99 The agent is concentrated in lipid-containing tissues such as breast, pancreas, liver, lymphoid tissue, and kidney. We found about 40% of the plasma concentration in the aqueous of patients with quiescent uveitis under therapy with ciclosporin and undergoing cataract surgery.100 Ciclosporin tablets are now available.

The agent is metabolized in the liver by the cytochrome P450 microsomal enzyme system. The ring structure is maintained throughout the metabolic process, with only 0.1% of the drug not undergoing metabolic changes. At least 15 metabolic products of ciclosporin are known. The parent structure appears to be the most active form. Drugs that interfere with cytochrome P450 activity will slow ciclosporin metabolism and will affect ciclosporin levels. Ketoconazole is one such agent, permitting a reduction by up to 90% of the oral dose of ciclosporin.101 Other medications that inhibit ciclosporin metabolism include oral contraceptives, androgens, and erythromycin.

Ciclosporin has been demonstrated to have a far more restricted effect on the immune system than any other immunosuppressive agent or other monoclonal antibodies. Although theoretically ciclosporin would affect any cell with its binding protein, its major clinical effect is actively directed against the factors that promote T-cell activation and recruitment. The exact point at which ciclosporin intervenes in this scheme is debated (Fig. 7-9). It appears that ciclosporin enters the cell and is bound to an immunophilin (cyclophilin) meeting it at the cell membrane, similar to the action seen with corticosteroids. It then is escorted into the nucleus, where it affects messenger ribonucleic acid (mRNA) production and ultimately protein synthesis. Although the mechanism still remains to be definitely

mRNA

Proteins

Ciclosporin (CSA)

Interleukin 2 (IL-2)

Interferon gamma

Figure 7-9.  Proposed mechanisms of ciclosporin on T-cell circuitry.

shown, much has been elucidated.102 Ciclosporin blocks the activation of genes in T cells.103 One intriguing notion is that ciclosporin binds to proteins binding to the interleukin (IL)-2 (IL-2) enhancer (such as NF-AT and octamerassociated protein), which helps in the activation of the transcription of the IL-2 gene. These sites have been shown to be sensitive to ciclosporin.104

On the basis of several in vitro systems, different observations have been made concerning the mode of action of ciclosporin. Larsson105 reported that ciclosporin blocked the acquisition of IL-2 receptors and thereby prevented resting

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

cells from becoming activated and responding to IL-2. This theme has been less emphasized in the more recent literature. Others, such as Bunjes and coworkers,106 have suggested that ciclosporin affects the release of IL-2 but that the acquisition of these receptors was not inhibited by ciclosporin. The blockage of ciclosporin production was noted by Kaufman and colleagues107 in a T-cell hybridoma that produces IL-2 but does not bear IL-2 receptors. It may be that ciclosporin’s mode of action depends on the state of T-cell activation and the type of stimulus for T-cell activation.108 It is clear, however, that ciclosporin was unique in mediating its action through the T-cell circuitry.

The T cell most affected seems to be the inducer T-cell subset. We have noted that recruitment of inducer T cells into the draining lymph node of a site of S-antigen immunization is markedly diminished with ciclosporin administration. Shifts in the kinetic T- and B-cell response are also noted when animals are given ciclosporin.

Dosages and Indications

The dosage schedule for ciclosporin administration has undergone much change.109 In our early studies110 on the use of ciclosporin in ocular inflammatory disease patients were given an initial dose of 10 mg/kg/day, which at the time was thought to be rather modest inasmuch as often two to two and a half times this dose was being given to treat recipients of whole organ transplants. However, it became clear that dose-induced renal alterations made this starting dose no longer acceptable (see later discussion of toxicity). Studies have suggested that a lower initiating dose of ciclosporin may not induce any or at least considerably lessen the possibility of renal toxicity111 (to be discussed). It is usually suggested that ciclosporin be given at a starting dose of 5 mg/kg/day (Fig. 7-10; see also Table 7-2), either as a single dose or as a twice-daily regimen. The twice-daily regimen is more commonly employed to avoid large spikes in serum ciclosporin levels, which may predispose the patient to renal toxicity. A recommended maximum dose of 7 mg/kg/day can be considered in special cases, such as children or patients with documented low ciclosporin serum levels. Ciclosporin is often used in combination with prednisone,

Sandimmun (CyA) therapy scheme for endogenous posterior uveitis

D7 mg/kg/d CyA 0.6 mg/kg/d prednisone, for maximally 3 weeks

E Stepwise tapering of CyA to a maintenance dose (.5 mg/kg/d)

Figure 7-10.  Therapeutic scheme for treatment of sight-threatening bilateral endogenous uveitis with ciclosporin. (Reproduced with permission from Ben Ezra D, Nussenblatt RB, Timonen P: Optimal use of Sandimmune in endogenous uveitis. With kind permission of Springer Science & Business Media.)

usually at 10–20 mg/day, but for short periods at even higher levels.

A relative contraindication for the initiation of therapy is poorly controlled hypertension or a history of renal disease accompanied by reduced creatinine clearance or both. In addition, older patients (over 55 years of age) must be evaluated particularly closely because they lack an adequate renal reserve. If the patient is currently being treated with cytotoxic agents, we would discontinue the medication for at least 1 month before ciclosporin is given. Those taking steroids orally continue to do so, with a slow taper to the 10–20 mg/day range. The ocular response to ciclosporin may be relatively slow (weeks to months), but preset goals should be established and should be met by about 3 months of therapy. The serum creatinine level should not be permitted to rise to 30% over baseline. Optimal decreases in ciclosporin dosages are usually between 50 and 100 mg/day at a time. Stopping the medication abruptly is ill advised because a rebound of the ocular disease may ensue.

The question of how long one needs to treat patients with ciclosporin is somewhat open-ended. It appears that an immunologically tolerant state is not induced with this medication, and therefore an extended therapeutic course is indicated in most patients. We have stopped the medication in some patients with no recurrence of their disease, which may be explained by the fact that the disease has run its course.

On the basis of our early observations,110,112,113 ciclosporin was used in patients with active bilateral sight-threatening noninfectious uveitis who were unable to tolerate systemic corticosteroid therapy at a moderate dose (>25 mg of prednisone) necessary for the treatment of their intraocular inflammatory disease.114 Of special interest was the particularly positive clinical effect seen in patients with Behçet’s disease who were treated with this medication.115 This has been supported by a randomized, masked study in Japan116 and in a study carried out by Diaz-Llopis and colleagues,117 who found that with a dose of 5 mg/kg/day and a maintenance dose of 2 mg/kg/day, a good response was seen in 86% of patients, with a disappearance of attacks in 43%. This appears to be the one disease in which ciclosporin might be considered as an initial therapeutic agent combined with a moderate amount of prednisone, but only if specific criteria are met (see Chapter 26).

Several reports support the use of ciclosporin in various types of intraocular inflammatory disease. Ciclosporin is now usually used in conjunction with another immuno­ suppressive agent, probably most frequently with corti­ costeroids. Towler and coworkers118 treated 13 patients with chronic intraocular inflammation with a mean ciclosporin dosage of 4.1 mg/kg/day, combined when needed with 15 mg or less of prednisone per day. They found that 10 patients had improved visual acuity, and in the other three acuity remained stable. One patient needed to return to an alternative form of immunosuppression. Secchi and colleagues,119 in an open, noncontrolled, multicenter long-term study of the use of ciclosporin, found it useful in the treatment of patients with posterior and intermediate uveitis, reducing the number and severity of attacks while improving visual acuity and reducing inflammation. Leznoff and coworkers120 reported a therapeutically positive response with ciclosporin in patients with sympathetic ophthalmia, as well as in a patient with a corneal transplant, but a

questionable response in patients with intermediate uveitis and serpiginous choroiditis. Pascalis and colleagues84 reported the use of ciclosporin (initial dose of 5 mg/kg/day) combined with fluocortolone and low-dose methotrexate in treating 32 patients with difficult-to-control noninfectious uveitis. They noted that 20 patients had a return to normal visual acuity, and all had a disappearance of ocular inflammatory activity. The follow-up period was from 6 to 18 months, during which they noted no signs of hepatic or renal toxicity. Ciclosporin is well tolerated by children,121 with Walton and coworkers reporting improvement in 64% or stabilization in 75% of eyes treated in children and adolescents with uveitis. Hesselink et al.122 felt that the smaller dose used now reduced the efficacy of ciclosporin. This may be true, but the medication remains a very useful addition to the armamentarium. A recent subgroup analysis of the SITE study (see last paragraph of this chapter) evaluated 373 patients starting ciclosporin montherapy.123 As was noted in our randomized study, about half gained sustained complete control of their inflammation by 1 year. The authors felt that, along with corticosteroid therapy, ciclosporin was modestly effective for controlling ocular inflammation. Adult dosing, based on the results of this study, ranged from 150 to 250 mg/day. Other agents were probably preferable for patients over the age of 55.

Like corticosteroids, ciclosporin has been placed into slow-release implants. Gilger and coworkers124 reported that ciclosporin implants decreased the severity of experimental uveitis in horses. A pilot study at the National Eye Institute was initiated to evaluate the safety of such a device and to elicit observations to determine its effectiveness. The implants were tolerated in the small number of patients treated, but a marked therapeutic effect was not seen.125 Most patients continued to have cystoid macular edema and required systemic immunosuppressive therapy. Slow-release ciclosporin implants will probably be continued to be investigated, but at present they appear to be directed towards treating ocular surface disease.

A topical preparation of ciclosporin is now commercially available and has been shown to be effective in treating moderate to severe dry eye.126 Although perhaps important for treatment of immune diseases involving the ocular surface, this method of application does not result in sig­ nificant amounts of drug entering the eye because of the physical properties of the medication. Therefore, topical application does not appear to a useful therapeutic approach for severe intermediate and posterior uveitis in the formulations currently available.

Secondary Effects

Table 7-3 lists the secondary effects we have noted with ciclosporin. However, these were observed when ciclosporin was administered as the sole immunosuppressive agent at 10 mg/kg/day, which we no longer do. At lower doses of ciclosporin the secondary effects noted by our patients have diminished considerably. When these side effects do occur, they are usually well tolerated by this group of highly motivated patients. However, the two secondary problems that cause the most concern for the treating physician are hypertension and renal toxicity. Depending on one’s definition of renal toxicity, it develops in as many as 75–100% of patients treated with ciclosporin.100,127 It is not clear what the inci-

Nonsurgical therapeutic options

Table 7-3  Secondary effects associated with administration of ciclosporin (10 mg/kg/day) in patients with uveitis

Figure 7-11.  Renal biopsy from patient receiving ciclosporin for uveitis. Interstitial fibrosis and marked patchy loss of renal tubules suggest toxicity due to this agent. Serum creatinine level was within normal limits at the time of biopsy.

dence of irreversible renal toxicity will be with the lower dosage of ciclosporin now recommended. At a higher dosage the alterations we noted on renal biopsy, after an average of 2 years of therapy, were renal tubular atrophy and interstitial fibrosis, with the glomeruli remaining mainly intact. Renal vascular alterations can also appear127 (Fig. 7-11). These alterations were noted histologically when the mean serum creatinine level of the patients undergoing biopsy was 1.5 mg/dL, within the upper limits of normal. It would appear that there is a reversible and irreversible component to the renal toxicity induced by ciclosporin. It may be that

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