Sirolimus eye injections given orphan drug status

Sirolimus has been given orphan drug status, which suggests that the studies carried out at various institutions have shown positive results. It is still being trialled as  part of a phase 3 study (see attached link.)

This drug given as an invitreal injection, was discussed at the Birdshot Day 2012. We were told that the risk of developing glaucoma and cataracts as an adverse effect of sirolimus may be lower than the risk associated with steroid treatment.

We await more information, but it is possible sirolimus might be a useful alternative treatment for people with Birdshot, especially for those who fail to achieve remission on the Cellcept (mycophenolate mofetil)/ cyclosporin formula.

Vitamin D Research

Recent research into Vitamin D  reported in Food Consumer, the Daily Mail, and the Daily Express, amongst many, shows a potentially interesting relationship between Vitamin D levels  and eye health.  The research funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have found that vitamin D reduces the effects of ageing in mouse eyes and improves the vision of older mice significantly.

The research was carried out by a team from the Institute of Ophthalmology at University College London and is published in the current issue of the journal Neurobiology of Ageing.

Professor Glen Jeffery, who led the work, explains “In the back of the eyes of mammals, like mice and humans, is a layer of tissue called the retina. Cells in the retina detect light as it comes into the eyes and then send messages to the brain, which is how we see. This is a demanding job, and the retina actually requires proportionally more energy than any other tissue in the body, so it has to have a good supply of blood. However, with ageing the high energy demand produces debris and there is progressive inflammation even in normal animals. In humans this can result in a decline of up to 30% in the numbers of light receptive cells in the eye by the time we are 70 and so lead to poorer vision.”

The researchers found that when old mice were given vitamin D for just six weeks, inflammation was reduced, the debris partially removed, and tests showed that their vision was improved.

Professor Jeffery said “Researchers need to run full clinical trials in humans before we can say confidently that older people should start taking vitamin D supplements, but there is growing evidence that many of us in the Western world are deficient in vitamin D and this could be having significant health implications.”

Birdshot Uveitis Society is very interested to find out more about this piece of research, particularly as one or two of our members have told us that they believe that vitamin D may have helped their eye problems.    We are contacting the researchers to  find out more about this.

Four important points to note:

  • At this stage there is only scientific evidence that the eye sight of the mouse improves.  There have yet to be trials on humans.
  • Too much Vitamin D can be harmful, so it needs to be monitored.
  • We would never advocate that members add in extra supplements without first discussing  with the specialists who treat them.
  • Seemingly harmless supplements can put extra strain on your liver and kidneys or interact with your other medications

Possible increased risk of opportune infection

BUS did not think that the results of this study were really that surprising, given the fact that immuno-suppressants suppress the immune system it is likely that you may suffer from infections of various sorts, whether it is cystitis, sinusitis, colds or flu or something more serious like cytomegalovirus colitis and viremia.

The following paper entitled “Cytomegalovirus colitis and viremia from mycophenolate mofetil monotherapy in birdshot chorioretinopathy” was published in Ocul. Immunol. Inflamm. 2011 Dec; vol. 19(6) pp. 450-2.

Author: Pantanelli SM, Khalifa YM

The paper describes a case of cytomegalovirus (CMV) viremia and colitis in a patient on mycophenolate mofetil (MMF) monotherapy for birdshot chorioretinopathy. It showed that treatment with MMF 1.5 g twice daily for 5 years led to leucopenia and a CD4 count of 299, which resulted in active CMV infection.

The papers conclusion was that treatment with MMF alone may put otherwise immune-competent individuals at risk for opportunistic CMV infection. It is hope that awareness of this possible association may allow for better monitoring, earlier detection, and treatment in future cases.

PMID: 22106917

URL – http://www.ncbi.nlm.nih.gov/pubmed/22106917?dopt=Citation

HLA-A29 and Birdshot Chorioretinopathy

The link between HLA- A29 and Birdshot Chorioretinopathy is one that interests many people and the paper published by:  Brézin AP, Monnet D, Cohen JH, Levinson RD, on this subject asks the question:

Why do people of European descent tend to get Birdshot, whilst other ethnic groups who also carry the HLA A29 antigen do not?

The paper explains that there are two different subtypes of HLA29A:- HLA29:02 is most frequent in caucasians, whilst HLA29:01 is most frequent in Asians.

It used to be thought that the disease only appeared in people with the HLA-A29:02 version of the antigen.  The paper tells us that is no longer a valid argument.   It suggests that another factor, probably not HLA linked, is either protective in Asians and in Africans or, alternatively, triggers an autoimmune reactivity that is possibly present in Caucasians of european descent and absent in Asians and in Africans.

We might start to make progress if scientists can find the answer to what this might be.

We are trying to get hold of the full research paper so that we can review it in detail.

 

Using Indocyanine Green Angiography for Birdshot

We came across a piece of French research (published in September 2011) that is very timely in reminding professionals that ICG – Indocyanine Green Angiography (green dye is injected into blood stream and quickly reaches the blood vessels at the back of the eye, which can then be photographed) is still a very useful tool for people with Birdshot as it can identify leakages that are hard to see by other methods such as Optical Coherence Technology (OCT).

This is yet another example of an ‘old’ method that, although superseded by a range of new methods, still has a part to play in our disease and should remain as one of the several monitoring and diagnostic tools used for Birdshot.

Here is an abstract from that research:

Desmettre T, Cohen SY, Devoisselle JM, Gaudric A

“A full interpretation of indocyanine green angiography images involves not only optical issues but also pharmacokinetic and biochemical aspects. These issues may involve biochemical changes in the fluorescence yield and the affinity of the molecule for lipoproteins and phospholipids. For age-related macular degeneration (AMD), the advent of photodynamic therapy and especially anti-VEGF drugs has increased the use of OCT in assessing treatment response and guiding retreatment. The ease and advantages of OCT have become increasingly associated with a decreasing interest in ICG angiography, which is becoming less well suited for the current management of AMD. An aging population, the efficacy of anti-VEGF drugs and the relative rarity of polypoidal choroidal vasculopathy (PCV) in Europe are factors contributing to our proportional increase in AMD patients. However, aside from AMD, the indications for ICG angiography remain little changed over the last decade: it remains important in diagnosing PCV and choroidal hemangiomas, since their prognosis and treatment are specific. Similarly, for certain inflammatory conditions such as Multiple Evanescent White Dot Syndrome (MEWDS) or Birdshot chorioretinitis, the value of ICG angiography remains significant. In addition, for the treatment of chronic Central Serous Chorioretinopathy, ICG angiography helps to find sites of leakage which otherwise might have been missed. The ICG angiographic appearance in this setting may also have prognostic value. Although the indications for ICG angiography are currently decreasing for AMD, these other conditions represent a large enough number of patients to justify the continued use of this original test, which remains complementary to other chorioretinal imaging techniques.”

The full article can be found at: http://www.ncbi.nlm.nih.gov/pubmed/21907446?dopt=Citation

Topical Interferon Gamma for Macula Oedema caused by Uveitis

We have a report on a clinical trial that seems to be still recruiting participants (although it is expecting to complete its primary investigations this month). It is being carried out by Robert Nussenblatt at the National Eye Institute in Bethesda in the US. This trial is researching Interferon Gamma–1b administered topically in a drop form rather than by infusion for people who have macular oedema as a result of uveitis (macular oedema can be a complication of Birdshot). This trial may be of interest to our US members, and more information can be found at

http://clinicaltrials.gov/ct2/show/NCT01376362

The trial will be looking for the change in excess central macular thickening as measured by OCT in response to interferon gamma-1b.

Below, we give a brief summary of the trial and who they are looking for:

Brief Summary

Background: – Uveitis is a serious eye condition in which the immune system attacks the eye and can cause vision loss. A common problem related to uveitis is macular edema. This is a swelling of the central part of the retina. This part of the retina is needed for sharp, clear vision. This swelling can lead to more vision loss. – Interferon gamma-1b is a lab-created protein that acts like the material made by the white blood cells that help fight infection. It changes the way the immune system reacts to the cells in the eye and may help to lessen the swelling in the back of the eye. It has been used as an injection to treat other immune diseases, but it has not been tested as an eye drop for use in uveitis other than a safety trial done at NIH in 2010.

Objectives: – To test the effectiveness of interferon gamma eye drops to treat macular edema caused by uveitis.

Eligibility: – Individuals at least 18 years of age who have autoimmune uveitis in one or both eyes, have had it for at least 3 months, and as a result have macular edema in at least one eye.

Design: – This study requires three visits to the study clinic over about 2 weeks. Each visit will last 1 to 2 hours.

Pars Plana Vitrectomy for people with Birdshot?

Some of us with Birdshot experience real problems with floaters. Most affected individuals manage to get used to floaters and find a way of seeing ‘past’ them, but for a minority, the floaters cause significant visual problems on a daily basis.

When we face this situation, we may be told that getting rid of the floaters by undergoing a vitrectomy may cause more problems than it solves, especially if we are in flare-up or have active inflammation, so few people are offered a vitrectomy. Vitrectomy is the surgical removal of the vitreous gel from the middle of the eye, where the floaters are.

This research study, which was conducted in Spain, evaluated the anatomical and functional outcomes of using the pars plana vitrectomy (PPV) in the treatment of vitreoretinal complications (floaters) of Birdshot. The pars plana is part of the uvea choroidea, one of the three layers that comprise the eye.

This was a small study, looking at 9 patients with 16 affected eyes who had received a pars PPV and the study concluded that PPV seems to be a safe and effective treatment of vitreoretinal complications in patients with Birdshot.

Obviously, this is a very small study and it is difficult to draw too many conclusions from it, but for those of us who are very badly affected by floaters, it may be something you wish to talk to your consultant about so you can fully understand both the risks and the benefits.

You can get full details of the study at: PMID: 21823933  URL – http://www.ncbi.nlm.nih.gov/pubmed/21823933?dopt=Citation

Adalimumab (Humira ®) Long-term Safety Trial

Some of us with Birdshot are currently using adalimumab (Humira®). Rea from BUS is one of those people. We recently came across a study looking at the safety and effectiveness of long-term use of adalimumab for people with intermediate-, pan- and posterior-uveitis. This study is currently recruiting by invitation only as you do need to have been involved in the previous related studies in order to qualify.

It is being conducted across 63 locations in the US, Europe and the UK.  In the UK there are three sites: London, Bristol and Aberdeen.

This study is a Phase 3, open-label multicentre study designed to evaluate long-term safety and efficacy of adalimumab in a group of  adult subjects with non-infectious intermediate, posterior, or pan-uveitis.

If any of our members are enrolled in this study, we would be grateful for feed-back on this.

URL: Long term safety and efficacy of adalimumab in subjects with intermediate, posterior and panuveitis

 

 

 

 


Methotrexate Drug Used as an Invitreal Injection

Some weeks ago we wrote about a novel treatment trial Involving a relatively old immunosuppressant – sirolimus – being used in a new way as an invitreal injection. https://birdshot.org.uk/sirolimus-eye-injections-given-orphan-drug-status/.

Recently we discovered a similar trial, but this time using a different immunosuppressant – methotrexate – as an invitreal injection.

The trial is looking at people who have chronic macular edema (the American spelling – in the UK we spell it oedema) as a secondary or complication to their Birdshot or other form of intermediate or posterior uveitis. The macular edema must affect at least one eye that has not responded to conventional immunosuppressive therapies over the previous 3 months or has recurred while on conventional immunosuppressive therapies. Methotrexate is injected on a monthly basis for 3 months and then as needed. This trial is openly recruiting in Bethesda USA.

This information might be useful for our American members. If you are interested in more information about it you can contact Patient Recruitment and Public Liaison Office prpl@mail.cc.nih.gov (800) 411-1222 TTY 1-866-411-1010

If any of our American members are already on the trial or are thinking of registering for it, we would be really grateful to hear about your experiences. If this therapy proves to be successful, we hope that this will add to the growing range of medications that help us preserve our visual acuity.

Here is a brief summary of the research:-

Uveitis comprises a group of diseases associated with inflammation of the eye that can lead to vision loss. Some people with uveitis also have macular edema (swelling of the retina at the back of the eye). Uveitis and macular edema are treated with medications and sometimes surgery, but treatment does not always prevent vision loss. Previous research has shown that injections of methotrexate into the eye of people with eye disease other than uveitis can help relieve the inflammation, or swelling, that causes macular edema and can slow visual loss. However, it has not yet been approved as a treatment for macular edema associated with uveitis. The objective of the study is to evaluate the safety and effectiveness of methotrexate injections as a treatment for macular edema associated with uveitis. This study requires at least nine visits to the National Eye Institute study clinic over a period of 6 months (24 weeks). Participants will be screened with a full physical and ophthalmic examination, a medical history, blood and urine tests, and additional eye and other tests as needed. An oral dose of folic acid is taken the day after the injection. Participants who tolerate the initial injection may continue to receive injections in their study eye every month for 6 months. After 6 months, participants who show improvement from the injections may be evaluated to receive additional injections every 4 to 8 weeks until researchers end the study.

URL:  Trial using Methotrexate drug as an invitreal injection

T cell response to retinal proteins

Various diseases can be diagnosed by testing for biomarkers, a particular substance in the blood or tissue (e.g. troponin to determine whether someone has had a recent heart attack). So far there are no specific biomarkers for determining whether a patient has non-infectious uveitis. Using a mouse model of autoimmune uveitis, Mattapallil et al. found T-cells activated against a particular protein in the retina (retinal arrestin). This provides support for the theory that autoimmune uveitis is caused by the body attacking the retina and may lead the way to developing a blood test for diagnosing this disease.

Uveitis-Associated Epitopes of Retinal Antigens Are Pathogenic in the Humanized Mouse Model of Uveitis and Identify Autoaggressive T Cells.  (Journal of immunology (Baltimore, Md. : 1950). 2011 Jul 15;PMID: 21765017)

URL – http://www.ncbi.nlm.nih.gov/pubmed/21765017?dopt=Citation