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PERSPECTIVEGuidelines for the Use of Immunosuppressive Drugs in Patients

With Ocular Inammatory Disorders: Recommendations of anExpert Panel

DOUGLAS A. JABS, MD, MBA, JAMES T. ROSENBAUM, MD, C. STEPHEN FOSTER, MD,GARY N. HOLLAND, MD, GLENN J. JAFFE, MD, JAMES S. LOUIE, MD,

ROBERT B. NUSSENBLATT, MD, E. RICHARD STIEHM, MD, HOWARD TESSLER, MD,RUSSELL N. VAN GELDER, MD, P H D, SCOTT M. WHITCUP, MD, AND

DAVID YOCUM, MD

PURPOSE : To provide recommendations for the use ofimmunosuppressive drugs in the treatment of patientswith ocular inammatory disorders. PARTICIPANTS : A 12-person panel of physicians withexpertise in ophthalmologic, pediatric, and rheumatologicdisease, in research, and in the use of immunosuppressivedrugs in patient care. EVIDENCE : Published clinical study results. Recom-mendations were rated according to the quality andstrength of available evidence. PROCESS : The panel was convened in September of

1999 and met regularly through May 2000. Subgroups ofthe panel summarized and presented available informa-

tion on specic topics to the full panel; recommendationsand ratings were determined by group consensus. CONCLUSIONS : Although corticosteroids representone of the mainstays in the management of patients withocular inammation, in many patients, the severity of thedisease, the presence of corticosteroid side effects, or therequirement for doses of systemic corticosteroids highlylikely to result in corticosteroid complications supportsthe rationale for immunosuppressive drugs (for example,antimetabolites, T-cell inhibitors, and alkylating agents)being used in the management of these patients. Because

of the potential for side effects, treatment must beindividualized and regular monitoring performed. Withcareful use of immunosuppressive drugs for treatment ofocular inammatory disorders, many patients will benetfrom them either with better control of the ocularinammation or with a decrease in corticosteroid sideeffects. (Am J Ophthalmol 2000;130:492513. 2000 by Elsevier Science Inc. All rights reserved.)

O CULAR INFLAMMATORY DISORDERS HAVE GREATpotential for visual morbidity and visual loss. Inone large series of patients with uveitis, 35% hadvisual loss to a level of worse than 20/60 in at least one eyeand 22% became unilaterally or bilaterally blind (worsethan 20/200). 1 Cicatricial pemphigoid, if untreated, oftenresults in blindness. Scleritis, particularly necrotizing scle-ritis, and necrotizing keratitis may threaten the structuralintegrity of the eye and may herald the onset of apotentially life-threatening systemic vasculitis. As such,the correct treatment of ocular inammatory disorders isimportant for preserving vision and for preventing bothocular and nonocular morbidity.

Corticosteroids have been the mainstay of therapy forocular inammatory diseases since their development.Corticosteroids may be administered either topically, as

Accepted for publication Jul 14, 2000.From The Wilmer Eye Institute and the Departments of Ophthalmol-

ogy and Medicine, The Johns Hopkins University School of Medicine,Baltimore, Maryland (Dr Jabs); Casey Eye Institute, Departments of Ophthalmology and Medicine, Oregon Health Sciences University,Portland, Oregon (Dr Rosenbaum); Massachusetts Eye and Ear Inrmary,Department of Ophthalmology, Harvard Medical School, Boston, Mas-sachusetts (Dr Foster); Jules Stein Eye Institute, Department of Ophthal-mology, University of California, Los Angeles, Los Angeles, California(Dr Holland); Duke University Eye Center, Durham, North Carolina (Dr Jaffe); Department of Medicine, HarborUniversity of California, Los

Angeles, Medical Center, Los Angeles, California (Dr Louie); The National Eye Institute, Nat ional Institutes of Health , Bethesda, Maryland(Drs Nussenblatt and Whitcup); Department of Pediatrics, University of California, Los Angeles, Los Angeles, California (Dr Stiehm); Universityof Illinois Eye and Ear Inrmary, Chicago, Illinois (Dr Tessler); Depart-ment of Ophthalmology and Visual Sciences, Washington University, St.Louis, Missouri (Dr Van Gelder); and Department of Medicine, Univer-sity of Arizona Health Science Center, Tucson, Arizona (Dr Yokum).

This work was supported in part by grants from The Caryll M. and Norman F. Sprague, Jr., Foundation, Los Angeles, California and TheAmerican Uveitis Society.

Requests for reprints to Douglas A. Jabs, MD, MBA, 550 NorthBroadway, Suite 700, Baltimore, MD 21205; fax: (410) 955-0629; e-mail:[email protected]

Additional information is available online at ajo.com.

2000 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED.492 0002-9394/00/$20.00PII S0002-9394(00)00659-0

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periocular injections, or systemically (primarily orally butalso by the intravenous or intramuscular route). Topicalcorticosteroids penetrate well only into the anterior seg-ment of the eye and are useful in the management of anterior uveitis and episcleritis. Periocular corticosteroidsare useful in the management of intermediate uveitisassociated with decreased vision, the management of macular edema in association with panuveitis or posterioruveitis, and in selected other situations. The periocularroute results in high local concentrations of corticosteroidsin both the anterior and posterior segments of the eye

typically without systemic side effects. However, eitherbecause of the nature of the disease or because of problemswith the local (periocular) administration of corticoste-roids (for example, corticosteroid-induced ocular hyper-tension) many patients will need systemically administeredcorticosteroids, typically oral prednisone. In patients withacute or episodic disease, a short course of oral corticoste-roids may be useful for the suppression of the inamma-tion. In patients with chronic disease, initial treatmentwith high-dose oral prednisone, followed by tapering tolow-dose oral prednisone, and long-term suppressive cor-ticosteroid therapy may be necessary to control the inam-mation.

However, in some patients systemic corticosteroids areinsufcient to control the disease, and immunosuppressivedrug therapy is required. In other patients, corticosteroid sideeffects result in the need for a corticosteroid-sparing agent,and in many patients the long-term use of systemic cortico-steroids at the dose required to suppress the ocular inamma-tion is sufciently likely to produce side effects that acorticosteroid-sparing agent is warranted. In these situations,immunosuppressive drugs have a role to play in the manage-ment of patients with ocular inammatory disease.

A panel of physicians with expertise in clinical investi-gation, ophthalmology, rheumatology, pediatrics, and pa-

tient care in the eld of inammatory diseases wasconvened to review the role of immunosuppressive drugs inthe management of ocular inammation. The panel re-viewed available data and developed recommendations forthe use of these drugs. The recommendations were ratedaccording to the strength and quality of the supportingevidence presented using a system similar to that devel-oped by the US Public Health Service/Infectious DiseasesSociety of America (Table 1). 2 The goals of this report areto assist clinicians in determining when an immunosup-pressive drug might be appropriate in the management of

ocular inammatory disease, to aid general ophthalmolo-gists in the selection of patients for referral, and to provideguidelines for the use of these drugs.

ORAL CORTICOSTEROIDSCORTICOSTEROIDS ARE USED WITH GREAT BENEFIT FORinammatory diseases of a noninfectiouscause. Corticoste-roids are the initial drug for many autoimmune diseases,such as systemic lupus erythematosus, polymyositis, vascu-litis, and sarcoidosis, and are effective in ares of rheu-matoid arthritis, asthma, atopic dermatitis, and clinicalsubsets of other inammatory and occasionally postinfec-tious diseases. This clinical utility is limited by side effectsattendant to the chronic corticosteroid use, particularly inchildren who have not completed their growth. However,long-term studies of patients with sarcoid uveitis haveshown that oral corticosteroid therapy is associated withsubstantially better visual outcomes, suggesting that sys-temic therapy has an important role to play in themanagement of patients with chronic uveitis. 3 Prednisoneis the most commonly used oral corticosteroid, but forpersons with serious liver dysfunction, prednisolone, theactive form of prednisone, often is prescribed. The initial

TABLE 1. Levels of the Strength and Quality of Evidence-considered Categories of the Strength of a Recommendation

(A) Strong evidence of efcacy and substantial clinical benet support recommendation for use; should always be offered(B) Moderate evidence of efcacy or strong evidence of efcacy, but only limited clinical benet supports recommendation for use;

should generally be offered(C) Evidence of efcacy is insufcient to support a recommendation for or against use or evidence of efcacy may not outweigh

adverse consequences, such as toxic effects, drug interactions, or cost of the chemoprophylaxis or alternative approaches;optional

(D) Moderate evidence of lack of efcacy or of adverse outcome supports a recommendation against use; should generally not beoffered

(E) Good evidence of lack of efcacy or of adverse outcome supports a recommendation against use; should never be offered(I) Evidence from at least one properly randomized controlled trial(II) Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies, or from

multiple time-series studies, or dramatic results from uncontrolled experiments(III) Evidence from opinions of the panel

Recommendations were rated according to the strength and quality of available evidence. The categories have been adapted from Grossand associates. 2

CONSENSUS PANEL ON IMMUNOSUPPRESSION FOR OCULAR DISEASEVOL. 130 , NO. 4 493

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dose of prednisone typically is 1 mg per kg per day, forexample, 60 to 80 mg per day in an adult. Methylpred-nisolone (Medrol; Pharmacia and Upjohn, Peapack, New Jersey) dose packs are not expected to be useful in chronicuveitis, because the corticosteroids are tapered too rapidly.For immediate control of vison-threatening diseases, meth-ylprednisolone sodium succinate (Solu-Medrol; Pharmaciaand Upjohn, Peapack, New Jersey) can be given intrave-nously over a period of more than 30 minutes. The usualregimen consists of 1 g pulses per day given on 3 consec-utive days and is followed by oral corticosteroid therapy. 4

Typically high-dose oral corticosteroids are continuedfor no longer than 1 month. If the patients disease worsenson high-dose prednisone, or if there is no response after 2to 4 weeks, an immunosuppressive agent should be added.Similarly, if the disease is not completely quiet after 4weeks of high-dose oral prednisone, an immunosuppressivedrug should be considered.

After a satisfactory anti-inammatory response, the oralcorticosteroids should be tapered and discontinued if possible.For patients with chronic disease on prednisone therapy, arepresentative tapering regimen is outlined in Table 2. If theinammation exacerbates during the tapering schedule, re-sume a higher dosage for another month or until the diseaseis quiet and taper back to just above the threshold at whichthe disease reactivated. If chronic oral corticosteroid therapyis needed, some clinicians will convert the prednisone to analternate day schedule, which may reduce toxicity but alsomay be less effective. If chronic suppression of disease requiresmuch more than 10 mg per day of prednisone or its equiva-lent, an immunosuppressive drug should be considered. It iswise to caution the patient that the hypothalamicpituitaryaxis may not return for 6 to 12 months after tapering of chronic oral corticosteroid therapy. Many patients wear abracelet or carry a wallet card that alerts emergency personnelthat the patient is taking or has taken exogenous corticoste-

roids and should receive a supplemental dose when injured orunconscious.

Some patients with acute ocular inammation or with anacute are of the ocular inammation may benet from ashort course of oral corticosteroids. In this case, the durationof oral corticosteroid therapy typically is shortened to a totalof 3 to 6 weeks. A representative approach would be to use aninitial dose of 1 mg per kg per day for 1 week, and then taperusing the same increments as outlined in Table 2 butdecreasing them every 1 to 2 days, instead of every 1 to 2weeks. Although the hypothalamicpituitary axis may not be

affected if the total duration of oral corticosteroid therapy isless than 3 weeks, too rapid tapering of the oral corticosteroidmay result in a rebound of the ocular inammation. There-fore, tapering is recommended. As each patients ocularinammation will vary in its response to treatment, treatmentneeds to be individualized.

ADVERSE EVENTS AND MONITORING : The patientmust be counseled about 1) the Cushingoid changes of facial and body appearance (moon facies, weight gain, fatredistribution, and increased acne) when prednisone isadministered at larger than the physiologic doses of 5 to 10mg per day and 2) the dangers of abrupt discontinuation of corticosteroids after the adrenal glands have been sup-pressed. Children below the age of 15 years are likely toexperience delay of pubertal growth even with alternateday prednisone therapy. 5 Discussion should ensue aboutthe need to monitor for infection, hypertension, uidretention, diabetes mellitus, hyperlipidemia, atherosclero-sis, osteoporosis, glaucoma, and cataracts. Other potentialside effects include anxiety, sleeplessness, mood changes,easy bruising, and poor wound healing.

Blood pressure and blood glucose should be monitoredevery 3 months. Bone mineral density evaluations and

TABLE 2. Suggested Guidelines for the Use of Prednisone for Chronic Ocular Inammation

Parameter Suggested Guideline

Initial dose 1 mg/kg/day*Maximum adult oral dose 6080 mg/dayMaintenance dose (adult) 10 mg/dayTapering schedule Over 40 mg/day, decrease by 10 mg/day every 12 weeks

4020 mg/day, decrease by 5 mg/day every 12 weeks2010 mg/day, decrease by 2.5 mg/day every 12 weeks100 mg/day, decrease by 1 to 2.5 mg/day every 14 weeks

Monitor Blood pressure, weight, glucose every 3 monthsLipids (cholesterol and triglycerides) annuallyBone density within rst 3 months and annually thereafter

Supplemental treatment Calcium 1500 mg daily and vitamin D 800 IU dailyEstrogens and antiresorpative agents as needed

*In selected situations, where an immediate effect is needed, some investigators will begin withintravenous methylprednisolone at a dosage of 1 gm/day for 3 days and then start oral prednisone.

AMERICAN JOURNAL OF OPHTHALMOLOGY494 OCTOBER 2000

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blood cholesterol and lipids should be monitored on anannual basis. Patients who are prescribed more than 7.5 mgper day and more than 30 mg per day of prednisone lose10% to 15% and 30% to 50%, respectively, of thetrabecular bone of the lumbar spine within 1 year. 6 Thus,most experts recommend 1500 mg of calcium and 800 IUof vitamin D daily, replacement of the sex hormones if decreased or if postmenopausal, and weight-bearing exer-cises for all who take chronic oral corticosteroids, partic-ularly in the rst 6 months of glucocorticoid therapy whenthe bone loss is the greatest. 7 Bone mineral densitymeasurements should be performed on patients with an-ticipated duration of corticosteroids over 3 months at 3months or less of therapy and annually thereafter. If bonemineral density studies show osteoporosis, antiresorptiveagents such as calcitonin, alendronate, etidronate, orresidronate are prescribed. 8

Less common but more severe adverse reactions mayrequire adding immunosuppressive drugs to facilitate moreaggressive tapering of the oral corticosteroids. Pancreatitis,aseptic necrosis of bone, insulin-dependent diabetes mel-litus, myopathy, and psychosis usually prompt the additionof immunosuppressive drugs to reduce the dose of pred-nisone. Daily doses of prednisone over 60 mg for the rstmonth of therapy and over 20 mg for the rst 6 months of therapy are associated with a 15% to 20% risk of asepticnecrosis of bone. 9,10 The incidence of ulcer disease is notincreased by any substantial degree (if at all) in patientstreated with oral corticosteroids, and the routine use of H 2blockers for patients taking prednisone is unnecessary. 11,12

However, all nonsteroidal anti-inammatory drugs areassociated with an increased risk of gastric ulceration, andthe concomitant use of oral corticosteroids and oral non-steroidal anti-inammatory drugs is associated with afourfold rise in the occurrence of gastric ulceration. Allpatients on oral nonsteroidal anti-inammatory drugs, andin particular those on concomitant oral corticosteroids,should be monitored for the occurrence of gastrointestinalsymptoms, and such symptoms should be evaluated andtreated appropriately. Rapid intravenous administration of methyl prednisolone has been reported to induce arrhyth-mia, cardiovascular collapse, myocardial infarction, andsevere infection. It seems prudent to administer the glu-cocorticoid over a period of 30 minutes or longer. Finally,studies of patients with rheumatoid arthritis have suggestedthat long-term corticosteroid therapy (several years) maybe associated with an increased mortality. 13

SUMMARY : Oral corticosteroids are an effective therapyfor the control of acute and chronic inammation atten-dant to autoimmune diseases. With long-term administra-tion of these drugs, the adverse effects temper the overalleffectiveness. As such, patients who require chronic oralcorticosteroid therapy, especially at doses greater than 10mg per day, may require immunosuppressive drug therapy.

IMMUNOSUPPRESSIVE DRUGSIMMUNOSUPPRESSIVE DRUGS CAN CONVENIENTLY BEgrouped as antimetabolites, T-cell inhibitors, and alkylat-ing agents. The antimetabolites include azathioprine (Imu-ran; Faro, Bedminster, New Jersey), methotrexate(Rheumatrex; Lederle Laboratories, Wayne, New Jersey),and mycophenolate mofetil (Cellcept; Roche, Basel,Switzerland). The T-cell inhibitors include cyclosporine(Sandimmune and Neoral; Novartis, Basel, Switzerlandand SangCya; Sangstat, Fremont, California), and tacroli-mus (Prograf; Fujisawa, Osaka, Japan). The alkylatingagents include cyclophosphamide (Cytoxan; Bristol-My-ers/Squibb, New York, New York) and chlorambucil (Leu-keran; Glaxo Wellcome, Middlesex, United Kingdom).These drugs are summarized in Table 3. Because most of these drugs take several weeks to have an effect, immuno-suppressive drug regimens for initial therapy of ocularinammation typically include high-dose oral corticoste-

roids as well. Once the disease is quiet, the corticosteroidsare tapered either to a low level or, if possible, discontin-ued. If an immunosuppressive drug is added to an oralcorticosteroid regimen for a patient with chronic diseaseand the ocular disease is quiet, then the immunosuppres-sive drug is added at the appropriate dose and tapering of oral corticosteroids begun 4 to 8 weeks later. If the diseaseis active despite corticosteroid therapy, then the patient istreated as one would for initial therapy with high-dosecorticosteroids and the immunosuppressive drug. Oralcorticosteroids typically are needed in these situationsbecause of their immediate anti-inammatory effect and

the ability to suppress the inammation while immuno-suppressive drugs are having their slower onset of effect.

AZATHIOPRINE : Mechanism of Action. Azathioprine is apurine nucleoside analog. It interferes with adenine andguanine ribonucleotides by suppression of inosinic acidsynthesis, which in turn interferes with DNA replicationand RNA transcription. 14 Immunologically, azathioprinedecreases the numbers of peripheral T and B lympho-cytes,15 and reduces mixed lymphocyte reactivity, interleu-kin-2 synthesis and IgM production. 16

Pharmacokinetics. Azathioprine is well absorbed orallyand cleaved to 6-mercaptopurine, which is metabolized incells to thioinosinic and thioguanylic acid by the action of hypoxanthine phosphoribosyltransferase. These metabo-lites affect ribonucleotide synthesis. 17 There is an up tofourfold individual variation in the rate of metabolism of azathioprine. Because the metabolism of azathioprine isdependent on xanthine oxidase, care must be taken whenusing it in combination with allopurinol, which inhibitsthis enzyme.

Nonophthalmic Uses. The most common use of azathio-prine is in transplantation, especially in combination with


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other agents such as prednisone and cyclosporine. Azathio-prine also has been approved by the US Food and DrugAdministration for use in rheumatoid arthritis. Placebo-controlled trials also have shown efcacy in psoriaticarthritis, Reiter syndrome, and systemic lupus erythemato-sus.18,19

Clinical Experience for Inammatory Eye Disease. Uncon-trolled case series of azathioprine suggested that it waseffective for the treatment of chronic uveitis, usually incombination with corticosteroids. 20,21 In a placebo-con-trolled trial of 73 patients with Behcet disease, azathio-prine was effective in decreasing the occurrence of eye

TABLE 3. Immunosuppressive Drugs for Ocular Inammation

ClassGeneric Name(Trade Name) Oral Formulation Initial Dose Maximum Dose

Antimetabolite Azathioprine (Imuran) 50-mg tablet 1 mg/kg/day 2.54 mg/kg/day

Methotrexate(Rheumatrex)

2.5-mg tablet 7.512.5 mg/wk 25 mg/wk PO,SC, or IM

Mycophenolatemofetil (Cellcept)

250-mg capsule500-mg capsule200-mg/ml oral suspension

500 mg BID 1.5 gm BID

Leunomide (Arava) 10-mg, 20-mg, 100-mg tablet 100 mg QD 3,then 20 mgQD

20 mg QD

T-cell inhibitor Cyclosporine(Sandimmune,Neoral, SangCyA)

Sandimmune 25-mg, 50-mg, 100-mgcapsule, 100-mg/ml oralsuspension; Neoral 25-mg, 100-mg capsule, 100-mg/ml oralsuspension

2.5-5.0 mg/kg/ day (divideddose)

10 mg/kg/day

Tacrolimus (Prograf) 0.5-mg, 1-mg, 5-mg capsule5-mg/ml oral suspension

0.150.30 mg/ kg/day

0.30 mg/kg/day

Alkylatingagent

Cyclophosphamide(Cytoxan)

25-mg, 50-mg tablet 2 mg/kg/day 3 mg/kg/day

Chlorambucil(Leukeran)

2-mg tablet 0.1 mg/kg/day 0.2 mg/kg/day

Continued on next page


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disease in those without ocular involvement and decreas-ing the occurrence of second eye disease in those withunilateral disease. 22

Dosage and Administration. Azathioprine is administeredorally at a dose of 1 to 3 mg per kg per day. The mosteffective dose appears to be 2 mg per kg per day. The dose

should be decreased when used with allopurinol. Dosingusually needs to be adjusted based on the clinical responseand side effects.

Side Effects and Monitoring. The most common severeside effect of azathioprine is reversible bone marrowsuppression, which is unusual when azathioprine is used in

TABLE 3. (Continued) Immunosuppressive Drugs for Ocular Inammation

Mechanism Expected Onset Lab Test* Representative Side-effects Comments

Alters purinemetabolism

13 months CBC Q 46 weeksChemistry Q 12

weeks

Bone marrow suppression(leukopenia

thrombocytopenia), GIupset, hepatitis

Can be given once daily,or as divided dose

twice daily.

Antimetabolite; inhibitorof dihydrofolatereductase

2 weeks to 3months

CBC, LFTs Q 68weeks

Bone marrow suppression(leukopeniathormbocytopenia),stomatitis, hair loss,nausea/vomiting, GIupset, hepatotoxicity(hepatitis, cirrhosis),pneumonitis, fetal loss

Folic acid 1 mg/day

IMP dehydrogenaseinhibitor (purinesynthesis)

2 weeks to 3months

CBC, chemistriesQ month

Diarrhea, nausea,neutropenia, infection

Possibly better toleratedthan azathioprine, notwell studied for uveitis

Dihydroorotatedehydrogenaseinhibition (pyrimidinesynthesis)

2 weeks CBC Q 6 weeks,chemistry Q 12weeks

Cytopenias, fetal loss,diarrhea, hypertension

Not studied in uveitis

T-cell inhibitor 26 weeks CreatineQ month, CBC,

LFTs, and Mg 2

Q 12 weeks

Renal dysfunction, tremor,hirsutism, hypertension,gum hyperplasia

Neoral has a greaterbioavailability thanSandimmune.

Follow BP

T-cell inhibitor CBC, chemistry,and Mg 2 Qmonth

Nephrotoxicity, HBP,neurotoxicity,hyperkalemia,hypomagnesemia,hepatitis, diabetes

Follow BP

Lymphotoxicity 28 weeks CBC, UA Q 14weeks

Bone marrowsuppression, infection,hematuria andhemmorrhagic cystitis,increased riskmalignancy, sterility,alopecia

May be given as IVpulse but not usuallyfor uveitis

Lymphotoxicity 412 weeks CBC Q 14 weeks Bone marrow suppresson,infection, increased riskmalignancy, sterility

BID twice daily; BP blood pressure; CBC complete blood count; D day; GI gastrointestinal; HBP high blood pressure; IMintramuscular; IV intravenous; LFTs liver function tests (primarily aspartate and alanine aminotransferases); PO orally; Q every;

SC subcutaneously; UA urinalysis.*Laboratory tests are obtained more frequently at the initiation of therapy; if the dose of the drug is changing, and if borderline toxicity or

rapidly changing laboratory values are encountered. Space precludes listing all potential adverse effects.


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the lower dosage range. Although an increased risk of malignant disease (especially non-Hodgkin lymphoma)has been reported in renal transplant patients treated withazathioprine, whether the risk is increased in patients withautoimmune diseases is unclear. 23 Other serious side effectsinclude hepatoxicity, which occurs in less than 2%. Themost common side effect is gastrointestinal intolerance,primarily manifested as gastrointestinal upset, nausea, andless commonly vomiting, which may be seen in up to 25%of patients and may result in discontinuation of therapy.When using azathioprine, a complete blood count andplatelet count should be performed every 4 to 6 weeks. Inaddition, the liver function tests aspartate aminotransfer-ase and alanine aminotransferase tests should be performedevery 12 weeks. When toxicity occurs (liver function testgreater than 1.5 times upper limit of normal), the doseshould be decreased by 25 to 50 mg per day, and the liverenzyme level reevaluated after 2 weeks. If there is markedenzyme elevation (for example, greater than ve times

upper limit of normal), then azathioprine therapy shouldbe discontinued, at least temporarily. Once liver enzymesreturn to normal, resume every 4 to 6week and 12-weeklaboratory evaluations.

METHOTREXATE : Mechanism of Action. Methotrexate isa folic acid analog and an inhibitor of dihydrofolatereductase, the enzyme responsible for the conversion of dihydrofolate to tetrahydrofolate. This action inhibits theproduction of thymidylate, which is essential for DNAreplication. 24 As such, methotrexate inhibits rapidly divid-ing cells, such as leukocytes, producing an anti-inamma-

tory effect.

Pharmacokinetics. When given orally, up to 35% may bemetabolized by the intestinal ora before absorption. Thepercentage of absorption decreases as the dose increases.When given parenterally, methotrexate is completely ab-sorbed. Methotrexate is eliminated primarily through thekidney. The half life is approximately 3 to 10 hours,although at higher dosages the half life may be prolongedto 8 to 15 hours.

Nonophthalmic Uses. Methotrexate has been shown tobe effective in the management of several systemic inam-matory diseases, including rheumatoid arthritis, juvenilerheumatoid arthritis, psoriatic arthritis, and systemic lupuserythematosus. 25 One advantage of methotrexate is theextensive experience with and the relative safety of its usein children with juvenile rheumatoid arthritis. 26 Metho-trexate also is used as an antineoplastic agent at dosesmuch higher than those used to treat systemic inamma-tory conditions.

Clinical Experience for Inammatory Eye Disease. Threesmall, uncontrolled, case series each of 11 to 22 patientshave used methotrexate to treat various ocular inamma-

tory diseases, including vasculitis, panuveitis, intermediateuveitis, vitritis, scleritis, orbital pseudotumor, myositis, andsarcoid-associated panuveitis. 2729 In general, preserved orimproved visual acuity, decreased corticosteroid use, anddecreased ocular inammation were reported.

Dosage and Administration. Methotrexate typically isadministered at a dose ranging from 7.5 to 25 mg once perweek in a single undivided dose. The most common dose is15 mg once weekly. Although many clinicians will initiatetherapy at 7.5 mg per week and increase the dose to 15 mgper week over 1 to 4 weeks, others will start with higherdoses. Although it is most often given orally, in some casesmethotrexates efcacy may be enhanced and its sideeffects minimized by intramuscular or subcutaneous injec-tion. Typically, folate (1 mg per day) is administeredconcurrently with methotrexate to minimize nausea. Thefull effect from methotrexate therapy takes 6 to 8 weeks tooccur. 28

Side Effects and Monitoring. The most serious sideeffects of methotrexate are hepatoxicity, cytopenias,and interstitial pneumonia. Abnormal liver functiontests occur in 15% of patients on methotrexate, buthepatic cirrhosis occurs in only 0.1%. The most com-mon side effects are gastrointestinal and include stom-ach upset, nausea, stomatitis, and anorexia occurring in5% to 25% of patients. Alopecia and rash occur lesscommonly. Methotrexate is a teratogen and is contra-indicated in pregnancy. At the initiation of methotrex-ate therapy, a complete blood count, serum chemistryprole, hepatitis B surface antigen, and hepatitis Cantibody are obtained. Complete blood count and liverfunction tests are obtained every 1 to 2 months. If theaspartate aminotransferase or alanine aminotransferaseis more than two times normal on two separate occa-sions, the dose should be reduced. Liver biopsy isobtained if abnormalities in liver function tests persistafter discontinuation of the drug. 30 Rarely cirrhosis mayoccur even in the absence of abnormal liver functiontests. Because of potential hepatotoxicity, patientsshould be advised to abstain from alcohol consumption

while receiving methotrexate therapy. MYCOPHENOLATE MOFETIL : Mechanism of Action. My-cophenolate mofetil is a selective inhibitor of inosinemonophosphate dehydrogenase that interferes withguanosine nucleotide synthesis. Its major effects are on Tand B lymphocytes. It prevents lymphocyte proliferation,suppresses antibody synthesis, interferes with cellular ad-hesion to vascular endothelium, and decreases recruitmentof leukocytes to sites of inammation.

Pharmacokinetics. The drug has high oral bioavailabilitybut should be ingested on an empty stomach. It is metab-


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olized to the active compound mycophenolic acid, whichis excreted renally.

Nonophthalmic Uses. Mycophenolate mofetil has beenused in the prevention of allograft rejection in cases of renal and cardiac transplantation. The addition of myco-phenolate mofetil to oral corticosteroids and cyclosporinesignicantly reduces the occurrence of graft rejection. 31When compared in randomized trials to azathioprine, andused in combination with oral corticosteroids and cyclo-sporine, mycophenolate mofetil was associated with areduced rate of early graft failure, but signicant long-termdifferences in efcacy could not be detected. 32 In trans-plant situations, it may be less well tolerated than azathio-prine, with higher rates of viral infections and diarrhea 32 ;however, it has been the experience of some panel mem-bers that it may be better tolerated than azathioprine bypatients being treated for rheumatological disorders.

Clinical Experience for Inammatory Eye Disease. Pub-lished experience on the use of mycophenolate mofetil forocular inammatory disease is limited. Two uncontrolledcase series, totaling 26 patients, have reported that myco-phenolate mofetil is an effective agent in the treatment of ocular inammatory diseases. 33,34 Mycophenolate mofetiloften was used in combination with other agents, partic-ularly oral corticosteroids, and in some cases cyclosporine.A variety of ocular inammatory disorders were treated,including uveitis and scleritis. Success typically was mea-sured by the ability to control the inammation and reducethe dose of corticosteroids and/or cyclosporine. It was the

clinical impression of both groups of investigators thatmycophenolate mofetil was effective for control of ocularinammatory disease, when used in combination withother agents. Its efcacy relative to other immunosuppres-sive drugs for treatment of ocular inammatory diseasecannot be determined from published reports. It may be anacceptable alternative to azathioprine or methotrexate,especially in patients intolerant of other agents.

Dosage and Administration. Mycophenolate mofetil isgenerally used at an oral dose of 1 g twice daily. A dose of 3 g daily appears to have increased toxicity, whereas dosesless than 2 g daily are believed to be less effective.Mycophenolate mofetil should be used with caution inpatients with renal impairment and in those with gastro-intestinal disorders, which might affect absorption.

Adverse Events and Monitoring.. Gastrointestinal prob-lems (pain, nausea, vomiting, and diarrhea; up to 31%)were common side effects of mycophenolate mofetil inpatients receiving the drug for prevention of allograftrejection. 31,32 Other reported complications in transplantpatients receiving 3 g daily included leukopenia (up to19%); lymphoma (1%); nonmelanoma skin cancers (9%);and opportunistic infections (up to 46%, the majority

being cytomegalovirus and herpes simplex infections, withless than 2% being fatal). It should be remembered thatthese patients are also receiving other immunosuppressivedrugs in combination with mycophenolate mofetil.

Larkin and Lightman 33 reported that only one of 11patients treated with mycophenolate mofetil for oculardisease developed an adverse event, which consisted of nausea and headache, symptoms that did not recur whentreatment was reinstituted at a dose 500 mg twice daily.Kilmartin and associates 34 reported that six of nine pa-tients treated with mycophenolate mofetil at a dose of 1 gtwice daily developed mild adverse reactions, includingmyalgia, fatigue, headache, and nausea.

Patients should be monitored with complete bloodcounts on a weekly basis for 4 weeks, then on a twicemonthly basis for 2 months, with monthly testing there-after. Members of the panel also monitor liver functiontests every 3 months.

CYCLOSPORINE : Mechanism of Action. A natural prod-uct of fungi, including Beauveria nivea, cyclosporine (cy-closporine A) is an 11-amino acid cyclic peptide.Cyclosporine appears to affect preferentially immunocom-petent T lymphocytes that are in the G0 and G1 phase of their cell cycle, and its effect appears to be a specictranscriptional inhibition in these cells, blocking replica-tion, as well as their ability to produce lymphokines, suchas interleukin-2. 35

Pharmacokinetics. Absorption of cyclosporine throughthe gut varies widely. Two oral preparations of cyclospor-

ine, one a microemulsion (Neoral) and the other gelatincapsules (Sandimmune) 9 are available. The microemulsionpreparation has greater bioavailability than the gelatinpreparation; the two are not bioequivalent and cannot beused interchangeably. The drug is metabolized in the liverand excreted in the bile, with very little of the parent drugor its metabolites appearing in the urine. It is estimatedthat the terminal half-life of cyclosporine in the blood isapproximately 8 hours, with a range of 5 to 18 hours.Within the vasculature, the drug distribution at steadystate is approximately 35% to 45% in plasma and 40% to55% within erythrocytes. Some 90% of the plasma portionof the drug is bound, mostly to lipoproteins. Cyclosporineleaves the vasculature readily and has been found in theintraocular uids of uveitis patients. 35

Nonophthalmic Uses. In the United States, cyclosporineis approved by the US Food and Drug Administration forthe prevention and treatment of graft rejection, the treat-ment of severe, active rheumatoid arthritis that is poorlyresponsive to methotrexate, and for the treatment of severe, recalcitrant, plaque psoriasis in adults. 36

Clinical Experience for Inammatory Eye Disease. Uncon-trolled case series suggested that cyclosporine was effective


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for a variety of uveitis conditions as sole therapy at a doseof 10 mg per kg per day,37 a dose that is higher than thatcurrently used. In a randomized, controlled clinical trial of 56 patients with uveitis, cyclosporine was found to besimilar to oral corticosteroids in terms of efcacy. 38 Theauthors noted enhanced efcacy of the two agents to-gether. An uncontrolled, retrospective study of 15 childrenand adolescents with uveitis treated with cyclosporinereported that 82% of those patients had an improvementin their clinical disease, and that the drug was welltolerated. 39 A randomized controlled trial in Japan dem-onstrated that cyclosporine at a starting dose of 10 mg perkg per day was superior to colchicine in the treatment of the ocular complications of Behcet disease. 40 A goodresponse was seen in approximately 50% of the patientstreated with cyclosporine.

Dosage and Administration. For ocular disease, cyclospor-ine usually is given at a dose of 2 to 5 mg per kg per day,

administered in an equally divided twice daily doses. Someclinicians will begin cyclosporine therapy with the micro-emulsion preparation (Neoral) at 2 mg per kg twice dailyor with the gelatin capsules (Sandimmune) at 2.5 mg perkg twice daily and adjust the dose based on response andside effects.

Adverse Events and Monitoring. The most worrisome sideeffect of cyclosporine is nephrotoxicity. At the 10 mg perkg per day dose, all patients developed some evidence of nephrotoxicity. 41 At the currently used doses (2 to 5 mgper kg per day) the probability of nephrotoxicity appears to

be reduced substantially. The other commonly encoun-tered side effect is hypertension. Less commonly encoun-tered side effects include hepatotoxicity, gingivalhyperplasia, myalgias, tremor, paresthesiae, hypomag-nesemia, and hirsutism. The patients blood pressureshould be checked at every visit and no less frequentlythan monthly initially and every 3 months for patients onlong-term therapy. Serum creatinine should be checkedevery 2 weeks initially and monthly once dosage hasstabilized. Serum concentrations of the drug may be usedto monitor serum absorption, but do not correlate wellwith efcacy for autoimmune disorders, and are not neededroutinely.

TACROLIMUS : Mechanism of Action. Tacrolimus is amacrolide antibiotic produced by Streptomyces tsukubaensis.Tacrolimus inhibits the activation of T lymphocytes by amechanism similar to that of cyclosporine. 42

Pharmacokinetics. Absorption of tacrolimus from thegastrointestinal tract is both incomplete and variable. Theplasma protein binding of tacrolimus is approximately99%. Tacrolimus primarily is metabolized by the cyto-chrome p-450 system; fecal elimination accounts for over90% of the elimination. In healthy research subjects, the

half-life of orally administered tacrolimus was 34.8 11.4hours. Rate and extent of oral absorption of the drug arelimited when the drug is taken with food.

Nonophthalmic Uses. Tacrolimus is used for preventionand treatment of solid organ transplant rejection. Ran-domized controlled clinical trials of liver transplant recip-ients showed lower rates of rejection in patients treatedwith tacrolimus when compared with cyclosporine-treatedpatients. 43,44

Clinical Experience for Inammatory Eye Disease. Small,uncontrolled case series have suggested that tacrolimusmight be effective for the treatment of noninfectiousuveitis. Success rates were on the order of 62% to 76% forcontrol of the intraocular inammation. 4548

Dosage and Administration. Tacrolimus is available forboth intravenous and oral administration, but most pa-

tients with uveitis have been treated with oral tacrolimus.An initial oral dose of 0.10 to 0.15 mg per kg per day isrecommended for adult patients who have had livertransplants. An initial dosage of 0.05 mg per kg per daymay be effective for uveitis. Monitoring of blood concen-trations may be necessary, as absorption varies.

Adverse Events and Monitoring. Major side effects in-clude renal impairment (28%), neurologic symptoms(21%), gastrointestinal symptoms (19%), and hyperglyce-mia (13%). 45 Adverse effects resolve or improve whentacrolimus is stopped or when the dosage is reduced. Other

reported adverse events include hypomagnesemia, tremor,headache, trouble sleeping, paresthesias, and hypertension.Tacrolimus should not be given with cyclosporine becauseof the similar risks of renal toxicity. Patients should bemonitored closely for the occurrence of adverse events.Patients should undergo weekly laboratory assessment of the following: liver enzymes; bilirubin; blood urea nitro-gen; creatinine; electrolytes including calcium, magne-sium, and phosphate; cholesterol and triglycerides; glucose;and complete blood counts, at least initially. With stabledosing the frequency may be reduced to monthly. Bloodpressure should also be monitored at every visit, at leastmonthly initially, and subsequently at least every 3months.

CYCLOPHOSPHAMIDE : Mechanisms of Action. Cyclo-phosphamide is a nitrogen mustard-alkylating agent theactive metabolites of which alkylate purines in DNA andRNA, resulting in cross-linking, aberrant base pairing, ringcleavage and depurination. 49 This process results in celldeath, because the cells are unable to replicate. Cyclophos-phamide is cytotoxic to both resting and dividing lympho-cytes. In patients, it decreases the number of activated Tlymphocytes, suppresses helper T lymphocyte functions,and decreases B lymphocytes for months. 50 Cyclophosph-


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amide suppresses both primary and established cellular andhumoral immune responses, including delayed-type hyper-sensitivity, mixed lymphocyte reactions, mitogen-inducedand antigen-induced blastogenesis, and production of cy-tokines.

Pharmacokinetics. Cyclophosphamide is well absorbedand is enzymatically converted by the hepatic microsomalenzymes to multiple metabolites, of which phosphoramidemustard is thought to be the most active. 51 It is extensivelymetabolized before excretion, primarily by the kidney, withless than 25% remaining unchanged in the urine. 51,52 Oneof these metabolites, acrolein, is thought to be responsiblefor the urologic toxicity. 53 The use of 2-mercaptoethanesulfonate may detoxify acrolein and reduce bladder toxic-ity. Both allopurinol and cimetidine inhibit hepatic mi-crosomal enzymes, increasing the metabolites of cyclophosphamide. 51 Doses should be reduced 30% to 50%for renal failure.

Nonophthalmic Uses. The most common use of cyclo-phosphamide is in oncology as an antineoplastic agent, forwhich it is approved by the US Food and Drug Adminis-tration. It is used in several autoimmune diseases, the mostcommon being systemic lupus erythematosus and vasculi-tis, particularly Wegener granulomatosis. 5459 It also hasbeen used for rheumatoid arthritis, primarily in patientswith the secondary complication of vasculitis. Althoughthere are placebo-controlled trials in both systemic lupuserythematosus and rheumatoid arthritis, there are none invasculitis. Cyclophosphamide appears to be most benecial

when used on a daily oral basis,59

although monthlyintravenous administration is effective for lupus nephritis.

Clinical Experience for Inammatory Eye Disease. Themajority of the studies of cyclophosphamide for oculardiseases have been uncontrolled case series. 6063 Intrave-nous pulsed cyclophosphamide appears to be less effectivethan oral daily cyclophosphamide and not particularlyeffective for uveitis. 61,62 In a small randomized, controlled,clinical trial, cyclophosphamide and corticosteroids weremore effective than corticosteroids alone for mucous mem-brane pemphigoid with ocular involvement, both in termsof initial control of the disease and the ability to success-fully taper the corticosteroids. 64

Dosage and Administration. Orally, cyclophosphamide isgiven at 1 to 3 mg per kg per day. Many clinicians begintherapy at 2 mg per kg per day and adjust the dosedepending on response and toxicity. The daily dosagetypically is decreased by 25 to 50 mg for toxicity.

Adverse Events and Monitoring. The most common typeof side effect seen with cyclophosphamide is bone marrowsuppression, which is dose dependent, reversible, and morecommon in older individuals (older than 65 years). 40 Some

investigators strive to lower the white blood count to alevel of 3000 to 4000 cells per l to induce a therapeuticeffect. Substantial granulocytopenia to an absolute neutro-phil count below 1000 cells per l is associated with anincreased risk of bacterial infections, in particular sepsis.Therefore, most clinicians will discontinue alkylatingagents at a white count of 2500 cells per l or below toavoid this complication. Rarely, myelodysplasia can beseen with long-term oral therapy. The second seriouscomplication seen is hemorrhagic cystitis, which is uncom-mon and seen primarily in individuals with bladder stasisor those unable to take adequate uids. Initially, thistoxicity manifests as microscopic hematuria, but it candevelop into gross hematuria and hemorrhagic cystitis. Allpatients on cyclophosphamide therapy should be encour-aged to drink two or more liters of uid per day to maintaina good urine ow and minimize toxicity. Bladder toxicityfrom cyclophosphamide requires discontinuation of cyclo-phosphamide. For patients who have a potentially fatal

disease, such as Wegener granulomatosis, investigation of the bladder wall by cystoscopy followed by consideration of reinstitution of cyclophosphamide after resolution of thetoxicity may be tried. Intermittent intravenous pulsecyclophosphamide with concomitant 2-mercaptoethanesulfonate therapy is one approach to avoid bladder toxic-ity. Conversely, for eye disease, some clinicians will dis-continue cyclophosphamide with the occurrence of bladder toxicity and switch to an alternative approach.Chlorambucil, because it does not cause bladder toxicity,may be substituted for cyclophosphamide in this situation.

Other toxicities include teratogenicity (cyclophospha-

mide is contraindicated in pregnancy), ovarian suppres-sion, testicular atrophy, and azospermia. Ovarian failure isage related with younger individuals being less affected(women under age 25 years have less than a 30% chanceof ovarian failure as compared with greater than 50% overthe age of 30 years). For patients beginning cyclophosph-amide therapy, cryopreservation of eggs or sperm may beconsidered. Concomitant use of a gonadotropin-releasinghormone agonist also may prevent sterility in womenreceiving cyclophosphamide. 6567 Less severe adverseevents include alopecia, nausea, and vomiting. Alopeciaoccurs in up to 50% of individuals receiving cyclophosph-amide. However, after therapy is complete, hair growthreturns. Nausea and vomiting can be decreased withantiemetics and, to some degree, by adequate hydration.

In addition to granulocytopenia, lymphopenia is in-duced. Associated with lymphopenia is the possibility of opportunistic infections. In one randomized, controlledclinical trial of 50 patients, comparing intermittent intra-venous pulse to oral daily cyclophosphamide for thetreatment of Wegener granulomatosis, 70% of the patientstreated with oral daily cyclophosphamide developed infec-tions, including 30% who developed Pneumocystis cariniipneumonia. 50 Although there appears to be regional vari-ations in the frequency in P. carinii pneumonia in immu-


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malignancy. 77 These malignancies included bladder can-cer, skin cancer, and myeloproliferative malignancies. Inthis study, the rate of cancer was associated with a longerduration of treatment. Furthermore, the Kaplan-Meiercurves for the occurrence of cancer did not begin todiverge until after 5 years of follow-up, suggesting that theeffect is a long-term one. 78

Most of the underlying disorders in which an increasedrisk of malignancy has been associated with alkylatingagent therapy have been those with an intrinsic increasedrisk of malignancy. Therefore, the argument has beenadvanced that eye conditions, which may not be associatedwith an increased risk of malignancy on their own, maynot be associated with a substantial increased risk of malignancy when treated with alkylating agents. 79 In aretrospective analysis of 543 patients with eye disease, 330of whom were treated with immunosuppressive drugs,including 126 patients treated with alkylating agents, therewas no excess risk of malignancy among those patients

treated with immunosuppressive drugs. 79 However, in thisstudy, because of issues related to study power (drugs withdifferent malignancy risk were analyzed as a single group)and duration of follow-up (mean follow-up was approxi-mately 3 years, which may have been too short to detect anincreased risk of malignancy), an increased risk may havebeen missed. In this regard, the experience of the NationalInstitutes of Health with use of cyclophosphamide forWegener granulomatosis is instructive. Early studies pub-lished in 1973, 1974, and 1983 all suggested no increasedrisk of malignancies among patients treated with cyclo-phosphamide for Wegener granulomatosis. However, in a

series published in 1992, with 158 patients followed for upto 24 years, there was a 2.4-fold increased risk of cancercompared with the expected rate and a 33-fold increasedrisk of bladder cancer. 58 Although the manner in whichalkylating agents are used for ophthalmic disease (less than18 months duration of therapy) may decrease the proba-bility of inducing malignancies, it would seem prudent toadvise any patient being treated with chlorambucil orcyclosphosphamide of the potential for an increased risk of malignancy. Furthermore, because of the suggestion thathemorrhagic cystitis is a risk factor for subsequent bladdercancer in patients treated with cyclophosphamide, someclinicians would discontinue cyclophosphamide after theonset of hematuria to minimize any increased risk of bladder cancer.

SUMMARY : All of the agents above appear to haveefcacy in the treatment of ocular inammation. Cyclo-sporine 40 and azathioprine 22 have been demonstrated to beeffective in randomized, controlled clinical trials for thetreatment of ocular inammatory diseases (I; see Table 1).Methotrexate, mycophenolate mofetil, tacrolimus, cyclo-phosphamide, and chlorambucil all appear to have efcacyin uncontrolled case series (II), and cyclosphosphamidehas been shown to be effective for the treatment of ocular

involvement in mucous membrane pemphigoid in a ran-domized, controlled clinical trial (I). 64 Long-term treat-ment of the ocular inammation may be needed withantimetabolites and T-cell inhibitors, whereas treatmentwith alkylating agents may result in long-term drug-freeremissions (III).

Once a patient has been started on an immunosuppres-sive drug, and an effective drug and dose found, it typicallyis continued for 6 to 24 months. At that time attempts maybe made to taper the medication over a period of 3 to 12months. Tapering typically occurs at monthly to 6-weekintervals because of the duration of effect of these drugs.However, some patients may need long-term or evenindenite treatment. Relative efcacy among the differentagents has not been determined, and individual variationin response exists. As such, treatment should be individu-alized based on the patients desires (for example, preg-nancy) and other medical considerations.

COMBINATION THERAPY : The therapeutic strategy tocombine medications is employed frequently in the treat-ment of cancer. The immune system also lends itself to amultipronged attack, because a medication that preferen-tially affects one arm of the immune system (for example,antigen presenting cells, T lymphocytes, B lymphocytes,specic cytokines, or cell adhesion molecules on endothe-lial cells) could be effectively combined with a medicationthat targets a different arm. The hope is that such acombination would lead to enhanced immunosuppressionwithout encountering dose-limiting toxicity.

Examples from Rheumatic Diseases. The strategy of com-bined therapy has been effectively employed in the treat-ment of rheumatic diseases. Examples include the use of hydroxychloroquine, sulfasalazine, and methotrexate totreat rheumatoid arthritis 80 ; the combination of cyclospor-ine and methotrexate to treat rheumatoid arthritis 81 ; or theuse of tumor necrosis factor inhibition in combinationwith methotrexate to treat rheumatoid arthritis. 82 In eachof these examples, randomized, controlled clinical trialshave established the superiority of the combined therapyover the use of a single agent (monotherapy). In addition,corticosteroids routinely are added to various regimens forimmunosuppression, such as in the therapy of polyarteritisnodosa, Wegener granulomatosis, or lupus nephritis withcyclosphosphamide. Most patients who undergo vital or-gan transplantation receive a combined immunosuppres-sion regimen, such as azathioprine and cyclosporine.

Clinical Experience for Inammatory Eye Disease. Norandomized, controlled, clinical studies exist to evaluatethe role of combined immunosuppressive therapy for in-ammatory eye disease. Most practitioners who prescribe amedication such as cyclosporine, methotrexate, azathio-prine, or cyclophosphamide also will prescribe a course of oral corticosteroids, at least initially. Corticosteroids en-


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hance the immunosuppressive and anti-inammatory ef-fects of almost any modality of immunosuppression. Oneuncontrolled case series for the treatment of uveitis re-ported substantial benet by combining methotrexate withcyclosporine and a corticosteroid. 83 Five eyes of threepatients with serpiginous choroidopathy treated with thecombination of azathioprine, cyclosporine, and corticoste-roids have been reported with encouraging clinical re-sponses.84 The combination of an antimetabolite (forexample, azathioprine, methotrexate, or mycophenolatemofetil) with cyclosporine is appealing, because the drugshave different toxicities and are frequently employedtogether in other situations, such as transplantation. Al-though alkylating agents are frequently combined withcorticosteroids, they typically are not combined with otherimmunosuppressive drugs because of concerns about tox-icity (for example, bone marrow suppression) and thedegree of immunosuppression and the occurrence of infec-tion.

Dosage and Administration. In general dosage shouldnever exceed that given for individual medications, andthe dosage may be reduced when combinations are em-ployed. One goal of combination regimens is to minimizecorticosteroid dosage.

Adverse Events and Monitoring. Ofce visits and labora-tory testing should correspond to what is indicated for eachindividual medication in the combination. Monitoring, if anything, should become more vigilant when combina-tions are employed, because the number of potential

complications and interactions increases with combina-tions. One major drawback to combination therapy is theincreasing complexity of the regimens and the attendantproblems with compliance.

SPECIFIC DISEASES NEARLY ANY OCULAR INFLAMMATORY DISORDER REQUIR-ing chronic systemic corticosteroid treatment may requireimmunosuppressive drugs in an effort to reduce the dose of corticosteroids. The probability of using an immunosup-pressive drug will vary depending on the severity of theunderlying disease. For example, published series havesuggested that 15% of patients with pars planitis will needimmunosuppression, 85 but that 69% of patients with sym-pathetic ophthalmia will. 86 However, selected diseases,because of their poor natural history, are candidates forimmunosuppressive drug therapy from the onset. Thesediseases include Behcet disease with posterior segmentinvolvement and mucous membrane pemphigoid withocular involvement. Other diseases, such as scleritis withsystemic necrotizing vasculitis, require immunosuppressivedrugs for treatment of the underlying disorder. Finally,some forms of posterior uveitis, such as serpiginous choroi-

dopathy, appear to benet from immunosuppressive drugtherapy, but the disease is sufciently uncommon thatrecommendations are less certain. Because of the effect of immunosuppressive drugs on the immune system, andbecause of their potential for side effects, accurate diagno-sis of the ocular inammatory disorder, particularly theexclusion of infection or malignancy, before the institutionof such therapy is important.

BEHC ET DISEASE : Clinical Features. The classic triad of Behcet disease is oral ulcers, genital ulcers, and uveitis.Oral ulcers are the most common manifestation and arepresent in 98% to 100% of cases, whereas ocular diseaseoccurs in 68% to 100% of patients. Other manifestationsinclude cutaneous lesions, such as erythema nodosum andsupercial migratory thrombophlebitis, arthritis, vasculardisease, including thrombotic lesions, and central nervoussystem disease.8790

Anterior uveitis with or without a hypopyon is present

in the majority of patients with ocular involvement fromBehcet disease. 88 The more devastating ocular complica-tion is posterior segment involvement, including vitritis,retinal vasculitis, focal necrotizing retinitis, and posterioruveitis, 8891 which is associated with a poor visual outcomeif untreated. Natural history studies show that 73% of patients with ocular Behcet disease develop blindness andthat among those who develop no light perception vision,the average time to do so was 3.5 years. 91 Furthermore, itappeared that systemic corticosteroid therapy delayed thetime to blindness but did not alter the long-term out-come. 91 As such, the occurrence of posterior uveitis in

patients with Behcet disease usually is considered anindication for immunosuppressive drug therapy.

Clinical Experience with Immunosuppressive Drugs. Earlyexperience in the use of immunosuppressive drugs for thetreatment of Behcet disease was with chlorambucil. Thesereports typically consisted of uncontrolled, case seriesdemonstrating an arrest of disease in patients treated withchlorambucil, followed by drug-free long-term remissionsafter 2 years of therapy. 7274 No randomized controlledtrials were done, but this experience compared favorablywith the natural history and suggested that chlorambucilwas effective in the treatment of patients with ocularBehcet. Although there are few published data usingcyclosphosphamide for the treatment of ocular Behcetdisease,92 some clinicians consider it equally effective andeasier to use than chlorambucil and will use cyclophosph-amide rather than chlorambucil in this situation.

Cyclosporine has been used extensively for treatment of uveitis in patients with Behcet disease. A randomized,double-masked, controlled clinical trial of 96 patientsdemonstrated that cyclosporine was signicantly betterthan colchicine for ocular Behcet disease. 40 Nearly 50% of patients treated with cyclosporine had a good response(75% to 100% reduction) for the frequency of ocular


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attacks and a good response for the severity of ocularattacks. However, nearly 25% of the cyclosporine-treatedpatients had a slight reduction, no change, or worsening of the frequency of ocular attacks, and 33% had a slightreduction, no change, or worsening of the severity of ocular attacks. These data suggest that cyclosporine maynot be benecial for all patients with ocular Behcetdisease. Furthermore, this study used a higher dose of cyclosporine (10 mg per kg per day) than is recommendedcurrently (5 mg per kg per day).

A randomized, controlled, clinical trial of 73 patientscompared azathioprine therapy, at a dose of 2.5 mg per kgper day, with placebo and showed that azathioprine waseffective in preventing eye disease among those withouteye disease at randomization and was effective in decreas-ing contralateral eye involvement among those with uni-lateral disease. Azathioprine was not completely effective,because 22% of the patients developed ocular diseaserequiring intravenous methylprednisolone therapy. 22

Summary and Recommendations. Taken together, thesedata suggest that patients with posterior segment involve-ment from ocular Behcet disease should be treated withimmunosuppressive drugs as early as possible in theircourse (AI; see Table 1). Azathioprine (BI), cyclosporine(BI), and the alkylating agents chlorambucil and cyclo-phosphamide (BII), all appear to be effective. However,none of these agents appears to be universally effective.Treatment with alkylating agents may have the potentialfor long-term, drug-free remissions, but these data comefrom uncontrolled case series rather than from randomized

controlled clinical trials (BII). The choice of agents willdepend on the patient and other features, including theactivity of the other manifestations of Behcet disease, thepresence of neurologic disease, renal function, fertilityissues, and bone marrow status.

BIRDSHOT RETINOCHOROIDOPATHY : Clinical Fea-tures. Birdshot retinochoroidopathy is a clinically distinctbut uncommon form of chronic posterior uveitis charac-terized by bilateral, multiple, hypopigmented postequato-rial retinal pigment epithelial and choroidal inammatorylesions, with associated inammatory cells in the vitreous.The cause is unknown, but its strong association with theHLA-A29 phenotype suggests that it may be an autoim-mune disease. Patients with birdshot retinochoroidopathycommonly present with complaints of painless vision loss,especially nyctalopia, and with complaints of vitreousoaters. Disturbances in color vision also are common, andvisual complaints are often out of proportion to themeasured visual acuity, indicating diffuse retinal dysfunc-tion, which can be documented by electroretinography.The most common complication of birdshot retinochoroi-dopathy is chronic cystoid macular edema, occurring inover 50% of cases, and macular edema is the most frequentcause of reduced central visual acuity. Epiretinal mem-

brane formation occurs in at least 10% of cases, and 6% of patients may eventually develop breaks in Bruch mem-brane, allowing the development of subretinal choroidalneovascularization. 9395

Clinical Experience with Immunosuppressive Drugs. A de-nitive strategy for the care of patients with birdshot hasnot been established, and the mainstay of treatment hasbeen the use of either periocular or systemic corticoste-roids. However, the efcacy of such therapy has beeninconsistent, and given the chronicity of this disease, thecomplications of repeated or chronic corticosteroid usemay be problematic. In one series, less than 15% of patients treated with systemic corticosteroids achieved anadequate clinical response and were able to be maintainedon low to moderate doses of prednisone. 96

Uncontrolled case series have suggested that cyclosporinemay be effective for birdshot retinochoroidopathy. 9699 Com-pared with corticosteroid therapy alone, Vitale and associ-

ates97 found that vitreous inammation was controlled in85% of the patients treated with cyclosporine, and visualacuity improved or stabilized in 83%. In contrast, 54% of patients treated with corticosteroids alone experienced adeterioration in visual acuity over the follow-up period.Treatment typically lasted for 24 to 48 months.

MULTIFOCAL CHOROIDITIS WITH PANUVEITIS : Clini-cal Features. Multifocal choroiditis with panuveitis is anidiopathic, bilateral, ocular inammatory disease. Theappearance of the chorioretinopathy is similar to thatproduced by the presumed ocular histoplasmosis syndrome,

but with more widespread chorioretinitis and, unlike thepresumed ocular histoplasmosis syndrome, with vitrealinammation. The clinical characteristics of multifocalchoroiditis with panuveitis include panuveitis, with ante-rior chamber cells, vitreal cells, and round to ovoidchorioretinal lesions, ranging from 50 to 200 m indiameter, scattered throughout the entire retina. In theresolving phase from active inammation, the perimeter of the lesions becomes pigmented, and the lesions take on apunched out appearance. The disease tends to be chronicand vision damaging. Vision-limiting consequences in-clude chronic macular edema, subretinal neovasculariza-tion, and optic neuropathy. 100103

Clinical Experience with Immunosuppressive Drugs. Thenatural history of the disease is one of great chronicity,with a high rate of vision loss. 102 Conventional therapy formultifocal choroiditis has been with corticosteroids, mostoften oral corticosteroids, and this form of treatmentappears to be moderately effective with response rates at50% or more. 103 However, because of the chronicity of thedisease, the rate of corticosteroid-induced side effects maybe high. Nussenblatt and associates 104 have stated that intheir experience at least the consideration of addition of other immunosuppressive agents is a common decision


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that has to be made at some point in the care of patientswith multifocal choroiditis with panuveitis.

SERPIGINOUS CHOROIDOPATHY : Clinical Features. Ser-piginous choroidopathy generally presents with scotoma,decreased central vision, or metamorphopsia. The eye doesnot appear inamed. The characteristic ndings early inthe disease are gray-white to yellow-white subretinal fun-dus lesions, beginning in a peripapillary location andspreading centrifugally. There usually is evidence of inac-tive disease in the other eye; disease progression is oftenasymmetric. As the disease progresses, these lesions coa-lesce into a serpentine formation, with pigmentary changesin the retinal pigment epithelium, and atrophy of theunderlying choriocapillaris and choroid. Fluorescein an-giography demonstrates typical early blocking with latestaining of lesions. Serous retinal detachment, subretinalneovascularization, and subretinal brosis are late compli-cations of the disease. 105108

The natural history is asynchronous, bilateral progres-sion over many years. Disease progression tends to beepisodic and recurrent. Flare-ups, with extension of exist-ing lesions or development of new lesions, occur for severalmonths at a time. Disease activity may recur after monthsof remission. Acute lesions cause absolute scotomata,which will cause loss of central vision if progressionproceeds into the fovea; some recovery of scotomata hasbeen noted in cases where there is minimal progression. No large studies have documented the risk of central visionloss in this disease, but current estimates of vision loss are50% with long-term follow-up. 105107

Clinical Experience with Immunosuppression. No consen-sus exists for the treatment of serpiginous choroidopathy,and there is a scarcity of data in the literature. Descriptionsof the clinical effect of oral or periocular corticosteroidmedication are inconsistent, with some authors reportingclinical response in small case series 108 and others unableto demonstrate effect. 84 In those cases showing response,clinical effect was generally seen after 1 month of treat-ment; because the disease can spontaneously remit overthe same time course, the efcacy of treatment in thesecases is unclear. Uncontrolled case series have suggestedthat cyclosporine monotherapy may be successful, 109 butnot all cases have been treated successfully. 110 One smallseries of ve eyes treated with triple immunosuppression(prednisone 1 mg per kg per day, cyclosporine 5 mg per kgper day, and azathioprine 2 mg per kg per day) reportedresolution of activity within 2 weeks of initiation of therapy in all affected eyes. Two eyes rapidly developedrecurrences on weaning of medication, but both respondedpromptly to reinitiation of therapy. 84 The need for tripleimmunosuppression is unknown, because no cases treatedwith combination azathioprine and prednisone have beenreported in the literature.

Summary. The posterior uveitides, birdshot retinocho-roidopathy, multifocal choroiditis with panuveitis, andserpiginous choroidopathy, all appear to have a poorlong-term outcome history and variable benet from cor-ticosteroid therapy. Although chronic corticosteroid ther-apy may control the disease in some patients, manypatients may require an immunosuppressive drug (BIII).The most frequently used drug has been cyclosporine (II),although combination immunosuppressive drug therapyappears to be effective for serpiginous choroidopathy (II).It has been the experience of some panel members thatalkylating agents may be of benet for these disorders (III).

SCLERITIS : Clinical Features. Scleritis is a severe, painful,and potentially sight-threatening disorder, often associatedwith an underlying systemic disease. Scleritis can bedivided into anterior and posterior disease. Anterior scle-ritis has been further classied into the following catego-ries: diffuse, nodular, necrotizing, and scleromalaciaperforans. 111 Scleritis is characterized usually by pain andby redness of the sclera and episclera. Scleritis is bilateralin over 50% of patients but frequently starts in one eye. Necrotizing scleritis is a severe form of the disorder,frequently associated with both blinding ocular disease andlife-threatening systemic disease. 111113 An associated sys-temic autoimmune disease is present in 40% to 50% of thepatients with scleritis. 111,112 Inammation leads to scleralthinning, allowing the underlying choroid to becomevisible. Uveitis is often associated with severe cases of scleritis.

Scleritis has been associated with several forms of systemic necrotizing vasculitis, including Wegener granu-lomatosis and polyarteritis nodosa. Necrotizing scleritis isthought to be associated with more severe disease inpatients with rheumatoid arthritis 112 and may be anindication for systemic immunosuppression in these pa-tients. Wegener granulomatosis is a multi-organ diseasecharacterized by a necrotizing granulomatous vasculitis.The disease involves the kidneys and respiratory tract; theeye is involved in over 50% of patients. Polyarteritisnodosa is also a systemic vasculitis that affects small-sizedand medium-sized arteries and is associated with visceralorgan involvement, myalgia, peripheral neuropathy, andrenal disease. Like Wegener disease, eye involvement canoccur.

Clinical Experience with Immunosuppression. Oral non-steroidal anti-inammatory drugs may control inamma-tion in mild cases of anterior scleritis. For more severeforms of the disease, oral corticosteroids or systemic im-munosuppressive agents often are required. 111,113 The scle-ritis associated with necrotizing systemic vasculitis may bediffuse, nodular, or necrotizing, and treatment with immu-nosuppression is required to control the underlying vascu-litis, because mortality is high in untreated patients. 5659


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Necrotizing scleritis is difcult to treat and nearly alwaysrequires systemic immunosuppressive therapy. 113

There are no randomized, controlled clinical trials of treatment for scleritis. Several studies have evaluatedtreatment of scleritis associated with necrotizing systemicvasculitis. Treatment of scleritis in patients with necrotiz-ing systemic vasculitis should be guided both by theophthalmic response and control of the underlying disease.The antineutrophil cytoplasmic antibody test may be auseful laboratory measure of the therapeutic response inpatients with Wegener granulomatosis. Cyclophospha-mide, starting at a dose of 2 mg per kg per day, is the drugmost often used for necrotizing systemic vasculitis (AII)and is often used for refractory necrotizing scleritis (BII).Concomitant prednisone at a dose of 1 mg per kg per dayis needed for initial therapy. Oral corticosteroids usuallycan be tapered and often discontinued over the rst 2 to 4months of cytotoxic therapy. Other immunosuppressiveagents, including methotrexate, azathioprine, cyclospor-

ine, and chlorambucil, have been used successfully for thetreatment of necrotizing systemic vasculitis, but reports areanecdotal (BIII).

MUCOUS MEMBRANE PEMPHIGOID : Clinical Features.Mucous membrane pemphigoid (previously known as cic-atricial pemphigoid) describes a group of chronic autoim-mune disorders affecting the mucous membranes.Although skin involvement may occur, it is present in aminority of patients (approximately 20%). Oral mucousmembranes are involved most commonly, and ocularinvolvement occurs in approximately 80% of patients. The

characteristic immunopathologic feature of mucous mem-brane pemphigoid is the linear deposition of immunoglob-ulin or complement at the epithelial basement membranezone of mucous membranes, such as the conjunctiva.

The clinical features of ocular mucous membrane pem-phigoid are chronic conjunctivitis, sometimes unilateral atrst, but eventually bilateral, resulting in chronic scarring(cicatrization) with progressive subepithelial brosis, for-nix foreshortening, symblepharon, trichiasis, distichiasis,and keratopathy. The end result is corneal scarring, neo-vascularization, and ulceration. The natural history of thedisease is that of slow progression with only rare casesgoing into long-term sustained spontaneous remissions.The eventual result is progression to bilateral blind-ness.64,114 Topical and local therapies have failed to haltthe progression of the disease.

Clinical Experience with Immunosuppressive Drugs. Al-though corticosteroids may halt the progression of thedisease, high doses are required, and the disease recurs withtapering oral corticosteroids. 64 Dapsone is effective forimproving the symptoms and may control conjunctivalinammation for a period of time 115 ; however, long term,most patients escape control with dapsone alone. Uncon-trolled case series63,114 suggested that oral daily cyclophos-

phamide was effective in controlling mucous membranepemphigoid affecting the conjunctiva. Subsequently, arandomized, controlled study 64 conrmed these observa-tions. Better control of the disease was established with theuse of oral daily cyclophosphamide and oral corticosteroidsthan with corticosteroids alone, and the corticosteroidswere successfully tapered in those patients given cyclo-phosphamide. In addition, after 12 to 18 months of treatment with cyclophosphamide, some patients mayenter a long-term, drug-free remission.

Summary. The natural history of mucous membranepemphigoid with ocular involvement is poor, and systemicanti-inammatory medications are required (AII). Al-though corticosteroids, dapsone, and other immunosup-pressive drugs may be of benet, for those with severedisease, the alkylating agent cyclophosphamide appears tobe most effective (BI). It is the opinion of some membersof the panel that for patients with ocular involvement from

mucous membrane pemphigoid who experience bladdertoxicity from cyclophosphamide, chlorambucil may besubstituted successfully (BIII). Experience with other im-munosuppressive agents for mucous membrane pemphi-goid is limited, but antimetabolites may have value inselected patients (BIII), particularly those who cannottolerate alkylating agents. However, some clinicians con-sider them less effective than the alkylating agents in thissituation.

BIOLOGICS AND FUTURE DIRECTIONSTHE BASIC UNDERSTANDING OF THE IMMUNE SYSTEM ISrapidly improving. With new insight, new pharmaceuticalapproaches are being been designed (Table 4), sometimesreferred to as biologics. Examples include monoclonalantibodies to proteins, such as cytokines (for example,tumor necrosis factor- ), cell adhesion molecules, cytokinereceptors (anti-interleukin-2 receptor), or T-cell subsets(anti-CD4). Soluble tumor necrosis factor receptors, suchas etanercept (Enbrel; Immunex, Seattle, Washington), fortumor necrosis factor inhibition are now in clinical use. Asof June 2000, a naturally occurring interleukin-1 receptorantagonist was undergoing evaluation for the treatment of rheumatoid arthritis. Additional new approaches to immu-nosuppression include leunomide (Arava; AventisPharma USA, Parsippany, New Jersey), an antimetabolitethat may have T-lymphocyte specicity, immunoadsorp-tion columns, and intravenous immunoglobulin. Oral tol-erance is based on the premise that the immune responsecan be inhibited systemically by oral exposure to anantigen.

Nonophthalmic Studies. Etanercept has had success inthe treatment of rheumatoid arthritis and juvenile rheu-matoid arthritis, and currently is being studied for other


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immune-mediated diseases. Antibodies to CD4 or to theinterleukin-2 receptor have been benecial in treatingacute transplant rejection. Leunomide has been approvedby the US Food and Drug Administration for the treat-ment of rheumatoid arthritis. The immunoadsorption col-umn also is approved for the treatment of rheumatoidarthritis, but extrapolating this result to diseases notcharacterized by a similar contribution from immunoglob-ulin is problematic. Intravenous immune globulin hasshown modest benet in specic immune-mediated dis-eases, such as Guillain-Barre syndrome and idiopathicthrombocytopenic purpura. Trials of additional biologic orimmunomodulatory drugs are ongoing for other potentiallynovel targets within the immune system.

Clinical Experience for Inammatory Eye Disease. Onesmall, uncontrolled case series found that daclizumab(Zenapax; Roche, Basel, Switzerland), a monoclonal anti-body to the interleukin-2 receptor (anti-Tac), facilitatedthe reduction in immunosuppressive therapy for patientswith uveitis. 116 One small, randomized controlled trial onoral feeding with retinal S antigen demonstrated equivocalbenet in patients with uveitis. 117 Additional trials havebeen halted because of a dearth of available antigen. Onesmall, uncontrolled case series reported that approximately50% of patients with uveitis that was refractory to immu-nosuppressive medication could benet from intravenousimmune globulin. 118 Interferon -2B appeared to be of value for ocular Behcet disease in a randomized controlledclinical trial. 119 Studies evaluating the use of etanercept inthe treatment of uveitis associated with juvenile rheuma-toid arthritis and the use of leunomide for uveitis in adultsare ongoing as of June 2000.

Adverse Events and Monitoring. Toxicity depends on theindividual medication. Etanercept has been associatedwith local injection site reactions and rarely with seriousinfections. Concern remains with regard to the inhibitionof tumor necrosis factor and the risk of malignancydevelopment. Intravenous immune globulin is associatedwith headaches, malaise, thrombophlebitis, sterile menin-gitis, and serious vaso-occlusive events, such as stroke.Immunoglobulin is a blood product that could potentiallytransmit infection. 118 Anti-interleukin-2 receptor therapyfor uveitis has been associated with rashes, edema, granu-lomatous reactions, and viral respiratory infections. 116

Summary. It is hoped that one day we will regardcurrent nonspecic approaches to immunosuppression ashaving too nonselective an effect and as being too toxicand that we will be able to use more selective immuno-modulating agents. Etanercept currently is the most widelyused biologic, and its use to treat rheumatoid arthritis hasbeen marked by substantial clinical response. At present,the use of biologics to treat uveitis is restricted because of

T A B L E 4

. B i o

l o g i c A g e n t s f o r I m m u n e M o d u l a t i o n

C l a s s

G e n e r i c N a m e

( T r a d e N a m e )

I n i t i a l D o s e

M a x i m u m D o s e

M e c h a n i s m

E x p e c t e d

O n s e t

R e p r e s e n t a t i v e S i d e - e

f f e c t s

C o m m e n t s

C y t o k i n e

i n h i b i t o r s

E t a n e r c e p t ( E n b r e l )

2 5 m g 2 / w e e k

S C *

T N F i n h i b i t i o n : s o l u b l e

T N F r e c e p t o r

1 8

w e e k s

S e p s i s , l y m p h o m a

,

a u t o a n t i b o d i e s , s k i n

r e a c t i o n s , c o s t

I n i x i m a b ( R e m i c a d e )

a n t i b o d y

3 m g / k g / d a y I V Q

8 w e e k s

1 0 m g / k g I V Q

4 w e e k s

T N F i n h i b i t i o n : - T

N F

m o n o c l o n a l

a n t i b o d y

1 8

w e e k s

S e p s i s , l y m p h o m a

,

a u t o a n t i b o d i e s , c o s t

D a c l i z u m a b

( Z e n a p a x )

1 m g / k g I V Q 2

w e e k s

5

( r e n a l t r a n s p l a n t

d o s e )

I L - 2

i n h i b i t i o n : - I

L - 2

r e c e p t o r a n t i b o d y

D a y s

G r a n u l o m a t o u s

i n a m m a t i o n

,

i n f e c t i o n

, c o s t

P h a

s e I f o r u v e i t i s d o n e ;

m

a i n i n d i c a t i o n i s

t r a n s p l a n t

I L - 2

i n t e r l e u k i n - 2

; T N F

t u m o r n e c r o s i s f a c t o r . O t h e r a b b r e v i a t i o n s a s i n T a b

l e 2

.

* T h e p e d i a t r i c d o s e i s 0

. 4 m g / k g t w i c e p e r w e e k .

I n i x i m a b i s a d m i n i s t e r e d a t 0

, 2

, a n d 6 w e e k s b e f o r e t h e m a i n t e n a n c e s c h e d u l e o f e v e r y 8 w e e k s

.


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lack of adequate clinical experience, but ongoing studiesmay change this recommendation.

PREGNANCY AND CHILDRENBECAUSE OF THE POTENTIAL FOR TERATOGENICITY OR THE

lack of sufcient data to evaluate safety in pregnancy,appropriate contraception should be employed throughoutthe duration of any immunosuppressive drug use. Metho-trexate is a teratogenic and, at high doses, an abortifacient.For methotrexate, there is a suggestion that its use in menmay increase the possibility of malformations should theyfather children while on methotrexate. As such, it isprudent to continue contraception for 3 months afterdiscontinuation of methotrexate in men and for at leastone ovulatory cycle in women. As noted above, alkylatingagents are not only teratogenic, but may cause sterility. Formycophenolate and tracolimus, there are insufcient data

to evaluate their use in pregnancy. Because it is anantimetabolite, concerns persist that azathioprine may beteratogenic. Although azathioprine is best avoided duringpregnancy, large-scale studies in transplant patients havedemonstrated that azathioprine may be fairly well toleratedduring pregnancy, with the major neonatal risks beingprematurity and small for gestational age neonates. 120Although there are few data on cyclosporines use inpregnancy, the available human data do not demonstrate asubstantially increased risk of malformations. Some studieshave suggested no increased rate of pregnancy complica-tions, whereas others have suggested higher rates of spon-

taneous abortion, premature labor, and offspring that aresmall for gestational age. 120 Prednisone appears to be thesafest, most widely used, and best-tolerated systemic anti-inammatory drug for use in pregnancy. Although animalstudies have shown an increased rate of clefting withsuperpharmacologic dosing, human studies have failed tosubstantiate any signicant teratogenic effects. 120 Use of oral corticosteroids in pregnancy should be carefully coor-dinated with the patients obstetrician.

Children receiving systemic corticosteroids or immuno-suppressive drugs require special attention because of theeffect of these agents on growth, nutrition, school andrecreational activities, infectious diseases, and fertility.Unique to children is the effect of treatment on growthand development. 5 Suppression of growth by corticoste-roids is dose related; for most children, growth will ceasecompletely at doses greater than 2 mg per kg per day or 40mg per M2 per day. Growth suppression cannot be reversedwith human growth hormone. Immunosuppressive drugsdo not affect linear growth directly but can interf

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