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POSTERIOR UVEITIS:

ANUNDER-RECOGNIZED ADVERSE

EFFECT OF PAMIDRONATE:2 CASE REPORTS

HAVERBEKE G.*, PERTILE G.*, CLAES C.*,ZEYEN T.*

SUMMARY

Ocular adverse effects of pamidronic acid are rarebut well documented. Pamidronate, an inhibitor ofbone resorption used primarily in the managementof tumor-induced hypercalcemia and Pagets dis-ease, is reported to cause conjunctivitis, anterioruveitis, and infrequently episcleritis and scleritis.It is hypothesized that an allergic or immunologicphenomenon caused by drug-induced immune com-plex formation is at fault. The reason why the uveais a target organ is unclear. The acute inflammatoryresponse seems unrelated to the dose of the drug,the way of administration, or the activity of Pagets

disease or malignancy.We report two cases of pamidronate-induced poste-rior uveitis, following the WHO Causality Assess-ment Guide of Suspected Adverse Reactions.Uveitis and scleritis have been reported in associa-tion with a variety of topical, intraocular, periocular,and systemic medications. Seven criteria were pro-posed to establish causality of adverse events bydrugs. Only systemically administered biphospho-nates meet all seven criteria.Where pamidronate is currently considered as thedrug of choice in diverse strategies, the adverse ocu-lar effects should be well known to physicians in

order to make rapid diagnosis and stop the drugcausing adverse reaction.

SAMENVATTING

Oftalmologische nevenwerkingen veroorzaakt doorpamidronaat zijn uitzonderlijk doch goed gedocu-menteerd. Conjunctivitiden, anterieure uvetiden enzelden episcleritiden zijn gerapporteerd bij het ge-bruik van pamidronaat, een inhibitor van de botre-sorptie, dat wordt gebruikt bij het behandelen vansecundaire tumorale hypercalcemie en bij de ziektevan Paget.

De gangbare hypothese is een allergisch of een im-muun-gemedieerd fenomeen, veroorzaakt door vor-ming van immuuncomplexen. Het is onduidelijk waar-om de uvea wordt aangetast. Daarbij blijkt het dat

de inflammatoire reactie niet reletateerd is met dedosering van het product, noch met de graad van ac-tiviteit van de ziekte van Paget of de maligniteit.

Wij beschrijven twee gevallen van posterieure uvetisgenduceerd door pamidronaat, volgens de WHOCausality Assessment Guide of Suspected AdverseReactions.

Uvetis en scleritis zijn gerapporteerd in associatiemet een reeks topicale, peri-oculaire en intra-ocu-laire geneesmiddelen. Zeven criteria zijn voorgesteldom een causaliteit te bewijzen van de medicamen-teuze nevenwerkingen. Slechts systemisch toege-

diend pamidronaat beantwoordt aan deze criteria.Pamidronaat heeft nu zijn vaste plaats in de behan-deling van bepaalde aandoeningen, en het herken-nen van de oftalmologische nevenwerkingen wordtnu essentieel voor de behandelende geneesheer omde diagnose te stellen en de toediening van het ver-antwoordelijke product te stoppen.

RSUMLes effets secondaires de lacide pamidronique sontrares mais bien documents. Le pamidronate, un in-

hibiteur de rsorption osseuse utilis dans la prise

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* Dept.of Ophthalmology, AZ Middelheim, Antwerp,Belgium.

received: 23.07.03

accepted: 12.11.03

71Bull. Soc. belge Ophtalmol., 290, 71-76, 2003.

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en charge dhypercalcmie tumorale secondaire etde la maladie de Paget, est rapport tre la causede conjonctivites, uvites antrieures et infrquem-ment dpisclrites et de sclrites.Lhypothse propose est quil sagit dun phnom-ne allergique ou immunologique caus par la forma-

tion de complexes immuns. Il nest pas clair pour-quoi luve est le tissu cible. La rponse inflamma-toire aigu ne semble pas en relation avec la dosedu produit, ni la voie dadministration, ni lactivitde la maladie de Paget ou de la malignit.Nous rapportons deux cas duvite postrieure in-duits par le pamidronate, respectant le Guide de fia-bilit de la causalit des effets secondaires suspectsde lOMS.Luvite et la sclrite ont t dcrites en association une varit de types de mdicaments topicaux, pe-ri-oculaires en intra-oculaires. Sept critres ont tproposs pour tablir la causalit de ces effets se-

condaires mdicamenteux. Uniquement les biphos-phonates administrs de manire systmique rpon-dent aux sept critres.Sachant que les biphosphonates ont leur place dansle traitement de diffrentes pathologies, il est im-portant de connatre les effets secondaires oculairesafin de poser un diagnostic rapide et dinterrompreladministration de lagent causal.

KEY-WORDS

Pamidronate, posterior uveitis, scleritis,

adverse effects

MOTS-CLS

Pamidronate, uvite postrieure, sclrite,effets secondaires

INTRODUCTION

Pamidronate disodium (3-amino-1hydroxy-pro-pylidene-1, 1-biphosphonatepentahydrate), isa second-generation aminobiphosphonate.Biphosphonates are analogues of pyrophos-

phate that bind to hydroxy-apatite at sites ofbone remodelling.The major effects of the biphosphonates onbone are to inhibit skeletal and extraskeletalcalcification and to act like inhibitors of osteo-clastic bone resorption by binding to hydroxy-apatite crystals.The consequences are that fewer functional os-teoclasts are available for recruitment to ero-sion sites, and the activation of new remodel-ling sites may be decreased.

Biphosphonates are approved for treatment ofcomplications of osteolytic bone metastases (inbreast cancer), hypercalcemia, multiple myelo-ma stage III, Pagets disease, and vertebral frac-tures in osteoporosis (1).Pamidronate (Arediat) is reported to cause con-junctivitis, anterior uveitis (2,7,10,15), epis-cleritis (11,16), scleritis (5), nerve palsy (8),ptosis (8), retrobulbar neuritis (3) and idiopath-ic orbital inflammation (15).Althoughuncommon,theincidenceofpamidro-

nate-induced ocular complications was esti-mated at 0.046% in a drug surveillance study(8) and at 1% in a therapeutic trial in 400 pa-tients (17).Only the biphosphonates containing a nitratederivative have been reported to induce ocularadverse effects, with cross-reactions betweenthese different drugs (14).More recently developed oral aminobiphospho-nates have also been associated with scleritis(9, 13).

We present two cases of posterior uveitis con-firmed by rechallenge and dechallenge with pa-midronate, following the WHO Causality As-sessment Guide of Suspected Adverse Reac-tions (5).

PATIENTS ANDMETHODS

We report two cases of pamidronate-inducedconjunctivitis, uveitis and scleritis, both occur-

ring in February 2002.

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Case reports

Case 1 G A 03/08/1939

The patient is known with a prostate carcino-ma in the stage T3G2N+M+. In 1998, he had

a trans-urethral prostate resection. At the mo-ment of first contact, he was taking Eulexint/Decapeptylt, Durogesict 75, Estracytt 4 andRivotrilt. On 28/02/02, radiotherapy was start-ed for bone metastasis in the right hip and inT3-T7. On 04/03/02, intravenous Arediat 60mg was started for persistent pain. On 06/03/02, the patient developed conjunctivitis in theleft eye, which was treated locally. On 11/03/02, a second treatment with Arediat 60 mgwas given. On 13/03/02, uveitis in the left eye

was diagnosed, and treated with Cocaine 2 dropsfor synechiolysis, Atropine 2 drops, Pred Fortetone drop/hour. On 18/03/02, we had an echo-graphic suspicion of scleritis of the left eye (fig.1). The treatment was modified to Pred Fortet6 drops a day and a non-steroidal anti-inflam-matory drug for the pain. On 08/04/02, a third

treatment with Arediat 60 mg was adminis-tered, with a recurrence of anterior uveitis inthe left eye on 10/04/02. We started Pred Fortet6/d again. At this moment, the drug-inducedadverse reaction was suspected and we ad-vised to stop Arediat. No further episodes of

inflammation were noted.

Case 2 T G 20/09/1932

This patient was diagnosed on 09/02/02 witha Prostate Carcinoma stage T4N+M+. The fol-lowing treatment was started: Estracytt, Da-falgant, Zantact, Lopressort, Dexametha-sonet. On 14/02/02, Arediat 60 mg was start-ed for disseminated bone metastases. On16/02/02, he developed conjunctivitis in the

left eye. The initial local treatment, started bythe general practitioner (non-steroidal anti-in-flammatory eye-drops), didnt work and we sawthe patient with severe anterior uveitis on21/02/02. We performed a diagnostic vitrec-tomy with collection of microbiological sam-ples and administrated intra-vitreal Vancomy-

Fig 1. Echographic image of suspicious posterior scleritis

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cin and Tobramycin as endogenous panoph-thalmitis was suspected clinically. A topicaltherapy of corticosteroids combined with anti-

biotics (Tobradext

guttae) was started. CT-scanof the orbit showed the possibility of a tempo-ral scleritis (fig.2). Because of the general con-dition, Arediat 60 mg was given on 25/03/02and 25/04/02, and this under cover of Tobra-dext 4/d. On 08/05/02, we decided to stop thetopical corticotherapy. Two days later, on 10/05/02, the patient developed an anterior uveitisin the left eye, with a rapid reaction to topicalcorticotherapy. Arediat couldnt be stopped andwas carefully administrated on the 25/05/02and 26/06/02 at a dose of 60 mg under coverof Pred Fortet 4/d. No reaction was seen. InAugust 2002, the patient died from his generaloncological condition.

DISCUSSION

The WHO Causality Assessment Guide of Sus-pected Adverse Reactions classifies the report-ed drug-related events into 6 categories: cer-tain, probable/likely, possible, unlike-ly, conditional/unclassified, and un-

assessible/unclassifiable (5).

The three main criteria in the WHO Classifica-tion Assessment Guide of suspected AdverseReactions are

1/ plausible time relationship to drug admini-stration,2/ positive rechallenge-dechallenge data3/ the absence of other drugs or chemicals orconcurrent disease that could explain the ad-verse effects.The certain category includes a plausible timerelationship to drug administration and that theadverse effects cannot be explained by concur-rent disease or other drugs or chemicals. Dechal-lenge data are necessary and rechallenge datashould be positive. Probable is the same ascertain without positive rechallenge data.Possible is an adverse event in a reasonabletime sequence to administration of the drug butcould be explained by concurrent disease orother drugs or chemicals. Positive dechallengedata are lacking or unclear in this category.

Only systemically administered biphosphonatesmeet all seven criteria proposed by Naranjo etal to establish causality for uveitis (10, 11). Theseven criteria for an adverse event are the fol-

lowing: a frequently described event that is well

Fig 2. CT-scan image of possible posterior scleritis of left eye

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documented, the event improves upon with-drawal of the drug, other possible causes forthe event have been excluded, the adverse eventis documented by objective evidence, the eventbecomes more severe when the dose of thedrug is increased, the adverse event should oc-

cur in a given patient with similar drugs, theevent should recur on rechallenge with the sus-pected drug.

In the first case, the adverse ocular events as-sociated with pamidronate disodium had a veryplausible time relationship to drug administra-tion with occurrence of respectively conjunc-tivitis and anterior uveitis within 48 hours.

The posterior uveitis and possible scleritis wereechographically diagnosed some 7 days after

the second administration, when the patientwas already under treatment for anterior uvei-tis.

Because of persistent bone pain, it was decidedto administer a third treatment with pami-dronate 60 mg, with positive rechallenge mani-festing as anterior uveitis.

It was then decided to stop the aminobiphos-phonates, and the dechallenge data confirmedthe causality.

We treated the second patient initially as an en-

dogenous panophthalmia with intravitreal Van-comycin and Tobramycin, considering his generalcondition after chemotherapy treatment. On theCT-scan we noticed possible posterior scleritisand were thinking more in the direction of toxi-city of chemotherapy to explain the clinicalpicture. The microbiological cultures remainedsterile.

It was only when we stopped the corticoste-roid treatment and with the development of an-terior uveitis that we linked the pamidronate di-

sodium with the first episodes of severe poste-rior uveitis. We couldnt stop the pamidronatetreatment because of the general condition, andunder cover of corticotherapy, the patient didntdevelop any further adverse effects.

In posterior scleritis, the signs are variable anddepend primarily on the site of maximal in-volvement. Associated anterior scleritis is presentin about 80% of all cases.

It is hypothesized that an allergic or immuno-

logic phenomenon caused by drug-induced im-

mune complex formation is at fault. The rea-son why the uvea is a target organ is unclear.In the differential diagnosis we have to excludethe following causes and associations: idio-pathic, surgically induced, rheumatic disorders,connective tissue disorders, enteropathies, sys-

temic vasculitides, granulomatous diseases andskin diseases.

A recent report described 17 cases of unila-teral scleritis and one case of bilateral scleritisoccurring usually within 6 hours to 2 days af-ter intravenous pamidronate disodium admini-stration (5). In the same study, six patients hadpositive rechallenge testing with the scleritis oc-curring after a repeated drug exposure. Otherocular side effects with positive rechallenge

data, associated with pamidronate disodium,included blurred vision, non-specific conjunc-tivitis, ocular pain, bilateral anterior uveitis andepiscleritis.The acute inflammatory response seems unre-lated to the dose of the drug, the way of ad-ministration, or the activity of Pagets diseaseor malignancy.

CONCLUSION

The two cases presented here are examples ofocular adverse reactions induced by aminobi-phosphonates as we had a very plausible timerelationship to drug administration and positi-ve dechallenge as well as rechallenge data. Theabsence of other drugs or chemicals or of con-current disease that could explain the adverseeffects confirms the hypothesis.

Uveitis and conjunctivitis are well-documen-ted adverse effects of biphosphonates.Pamidronate disodium can cause vision-threat-ening diseases, which may require discon-tinuing or adapting the drug in some uveitiscases and all the cases of scleritis.

BIBLIOGRAPHY

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(2) DE S., MEYER P., CRISP A.J. Pamidronate

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(3) DES GROTTES J.M., SCHROOYEN M., DU-MON J.C., BODY J.J. Retrobulbar optic neu-ritis after pamidronate administration in a pa-tient with a history of cutaneous porphyria. ClinRheumatol 1997; 93-5.

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(7) GHOSE K., WATERWORTH R., TROLOVE P.,HIGHTON J. Uveitis associated with pa-midronate. Aust N Z J Med 1994; 24: 320.

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(12) ODONNELL N.P., RAO G.P., AGUIS-FERNAN-DEZ A. Pagets disease: ocular complica-tions of disodium pamidronate treatment. BrJ Clin Pract 1995; 49: 272-3.

(13) PRESCRIRE REDACTION. Ocular adverse ef-fects of alendronic acid. Rev Presc 2001; 21

(213): 37.(14) REY et al. Uveitis, an under-recognized adver-se effect of pamidronate. Case report and lite-rature review. Joint Bone Spine; 2000; 67:337-40.

(15) RYAN P.J., SAMPATH J. Idiopathic orbital in-flammation following intravenous pamidrona-te. Rheumatology 2001; 40: 956-7.

(16) SIRIS E.S. Biphosphonates and iritis. Lan-cet 1993; 341: 436-7.

(17) STEWART G.O., STUCKEY B.G., WARD L.C.,PRINCE R.L., GUTTERIDGE D.H., CONSTABLE

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Iritis following intravenous pamidrona-te. Aust N Z J Med 1996; 26: 414-5.

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Correspondence to:Prof.dr.Thierry ZeyenDept. of Ophthalmology

A.Z. MiddelheimLindendreef 1B-2020 AntwerpenBelgium

Tel: 0032 3 2803105E-mail: thierry.zeyen @ skynet.be

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