Is low dose methotrexate an effective Birdshot treatment ?

Methotrexate is a cancer drug that has been used since the 1950s. It acts by inhibiting the metabolism of folic acid. In low doses, methotrexate is a safe and well-tolerated drug in the treatment of certain autoimmune diseases.

A study in Holland (by Rothova A, Norel AO, Los LI, Berendschot TT) looked at the effectiveness of low-dose methotrexate treatment for Birdshot Chorioretinopathy and how well it prevented visual loss in Birdshot

The retrospective case series involved 76 patients with HLA-A29 positive BSCR. 46 of these patients were followed for 5 years, 18 for longer than 10 years.

The treatment regimens were divided into the three groups:

1) No systemic immunomodulatory treatment

2) Treatment with systemic corticosteroids

3) Treatments with methotrexate

The group of patients who had methotrexate treatment showed better visual outcomes than those patients on just corticosteroid-based treatment (visual outcomes remained unchanged). The untreated patients visual outcomes were worse.

(Retina 3 March  2011)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21386763

Birdshot Chorioretinopathy Research Network

We have finalised a date  for the inauguraBirdshot Research Network meeting, to be held in  Birmingham on Tuesday 18th October.  We have written to a few uveitis consultants, but it is possible that we may not have written to yours.  If you are keen for your consultant to be involved in the Birdshot Research Network you can ask them for us by printing off a copy of the letter that you  will find here  and giving it to them yourself.   We would love as many Birdshot specialists to be involved as possible, but unfortunately spaces at the meeting are quite limited, so they will need to get in touch with us  quickly to let us know of their interest.

Thanks

Annie and Rea

NB Unfortunately this post applies only to people in the UK.


Vitamin D – the Sunshine Vitamin

Many of us know from personal experience how osteoporosis can affect one’s quality of life. The drugs commonly used for Birdshot Chorioretinopathy treatment can put you at risk.

Bone health is something that anyone who is on prednisolone for any length of time must discuss with their her/his GP. The risk to your bones from steroids increases with higher doses of steroids (prednisolone) for periods of three months or more. The problem is that when you are first prescribed steroids for Birdshot, you just do not know how long you are going to be on them as no one can be sure how hard the disease is going to be to treat.

The question is what do you do to prevent bone loss?

Vitamin D is a crucial ingredient in the process of absorbing calcium and potassium into the body. Sadly more than 50% of the normal UK population have insufficient levels of vitamin D and 16% have a severe deficiency. (Pearce and Cheetham 2010/Hypponen and Chris Powers 2007).

Vitamin D has a complex absorption pathway. It is produced in the skin by a photochemical reaction that is stimulated by sun rays (ultra violet light). The amount of sunlight required to obtain adequate vitamin D is approximately 20 minutes a day (Holick 2002) outside of peak sunshine levels. So the best way to produce vitamin D is to have unprotected sunshine exposure for about 20 minutes a day, exposing only less sensitive skin parts such as the arms and legs in the morning and afternoon/evening.

Skin pigmentation comes into play as well. If you have dark skin you require approximately six times more sunshine than people with fair skin. Also people with a history of caridovascular disease, obesity, history of cancer, malabsorbtion disease and renal disease have a higher risk of being vitamin D-deficient.

If like most people with Birdshot, you are on immuno-suppressants as well as steroids at some point in your treatment, you are likely to be following the instructions to cover up and use high-factor sun creams to avoid the skin-cancer risks. You are therefore more likely to have low vitamin D levels.

Only a relatively few foods contain substantial amounts of vitamin D. The best sources are oily fish and cod liver oil. Farmed fish may have less vitamin D than wild fish. Egg yolk, oliver and wild mushrooms contain small quantities but the amount in most vegetables is negligible.

You might like to look at this website if you are interested in checking nutritional information for food.

The recommended daily intake for vitamin D is 400 IU per day for an adult and unless we consume this recommended amount, we are all at risk of osteomalacia and even rickets.

If you don’t already take a calcium-vitamin D supplement, please ask your GP about it because you may need it, at least whilst on steroids. (You can have blood tests to determine if you are deficient or not, and tests to check on your calcium absorption.)

Important message to take home:

  • Calcium should not be taken at the same time as mycophenolate mofetil (Cellcept ®) as it may decrease the absorption of mycophenolate by your body and hence reduce the effectiveness of the it. You should take calcium supplements as many hours apart as possible to reduce this potential.
  • It is really important to discuss taking calcium and vitamin D with your GP because, for some people, excess vitamin D can cause problems – e.g. if you have sarcoidosis (which can also affect the eyes) excess vitamin D can make sarcoidosis worse.
  • Weight-bearing exercise does help to promote healthy bones; go to the gym; take the stairs as opposed to the lift; wear a ruck sack with a litre bottle of water in it while you do the house work; go swimming; take up belly dancing or whatever you fancy. Remember that exercise is also great for reducing inflammation, and Birdshot is an inflammatory disease.
  • Exercise will also help to prevent the likelihood of falls and consequent broken bones because your muscles will be stronger.

We cannot emphasise enough that any exercise is better than none!

 

 

Sirolimus – New approach, Old Drugs

We read about a phase 2 trial on the Birdshot Lefora Forum. The trial is being conducted at Johns Hopkins University, USA with sirolimus, also known as rapamycin and Rapamune®. Sirolimus is an immunosuppressant that inhibits the response to interleukin-2 (IL-2), and therefore blocks activation of T- and B-cells. It has a similar immunosuppressive effect to tacrolimus, but tacrolimus inhibits the production of IL-2 (rather than inhibiting the response).

This seems like a promising trial and, depending on the results, sirolimus may well be yet another useful medication for people with Birdshot who do not respond so well to the ‘traditional’ medication regimen of prednisolone and mycophenolate mofetil.

The clinical trial information below was obtained from http://clinicaltrials.gov/ct2/show/NCT01280669

Phase 2 of the trial is looking at the safety and effectiveness of two different doses (440mcg/mcL and 880mcg/mcL) of sirolimus, administered intravitreally (injections inside the eye) in patients with uveitis.

The trial is examining whether these doses can be used to control inflammation in non-infectious uveitis, whilst avoiding the potential complications associated with systemic drugs (i.e. drugs that are administered orally, subcutaneously, intramuscularly, or intravenously and thus can affect the whole body). Therefore, if proven effective, it may offer a safer way of controlling inflammation.

It does seem that quite a lot of work is now being undertaken around a range of non-systemic solutions – we have already reported on Retisert® and Ozurdex® – and non-systemic therapy may well be a safer way forward.

Birdshot Patients’ experience

It is early days but this is the latest news on the novel sirolimus treatments that we have heard from 2 people who have been on this particular trial.

” I was in the first sirolimus clinical trial at Hopkins and I’m waiting for the second series to begin. It has been approximately 6 months that I have not received injections and I’ve only had a couple of flare-ups. I can not tolerate steroids and Cellcept®, LX211 was ok, but taking 12 pills a day was not something I liked to do. The shots are my choice, one in each eye every other month. There will be a new sirolimus trial beginning any day now. I recommend it.” February 2011

Here is another person’s positive experience. This time on Phase 2.

“It has now been 5 months and I think I am doing great! I am going thru a battery of tests next month, but I am hopeful I will receive good results. What I do know is I am off Cellcept® and Neoral®since November, and prednisone has been reduced from 60mg to 8. I no longer have floaters, flies or other types of bugs and the glare has greatly improved. So much in fact I can drive at night under certain conditions. Johns Hopkins is starting Phase 2 and 3 at the same time and they are having great results with more than one disease. I think it is wise to learn more about this trial.

I believe 200 hospitals will also be doing this trial very soon. Sirolimus is the drug that is injected. So far so good. The only side effect I have had so far is loss of hair, but it is slowing down on the amount of hair lost.” June 2011

A bit more about Sirolimus

Sirolimus (also known as rapamycin) is an old drug. It was approved by the FDA in 1999. It was originally developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties. It has since been shown to prolong the life of mice and might also be useful in the treatment of certain cancers.

What’s of interest for us?

 

  • Compared to calcineurin inhibitors (such as ciclosporin, tacrolimus, azathioprine), it is less likely to cause kidney damage.
  • It is available in generic versions so it is not prohibitively expensive.
  • It has been used for some time for other conditions (not for uveitis) so its side effects are generally known.
  • There should be no systemic side effects as it is being injected invitreally.

We look forward to hearing the full results of the study once it is completed. If it is being rolled out across 200 hospitals it is possible that some of these hospitals could be in the UK.

 

 

Research on targeting B Cells

A study, undertaken by scientists in Russia and published in June 2011 has looked at targeting B Cells as a potential way of controlling autoimmune diseases.

Some of us are already on a medication called Rituximab which targets B cells.  Rituximab is a monoclonal antibody which works on a protein found on the B Cells and which may be implicated in our auto-immune disease, Birdshot.  We know that Rituximab seems to work for some people but not for everybody, and we also know there are some side effects of Rituximab.

The Russian study looked at a way of more effectively targeting the B Cells with less toxic side effects, and the study seems to suggest that they have found a possible way forward.  Wonderful – yet another possibility for us.

The full study can be found at:

http://www.ncbi.nlm.nih.gov/pubmed/21677771?dopt=Citation

 

Invitreal implant for Non-infectious uveitis

This study looks at eyes receiving fluocinolone acetonide implants  (Retisert) over a 7 year period and concludes that there is a high risk of developing cataracts and increasing intraocular pressure  (glaucoma).   The study authors include people who were involved in the Bausch and Lomb trials.

This type of  implant is not currently licensed for use in the UK, so you would have to be an extremely special circumstance to qualify for this type of treatment at the moment.

However for those with Birdshot, with bad inflammation, who can not tolerate sytemic steroids they do provide a potential, if not ideal option for treating inflammation in the eye.

http://www.ophsource.org/periodicals/ophtha/article/S0161-6420(11)00229-6/abstract

You can also see  our earlier post about this type of device: –https://birdshot.org.uk/dexamethasone-for-ocular-inflammation/

Is green tea more than just good for you?

Some novel research has been undertaken into Green Tea.   It was published in Immunology letters 2011 May 20, and is entitled:- “Induction of regulatory T cells by green tea polyphenol EGCG.”

The study  provides evidence as to why green tea might help to modify  immune system behaviour and hopefully provides the foundation for future studies to further examine and evaluate dietary strategies to see if they might be used to help to control the immune system.

We are not sure how many of gallons of green tea you would need to consume to produce the required effect!

If you want to read more technical detail about this research, follow the link below.

URL – http://www.ncbi.nlm.nih.gov/pubmed/21621552?dopt=Citation

We know some of our members have told us that they like to drink green tea in the hope that it might do them some good.    If you are interested in some green tea recommendations – here are some  varieties to try, courtesy of our Ozzie friend Neil who has obviously got into it in  a big way on a work trip to China.

I had a ten day aid mission to Chong Qing central China and fell ill on inward flight with shocking cold and cough.

All meetings with Chinese involved a thermos of green tea.  I found it stopped my cough so I became the green tea monitor for the duration and the Chinese thought I was a definite convert!

For variety, try japanese green tea with baked rice flavour added.

Mid level good quality green tea is called Long Jin

Personally, I hadn’t thought of it for wider use than digestion.”  Neil

anti-VEGF treatment for complications of Birdshot

An important piece of research about treatment with anti-VEGF (anti vascular endothelial growth factor) for complications of Birdshot (and other inflammatory chorioretinal diseases) has been published.  The complications tend to be macular oedema (ME) and choroidal neovascularisation (NVC).  Some of you have been prescribed these anti-VEGFs – the most common of them being Lucentis (called ranibizumab) and Avastin (called bevacizumab).

The research findings seem to show that there have been positive results in retaining visual acuity for many people with complications when using these medications.  However, the researchers also point out that it has not been possible to undertake randomised clinical trials for people with uveitis who have macular oedema or neovascularisation and are on anti-VEGF, so they are suggesting that further trials and longer follow up is needed.   For us, it is another piece of preliminary good news, and another weapon in our armoury against Birdshot and its complications.  We recognise that further testing is required, but at least it gives us another option.

This research was conducted in Italy and we attach below a summary of the findings.

Dev Ophthalmol. 2010; vol. 46 pp. 84-95

Antivascular endothelial growth factors for inflammatory chorioretinal disorders.

Battaglia Parodi M, Iacono P, Verbraak FD, Bandello F

Macular edema (ME) and choroidal neovascularization (CNV) can complicate the course of several inflammatory chorioretinal diseases, leading to a severe visual function impairment. The most frequently involved clinical entities include for example multifocal choroiditis, presumed ocular histoplasmosis syndrome, Beçhet’s disease, multiple evanescent white dot syndrome, birdshot chorioretinopathy, acute multifocal posterior placoid pigment epitheliopathy, serpiginous choroiditis, and persistent placoid maculopathy. Results that have reported on antivascular endothelial growth factor (anti-VEGF) treatment in uveitic patients with CNV or ME have demonstrated positive results in many cases. However, bearing in mind that it has been proven impossible to perform randomized clinical trials with anti-VEGF in uveitic patients with CNV or ME, further studies with longer follow-ups are necessary to assess the value of this therapeutic approach.

PMID: 20703034
URL – http://www.ncbi.nlm.nih.gov/pubmed/20703034?dopt=Citation

Killer Immunoglobulin-like Receptor Genes

This piece of research was undertaken by Ralph D. Levinson who is based in California, USA.   It is published in the Ocular Immunology Inflammation Journal 2011 Jun; vol. 19(3) pp. 192-2011.

The research looked at the function and genetics of killer immunoglobulin-like receptors (KIRs) and of KIR genetic associations within uveitis by reviewing a number of previously published studies.

This is an important piece of research, and although we are not scientists or researchers, we are attempting a layman’s explanation of KIRs here.

KIRs are proteins which are found on certain cells of the immune system.  The cells that KIR are found on are called natural killer cells (NK).  In essence, the KIRs enable the NK cells of the immune system to detect and attack certain viruses and tumours.   KIRs seem to differ between individuals and there is a genetic component to what type of KIRs you have.  There is a view that auto-immune types of uveitis may predominate in certain individuals with certain kinds of KIRs.

Ralph D Levinson reviewed all the publications and research relating to KIRs and uveitis, particularly Birdshot, Vogt-Koyanagi-Harada (VKH) disease, HLA-B27-associated acute anterior uveitis (AAU) and axial spondyloarthropathy.  He found evidence that Birdshot appears to have a high incidence of particular patterns of KIRs and he has suggested that this shows evidence of the implications of these KIRs in Birdshot.  He suggests further research into this subject.

This complex research contributes towards a better understanding of  what is actually happening when we get Birdshot Chorioretinopathy.  We hope that this increased understanding may be an important step along the path towards better treatment for us all.

Below, there is an abstract from the research findings, which those of you with better scientific knowledge than us may be able to understand better than us!

Source

Ocular Inflammatory Disease Center, Jules Stein Eye Institute and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, USA.

Abstract

Purpose: to review the function and genetics of killer immunoglobulin-like receptors (KIRs) and studies of KIR genetic associations with uveitis. Methods: Review of published studies. Results: KIRs are receptors on NK and some T cells. They may inhibit or activate cellular function, such as cytotoxicity and cytokine production. Studies have been published examining KIR gene associations with birdshot chorioretinopathy (BCR), Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27-associated acute anterior uveitis (AAU) and axial spondyloarthropathy. Evidence for increased activating and/or less inhibitory KIR and HLA gene combinations was found for BCR and VKH disease. In HLA-B27-associated disease, a trend toward decreased activation and stronger inhibition was found, except for the weakly inhibitory 3DL1 and Bw4(T80) combination. This latter combination was also found to confer risk in BCR. Conclusions: KIR genetics are complex, as are the functions of KIR-bearing cells. Nonetheless, evidence for KIRs in the pathogenesis of uveitis has been found.

The results of the study showed that  KIRs are receptors on NK and some T cells. They may switch off  or switch on cellular function, such as cytotoxicity and cytokine production. Studies have been published examining KIR gene associations with Birdshot Chorioretinopathy , as well as other types of uveitis.    Evidence for increased activating and/or less inhibitory KIR and HLA gene combinations was found for Birdshot Chorioretinopathy. and VKH disease. In HLA-B27-associated disease, a trend toward the opposite was found, except for the weakly inhibitory 3DL1 and Bw4T80 combination. This latter combination was also found to confer risk in Birdshot.

The conclusion was that  KIR genetics are complex, as are the functions of KIR-bearing cells. Nonetheless, evidence for KIRs in mechanism by which the disease is caused in uveitis has been established.

You can read more at: http://informahealthcare.com/doi/abs/10.3109/09273948.2010.538798

or at PMID: 21595535

URL – http://www.ncbi.nlm.nih.gov/pubmed/21595535?dopt=Citation

 

 

Interleukin-17 and pro-inflammatory cytokines in the aqueous humour of birdshot patients

Dutch researchers from the University Medical Centre of Utrecht have reported a connection between raised intraocular levels of interleukin (IL)-17 and other immune mediators in birdshot chorioretinopathy (Kuiper, JJ et al. 2011).

Aqueous humour (AqH) and serum samples were taken from 16 patients with birdshot chorioretinopathy and these were compared to aqueous humour samples taken from 11 age-related cataract control patients. A multiplex immunoassay was performed on the samples to determine the levels of 23 different immune mediators (T-cell, pro-inflammatory and vascular-active mediators).

The results showed that the T-cell mediators interleukin IL-2 and IL-17, and the proinflammatory mediators IL-1β, IL-6 and tumour necrosis factor α, were significantly elevated in the aqueous humour samples from the birdshot patients compared with those from the control group. Also, the elevated aqueous humour levels of IL-1β, IL-17 and tumour necrosis factor α in the birdshot patients were higher than the levels in their serum samples. From these results, the researchers suggest the ‘novel concept’ that birdshot is an autoimmune inflammatory disease restricted to the eye and associated particularly with elevated IL-17 levels.

The link below goes to the article, which was published in 2011:

URL – http://www.ncbi.nlm.nih.gov/pubmed/21570674?dopt=Citation