Study reference

Study characteristics

Patient characteristics

Intervention (I)

Control (C)

Follow-up

Outcome measures and effect size

Comments

RITUXIMAB

Suhler, 2014

Type of study:

RCT

Country:

USA

Competing interests:

Three authors are paid consultants for diverse pharmaceutical companies. Study was in part supported by Genentech, but it had no role in design or conduct of the research

Inclusion criteria

Patients with noninfectious scleritis who had failed therapy with prednisone and ≥1 other systemic immunosuppressive drug or were intolerant to such therapy; ≥18 years of age; on stable dosage of prednisone and at least 1 steroid sparing agent 30 days prior to enrollment; active disease; selected patients on biologicals acceptable; concomitant autoimmune diseases sufficiently stable; no evidence of malignancy, infection or fibrosis; adequate renal function; men and women of reproductive potential must agree to use acceptable method of birth control

Exclusion criteria

Untreated thyroid disease; organ threatening disease, respiratory failure, seizures or psychosis, progressive neuropathy; positive hepatitis B or C; history of positive HIV; previous treatment with rituximab; known active infection; history of drug, alcohol abuse; pregnancy; concomitant or previous malignancies; significant cardiac or pulmonary disease; any other disease or condition that contraindicates use of investigational drug, may affect interpretation of results or render patient at high risk of complications

Group 1 (N=6)

500 mg infusions of rituximab at days 1 and 15

Treatment regimen:

See below

Group 2 (N=6)

1000 mg infusions of rituximab at days 1 and 15

Treatment regimen:

Each infusion was preceded by a prophylactic dose of oral acetaminophen (1 g), oral diphenhydramine hydrochloride (HCl) (50 mg) or equivalent dose of a similar agent, and intravenous methylprednisolone (100 mg). Patients returned to the clinic every 4 weeks for measurement of safety and efficacy endpoints. Patients who demonstrated an initial positive clinical response to rituximab, but relapsed at ≥24 weeks, were eligible for retreatment with 2 infusions of 1000 mg rituximab separated by 2 weeks.

Length of follow-up

24 weeks

Lost to follow-up

Group 1: 1/6=17% due to severe flare

Group 2: 1/6=17% due to exacerbations

Another patient was taken from study due to exacerbations but unclear to which group allocated.

Outcome measures

• reduction in the dose of systemic corticosteroid or immunosuppressive therapy by ≥50% by 24 weeks
• reduction in scleral inflammation ascertained by improvement in scleritis grading scale disease activity score of ≥ 2 and/or an overall score of ≤ 4 as measured by the previously described modified 25-point McCluskey/Wakefield grading system at 24 weeks.
• Pain decrease

Results

≥ 50% steroid decrease

Group 1: 1/6=17%

Group 2: 4/6=67%

P= not reported

Improvement in scleritis grade

Group 1: 5/6=83%

Group 2: 5/6=83%

P= not reported

Pain decrease

Group 1: 3/6=50%

Group 2: 4/6=67%

P= not reported

Adverse events

There were no significant adverse events that required study discontinuation.

Randomisation method and concealment of allocation not described.

Study was double-blind, but does not report who were blinded and how.

Very small sample size (imprecision)

Co-medication (indirectness of effect).

GRADE: very low quality of evidence

METHOTREXATE

Jachens, 2008

Type of study:

Retrospective chart review

Country:

USA

Competing interests:

None declared

Inclusion criteria

Patients with diagnosis of scleritis

Exclusion criteria

Not reported

Intervention (N=18 patients with 27 affected eyes)

methotrexate

Treatment regimen:

The most common starting dose of methotrexate was 10 mg weekly, with a range of 7.5 to 12.5 mg, estimated by the patient’s weight following the 0.15 mg/kg weekly dosing schedule. The most common maintenance dose was 20 mg

weekly, with a range of 10 to 30 mg weekly. The maximum dose delivered was 35 mg. Folic acid supplements were given to all patients, with a varying dose of 1 to 2 mg daily.

Length of follow-up

The mean duration of methotrexate therapy was 19 months (SD, 11 months

Lost to follow-up

None

Outcome measures

• Inflammation control, defined as resolution of inflammation in the affected eyes for three months or longer
• Corticosteroid-sparing success, defined as either any decrease in dose, a final dosage of 10 mg or less, or the lack of corticosteroid use during methotrexate treatment and inflammation control
• Visual acuity (improvement not defined)
• Adverse effects

Results

Inflammation control

11/18 (61%) patients

Corticosteroid-sparing success

10/11 (91%) patients

Visual acuity

14/27 (52%) eyes improved

Adverse effects

8/18 (44%) patients reported AE.

Most common: fatigue: 6 patients (one patient discontinued treatment due to unbearable fatigue).

Other adverse effects included muscle aches and weakness, nausea, alopecia, and epi-

staxis

Observational study (starts with low quality of evidence)

Selection bias may be considered because our practice is

a tertiary referral center and the patients included in the

study already were diagnosed, worked up, and treated by

other ophthalmologists by conventional means.

GRADE: low quality of evidence

MYCOFENOLAAT MOFETIL

Kolomeyer, 2012

Type of study:

Retrospective study

Country:

USA

Competing interests:

None declared

Inclusion criteria

Patients with non-infectious, non-necrotizing scleritis who were treated with MMF ≥ 6 months. All patients had active, recurrent scleritis at initiation of MMF therapy, and all other medication, except for tapering CS, remained stable during course of treatment.

Exclusion criteria

Mean time span between appointments > 3 months

Intervention (N=22 patients with 32 affected eyes)

Mycophenolate mofetil (MMF)

Treatment regimen:

Mean duration of MMF therapy was 19.1 months (range 6-54 months). Mean ± SD starting dose of MMF was 1.25±0.5 g, while mean maintenance dose was 2.0±0.75 g. maximum dose delivered was 2 g twice daily.

Length of follow-up

24 months

Lost to follow-up

Not described

Outcome measures

• Inflammation control, defined as total resolution of both signs and symptoms of scleral inflammation in the affected eye(s) for ≥ 2 months
• Corticosteroid-sparing success
• Visual acuity. Improvement not defined.
• Side effects

Results

Inflammation control

20/22=91% patients had inflammation control at 6 months. Mean time to control was 2.8 months (range 2-8 months).

Corticosteroid-sparing success

CS sparing was achieved in 100% of patients at all follow-up time points (17/17 (100%) patients at 6 months and 4/4 (100%) patients at 24 months). Mean starting CS dose of 30.8 mg was reduced by 91% to a mean final dose of 5.8 mg (p<0.05).

Visual acuity

Vison improved or remained the same in 24/32 (75%) eyes.

Side effects

14/22 (64%) patients reported side effects including leucopenia (n=7), gastrointestinal upset (n=4), abnormal liver function tests (n=3) and abnormal renal function tests (n=2).

Observational study (starts with low quality of evidence)

GRADE: low quality of evidence

NSAID’S

Kolomeyer,2012

Retrospective study

Country:

USA

Competing interests:

None declared

Inclusion criteria

Patients with non-infectious, non-necrotizing scleritis and episcleritis who were treated with selective or non-selective COXI ≥ 2 months. All patients had active, recurrent scleritis at initiation of MMF therapy, and all other medication, except for tapering CS, remained stable during course of treatment.

Exclusion criteria

Not stated

Intervention (N=69)

Selective COXI: N=37

Non-selective COXI: N=32

Treatment regimen:

Selective COXI:

Mean ± SD duration was 12.1 ± 12.3 months.

Mean starting dose and maintenance dose: 400 mg/day and 373.2 mg/day (celecoxib, n=28)

16 patients on CS concurrently.

Non-selective COXI:

Mean ± SD duration was 9.0 ±13.4 months.

Mean starting dose and maintenance dose: 148.1 mg/day and 150 mg/day (voltaren, n=27)

10 patients on CS concurrently.

Length of follow-up

Selective: 31.1 ± 31.4 months

Non-selective: 16 ± 15.4 months

Lost to follow-up

Outcome measures

• Control of inflammation. Defined as resolution of signs and symptoms of scleral inflammation in the affected eye(s) for ≥ 2 months
• Gastrointestinal side effects

Results

Control of inflammation

Overall, 29 (78%) patients on selective COXIs and 25 (78%) patients on non-selective COXIs achieved inflammation control after initial therapy regimen (p=1.0).

GI side effects

The overall rate of GI side effects was 1/37 (2.7%) for selective COXIs and 3/32 (9.4%) for non-selective COXIs (p=0.33) (one discontinued medication).

Observational study (starts with low quality of evidence)

GRADE: low quality of evidence

TRIAMCINOLONE ACETONIDE INJECTION

Sohn, 2011

Type of study:

Retrospective study

Country:

USA, Australia, Singapore

Competing interests:

Three authors are consultant for diverse pharmaceutical companies

Inclusion criteria

All patients who were treated with subconjunctival triamcinolone acetonide injection (STI) for non-necrotizing, noninfectious anterior scleritis (diffuse or nodular) at 1 of the participating hospitals; had diffuse or nodular anterior scleritis who were already receiving

topical drops (prednisolone, NSAID’s) for scleritis or systemic medication for scleritis and associated sys-

temic condition.

Exclusion criteria

Patients who had follow-up of less than 6 months after STI, ocular hypertension (defined as IOP > 21 mmHg), history of glaucoma or steroid response, necrotizing features (de-

fined as scleral thinning or destruction of the sclera, evidence of vascular closure on red-free examination, or uveal show), and associated infections.

Intervention (N=81 patients with 69 eyes)

subconjunctival triamcinolone acetonide injection (STI).

Treatment regimen:

Eyes were anesthetized with topical 0.5% proparacaine drops and cotton-

tipped applicators soaked with proparacaine. For nodular scleritis,

0.05 to 0.1 ml of triamcinolone acetonide (Kenalog 40 mg/ml;

Bristol-Myers Squibb Co., New York, NY) was injected with a 25- or 27-gauge needle under the conjunctiva immediately adjacent to the nodule. Those with diffuse scleritis received up to 0.2 ml per inflamed quadrant.

Median 1 injection per eye; average 1.6 injections per eye.

Length of follow-up

Median follow-up was 28 months (range, 6-100 months)

Lost to follow-up

24 eyes in 24 patients were excluded because follow-up was less than 6 months, 2 eyes were excluded for pre-existing necrotizing disease, and 2 eyes were excluded for infectious cause.

Thus, 68 eyes of 53 patients were enrolled in the study.

Outcome measures

• Recurrence
• Resolution of signs and symptoms (not defined)
• Adverse effects

Results

Recurrence

24 months after one injection, 22/68 (32%) of eyes had recurrence, whereas at 48 months, 34/68 (50%) of eyes had recurrence. Median time to recurrence was 6 months.

Resolution of symptoms

61/68 (90%) of eyes had complete resolution of signs and symptoms after one injection

Adverse effects

7/68 eyes (10.3%) had subconjunctival hemorrhage that resolved spontaneously. 14/68 eyes (20.6%) had ocular hypertension not requiring intraocular pressure lowering therapy. Two eyes (2.9%) were treated with topical IOP-lowering agents alone, and 2 eyes

required surgical intervention for glaucoma. None developed scleral necrosis or melt.

Observational study (starts with low quality of evidence)

Patient selection was limited to those with non-necrotizing, noninfectious scleritis with no history of steroid response, ocular hypertension, or glaucoma.

GRADE: low quality of evidence

Albini, 2005

Type of study:

Retrospective study

Country:

USA, Israel

Competing interests:

None declared

Inclusion criteria

Patients with active non-necrotizing, noninfectious anterior scleritis despite systemic or local anti-inflammatory therapy

Exclusion criteria

Patients with ocular hypertension (defined as IOP > 22 mmHg), history of glaucoma or steroid response, with necrotizing scleritis or necrotizing keratitis

Intervention (N=35 patients with 38 eyes)

subconjunctival triamcinolone acetonide injection (STI).

Treatment regimen:

The affected eyes were anesthetized with topical 0.5% proparicaine. A 25-gauge needle was used to inject triamcinolone acetonide. In eyes with nodular scleritis, 0.05 to 0.1 ml

was injected immediately adjacent to the nodule; areas of diffuse scleritis received 0.2 ml per inflamed quadrant

Length of follow-up

Median follow-up was 29 months (range, 1-48 months)

Lost to follow-up

None

Outcome measures

• Recurrence
• Resolution of symptoms (defined as lack of any pain, episcleral injection, or scleral edema)
• Adverse effects

Results

Recurrence

9/38 (23.7%) eyes had recurrence during follow-up. Median time to recurrence was 11 months.

Resolution of symptoms

36/38 (94%) eyes had complete resolution of symptoms after a single treatment by the 6-week follow-up

Adverse effects

Adverse events included subconjunctival

hemorrhages (5 eyes); transient ocular hypertension without evidence of glaucoma (4 eyes); cataract (2 eyes); and glaucoma (2

eyes) requiring medical management in one case and surgical management in the other.

Observational study (starts with low quality of evidence)

GRADE: low quality of evidence

Johnson, 2010

Type of study:

Retrospective study

Country:

USA

Competing interests:

None declared

Inclusion criteria

Patients with nonnecrotizing scleritis who underwent sub-Tenon corticosteroid injections and initial follow-up data within 5 weeks after injection

Exclusion criteria

Intervention (N=13 )

sub-Tenon triamcinolone acetonide (TA) injections

Treatment regimen:

All patients were receiving systemic medications before the time of

injection. Five patients were receiving NSAID’s, one of whom was concurrently being treated with methotrexate. Six patients were being treated with prednisone. Of these,

one was concomitantly receiving methotrexate and another simultaneously was taking mycophenolate mofetil.

Length of follow-up

Unclear

Lost to follow-up

2/13=15% (lost to FU)

Outcome measures

• Recurrence
• Improvement in inflammation (not defined)
• Adverse effects

Results

Recurrences

8/11 (73%) had recurrences. The mean time to recurrence was 18 weeks (range, 4 to 21 weeks); median time was 16 weeks. The rate of recurrence was 3.3 cases per person-year.

Improvement in inflammation

10/11 (90%) patients had improvement

Adverse effects

3/11 (27%) patients had adverse effects (2 with ocular hypertension, 1 with subconjunctival haemorrhage)

Observational study (starts with low quality of evidence)

Very small sample size (N=11) (imprecision)

GRADE: very low quality of evidence

DIVERS

Wieringa, 2013

Type of study:

Retrospective study

Country:

Netherlands

Competing interests:

None declared

Inclusion criteria

Patients diagnosed with scleritis and follow-up > 3 months

Exclusion criteria

Not described

Intervention (N=104)

NSAID’s: N=42 (N=33 also treated with topical steroids)

Oral corticosteroids: N=64 (usually

in combination with local steroids and sometimes with NSAID’s).

On average, patients used more than 7.5 mg daily oral corticosteroids for a mean ± SD of 65 ± 72.4 weeks (median, 42 weeks).

Methotrexate: N=36

The mean dose of MTX was 19 mg weekly (median, 20 mg; range,10–30 mg), with 1 patient using 30 mg weekly. All patients received folic acid supplementation 24 to 48 hours after their weekly dose of MTX.

Azathioprine: N=13

In addition to immunosuppressive regimen.

TNF-α antagonist: N=11

Most patients were treated with 1 or 2 other immunosuppressives in addition to a TNF- α antagonist.

Mycophenolate mofetil: N=10

Used as steroidsparing immunosuppressive treatment.

Cyclophosphamide: N=8

Often in combination with other immunosuppressives.

Treatment regimen:

At presentation, 31 patients were

treated with combinations of different drugs. In 23 patients, NSAID’s were combined with topical steroids, and MTX was combined with NSAID’s at presentation in 6 patients. Mycophenolate mofetil was combined with MTX in 1 patient, and another

patient was treated with topical steroids, topical NSAID’s, and

antibiotic eyedrops at presentation. None of the patients was taking oral corticosteroids at presentation, and 49 patients were not treated at presentation.

Length of follow-up

Mean follow-up was 38.2 months (range, 3–154 months).

Lost to follow-up

None

Outcome measures

Remission. Defined as a subjective and an observable inactive disease for longer than 3 months using less than 10 mg daily oral prednisone alone or in combination with corticosteroid sparing drugs.

Results

Remission (mean time to remission in weeks)

NSAID’s: 36/42=85.7% (48.8)

Oral corticosteroids: 19/64=29.7% (83.9)

Methotrexate: 17/36=47.2% (103.7)

Azathioprine: 1/13=7.7% (192.8)

TNF-α antagonist: 5/11=45.5% (32.6)

Mycophenolate mofetil: 5/10=50% (65.3)

Cyclophosphamide: 4/8=50% (68)

By multivariate regression analysis, bilateral disease was the strongest predictor of worse prognosis.

Observational study (starts with low quality of evidence)

The results of the current study are limited by the fact that the study was retrospective, the numbers of patients were small in some subgroups, there was a large

variability in follow-up, and the inclusion period was relatively long.

GRADE: low quality of evidence

Type of study:

Country:

Competing interests:

Inclusion criteria

Exclusion criteria

Intervention (N=)

Treatment regimen:

Length of follow-up

Lost to follow-up

Outcome measures

Results

GRADE: very low quality of evidence