Development of new treatments for uveitis
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Ophthalmology and Optometry
Summary of the impact
Research at the UCL Institute of Ophthalmology over the last 15 years has
developed new treatments for management of uveitis and its
sight-threatening complications, which have subsequently become standard
practice. Our work, in previously untreatable disease, has allowed
restoration of vision in many patients and prevention of further visual
loss in others. Many patients have been able to reduce systemic
medication, limiting adverse effects of treatment.
Uveitis is an uncommon eye condition, which affects two to five in every
10,000 people in the UK every year. Although rare, it is a leading cause
of visual impairment in patients of working age. Chronic uveitis is
associated with a high incidence of vision-threatening complications such
as cataract, macular oedema, and, most importantly, glaucoma, which may
cause irreversible visual loss. Research at UCL, over the last 15 years,
has developed new treatments for uveitis and its complications.
In 1999 we assessed the usefulness of mycophenolate mofetil (MMF), an
immunosuppressant used extensively in transplant medicine, but not
previously used in uveitis. Our findings indicated that MMF was a useful
immunosuppressive drug for controlling ocular inflammation ; it
proved to be more effective with fewer adverse effects than other drugs
used to treat uveitis (ciclosporin and methotrexate).
Further to this, in 2001 we undertook a pilot study in six patients with
idiopathic uveitis complicated by visually significant cystoid macular
oedema (CMO) that was resistant to periocular and/or systemic
corticosteroid treatment. We demonstrated that one injection into the eye
of the steroid triamcinolone (TA) was an effective short-term treatment
for resistant CMO in uveitis . This paper changed the way that
refractory macular oedema was considered in uveitis. Previously it was
thought that oedema was refractory because permanent blood-retinal barrier
breakdown had occurred. By demonstrating that vision could be improved by
injecting TA into the eye where previous systemic and periocular
medication had failed, the research had shown that oedema was reversible
using this method of steroid delivery. A larger study in 2005 confirmed
these findings, showing that in patients with uveitic CMO, intravitreal TA
can effectively reduce CMO and improve visual acuity. In some patients it
allows the cessation and/or major reduction of systemic immunosuppressive
therapy . For the first time, previously incurable visual loss
could now be treated, resulting in vision gain and subsequent improvement
in the quality of life for patients. This led to a profusion of papers on
TA and then to the licensing of longer acting intraocular steroids, now a
In 2009 we undertook a study to determine whether the use of topical
prostaglandin (PG) analogues to treat raised intraocular pressure (IOP) in
patients with uveitis resulted in an increase in uveitis reactivation or
CMO. This was thought likely and these drops were then contraindicated in
uveitis. We demonstrated that PG analogues are potent topical medications
for lowering raised IOP in patients with uveitis and are not associated
with an increased risk of CMO or uveitis reactivation . The
study allowed these very effective drops to be brought into the management
of uveitic glaucoma and reduced the need for surgery to prevent visual
In the same year we undertook a pilot study in 15 patients to evaluate
the use of intravitreal methotrexate (MTX) for the treatment of uveitis
and uveitic CMO as an alternative to intravital steroids. We showed that
in these patients, intravitreal MTX can improve visual acuity and reduce
CMO and, in some patients, allows the reduction of immunosuppressive
therapy . This study introduced intraocular methotrexate as a
successful treatment option for macular oedema in patients who cannot have
intraocular steroids — this led to an international series and widespread
use and for the first time offered a non-steroid intraocular treatment
regime for those in whom periocular/intraocular steroids are
contraindicated. Many of these patients were able to come off systemic
therapy as a result with good vision maintained.
Most recently, we assessed the visual prognosis of patients with ocular
Behçet disease, who have the worst visual prognosis of all patients with
uveitis, to determine factors predictive of visual loss and severe visual
loss. These patients are all young and both eyes are usually affected. We
showed that the use of anti-TNF-α drugs was associated with a
statistically significant reduction in the rate of severe visual loss,
with a greatly reduced risk of visual loss at 5 and 10 years .
This has led to the early introduction of biologics for treatment in these
References to the research
 Chang JH, McCluskey P, Missotten T, Ferrante P, Jalaludin B, Lightman
S. Use of ocular hypotensive prostaglandin analogues in patients with
uveitis: does their use increase anterior uveitis and cystoid macular
oedema? Br J Ophthalmol. 2008 Jul;92(7):916-21.
 Taylor SR, Singh J, Menezo V, Wakefield D, McCluskey P, Lightman S.
Behçet disease: visual prognosis and factors influencing the development
of visual loss. Am J Ophthalmol. 2011 Dec;152(6):1059-66. http://dx.doi.org/10.1016/j.ajo.2011.05.032
Details of the impact
Our research over the last 15 years has developed new local and systemic
treatments for uveitis, and these have become standard practice. Our work
has introduced new treatments where none existed, specifically patients
with uveitis that is not responsive to steroid therapy or in which steroid
therapy is contraindicated because of adverse effects. For these patients,
treatment with mycophenolate or intraocular methotrexate may be
sight-saving. In other patients, as a result of these treatments, vision
has been restored and the dose of systemic steroids reduced or stopped
completely. MMF is now the major second-line drug used in management of
uveitis. Our demonstration of its effectiveness in 1999 was key in
bringing the potential of this drug to the attention of the inflammatory
eye disease community. Our study was also quoted in US guidelines in 2000
[a] and provided the impetus for several additional studies over
the years (e.g. Teoh et al 2008 [b]). A recent review of the
management of uveitis demonstrates that the use of MMF is established
A further recent article states: "Antimetabolites now enjoy favor as a
first choice of treatment with IMT [immunomodulatory therapy] in most
cases of posterior uveitis." Two of the key drugs used are MMF and
MTX [d]. The importance of MMF and MTX as treatments for uveitis
is further emphasised by a recently commenced clinical trial that compares
the two agents as first line therapy for steroid unresponsive uveitis [e].
Robust data concerning the numbers of patients affected globally by
uveitis where steroids are either ineffective or toxic are not available.
However, from our own institution MMF is the major drug used with steroids
in about 80% of these patients [f].
Cystoid macular oedema is a particularly challenging complication of
uveitis and is the most common cause of blindness and visual impairment in
chronic uveitis patients occurring in up to one third. Our studies have
contributed greatly to the present best practice in the management of this
condition. We demonstrated that vision could be improved by injecting TA
into the eye where systemic and periocular medication had failed. This led
to a profusion of papers on TA and then to the longer acting intraocular
steroids being developed. Our research also introduced intraocular
methotrexate as a successful treatment option for macular oedema in
patients who cannot have intraocular steroids. A recent review notes the
use of both intraocular TA and methotrexate in the management of uveitic
cystoid macular oedema. Regarding the former, it notes that "intravitreal
triamcinolone (various formulations) is commonly used for CME" [g].
A number of studies are cited, of which ours was notably the first and
largest. Our paper on intraocular methotrexate is also cited in both this
review, and another from India in 2013 [h].
A further complication of uveitis is glaucoma, which developes in up to
20% of patients. Prior to our research, ocular hypotensive prostaglandin
analogues had been used successfully in primary open angle glaucoma
but there was major concern about their use in uveitis patients. Our study
allowed these very effective drops to be brought into the management of
uveitic glaucoma and reduced the need for surgery [i].
Our demonstration in 2011 that anti-TNF drugs can reduce the risk
of visual loss in patients with Behcet's disease, who have the worst
visual prognosis of all patients with uveitis, is now being quoted
worldwide in support of this treatment [j].
Sources to corroborate the impact
[a] Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS,
Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D.
Guidelines for the use of immunosuppressive drugs in patients with ocular
inflammatory disorders: recommendations of an expert panel. Am J
Ophthalmol. 2000 Oct;130(4):492-513.
[b] Teoh SC, Hogan AC, Dick AD, Lee RW. Mycophenolate mofetil for the
treatment of uveitis. Am J Ophthalmol. 2008 Nov;146(5):752-60, 760.e1-3.
doi: 10.1016/j.ajo.2008.03.004. Epub 2008 May 2. http://dx.doi.org/10.1016/j.ajo.2008.03.004
Cites two of our papers - see references 11 and 14.
[c] Gallego-Pinazo R, Dolz-Marco R, Martínez-Castillo S, Arévalo JF,
Díaz-Llopis M. Update on the principles and novel local and systemic
therapies for the treatment of non-infectious uveitis. Inflamm Allergy
Drug Targets. 2013 Feb;12(1):38-45.
[f] Moorfields pharmacy data provided by Chief Pharmacist. Copy available
[i] Horsley MB, Chen TC. The use of prostaglandin analogs in the uveitic
patient. Semin Ophthalmol. 2011 Jul-Sep;26(4-5):285-9. http://dx.doi.org/10.3109/08820538.2011.588650
[j] Pato E, Muñoz-Fernández S, Francisco F, Abad MA, Maese J, Ortiz A,
Carmona L; Uveitis Working Group from Spanish Society of Rheumatology.
Systematic review on the effectiveness of immunosuppressants and
biological therapies in the treatment of autoimmune posterior uveitis.
Semin Arthritis Rheum. 2011 Feb;40(4):314-23.