- •
Therapy must be geared to the anatomic position of the inflammatory process; topical medication will not treat posterior pole disease.
- •
Corticosteroid therapy can be used in acute situations, but steroid-sparing therapies must be added by 3 months if it is clear that continued therapy is needed.
- •
Establish goals that should be met with therapy. If not met, consider altering therapy.
- •
Patients needing immunosuppressive therapy need to be advised as to possible problems related to the therapy and expectations, and need to be carefully monitored for adverse affects.
This chapter represents in some ways the very heart of the treating physician’s role. How do you choose the best therapeutic agent for your patient? This decision is often tension provoking because patients requiring the types of therapy under discussion usually have bilateral sight-threatening disease, are afraid, and are depending on the physician to choose a therapeutic intervention that will quickly restore their vision. Often the task is fraught with difficulties, which must be explained to the patient. It is truly a partnership. The more the patient knows about the physician’s goals and concerns, the more the patient can help. It is fair to say that in recent years enormous advances have occurred in our understanding of how to use many of the drugs under discussion. There has been a recent shift in interest to the use of intraocular therapy and also to more specific therapies, such as the use of monoclonal antibodies that target specific parts of the immune cascade. Animal models have helped us better understand underlying mechanisms, which has led to a more rational decision-making process. Further, pharmacology is a burgeoning area with real hope for the future; indeed, other, yet untapped, sources may also provide new immunosuppressive drugs to the growing armamentarium. At present there may not be any one ideal drug, but treating physicians have some latitude in their choices. However, each of the agents discussed in this chapter is a powerful medication that must be evaluated with care and respect.
Goals and philosophy
In the treatment of uveitis the decision to intervene with any therapeutic agent should be based on both a thorough clinical evaluation and philosophic guidelines. In general, the approach to therapy should take into account at least the following considerations.
Pain, photophobia, and discomfort
Symptom relief is an important goal for several reasons. The first and foremost is, of course, the ethical imperative of the physician. However, practical considerations should not be overlooked. Pain relief helps in the establishment of a good patient–physician relationship, which is of primary importance in what is frequently a long therapeutic course with ups and downs. A second practical reason is that once pain relief is obtained the patient is able to cooperate more readily. The ability to examine the patient’s ocular condition in greater detail and to obtain more reliable test results, particularly visual acuity, is of immeasurable help to the physician.
Degree and location of inflammatory disease
The type and frequency of administration of any therapeutic choice depend on the physician’s evaluation of how ‘serious’ the inflammatory disease is and what ocular structures are being affected. For instance, if the sequela of an intraocular inflammation is limited to posterior synechiae, then the use of topical mydriatics and corticosteroids may be a reasonable approach to therapy. However, disease that is more posteriorly located would need to be approached by means of quite different strategies. If alternative therapies are available, the physician needs to decide which one to start initially. In addition, if vital structures, such as the macula, are involved, more aggressive immunosuppressive therapy may need to be used, even though the potential for side effects may be greater.
Evaluation of visual acuity and prospect of reversibility
In most cases of inflammatory disease involving the intermediate and posterior portions of the globe an alteration in the patient’s visual acuity is the reason for therapeutic intervention. It is also the major reason that the patient consults the physician – in the hope that therapy will positively affect the condition. It is therefore imperative that the physician attempts to define as clearly as possible why the vision has decreased. On this decision will hinge the therapeutic approach. Has the vision decreased because of recently developed macular edema, or because the patient’s cataract progressed as a result of recurrent bouts of anterior uveitis? Or have both occurred? Does the patient need a cataract extraction only? Is this surgery needed to better follow the effects of long-term immunosuppressive therapy? The physician must constantly question his or her decisions, seeking to confirm the original hypothesis, because these patients frequently have multifactorial reasons for vision changes. The use of various tests in the clinic can help in this evaluation, but the ultimate decision still lies with the treating physician.
Before embarking on any therapy that has a significant risk for the patient, the physician must weigh this inherent risk against any benefits. It is therefore necessary to decide whether any or all of the visual alteration is due to irreversible changes. Is there a macular hole so that the vision may never be better than 20/200, or should surgery be considered? Have subretinal neovascularization and the resultant scarring left little hope for good vision despite a possible surgical procedure? It is wrong to begin therapy if no reasonable hope for visual improvement exists. In addition, when does one commence therapy? Although the answer is highly variable, it is always based on the physician’s belief that the side effects of the therapeutic intervention are outweighed by the potential good. It is the physician’s duty to desist from inappropriate therapy as much as it is to institute beneficial treatment. There are generally pressures on the physician for action that make him or her more readily accepting of therapeutic intervention. Why not try? Often this is acceptable, but patients need to know if they are facing unfavorable odds, which makes their input in deciding if treatment should be given even more important.
Follow-up procedures and standardization of observations
It is imperative that a reasonable time be allotted to evaluate whether a specific therapy is effective. We have found that up to 3 months is a reasonable period in which to evaluate whether an acute problem will improve. One should remember that ocular changes due to uveitis may resolve slowly, and the observer must use changes – sometimes subtle – in the ocular examination to determine whether to continue therapy. The patient should adhere to a regular follow-up schedule and should know whom to contact if an emergency arises. At the start of systemic immunosuppressive therapy patients should be examined at least weekly. These initial weekly examinations can later be replaced by visits every 2 weeks, with the patient eventually returning monthly for the initial half year. The physician needs to preset the definition of a therapeutic ‘success’ and adhere to these criteria. Just as it is unwise to stop or alter therapy too soon, it is not reasonable to continue therapy if the minimal criteria for success are not met. Such criteria may include an increase of vision, a decrease in the amount of vitreous haze, a decrease in the number of cells in the anterior chamber, or a decrease in the photophobia the patient is having.
With the criteria that determine successful treatment there is a presupposition that tests are performed in a standard manner and that test results reflect a change in the ocular status rather than the fact that a different person performed the test. Standardization of observations is critical to the successful evaluation of these patients’ condition. We have taken great pains to standardize our visual acuity assessment and the evaluation of ocular inflammation.
One eye or two
We generally avoid the use of systemic drugs in patients who have unilateral chronic uveitis and no underlying systemic disease. In our experience it is rare that unilateral disease justifies long-term therapy, but it certainly happens. In the patient with sight remaining in only one eye, a value judgment needs to be made concerning whether local therapy should be used before systemic therapy is employed.
General health and age of patient
The very basic considerations of patient health and age must play a role in deciding what sort of therapy to use. We thoroughly evaluate all patients and examine therapeutic alternatives before starting systemic therapy, especially in children. The secondary effects of systemic immunosuppressive agents, such as steroids, can have a major and lifelong impact on a growing child. A diagnosis of diabetes may be a relative contraindication for systemic corticosteroid therapy, whereas uncontrolled hypertension or renal disease may make ciclosporin a poor therapeutic choice. The physician must be always aware that most of these therapies have significant systemic and local effects.
Patient reliability, preferences, and understanding
The patient has come for expert advice concerning what frequently is a sight-threatening disorder that is often irreversible. Time should be spent with the patient, who deserves an explanation of ocular (and systemic) findings, the seriousness of these findings, the type of therapy warranted, and the possible positive and adverse effects. We have found that the fully informed patient provides invaluable aid to the treating physician. Obtaining informed written consent may be a requirement under certain circumstances, such as with experimental therapies. Patients with uveitis usually require long-term care, and the more the patient understands medical concerns, uncertainties, and possible therapeutic alternatives early on, the easier is the treating physician’s task.
Nonsurgical therapeutic options
Corticosteroids
The corticosteroid family of medications has been the mainstay of therapy for ocular inflammatory disease since its introduction by Gordon in the early 1950s. Its use in ophthalmology began soon after its introduction into the medical armamentarium. The synthetic compounds usually used by the physician are variations of the compounds normally found in the body, and they profoundly affect many aspects of the organism’s physiology. The synthetic preparations available to the physician were developed because of their particularly effective mediation of one aspect of these hormones’ effects: immunosuppression. The treating physician should be totally at ease with the various therapeutic strategies available.
Mode of Action
In humans, corticosteroids are not considered to be cytotoxic agents. Human immune cells are not susceptible to lysis by corticosteroid administration, even at the higher dosages usually employed, unlike some of the agents to be covered in this chapter. Mice, rats, and rabbits are considered to be corticosteroid-sensitive animals, with their lymphocytes showing a marked tendency toward lysis after the administration of corticosteroids. Therefore, extrapolation from animal experiments must take place only after careful evaluation.
The mechanism of entry into the cell by steroids has been evaluated by means of several systems. The underlying point for the action of all the steroid hormones is the need for cellular receptors. The steroid is met at the cell surface by the appropriate receptor and then complexes with it in the cytoplasm of the cell. This complex then migrates to the nucleus, where it exerts its effect on DNA transcription, leading to changes in RNA production. These RNA alterations result in changes in protein production and cell function. In steroid-sensitive animals, such as the rat, cells with steroid receptors will be lysed. However, in humans this is not the case, and in vivo and in vitro testing is therefore needed to fully evaluate the effect of the hormone on the system in question.
The effects of steroids on the immune system are both local and systemic. Essentially all cellular components are affected. On the systemic level, a profound change is seen particularly with neutrophils and lymphocytes ( Fig. 7-1 ). For lymphocytes, Clamen and Fauci showed that a large number of the lymphocytes in the intravascular space continuously recirculate with the extravascular lymphocyte pool in organs such as the bone marrow, spleen, and lymph nodes. The addition of steroids induces a change in the recirculation pattern, with a large number of T cells, particularly the helper T subset, sequestered out of the intravascular circulation. This phenomenon results in a break in the recruitment of immunoreactive cells to the site of the inflammatory reaction. The effect on neutrophils appears to be quite striking as well. Steroid therapy induces a larger number of neutrophils to be produced by the bone marrow. In addition to this increased production, the circulating half-life of these cells on reaching the intravascular space is prolonged. Concomitant with these effects is an impeding of neutrophil migration from this space to the site of inflammation. Decreases in the number of circulating monocytes, eosinophils, and basophils have also been observed.
Although the changes in the immune system are profound, it is important to remember that they are temporary. Fauci demonstrated that T-cell subsets return to essentially the presteroid ingestion state after about 24 hours. This observation is most important in developing a strategy for the treatment of an acutely active inflammatory condition, whether in the eye or elsewhere.
Profound effects on cell function have been noted with the addition of a steroid. The effects on the various immune cell populations include a decrease in bactericidal activity, a decrease in delayed hypersensitivity reactions, a decrease in lymphokine production, and changes in immediate hypersensitivity reactions. In addition, steroid administration has a profound effect on local resident cells in an organ, particularly the vascular endothelium. A reduction in the leakage of fluid during an inflammatory episode from the capillary endothelium results from steroid administration, thereby reducing tissue swelling. Further, during an inflammatory response there is a decrease in the amount of intracellular fluid taken in by cells, thereby reducing cell swelling and avoiding the resultant decrease in function and ultimate lysis. The effect of steroids on lysosome membranes, thought at one time to be an important stabilizing factor, now remains unclear.
Other effects of steroids are beginning to become clear. Among the many factors involved in uveitis are the matrix metalloproteinases (MMPs). MMPs are a class of proteolytic enzymes that influence tissue architecture. Their products have been implicated in a wide range of physiologic and pathologic processes and diseases. MMPs have been described in the pathogenesis of blood–retinal barrier breakdown and increased vascular permeability. Furthermore, MMPs also have been shown to play a role in the breakdown of the blood–brain barrier and increased vascular leakage in experimental animal encephalomyelitis. Inflammatory cells themselves may also modulate the production of some MMPs, with some cytokines stimulating and others inhibiting their production. Some steroids, such as anecortave acetate, an angiostatic steroid which is presently under evaluation, inhibit the expression of some MMPs involved in angiogenesis.
Preparations, Dosage Schedules, and Complications
Many steroid preparations are now available. It should be remembered that they have varying potencies, and therefore sometimes quite different concentrations of each drug need to be used ( Table 7-1 and Fig. 7-2 ).
| Preparation | Systemic equivalent (mg) | Antiinflammatory potency |
|---|---|---|
| Hydrocortisone | 20 | 1.0 |
| Cortisone | 25 | 0.8 |
| Prednisolone | 5 | 4.0 |
| Prednisone | 5 | 4.0 |
| Dexamethasone | 0.75 | 26 |
| Methylprednisolone | 4 | 5 |
| Triamcinolone | 4 | 5 |
| Betamethasone | 0.6 | 33 |
Topical application of corticosteroids is an excellent way to treat certain uveitides. Our own preference has been the use of prednisolone formulations for severe intraocular inflammatory disease. The basis for this choice is not scientific but rather the result of usage and convenience, and hence knowing what to expect with this formulation. Although studies do show differences in corneal penetration between phosphate and acetate preparations of steroids, we have not noted a major difference in efficacy between the two preparations for treating active inflammation. When the diagnosis is made, it is imperative that initial treatment of the uveitis be aggressive. We frequently ask the patient to administer his or her drops every hour while awake. One can even consider asking patients to begin their topical therapy by taking a drop every 15 minutes for the first hour, as a sort of loading dose. Our opinion is that ‘failures’ of this therapy are often due to infrequent dosing schedules. Further, the longer the duration and the more chronic the disease, the more difficult it often is to bring under control. Once a dosing schedule has been found to be effective, as evidenced by a reduction in the flare and cells in the eye, we then see the patient often (every 2–3 days to once a week) and begin a very slow tapering of the drops. The schedule for tapering is unique to each patient, but persons who have had numerous attacks may need to receive one or two drops a day for weeks or even months.
A second option is to inject the corticosteroid periocularly. This method, which permits a relatively high concentration of material to be given rapidly, is an effective way to treat particularly severe inflammatory conditions. There is the general choice between long-acting preparations (in a depot vehicle) and shorter-acting soluble preparations. These injections can be given every 1–2 weeks for short periods. In addition to treatment of severe anterior segment disease in general, this is a useful approach for unilateral disease, at the time of surgery on an uveitic eye, and for patients in whom the systemic effects of steroids should be avoided. We have found this to be an effective way to treat cystoid macular edema, even in children, although the procedure may require that young children receive general anesthesia. In one study 25 of 28 eyes given a sub-Tenon’s injection of 40 mg triamcinolone had improved vision at 6 weeks post injection. In another study by Bui Quoc and colleagues, 61 patients with uveitis were given one or more periocular injections of triamcinolone. Intraocular pressure elevation was seen in 21% of patients and 52% of patients were thought to have effective therapy based on angiographic changes and an improvement in visual acuity.
Several approaches to periocular injections have been suggested, and it probably is best to use the approach with which one feels the most comfortable. The approach from the superotemporal aspect of the globe, as described by Schlaegel, is thought to reduce the possibility of penetration of the globe and to place the medication under Tenon’s capsule and in the region of the macula. Freeman and coworkers demonstrated that the temporal approach is efficient for placing the injected steroid close to the macula. Using any of these approaches, we rarely need to systemically premedicate an adult. Topical anesthetics are liberally used, and the area in which the injection is to be given (such as the superotemporal aspect of the globe) is further anesthestized with a cotton swab soaked in topical anesthetic (either 4% lidocaine or cocaine). If there are no contraindications, we generally inject triamcinolone (Kenalog) 40 mg in 1 mL because this preparation appears to cause less fibrosis. Some practitioners have suggested mixing the steroid preparation with a local anesthetic. We generally do not do this because the increased volume needed increases the pain of the procedure. An alternate approach that has become popular is to inject the steroid preparation directly through the lower lid or the inferior fornix (using a 25-gauge needle) while the patient looks upward. After the injection, for the patient’s comfort, we put a patch on the eye and give a mild analgesic. We have rarely found the need to inject the steroid anteriorly over the pars plana/peripheral retina, a technique that is thought to increase the chance of steroid-induced ocular hypertension. If the procedure is performed on an outpatient basis, the person will be observed for some time (30–90 minutes) to be sure there are no untoward problems. We will use periocular injections over a 4–12-week interval, giving a series of two to four injections before declaring this method ineffective ( Fig. 7-3 ). Finally, anecortave acetate, a corticosteroid that has been modified so that its corticosteroid activity has been eliminated, is also injected periocularly. The interest in this molecule is related to its retardation of blood vessel growth through inhibition of endothelial cell migration.
An additional local approach that has attracted great attention is the intraocular administration of corticosteroids. To date this route of administration has been achieved using three approaches. The first is the direct injection, usually of triamcinolone (2–4 mg), into the vitreous; the second is the use of a soluble pledget placed into the anterior or posterior chamber; and the third is placement of a slow-release fluocinolone acetonide-containing implant into the eye.
Intravitreal steroid injections have been reported to be effective for many intraocular problems, including choroidal neovascularization, CME secondary to uveitis, diabetes, central vein occlusion, and pseudophakia. In one study in which 2 mg of triamcinolone were injected into uveitic eyes with cystoid macular edema, five of six eyes showed a reduction in macular thickening in 1 week based on optical coherence tomographic measurements. Two of the five eyes could be maintained afterward with periocular injections. However, only a moderate improvement in visual acuity was seen despite the return of the macula to its anatomically normal configuration. In one 40-patient randomized study comparing orbital floor injection of steroid versus intravitreal injections for CME, foveal thickness increased with orbital floor injections but decreased with intravitreal injections, with CME improving in that group in 50% of patients. However, at 6 months there was no difference in the best corrected vision between the two groups. This perhaps underlines the issue that repeat injections are necessary for a sustained release, an approach that is being used less and less. The positives and negatives of this approach continue to be discussed, particularly with the significant increase in intraocular pressure and cataract formation. Regression of iris neovascularization has been reported using this approach as well. In one study of 113 patients treated with intravitreal triamcinolone for subretinal neovascularization, 30% developed an increase in intraocular pressure >5 mmHg within the first 3 months. In addition to an increase in pressure, a clinical picture resembling an endophthalmitis was reported, with the normal concern as to whether it was sterile or infectious. Further, the triamcinolone preparations currently being used contain alcohol, which has an unknown effect on the retina. An intraocular preparation free of such components is now available.
Fluocinolone acetonide (FA) intravitreous implants have been evaluated in several studies, and the results of a 3-year clinical trial have recently been published. In this study 110 patients received a 0.59 mg FA implant and 168 received a 2.1 mg FA implant, all placed intravitreously. Uveitis recurrence was reduced to 4%, 10%, and 20% during the 1, 2, and 3 year periods for the 0.59 mg implant. More implanted eyes had an improvement in vision than did nonimplanted eyes. However, glaucoma surgery was required in 40% of the implanted eyes, compared to 2% of the nonimplanted eyes. Additionally, 93% of the phakic eyes that were implanted needed cataract surgery, whereas only 20% of the nonimplanted eyes needed this surgery. The Retisert implant is FDA approved for use in uveitis. However, questions remain as to the overall use of this approach in uveitis patients. Because of equipoise in the community as a whole, the Multicenter Uveitis Steroid Treatment (MUST) trial was initiated. This is a phase IV randomized controlled clinical trial comparing two treatments, the FA implant versus standard therapy, for patients with vision-threatening noninfectious intermediate uveitis, posterior uveitis, or panuveitis. It is projected that the study will be complete in late 2011.
Ozurdex
Ozurdex is a sustained-release biodegradable intravitreal implant containing dexamethasone. The implant is placed in the vitreous using a 22-gauge applicator and the biodegradable polymers break down into H 2 O and CO 2 as dexamethasone is released. A clinical study comparing applicator and surgical placement of Ozurdex found that patients receiving applicator placement had a similar efficacy but a slightly lower rate of certain adverse effects than did those receiving surgical placement.
Ozurdex is currently FDA approved for macular edema associated with retinal vein occlusion and is also being developed for both diabetic macular edema and uveitis. A recent study demonstrated that Ozurdex was well tolerated and produced improvements in visual acuity, macular thickness, and fluorescein leakage in patients with persistent macular edema despite laser treatment or medical therapy. Eligible causes of macular edema in this study were diabetic retinopathy, retinal vein occlusion, uveitis, and Irvine-Gass syndrome. In a subgroup analysis of patients in this study who had macular edema due to either Uveitis or Irvine-Gass syndrome, those receiving the 700 mg Ozurdex implant had significantly greater improvement in visual acuity than did controls up to 6 month following a single application. Ozurdex was well tolerated, with no cases of endophthalmitis. The number of patients with an increase in intraocular pressure (IOP) ≥10 mmHg at any visit during the 6-month trial was 12% in the 350 µg Ozurdex group, 17% in the 700 µg Ozurdex group, and 3% in the control group. No patients required surgical treatment for glaucoma.
Secondary Effects
The topical application of steroid induces an increase in IOP in a significant number of persons. This should be monitored closely. It has been our experience that some patients with uveitis are extremely sensitive to steroid therapy, with dramatic increases in IOP noted even when topical steroids are administered on a very modest schedule. The reactivation of corneal herpes simplex infection can occur with topical steroid therapy. This is of even greater import in those patients undergoing corneal grafting, as a large proportion of these persons are undergoing this procedure because of corneal herpes.
The periocular injection of steroid has secondary effects unique to the procedure as well. (1) Although periocular steroid injections are an effective therapy for childhood uveitis, they may require general anesthesia, with the potential inherent side effects. (2) Possible penetration of the globe with the needle should be a constant concern to the ophthalmologist. (3) Continued periocular injections can induce orbital problems, such as proptosis of the globe and fibrosis of the extraocular muscles. (4) Retinal and choroidal occlusions after a posterior sub-Tenon’s injection given to treat cystoid macular edema have been reported. (5) Severe or intractable glaucoma can occur after periocular injections. This can become particularly problematic when a depot injection has been used. In such cases the depot may need to be removed surgically, which is sometimes a major undertaking. In a retrospective review of 64 patients, Levin and colleagues found that in nonglaucomatous eyes a history of a steroid-induced increase in intraocular pressure is a relative contraindication to injection. In another study of 53 patients who had a total of 162 posterior sub-Tenon’s steroid injections, an increase in IOP was seen in 36%. (6) Reactions to the vehicle in which the steroid injection has been placed can also occur ( Fig. 7-4 ). (7) In patients with scleritis and ocular toxoplasmosis, periocular injections can be problematic. In the former the injections could potentially inhibit new collagen growth to a point where perforation of the globe may occur. This theory is being questioned by some. With toxoplasmosis, the acutely high intraocular steroid dose may effectively prevent the body’s normal antitoxoplasma mechanisms, thereby causing an exacerbation of the ocular disease. Intraocular steroid injections or implants may also result in elevations of IOP in a large proportion of patients. The complications of intraocular steroid placement are just beginning to be reported. As mentioned earlier, they include increased IOP, endophthalmitis, and much rarer but always potential problems after any penetrating injury to the globe (i.e., vitreous hemorrhage and retinal detachment).
Systemic corticosteroids remain the initial drug of choice for most patients with severe bilateral endogenous sight-threatening uveitis. The striking exception to this rule is patients with Behçet’s disease (see Chapter 26 ). When initiating systemic steroid therapy, one should keep in mind several considerations. It is imperative that the treating physician (to the best of his or her ability) rule out the possibility of infection or malignant disease as a cause for the intraocular inflammation. Uppermost is the clinical impression, based on the ocular examination, that there is an inflammatory response that requires systemic therapy. It is also important for the practitioner to set standards by which to decide whether the therapy is successful or not. A detailed explanation should be given to the patient before starting therapy. The subject matter should include duration of therapy, goals, and side effects.
We generally find it advisable to begin therapy with prednisone 1–1.5 mg/kg/day ( Table 7-2 ). The relatively high dose and daily therapy appear to increase the efficacy of this approach, which takes into account the known effects of corticosteroids in humans, already described. The high doses of corticosteroids should be maintained until one sees a clinical effect, but it is clear that the treating physician must set a reasonable time limit to decide whether this form of therapy is truly worthwhile. If it is determined that the corticosteroids are having a beneficial effect, then a slow reduction of the therapeutic dose needs to be established. A too-rapid reduction can lead to recurrence. The slow-tapering plan permits the treating physician to see if the reduction will cause a reactivation, which frequently manifests as a mild ocular inflammation and perhaps a minimal decrease in visual acuity. Some patients may need only a periodic short course of systemic steroids, whereas others require long-term maintenance therapy. Antacids or other antiulcer medications and calcium supplements can be given to patients, particularly those receiving long-term therapy. We routinely give ranitidine, 150 mg once or twice a day, to all our patients receiving oral prednisone for any length of time.
| Agent | Usual dosage * |
|---|---|
| Prednisone | Oral: 1–2 mg/kg/day |
| Methylprednisolone | IV pulse: 1 g over 1–2 h |
| Intraocular triamcinolone | Intravitreal: 2–4 mg |
| Antimetabolites | |
| Methotrexate | Oral: 7.5–15 mg weekly; can be given intramuscularly |
| Azathioprine weight/day | Oral: 50–150 mg daily, 1–1.5 mg/kg, but up to 2.5 mg/kg body |
| Mycophenolate mofetil | Oral: 1 g twice per day |
| Alkylating agents | |
| Cyclophosphamide | Oral: 50–100 mg daily, up to 2.5 mg/kg body weight/day |
| IV pulse: 750 mg/m 2 (adjusted to kidney function and white blood cell count) | |
| Chlorambucil | Oral: 0.1–0.2 mg/kg/day |
| Ciclosporin | Oral: up to 5 mg/kg/day, usually given with prednisone, 10–20 mg/day |
| FK506 | Oral: 0.10–0.15 mg/kg body weight/day |
| Daclizumab | IV or SC: 1–2 mg/kg |
| Etanercept | SC: 25 mg twice weekly; children 0.4 mg/kg twice weekly |
| Infliximab | SC: 3–10 mg/kg |
| Interferon-α | SC: 3–6 × 10 6 IU qd × 1 mo, then qod; 3 × 10 6 IU three times per week |
* It is important to note that the dosages should ultimately be determined by a treating physician with experience using these medications on the basis of the medical state of the patient in question. Further, not all of these medications (or the route of therapy indicated) have been approved by various governmental agencies (i.e., U.S. Food and Drug Administration) for use in patients with uveitis. Therefore the physician needs to inquire about their specific use.
Alternate-day therapy is certainly a logical goal to aim for because side effects of such administration are much less than those with daily dosing. Fauci has suggested that one way to attain this is to double the daily maintenance dosage and then slowly reduce the alternate-day dosage by 5 mg until zero is reached. In our experience those patients with severe inflammatory disease or persistent macular edema often do not do well with alternate-day therapy, but it still remains a logical goal. It is important to stress the method outlined by Fauci, because it has been our experience in ophthalmology that the plan is rarely followed. If a patient is taking prednisone 20 mg/day and the decision has been made to attempt an alternate-day approach, then the treating physician needs to double the daily amount of prednisone from 20 to 40 mg/day and then begin a slow taper every other day.
How long does one treat? What is a reasonable long-term dosage? These are not easy questions to answer. Each patient’s requirements, capacities, and willingness for treatment are very different. Obviously the best dosage of steroid is none at all. However, being realistic, we believe that a reasonable daily adult maintenance dose is from 10 to 20 mg of prednisone, or as low a dose as is possible. This of course varies from patient to patient. For many patients with severe inflammatory disease we commonly see undertreatment, with therapy lasting only for 3–4 weeks followed by a rapid taper. Unfortunately, this therapeutic approach is wishful thinking and will not work in many patients. We will not consider lowering the steroid dosage below 10–20 mg unless the ocular disease appears quiescent for an extended period, usually about 3 months. In some diseases, such as sympathetic ophthalmia (see Chapter 23 ), we have elected to treat with maintenance dosages for at least a year, fearing a recurrence if therapy were stopped earlier. As a general tapering schedule, if the dose of prednisone is >40 mg/day, then one can reduce by 10 mg/day every 1–2 weeks; if the dose is between 20 and 40 mg/day, one can reduce by 5 mg/day every 1–2 weeks; if the dose is between 10 and 20 mg/day, one can reduce by 2.5 mg/day every 1–2 weeks; and if the dose is <10 mg, one can reduce by 1–2.5 mg/day every 1–4 weeks. As soon as it is clear that long-term (i.e., >3 months) therapy will be needed, we begin to think about adding a second agent (see below).
Intravenously administered ‘pulse’ corticosteroid therapy can also be employed. We have used this approach in patients who have a severe bilateral process that needs to be treated as rapidly as possible, administering 1 g of methylprednisolone intravenously and repeating daily for 3 days. Patients are hospitalized and examined by an internist before the administration of this therapy. It is not yet clear whether this method indeed renders better results than does giving a high dose of oral prednisone, such as 80 mg/day, but in our experience it certainly reverses an acute process very rapidly. This approach has been used to treat the Vogt–Koyanagi–Harada syndrome as well as the ocular manifestations of Behçet’s disease.
The potential side effects of corticosteroids should be familiar to those giving the medication. Some of the more common secondary problems are seen in Box 7-1 . Other adverse reactions have included nonketotic hyperosmolar coma in young nondiabetic patients receiving systemic corticosteroids for a short time, and central serous retinopathy.
FLUIDS, ELECTROLYTES
Sodium retention, potassium loss
Fluid retention
Hypokalemic alkalosis
Hyperosmolar coma
MUSCULOSKELETAL
Muscle weakness
Steroid myopathy
Osteoporosis
Aseptic necrosis of femoral and humeral heads
Tendon rupture
GASTROINTESTINAL
Nausea
Increased appetite
Peptic ulcer
Perforation of small and large bowel
Pancreatitis
DERMATOLOGIC
Poor wound healing
Easy bruisability
Increased sweating
NEUROLOGIC
Convulsions
Headaches
Hyperexcitability
Moodiness
Psychosis
ENDOCRINE
Menstrual irregularities
Cushingoid state
Suppression of growth in children
Hirsutism
Suppression of adrenocortical pituitary axis
Diabetes
OPHTHALMIC
Cataracts
Glaucoma
Central serous retinopathy
Activation of herpes (topical)
OTHER
Weight gain
Thromboembolism
The effects of long-term corticosteroid administration are a constant concern. Polito and coworkers studied the growth of 10 boys with glomerulonephritis who received prednisone (1.2 mg/kg) every other day for at least 2 consecutive years. They found that in six patients the peak growth velocity was delayed after age 15. However, after 16 years of age the growth velocity was significantly higher than expected and permitted these patients to reach their genetic height potential. We have also gained a heightened sensitivity to the development of osteoporosis with corticosteroid therapy. Corticosteroids affect many aspects of bone health, including calcium homeostasis, and sex hormones, which are inhibitors of bone formation, enhancing osteoclast-mediated bone resorption and reducing osteoblast-mediated bone formation. The effects of steroids can be seen within the first 6 months of therapy. The prevalence of vertebral fractures in patients with asthma treated with corticosteroids for at least 1 year is 11%. Most experts will recommend 800 IU of vitamin D daily as well as 1500 mg of calcium. Exercise is important, and hormone replacement therapy can be considered in menopausal women. Finally, antiresorptive agents such as alendronate, etidronate, and risedronate should be considered, particularly if bone density studies demonstrate osteoporosis or if patients are receiving long-term steroid therapy.
A question that must be constantly asked is whether the desired effect warrants the potential or real side effects. There is no easy answer, and a dialogue between the patient and the physician is the only way this question can be addressed. Although corticosteroids remain the mainstay of therapy for uveitis, the condition in some patients is resistant to steroids. For those receiving long-term steroid therapy the risk of developing unacceptable side effects at the dosages that need to be given to control the disease are real. In those patients other immunomodulatory agents are added as steroid-sparing agents so that lower steroid doses (or none at all) can be used. The combination of steroids with these agents provides reasonable and effective regimens for some patients and is discussed next. Although we may often begin therapy with corticosteroids, we will add a steroid-sparing agent if more than 3–4 months of significant amounts of steroids (15–20 mg) are needed to control the ocular inflammation. This philosophic shift to multiple agents sooner rather than later represents an important change in our therapeutic strategy.
Cytotoxic agents
It is curious to note that cytotoxic agents have their roots in instruments of destruction, namely chemical warfare. Although mustard gas was synthesized earlier, its use during World War I, with the resultant lymphopenia and lymphoid aplasia, led to the evaluation of this family of agents for therapeutic purposes. On a practical basis, two major categories of cytotoxic agent are used today in the treatment of ocular inflammatory disease: alkylating agents, such as chlorambucil and cyclophosphamide ( Fig. 7-5 ), and antimetabolites, such as azathioprine and methotrexate (see Fig. 7-8 ). They have been used by physicians for several decades, but their true efficacy in many ocular disorders remains unclear; however, more information has recently been gained in their use for other putative autoimmune diseases. The physician treating severe sight-threatening disease should be aware of these agents and how they may fit into the general scheme of nonsurgical therapy for uveitis. Although, when viewed as a group, they are associated with serious side effects, the role they play as steroid-sparing or -replacing agents cannot be denied. ,
Alkylating agents
Mode of Action
The alkylating agents have the ability to undergo reactions that result in the formation of covalent links (alkylation) of neutrophilic substances. In interacting with DNA strands alkylating agents are thought to interact with the 7-nitrogen guanine ( Fig. 7-6 ). This cross-linking of DNA would result in the inability of the cell’s DNA to properly separate during division, ultimately leading to the death of the cell.
Nitrogen mustards are unstable compounds, and alterations in their structures were invariably tried to increase stability. An aromatic modification of mustard gas is chlorambucil (see Fig. 7-5 ), a compound stable enough to be given by mouth. Cyclophosphamide is yet another modification, with a cyclic phosphamide group added. For cyclophosphamide to become an active agent it must be metabolized in the liver’s microsomal system. It is theorized that phosphoramide mustard (see Fig. 7-5 ) is the most active of the metabolites.
The effect of alkylating agents on the immune system is rather profound. Higher doses are thought to more acutely affect B-cell function than T-cell function, but long-term lower dosages may have an equal or even greater effect on T-cell function. Paradoxically, administration of alkylating agents to animals can result in the loss of suppressor cells, something that is certainly not advisable for patients with a poorly controlled immunoregulatory system. The alkylating agents are thought to be more potent in inducing a response than are the antimetabolites. However, with greater efficacy comes more potential for adverse secondary effects. These agents are thought to mediate ocular inflammatory disease through the killing of clones of cells that are causing damage in the eye. This may be occurring at some central location (e.g., lymph node or bone marrow) or at the end organ itself. The response is not specific and will theoretically affect any actively dividing cell.
Indications and Dosages
Buckley and Gills reported the efficacy of cyclophosphamide therapy in the treatment of intermediate uveitis. In addition, alkylating agents have been frequently used in the treatment of Behçet’s disease. The recommendations of the International Uveitis Study Group for the use of cytotoxic agents were decided upon in the early 1980s. Although somewhat dated, their basic concepts still seem to hold true. Treatment of Behçet’s disease was one absolute recommendation, because corticosteroid therapy was not thought to adequately control the retinal/retinal vascular disease frequently observed in these patients. In general, alkylating agents are indicated for severe bilateral sight-threatening endogenous uveitis. Again, it cannot be overly stressed that the treating physician must be confident that the disease being treated does not have an infectious component. Further, the physician should consider therapy only if there is vision to save. It should not be considered in end-stage disease just to be sure that ‘everything was tried.’ The potential side effects of these agents necessitate a good reason for their administration. The patient must be well informed of the physician’s intentions and expectations, as well as of any possible side effects. It is probably reasonable to ask the patient to sign a consent form. In addition, an internist should examine the patient to be sure that there is no systemic contraindication for therapy, and to help in the dosing and follow-up. Although this therapeutic approach is used in generalized life-threatening autoimmune diseases in children, we have not used it in pregnant women or children with uveitis because of the concern of the potential long-term side effects of these drugs. If these drugs are used in younger persons, the physician should discuss the side effects in depth. One important consideration is the possibility that the medication may induce azoospermia, and banking of sperm before the initiation of therapy might be considered. Harvesting of ova, although performed less frequently, might also be considered.
For cyclophosphamide, adult patients can start at about 2 mg/kg/day by mouth, with the usual starting dose for a rapid effect being between 150 and 200 mg/day (see Table 7-2 ). The drug should be taken on an empty stomach because it can be activated in the gastrointestinal tract if taken with food. The white blood cell count with differential must be monitored constantly, beginning with a baseline value. One may begin to see a drop in the white blood cell count within a few days to a week. Once this occurs, the dosage may be reduced by 25–50 mg, the object being a white blood cell count that stabilizes at no lower than 3000/mm 3 . The total neutrophil count should not fall to less than 1500–2000/mm 3 . Nevertheless, the dosage used should be based predominantly on the therapeutic effect of the drug on ocular inflammation.
Pulse cyclophosphamide (see Table 7-2 ) has been widely used in the treatment of systemic collagen vascular disease, such as the renal disease associated with systemic lupus erythematosus. This approach to therapy is thought to carry fewer risks than everyday oral therapy. Hoffman and associates found that intermittent cyclophosphamide therapy combined with steroid therapy yielded a long-term failure rate of 79% in patients with Wegener’s granulomatosis. We also have not found this approach to be particularly effective, as breakthroughs of disease activity tend to occur between therapeutic courses. Rosenbaum reported that in 11 patients with uveitis treated with pulse cyclophosphamide, five benefited but only two had a sustained improvement without the use of additional immunosuppressive therapy. Rosenbaum concluded that most patients with uveitis do not experience a prolonged benefit from this therapeutic approach. Systemic steroids can be administered along with the alkylating agent. This permits one to use lower dosages of both and thus avoid some of the side effects of both.
Godfrey and colleagues have used chlorambucil to treat several disorders, including Behçet’s disease and sympathetic ophthalmia. This medication can be administered on an outpatient basis. The total dose is usually between 6 and 12 mg/day. We generally give a lower initial dose (2 mg) to be sure that there are no idiosyncratic responses and then increase the dose. As with cyclophosphamide, the white blood cell count and differential must be constantly monitored.
A somewhat different approach was discussed by Tessler and Jennings, who reported the use of high-dose short-term chlorambucil in the treatment of Behçet’s disease and sympathetic ophthalmia. These authors believed that they induced remission in all patients, using an average total dose of 2.2 g over 23 weeks for the patients with Behçet’s disease and a total of 0.9 g over 11 weeks for the patients with sympathetic ophthalmia.
Secondary Effects
A wide range of side effects has been reported with alkylating agents. For these particular agents, leukopenia is a major effect, yielding immunosuppression. Thrombocytopenia and anemia also occur. An increased incidence of infection, particularly viral, is another great concern. Interstitial fibrosis of the lungs, testicular atrophy, and hemorrhagic cystitis are associated with cyclophosphamide therapy, the latter being a relative indication for discontinuation of the drug. Renal toxicity has been attributed to the metabolites of alkylating agents, and visual disturbances have been reported with high doses of cyclophosphamide. Teratogenicity is a major concern, and cyclophosphamide is excreted in breast milk.
Because sterility is a real concern for those receiving alkylating agents, semen can be banked and oocytes cryopreserved. Recently, a gonadotropin-releasing hormone (GnRH) agonist has been used to preserve ovarian function in patients receiving cyclophosphamide (Cytoxan) and treatment for lymphoma. This treatment induces a menopause-like state, in essence returning the ovaries to a prepubertal state; prepubertal ovaries are thought to be more resistant to the gonadotoxic effects of alkylating agents. Although this treatment is effective, there is a potential loss of bone density because of a relative estrogen deficiency. For those under 16 years of age the use of a GnRH agonistic analog is not recommended because of its unknown effect on bone development.
Perhaps the most disquieting adverse effects seen with these agents are those that may occur after long-term therapy. The first is the potential for secondary malignancy. Secondary urinary bladder cancer seems to occur in patients who have hemorrhagic cystitis. Of course the underlying disorder being treated may also predispose some patients to the development of these disorders, particularly myeloproliferative and lymphoproliferative neoplasms. A second troublesome observation is the finding of chromosomal damage with extended cyclophosphamide therapy. In the review of Hoffman and colleagues’ 158 patients with Wegener’s granulomatosis, a series of disturbing complications ascribed to cyclophosphamide therapy were reported: 73 patients had 140 serious infections that required hospitalization and intravenous antibiotic therapy; 43% had cystitis, 2.8% had bladder cancer, and 2% had myelodysplasia. Of the women treated, 57% ceased menstruating for 1 year, with test results supporting the diagnosis of ovarian failure. There was a calculated 24-fold increase in malignant conditions and a calculated 33-fold increase in bladder cancer, occurring 7 months to 10 years after the medication was stopped. In a longitudinal cohort study in patients with rheumatoid arthritis with a 20-year follow-up, 119 patients treated with cyclophosphamide between 1968 and 1973 were compared with 119 patients who did not receive cyclophosphamide. An increased risk of malignancy was seen in the cyclophosphamide group (relative risk 1.5%). Of interest were the nine bladder malignancies seen in the cyclophosphamide group versus none for those not receiving cyclophosphamide. Three of those malignancies occurred 14, 16, and 17 years after cyclophosphamide was stopped. Lane and colleagues reviewed 543 charts of patients with uveitis and compared those receiving corticosteroids with those receiving immunosuppression. No difference was noted.
It should be added that during the past few years, because of the aforementioned complications, alkylating agent therapy has been used less and less by internists for the treatment of putative autoimmune diseases. However, the anecdotal evidence certainly suggests a positive therapeutic effect in curtailing severe intraocular inflammatory disease. For life-threatening systemic vasculitis or in some patients with sight-threatening retinal vasculitis cyclophosphamide may be a most effective medication. Also, in the Third World this sort of therapy is readily available and relatively cheap, two very important considerations. As with many other problems in medicine, this class of drugs presents a dual-edged sword, and their use should be considered only after long reflection.
Many recommendations for cytotoxic agent therapy that the reader will find in the literature were written before the use of ciclosporin, tacrolimus (FK506), or monoclonal antibody therapy entered into clinical practice, as well as before the use of low-dose methotrexate or azathioprine. In our approach, cytotoxic agents are often used last – after corticosteroids, ciclosporin, and monoclonal antibody therapy – for sight-threatening intraocular inflammatory disease. We would use cytotoxic agents if the side effects of steroid or ciclosporin were simply intolerable, but the patient clearly was having an excellent therapeutic response to immunosuppressive therapy. We would make every effort to avoid using alkylating agents in children, as the long-term effects of these agents sometimes make the risk difficult to justify ethically. It should be stressed that until recently no comparative clinical trials have been attempted to evaluate the true efficacy of these agents in the treatment of uveitis, nor are most of these agents listed in the Physicians’ Desk Reference as indicated for the therapy of uveitis. There is, however, no reason to doubt that in some conditions these agents may be effective: for example, they have an apparent profound positive effect on the ocular manifestations of Behçet’s disease ; Tabbara, however, has questioned that assessment.
In our experience, mostly with the alkylating agents, cytotoxic drugs have not been as effective in controlling severe inflammatory conditions such as Behçet’s disease as had been previously suggested. We have had patients with Behçet’s disease discontinue ciclosporin therapy because of toxicity and then have a very poor therapeutic result with an alkylating agent, necessitating a third therapeutic approach. However, others seem to have done well. Although alkylating agents are tolerated reasonably well, the side effects, such as leukopenia, may last for some time even after discontinuance of the medication. We therefore advise caution when clinicians use these agents. The ophthalmologist should have someone well versed in this therapeutic approach actively involved in the care of the patient, should set strict goals in terms of the therapeutic effect that must be reached, and should avoid using these agents in children unless forced to do so, and then only with the in-depth understanding and permission of both the parents and the child. Locally administered methotrexate (or other agents) may prove to be a useful therapeutic approach to neoplastic disease with only a local reactivation in the eye.
Antimetabolites
In this category of medications, azathioprine and mycophenolate mofetil, which alter purine metabolism, and methotrexate, a folate analog, are the three most widely used ( Fig. 7-7 ).
Azathioprine
Mode of Action
Azathioprine (Imuran) is thought to be a prodrug. Upon metabolism it is converted into the active agent 6-mercaptopurine. Azathioprine is better absorbed, causes less gastrointestinal disturbance, and is less likely to be inactivated by liver enzymes than is 6-mercaptopurine. Once converted to its active form, it is thought to affect DNA and RNA metabolism by being converted to 6-thioinosine-5-phosphate (T-IMP) by the enzyme hypoxanthine guanine phosphoribosyltransferase. T-IMP is probably incorporated into nucleic acids, thus leading to false codes being generated. It appears that azathioprine has a greater effect on the afferent arm of the immune response when it is given before the antigenic challenge.
Indications and Dosages
For putative autoimmune diseases such as rheumatoid arthritis, the suggested dosage of azathioprine is about 1–2.5 mg/kg/day, , the average dose being 50–100 mg daily, given as one dose or in divided doses (see Table 7-2 ). The combination of azathioprine with low-dose steroid has been used in the treatment of uveitis by Andrasch and colleagues, with about half of their 22 patients showing a positive therapeutic effect and the others having either no response or severe adverse effects. Other authors have used the drug for the treatment of sympathetic ophthalmia, the Vogt–Koyanagi–Harada syndrome, and pars planitis. More than half of the patients with Behçet’s disease whom Aoki and Sugiura treated with azathioprine appeared to have an improvement of their ocular disease. Yazici and coworkers showed in a double-masked study that azathioprine (2.5 mg/kg/day) was superior to placebo in the prevention of new eye disease associated with Behçet’s disease. Hooper and Kaplan used an initial dosage of azathioprine of 1.5 mg/kg/day combined with steroid and ciclosporin for sight-threatening serpiginous choroidopathy (see Chapter 28 ). Certain drugs, such as allopurinol, can interfere with the metabolism of 6-mercaptopurine, and the dosage of the agent must be reduced accordingly.
In a recent subgroup analysis of the SITE study (see the last paragraph of this chapter) 145 patients were who were treated with azathioprine as a sole immunosuppressive agent were evaluated. It was noted to be moderately effective as a single steroid-sparing agent for control of disease and its steroid-sparing value. It required months to achieve a treatment goal and was tolerated by most patients. It appeared useful for patients with intermediate uveitis.
Secondary Effects
Antimetabolites can have serious side effects, but in the past few years the use of lower doses has prevented these from occurring or has made them more tolerable. For azathioprine, perhaps the most problematic acute adverse effects are leukopenia, thrombocytopenia, and gastrointestinal disturbances. Of great long-term concern is that chronic immunosuppression increases the risk of neoplasia. Connell and colleagues studied the risk of neoplasia in 755 patients with inflammatory bowel disease who were treated with azathioprine. These patients received a dose of 2 mg/kg/day for a median of 12.5 months, and no cases of non-Hodgkin’s lymphoma were reported. There appeared to be no difference in cancer frequency among 86 patients with chronic ulcerative colitis who received azathioprine and 180 matched patients who did not. It appears that the risk of neoplasia is lower in those patients treated for autoimmune disorders, such as rheumatoid arthritis, than in those receiving therapy for the prevention of transplantation rejection.
Mycophenolate mofetil
Mycophenolate mofetil (CellCept) is an agent becoming more and more frequently used. It has a molecular weight of 433.5 Da and metabolizes to mycophenolic acid, which reversibly inhibits inosine monophosphate dehydrogenase, inhibiting a pathway of guanosine nucleotide synthesis without incorporation into DNA. It affects both T and B cells and interferes with cellular adhesion to vascular endothelium. In animal models mycophenolate mofetil has prolonged the survival of allogeneic transplants. This agent has been used in preventing the expression of experimental autoimmune uveitis (EAU) (30 mg/kg/day) even after immunization, but at higher doses (60 mg/kg/day). It was first used in humans in combination with corticosteroids and ciclosporin for the prevention of organ rejection after allogeneic renal transplants. Mycophenolate mofetil is taken on an empty stomach and has high oral bioavailability. It may be considered a reasonable alternative to either azathioprine or methotrexate therapy. Several small studies have reported good results with mycophenolate mofetil. , Kilmartin and colleagues treated nine patients with uveitis with mycophenolate mofetil and saw an improvement in eight of them, with a follow-up of 10–36 weeks. These patients suffered from ciclosporin toxicity. In a study evaluating the National Eye Institute experience, 60 patients were treated with mycophenolate mofetil and it was found to be moderately effective. In Baltatzis and colleagues’ report of 54 patients it was an effective steroid-sparing agent in 54% of cases and was used also as a monotherapy. In their report, Larkin and Lightman also treated some patients with scleritis and reported success. Additionally the National Eye Institute’s experience with this drug in scleritis has been reported. In this small study, mycophenolate mofetil was found to be a useful steroid-sparing agent in patients with controlled scleritis but not as an effective adjunctive agent for patients with active scleritis. Others have found it also to be a very useful steroid-sparing agent with a manageable side-effects profile. In a recent retropective report it appeared to reduce ocular inflammation more rapidly than did methotrexate.
The dose of mycophenolate mofetil is usually 1 g orally twice daily. Some patients have received up to 3 g/day (1.5 g twice daily), but there does not seem to be an increased therapeutic effect although toxicity may increase. The most common adverse event appears to be gastrointestinal effects, with as many as 31% of patients reporting this problem. In two smaller reports of patients with uveitis, in addition to nausea, patients complained of myalgia, fatigue, and headache. In patients receiving transplants other problems have been noted, such as leukopenia, nonmelanoma skin cancers, and opportunistic infections, but these patients are usually heavily immunosuppressed.
Methotrexate
Mode of Action
Methotrexate is a folate analog, differing from folic acid only in that a hydrogen atom and hydroxyl group have been replaced by a methyl and amino group. Folate analogs are known to have profound effects on cellular metabolism by inhibiting dihydrofolate reductase activity. This enzyme is imperative for the production of tetrahydrofolate, an important coenzyme in cell metabolism. Tetrahydrofolate is needed for the production of thymidylate, an essential component of DNA, and mediates the production of purine nucleotides, also needed for RNA metabolism. Methotrexate demonstrates time-specific characteristics in that, under certain experimental conditions, an augmented immune response may be noted if the drug is given before antigenic challenge. Several effects on the immune system have been enumerated. Methotrexate has been shown to have an antiproliferative effect on endothelial cells, can reduce the synthesis of leukotriene B4 in neutrophils, has been shown to reduce the concentration of interleukin-1β in synovial fluid, and can suppress cell-mediated immunity. An added action of methotrexate is its inhibition of histamine release.
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. Holz and colleagues 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 colleagues 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 steroid- or ciclosporin-sparing agent as reported by Dev and coworkers in treating sarcoid uveitis. Pascalis and associates 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. One combination to be particularly careful of is methotrexate and leflunomide. Weinblatt and colleagues 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.
Methotrexate has been used periocularly for the treatment of malignant conditions. Rootman and Gudauskas 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. Good responses have been seen using 400 µg/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, , 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. Up to one-third of those receiving long-term weekly doses of methotrexate will have elevated serum aminotransferase levels. Liver enzyme levels twice normal warrant withholding or stopping the medication; the levels usually return to normal rapidly. Zachariae and coworkers 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.
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. 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. 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, slight elevations of transaminase levels were noted in four of 13 patients, partial alopecia in two, and nausea in three. A disturbing report from Zimmer-Galler and Lie 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 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. , 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. 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. 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 shown, much has been elucidated. Ciclosporin blocks the activation of genes in T cells. One intriguing notion is that ciclosporin binds to proteins binding to the interleukin (IL)-2 (IL-2) enhancer (such as NF-AT and octamer-associated protein), which helps in the activation of the transcription of the IL-2 gene. These sites have been shown to be sensitive to ciclosporin.
On the basis of several in vitro systems, different observations have been made concerning the mode of action of ciclosporin. Larsson reported that ciclosporin blocked the acquisition of IL-2 receptors and thereby prevented resting 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, 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 colleagues 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. 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. In our early studies 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 toxicity (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, 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, 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. Of special interest was the particularly positive clinical effect seen in patients with Behçet’s disease who were treated with this medication. This has been supported by a randomized, masked study in Japan and in a study carried out by Diaz-Llopis and colleagues, 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 immunosuppressive agent, probably most frequently with corticosteroids. Towler and coworkers 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, 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 coworkers 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 colleagues 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, with Walton and coworkers reporting improvement in 64% or stabilization in 75% of eyes treated in children and adolescents with uveitis. Hesselink et al. 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. 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 coworkers 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. 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. Although perhaps important for treatment of immune diseases involving the ocular surface, this method of application does not result in significant 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. , It is not clear what the incidence 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 appear ( 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 the starting dose of 10 mg/kg/day sets into motion the mechanisms leading ultimately to the changes noted histologically. Some have found that changes in renal function can develop even at lower starting doses of ciclosporin. However, most recent reports from investigators treating autoimmune conditions (other than uveitis) with lower starting and maintenance doses of ciclosporin have been heartening because little or no alteration in renal function associated with this agent has been noted. Feutren and Mihatsch reviewed 192 renal biopsy specimens from patients treated with ciclosporin for a variety of conditions, including diabetes mellitus, Sjögren’s syndrome, and uveitis. It was found that three independent variables distinguished the 41 patients with ciclosporin-induced nephropathy from those free of nephropathy: a higher initial dose of ciclosporin, a larger maximal increase in the serum creatinine concentration above baseline, and age. Therefore it has been suggested that to reduce the risk of nephropathy a dose of 5 mg/kg/day should be used, and serum creatinine levels should not rise more than 30% over the patient’s baseline level. Also, a retrospective analysis of 1663 patients who had undergone renal transplantation and were receiving long-term ciclosporin therapy demonstrated that progressive toxic nephropathy did not occur. The addition of bromocriptine to the regimen permits the use of a lower dose of ciclosporin, with the hope that a similar therapeutic result with less toxicity would be achieved. However, this approach is not being used. Ciclosporin interacts with many agents, and one must be very cognisant of this. The concomitant use of NSAIDS with ciclosporin will almost ensure decreased renal function. Other medications that can interact with ciclosporin can be seen in Box 7-2 .
| Effects | Incidence (%) |
|---|---|
| Symptoms | |
| Paresthesia/hyperesthesia | 40 |
| Epigastric burning | 20 |
| Fatigue | 24 |
| Hypertrichorism | 20 |
| Gingivitis | 20 |
| Reduced appetite | 5 |
| Breast tenderness/fibroadenoma | 8 |
| Hidradenitis | 4 |
| Signs | |
| Hypertension | 24 |
| Mild anemia | 24 |
| Hyperuricemia | 20 |
| Increased sedimentation rate | 75 |
| Abnormal liver function tests | 6 |
| Renal toxicity | ? |
| No opportunistic infections or lymphoma | |
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