Prevention of Steroid-Induced Intraocular Pressure Elevation

In the November 2003 issue of the ARCHIVES, William C. Stewart and the ISV-205 Study Group¹ reported on the use of prophylactic topical diclofenac, contained in a proprietary formulation, for preventing steroid-induced intraocular pressure (IOP) elevation. I believe that the problem of steroid-induced glaucoma is real and growing, and I commend the authors for tackling this difficult issue with an innovative product. Nevertheless, the study’s conclusions do not seem supported by the available data.

The study builds on experimental suggestions that a steroid-induced gene, TIGR, coding for a trabecular meshwork protein, myocilin, may be associated with steroid-induced glaucoma.^{2 - 4} The study looked at healthy individuals who may be at higher risk of developing steroid-induced glaucoma by virtue of having a close family relative with primary open-angle glaucoma. The study’s design compared 3 groups of patients, all of whom received 1% prednisolone for 6 weeks. The first group also received placebo drops, and the second and third groups received diclofenac drops in a proprietary formulation that contained 0.06% or 0.1% ISV-205 (InSite Vision Incorporated, Alameda, Calif), respectively.

The authors claim that ISV-205 facilitates the activity of diclofenac, which, it has been suggested, inhibits the induction of the TIGR gene that may be associated with steroid-induced IOP elevation.^{2 - 4} Their results suggested that among patients who received prednisolone, patients who also received the diclofenac/ISV-205 proprietary formulation had a lower incidence of elevated IOP. The authors’ conclusion, stated in the title, abstract, and introduction and twice in the conclusion of the article, was “that ISV-205 limited the IOP elevation associated with prednisolone treatment.” I believe that while the results are interesting and warrant further investigation, the data do not seem to support this conclusion.

Because the authors are building on the presumed effect of diclofenac on steroid-induced glaucoma, they state that the proprietary ISV-205 formulation “was designed to prolong the corneal contact of diclofenac to provide sufficient aqueous levels, which may not be available from the commercial preparation, to block TIGR/MYOC gene induction.”¹ However, no data to support any of this are offered.

Even if one believes that diclofenac can prevent steroid-induced glaucoma (through TIGR inhibition or not), the present study falls short on a basic design flaw. The study design simultaneously altered 2 variables without including appropriate controls. The study compared patients who were taking prednisolone plus placebo with patients taking prednisolone plus the proprietary diclofenac/ISV-205 polymer combination. Because this work rests on the argument that diclofenac alone may inhibit TIGR expression, the study should have compared patients taking diclofenac alone with patients taking diclofenac plus ISV-205 in addition to using a placebo control. In the absence of this direct comparison, it may be unfair to make the authors’ conclusions: it may be argued that diclofenac was responsible for all of the observed effect and that ISV-205 made no difference. Despite this, only ISV-205 is mentioned in the title, and the stated conclusions, such as the one quoted here, promote ISV-205. Meanwhile, diclofenac’s effects are not addressed, and a direct comparison between diclofenac and the proprietary ISV-205 formulation is never made.

The subject of a possible association between TIGR/myocilin and glaucoma is intriguing but controversial. In the discussion, the authors had an opportunity to address the subject thoroughly and provide important references. However, this was not done. For example, a well-done study on the possible association between myocilin gene mutations and steroid-induced glaucoma failed to reveal such an association.⁵ The authors did not discuss these findings. The authors refer to work that presumably showed that “diclofenac dose dependently inhibited the induction of TIGR/MYOC protein in human trabecular meshwork cells treated with dexamethasone. . . .” This, too, is a controversial conclusion, only scantily supported in the literature. In fact, to the best of my knowledge, no articles in the major peer-reviewed ophthalmology journals present such data. This also was not discussed by the authors. Instead, they referenced meeting proceedings, journal supplements, and abstracts.^{6 - 8}

In the absence of further analysis of diclofenac levels in the aqueous of their patients, alternative explanations for the observed effects may exist. These were neither presented nor discussed. Instead, the authors stated, “The reason why the IOP elevation was blunted is not known exactly, but it presumably was due to diclofenac in the ISV-205 formulation blocking the induction of the TIGR/MYOC protein. . . .” But if diclofenac was the active ingredient, why was the proprietary ISV-205 even needed? This point was not addressed because a direct comparison between diclofenac alone and diclofenac/ISV-205 was not made.

In summary, I believe that the authors chose an important subject to study and may have a unique and clever tool that may be shown in the future to help certain patients. The present study, however, falls short of the stated conclusions. Further research into the efficacy of diclofenac alone, and the possible contribution of ISV-205, may be warranted.

Correspondence: Dr Kahana, Mail Stop F4/3, Department of Ophthalmology and Visual Sciences, University of Wisconsin, 600 Highland Ave, Madison, WI 53705 (a.kahana@hosp.wisc.edu).