Study reference

Study characteristics

Patient characteristics

Intervention (I)

Control (C)

Follow-up

Outcome measures and effect size

Comments

Simonini, 2013

Type of study:

systematic review and meta-analysis

Competing interests: one of authors has received grants/research

support from Pfizer Inc.

Inclusion criteria:

(i) patients had vision-threatening non-infectious autoimmune uveitis; (ii) autoimmune uveitis was refractory to therapy with topical and/or systemic treatment, thus showing a chronic disease course with regard to steroid therapy according to the SUN criteria definition, that is persistent

uveitis characterized by relapse within 3 months after discontinuation of therapy; (iii) patients had disease onset at or before 16 years of age; (iv) patients received MTX as single immunosuppressant medication for the treatment of uveitis; (v) outcome measures to assess the effectiveness of MTX were collected according to the SUN criteria.

Exclusion criteria:

the concomitant use of other immunosuppressant

agents in addition to MTX; (ii) starting time of MTX admin-

istration after 16 years of age; and (iii) lack of applicability/

adherence to the SUN working group criteria definition of improvement in uveitis activity

N= 135

patients received MTX as

single immunosuppressant medication for the treatment

of uveitis.

Four studies reported a MTX dose between 7.5 and 30mg/m2 , weekly,

with 15mg/m2 the most commonly used dose. Four studies did not report the dose per m2 of body surface and the MTX dose varied from 7.5 to 40mg/week (median

dose/week 12.5mg); in one study MTX was administered at a dose of 0.5-1mg/kg, weekly.

NA

Length of follow-up:

median follow-up time of 22.5 months (range 1-96)

Primary outcome measure:

Improvement of intraocular inflammation as Tyndall (anterior chamber cells), according to the definition of improvement of the SUN working group criteria. Uveitis was defined as improved, and

MTX as successful, when its activity decreased by two

steps in the level of inflammation (anterior chamber cells and/or vitreous haze) or decreased to grade 0

Nine articles (N=135 children, 121 with JIA) were included in the review and meta-analysis.

Results:

95/135 (70%) children responded to MTX (= improvement of intraocular inflammation)

Pooled analysis:

Proportion of responding subjects was 0.73 (95% CI 0.66, 0.81). There was no evidence of heterogeneity across studies (P=0.5)

The majority of eligible studies only included patients with JIA, along with other diseases.

Due to small numbers, results could not be analysed separately according to the underlying disease.

The different steroid use, as systemic administration rather than eye drop, significantly changed over the considered time period, might be an additional potential caveat.

All the current evidence is from retrospective chart reviews.

Visual acuity not measured.

Macular oedema not reported.

Goebel, 2010

Type of study: retrospective multicentre study (chart review)

Country: Germany

Competing interests: none declared

Inclusion criteria: consecutive patients with JIA who were started on azathioprine treatment for severe chronic anterior uveitis between 1995 and 2007

Exclusion criteria:

Patients with other uveitis entities, such as

intermediate, Fuchs heterochromic cyclitis and

infectious uveitis syndromes

N= 41

Azathioprine monotherapy was instituted in patients with active uveitis, if they were being treated with topical (≥3 drops/day) and possibly also systemic corticosteroids (≥10 mg, or ≥0.15 mg/kg body weight), or in order to spare systemic corticosteroids. Moreover, azathioprine was considered as an additional immunosuppressive if uveitis remained active during treatment with any other immunosuppressive drug.

All of the patients had previously received topical corticosteroids, and 29.3% had received immunosuppressive drugs.

NA

Length of follow-up:

The mean follow-up after instituting azathioprine was 26 months ( range 3-107)

Primary outcome measure:

Inactivity of anterior uveitis. Defined as <1+ cells in the anterior chamber (SUN criteria)

Results:

Effect of azathioprine monotherapy on inactivity of uveitis (N=26):

16/26=61.5% patients

Effect of azathioprine in combination with other disease-modifying antirheumatic drugs on inactivity of uveitis (N=15):

10/15=66.7% patients

Potential confounders:

Uveitis activity, duration of uveitis and complication rates did not differ between the monotherapy and combination group.

The azathioprine dosages did not differ significantly between the responders and the non-responders (monotherapy p=0.3 and combined therapy p=1.0).

Visual acuity not measured.

Macular oedema not reported.

Tappeiner, 2009

Type of study: retrospective multicentre study (chart review)

Country:

Germany

Competing interests: none declared

Inclusion criteria:

children with confirmed JIA and associated chronic anterior uveitis (CAU)

N=82

treatment with CsA (Immunosporine ® ,

Sandimmune ® , or

Neoral ®)

The initial CsA dosage was 3.0mg/kg (range: 2.0–5.0 mg/kg), and the mean dosage at the end of treatment or the end of the follow-up, if CsA was continued, was 2.8mg/kg/

day (range: 1.5–5.0)

NA

Length of follow-up:

The mean follow-up/treatment time after starting

cyclosporine therapy was 3.9 years (range: 1.0–12.0)

Primary outcome measure:

Inactivity or activity of uveitis during the entire treatment period was analysed. Inactive anterior uveitis was defined as rare cells or less in the anterior chamber.

Results:

CsA as systemic immunosuppressive monotherapy (N=25):

6/25=24% patients (at mean follow-up of 2.0 years)*.

*Gender, age at the onset of arthritis or uveitis, JIA subgroup, ANA positivity, bilateral uveitis, and presence of complications at initial presentation had no significant influence on the response to treatment.

CsA in systemic combined immunosuppressive therapy* (N=72):

35/72=48.6 % patients (at mean follow-up of 3.3 years)

*Other immunosuppressives:

(MTX n=18, AZT n=11, others n=6)

Visual acuity not measured.

Macular oedema not reported.

Chang, 2011

Type of study: retrospective multicentre study (chart review)

Country: USA

Competing interests: none declared

Inclusion criteria:

all the patients with

autoimmune uveitis who started MMF therapy at or

before the age of 18 years and who were examined at the Massachusetts Eye Research and Surgery Institution, a tertiary uveitis referral centre, between July 2005 and

March 2009.

Exclusion criteria:

patients who had insufficient follow-up time after MMF therapy was initiated, defined as 6 months or less.

N=52

mycophenolate mofetil (MMF) monotherapy.

The median duration of the MMF therapy was 27 months (range: 0.5–50).

The median maximal dosage of MMF was 2000 mg daily (range: 600–3000).

NA

Length of follow-up:

median follow-up time after

therapy initiation was 33 months (range: 6–53)

Primary outcome measure:

Control of inflammation. Defined as

≤ 0.5+ anterior chamber cell/flare and vitreal haze in accordance with the SUN nomenclature and the study by Nussenblatt et al (1985).

Secondary outcome measure:

Visual acuity. A change of ≥ 2 lines on the Snellen visual acuity chart was considered clinically significant.

Results:

Control of inflammation:

38/52=73.1% patients

Visual acuity:

49/52=94.2% patients stable or improved. Three patients had significant vision loss due to cataract (n=1) or macular oedema (n=2)

Variable follow-up time

No statistical analysis to adjust for potential confounders

Doycheva, 2007

Type of study: retrospective multicentre study (chart review)

Country: Germany

Competing interests: none declared

Inclusion criteria:

all the children with chronic non-infectious uveitis who were treated with MMF and followed up at the University Eye Hospital Tuebingen, Tuebingen, Germany, between 2000 and 2005.

N=17

mycophenolate mofetil (MMF) monotherapy.

All patients were treated with steroids or other immunosuppressive agents before initiating treatment with MMF.

The dose of MMF given was that recommended in paediatric renal transplant recipients—600 mg/m 2 twice daily. The average maintenance dose was 1 g daily (range 750 mg to 2 g

daily). During the first week of treatment, the children received half the dose, which was subsequently increased to the desirable maintenance dose, given in two divided doses.

NA

Length of follow-up:

The average duration of follow-up after initiation

of MMF was 3 years (range 2–5)

Primary outcome measures:

Reduction in relapse rate —the number of relapses in 1 year. Effective defined as: no relapse or at least two relapses less than before MMF treatment.

Improvement in visual acuity. Change in visual acuity is given as change of lines in Snellen chart. Improvement not defined.

Results:

Reduction in relapse rate:

11/17=64.7% patients effective reduction.

16/17=94.1% patients had reduction.

Visual acuity:

13/17=76.5% patients stable or improved.

Three patients had vision loss due to epiretinal membrane (n=1), cataract (n=1) or progression of the glaucomatous optic disc damage (n=2)

Small sample size

Reduction in intraocular inflammation (defined as cells in anterior chamber) not measured.

Macular oedema not reported.

No statistical analysis to adjust for potential confounders.

Slabaugh, 2012

Type of study: retrospective study (chart review)

Country: USA

Competing interests: one author received research funding from Alcon Research Laboratories

Inclusion criteria:

all patients younger than 18 years treated with difluprednate at a referral uveitis clinic and a referral pediatric ophthalmology clinic from January 1, 2009, through January 1, 2010.

Exclusion criteria:

patients with fewer than 6 months of follow-up

Diagnosis:

Idiopathic chronic anterior and intermediate uveitis 29% (4/14)

Tubulointerstitial nephritis with uveitis 21% (3/14)

Juvenile idiopathic arthritis 14% (2/14)

Vogt-Koyanagi-Harada syndrome 14% (2/14)

Pars planitis 7% (1/14)

Multifocal choroiditis with panuveitis 7% (1/14)

Acute zonal occult outer retinopathy 7% (1/14)

N=14 (26 eyes)

topical difluprednate 0.05% adjuvant to systemic immunomodulatory therapy.

The median duration of therapy with topical difluprednate was 27 weeks (range, 4 to 63 weeks). The initial dosage regimen ranged from every 2 hours to 4 times daily, depending on disease activity. Changes in dosing frequency were made according to clinical response.

NA

Length of follow-up:

6 months

Outcome measures:

Reduction in anterior segment inflammation. Significant reduction defined as: ≥ 2-grade decrease or decrease to 0 in anterior segment cell, SUN Working Group criteria.

Visual acuity: significant improvement not defined.

Cystoid macular oedema (CME): significant improvement not defined.

Results:

Anterior segment inflammation:

22/25 (88%) eyes had significant reduction.

Visual acuity:

mean visual acuity improved by -0.08 logarithm of the minimum angle of resolution units (95% CI -0.17 to 0.02)

CME:

7/9 (78%) eyes improved.

Small sample size

Short follow-up

significant (clinically relevant) improvement in visual acuity and CME not defined.

No statistical analysis to adjust for potential confounders.

Thorne, 2010

Type of study: Retrospective study

Country: USA

Competing interests: one author consultant for Data and Safety Monitoring Committee of pharmaceutical companies

Inclusion criteria:

patients with JIA-associated uveitis who were seen at the Division of Ocular Immunology at the Wilmer Eye Institute at The Johns Hopkins School of Medicine between July 1984 and August 2005

Exclusion criteria:

not stated

Intervention: N=75

40 patients (60 eyes) received topical steroids

NA

Length of follow-up:

median follow-up period 4 years (mean, 4.6; range, 0.5–15)

Primary outcome measures:

Incidence of cataract development. Cataract was defined as the presence of 1+ nuclear sclerosis or 1+ cortical change or trace posterior subcapsular changes

Results:

Cataract

Incidence of cataract was 0.01/eye-year (EY) for eyes treated with ≤ 3 drops daily and 0.16/EY for eyes treated with > 3 drops daily. Among eyes receiving ≤ 2 drops daily, the incidence of cataract was 0/EY.

Using longitudinal data analysis and controlling for duration of uveitis, presence and degree of active uveitis, and concomitant use of other forms of corticosteroids in a time-updated fashion, treatment with

≤ 3 drops daily of topical corticosteroid was associated with an 87% lower risk of cataract formation compared with eyes treated with > 3 drops daily (relative risk, 0.13; 95% CI, 0.02–0.69; P=0.02).

A referral bias may exist because our institution is a tertiary care medical center, and it is

likely that more severe cases of JIA-associated uveitis were

referred to our center as suggested by high frequencies of

ocular complications and poor visual acuity, and by the long

duration of uveitis before presentation to our clinic.