Does Cyclosporin only work in young patients with Sjogrens syndrome?

[RAMESH DORAIRAJAN]

Dear Friends,

I am sharing a discussion in another group about the use of cyclosporine in all forms of dry eye.

I am curious what other think about the efficacy of Restasis for dry eyes.

Over the years I have tried Restasis on many patients and I have many patients who come to my practice already on Restasis. I always ask the same question, did your symptoms improve when you started Restasis? Over 90% of the time I get a blank stare and a response that they don’t know if it has made any difference. 

I just pulled the phase 3 study for Restasis (Two Multicenter, Randomized Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye Disease, Ophthalmology April 2000). I reread the study and I am attaching the study to this e-mail. 

If you are like me and have your doubts about the results you would have pulled this data from the study:

1. There was no significant difference in conjunctival staining comparing CsA to the Vehicle
2. There was no significant difference in Schirmer’s test WITHOUT anesthesia comparing CsA to the Vehicle
3. There was no significant difference in subjective dryness sensation comparing CsA to the Vehicle
4. There was no significant difference in subjective sandy/gritty sensation comparing CsA to the Vehicle
5. There was no significant difference in subjective itching sensation comparing CsA to the Vehicle
6. There was no significant difference in subjective burning and stinging sensation comparing CsA to the Vehicle
7. There was no significant difference in subjective pain sensation comparing CsA to the Vehicle
8. At 6 months the “Physicians Subjective assessment of Global response” for patients judged to have a slight response or better at 6 months was 68.5% in the CsA 0.05% group, 67.3% in the CsA 0.1% group, and 63% in the VEHICLE group. Hardly compelling!
9. All patients were allowed to use Refresh artificial tears as much as they wanted concomitantly during the study. These were provided fee if charge. It would be difficult to know how this altered the results. I am not sure this is a good study design. 
10. They used 2 concentrations of CsA in the study: 0.05% and 0.1%. The 0.1% performed worse than the 0.05% in almost all categories. In other words, there was no dose related response as you would normally see in a drug study. 


Although much of the results showed no difference from the Vehicle the following showed some improvement compared to the Vehicle.

1. At 4 and 6 months the CsA showed statistically less corneal staining compared to the vehicle. However, they graded corneal staining on a 0-5 scale. The actual difference between the groups looks like only 0.3 maximum on a 0-5 scale. Although a statistician found this to be statistically significant it seems somewhat bogus to me since 0.3 is an extremely minor difference on a 0-5 scale of corneal staining, that is somewhat subjective to begin with.

2. At 6 months CsA was showed a statistically significant improvement in Schirmer's Values WITH anesthesia. Again they used a 0-5 scale with the difference being the groups being only about 0.5. This would equate to a difference between 1mm and 2mm on the actual scale that we use. Again, this is minimal on a test that in my opinion is inherently inaccurate. 

So the bottom line is that CsA failed on many fronts to provide improvement but succeeded in two categories, both of which used scale values that seem inherently inaccurate. 

I encourage everyone to read the article themselves and give me their opinions. When I read the article my conclusion is that same that I have had in clinical practice. The improvement with CsA is minimal at best.

I should mention that the Vehicle is castor oil and there is a suggestion in the discussion that this in itself is providing relief to patients. I am not convinced the cyclosporine makes a huge difference despite the science behind it.

 

 

 

My patients who had the patience to use Restasis for at least 6 months were rewarded more often than not with improved comfort, and continued to imperceptible for another 6-18 months. NFI.

 

 

 

 

When I was practicing, I tried Restasis quite a bit, and was distinctly unimpressed, so no Matt, I don't think you are wrong. I think for those patients who had aqueous dry eye related to aging, hormone depletion, etc, it did nothing that was clinically significant. In addition, I had very few patients who would be willing to use a somewhat expensive drop bid for a six month trial, so I think compliance with the drug was significantly poorer than with glaucoma meds. That said, I did think it worked somewhat in those patients that had a true Sjogren's syndrome, ie definite diagnosis of an autoimmune connective tissue disease or positive test for Sjogren's antibodies. That made sense to me since the drug is an immune suppressant. Since I have now been retired 3+ years, i have no experience with Xiidra That's my two cents.

 

 

the effect of Restasis takes 3 -6 months to maximally kick in and 3 months or more to kick out.   After 1 or 2 months there might not be that much difference between 2 eyes but I can tell you from personal experience that Restasis does work to reduce LG staining and improve patients with aqueous deficiency dry eye.  I had a problem myself as did my office manager and we both benefitted from it’s use but it takes a long time to work and in the beginning we both hated it.    It does not work well for little old ladies with blepharitis but it can be a god send for younger patients with Sjogrens.

 

 

 

 

 

I don't have a ton of experience but will chime in because I too frequently see patients who are already on Restasis and who ask me if it is helping.  I turn the question back on them and they almost always shrug their shoulders.

 

When I was a fellow one of my mentors (I believe Andrew Huang) used to ask these patients to stop taking it in one eye only for a month or so (if they were interested).  If, after a month or two the two eyes felt the same they would just stop it.  If at any time they felt the eye being treated felt better than the untreated eye they would restart in the other eye.

 

If I remember correctly 99.9% of the patients concluded that it was basically an expensive artificial tear and stopped it.   Interestingly, an allergan rep recently gave me coupons for Restasis and stated something along the lines of: "If the patient uses one vial per day and buys 90 days at a time with this coupon it will actually be cheaper than artificial tears".  Made me laugh.  Didn't Allergan pull Endura off the market once Restasis was available? 

 

 

 

Thank you for taking the time to share this.  Before trialing Restates on patients, I share my experience and observations with them:  about 25% like it and feel it helps them and the remaining 75% are equally divided between those who feel it does nothing and those to hate it because of burning/ stinging issues.  I also tell them to trial the drop for at least 3 months before making a decision.  I'd appreciate folk's opinion on Xiidra compared with Restates.