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Scottish

Uveitis National Managed Clinical Network

Treatment Guidelines

Uveitis NMCN Treatment Guidelines Revised September 2010

1

Introduction ..................................................................................................4

Uveitis Treatment Pathways.........................................................................5

When to immunosuppress ?.........................................................................9

Which immunosuppressive agent to use ?...................................................9

Immunosuppressive Therapy .....................................................................12

Prednisolone.....................................................................................................13

Azathioprine......................................................................................................15

Methotrexate.....................................................................................................17

Mycophenolate mofetil......................................................................................19

Ciclosporin........................................................................................................21

Tacrolimus ........................................................................................................23

Alkylating Agents........................................................................................25

Cyclophosphamide ...........................................................................................25

Biological therapies ....................................................................................28

Tumour necrosis factor (TNF) alpha inhibitors..................................................29

Adalimumab......................................................................................................30

Infliximab ..........................................................................................................33

Interferon α .......................................................................................................36

Daclizumab.......................................................................................................40

Campath (Alemtuzumab)..................................................................................43


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Rituximab..........................................................................................................46

Anakinra ...........................................................................................................49

Other biological therapies .................................................................................51

Summary of use of second line and biologic agents.........................................52

Combination Therapy.................................................................................54

Appendices ................................................................................................55

Appendix 1: Posterior Uveitis requiring early immunosuppressive therapy ......55

Appendix 2: Treatment of Inflammatory choroidal neovascularization (CNV)...58

Appendix 3: Management of uveitis-associated glaucoma...............................60

Appendix 4: Management of uveitis in the perioperative period .......................61

Appendix 5: Immunosuppression during pregnancy.........................................62

Appendix 6: Paediatric guidelines.....................................................................68

Appendix 7: Guidelines for Screening for Uveitis in Juvenile Idiopathic Arthritis

(JIA) ..................................................................................................................76

Appendix 8: Membership of NMCN treatment guideline development group and

stakeholders group ...........................................................................................80

Appendix 9: Evidence Base..............................................................................83


3

Preface

Ophthalmologists within Scotland with an interest in uveitis met in January 2005 to consider

how the care of patients with sight-threatening uveitis could be delivered in a more uniform

manner. A decision was made to develop a Scottish Uveitis Network involving clinicians and

the Uveitis Information Group, a United Kingdom based patient organisation. Since then, the

group has developed as a National Managed Clinical Network, under the auspices of

National Services Division, NHS National Services Scotland. As part of its remit it has set

out to develop guidelines for the management of uveitis.

The aim of this document is to help guide ophthalmologists as to which patients require

referral to a uveitis specialist and aid in the prescription of immunosuppressive therapy for

ocular inflammatory disease.

This document does not replace the advice given by the British National Formularly, nor the advice given by manufacturers.

Introduction

Despite the relatively limited evidence for the efficacy of immunosuppressive treatment in

uveitis(1) it is generally accepted that delay in referral to a uveitis specialist, delay in

commencement of immunosuppression or inadequate immunosuppression all result in

poorer visual prognosis of ocular inflammatory disease (2)

‘Early on you regret too little, late on you regret too much’. (Andy Rees).

Central to the management of ocular inflammatory disease and the use of systemic

immunosuppression is the patient’s understanding of the disease and its treatment. All

these therapies have potentially life-threatening complications and by educating patients

about their treatment and re-enforcing the importance of regular blood tests where

appropriate, hopefully if complications do arise then they will be identified early.

All immunomodulatory drugs used in ocular inflammatory disease were initially developed

for use in other medical specialities, either as chemotherapeutic agents or for

immunosuppression in transplant medicine. Although all these medications are licensed for

other indications none are currently licensed for ocular inflammatory disease and are used

at the discretion of the prescribing consultant. It is important that the patient is aware and

accepting of this prescribing situation.


4

Immunomodulatory drugs have different side effect profiles and so the treatment regime

needs to planned for each patient aiming to produce a treatment regimen that is well

tolerated and is able to to suppress the ocular inflammation.

The document is intended as a guideline rather than a set of protocols. The aim is to assist

the ophthalmologist in making decisions about when to initiate treatment and which type of

treatment is appropriate. It is expected that ophthalmologists will refer on to a uveitis

specialist or ask for assistance from physician colleagues if they do not feel competent to

move on to the appropriate step in the treatment pathway.

Although the guidelines are primarily intended for the use of ophthalmologists, they may be

found helpful by some patients, general practitioners and optometrists in gaining a greater

understanding of uveitis management.

The majority of patients with uveitis will have acute anterior uveitis which settles promptly

with topical treatment. However, the guidelines appropriately cover in greater detail the

minority who require systemic therapy and who generally have more sight threatening

disease.

These guidelines do not apply to infectious uveitis, which should always be considered,

along with malignancy, in patients presenting with uveitis.

In unilateral disease intra-orbital or intra-vitreal steroid may be considered as an alternative

to systemic steroids.

The points emphasised in the treatment pathways such as macular oedema, retinal

vasculitis and steroid dose should be considered ‘red flags’ highlighting indicators of sight

threatening uveitis and of systemic complications of therapy.

Uveitis Treatment Pathways

The following flow diagrams aim to simplify and demystify the treatment of uveitis. By

providing a clear route for treatment we would hope to identify those patients with sight-

threatening uveitis at any earlier stage. These pathways are intended for use by

ophthalmologists involved in the management of patients with uveitis. This will allow prompt,

appropriate referral to a uveitis specialist for consideration of systemic immunosuppression.

These pathways are not applicable to infectious uveitis


5

.

Anterior Uveitis

No

Posterior synechiae

Systemic and topical steroids

Topical mydriatic

Yes No

Topical steroid Topical mydriatic

Try staged mydriasis. If fails

then subconjunctival

steroids and Mydricaine.

Macular oedema

Yes

Taper therapy

Resolving?

No Yes


6


7

Intermediate Uveitis

Macular oedema

No Yes

Vitritis causing reduced vision Systemic

steroids

No

Intra-orbital or

intravitreal steroids

Topical steroids

Observation only

Posterior/Panuveitis

Yes

Macular oedema

Non-occlusive

Vitritis causing reduced vision

Occlusive

Yes

No Systemic steroids

Retinal vasculitis

No

Observation may be appropriate

Central

If observation not appropriate

Peripheral No


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When to immunosuppress ?

Which immunosuppressive agent to use ?

Immunosuppressive therapy should be considered in the following situations:

• All patients requiring chronic steroid therapy greater than 7.5mg a day (osteoporosis

guideline) should be considered for immunosuppressive therapy to allow reduction in

the steroid therapy.

• Most patients requiring systemic steroid therapy who relapse on steroid withdrawal

will require systemic immunosupression to reduce long-term steroid exposure.

• Early indications for immunosuppression would be ineffect of prednisolone despite

adequate dosing.

• Reactivation while reducing the steroid therapy usually requires an increase in the

prednisolone dosage to ensure rapid control of the disease.

• Immunosuppression is recommended at the outset in a number of inflammatory eye

diseases due to the chronicity and potentially poor prognosis that these conditions

have if untreated.

• Patients requiring ongoing systemic steroid therapy do so because they have

disease that is either steroid-dependent, steroid-resistant or relapsing disease.

• When starting immunosuppression it is important to determine whether the patient

requires a steroid sparing agent or an agent to induce remission of disease as

agents differ in their ability to induce disease remission.


9

Summary of side effect profiles

Immunosuppressive agent Pred AZA MTX MMF CSA TAC CphosCirculatory system Hypertension ● ● ● Hypercholesterolaemia ● ● ● Heart failure ● Atherosclerosis ● ● ● Cardiomyopathy ● Digestive System ● ● ● ● ● ● Liver dysfunction ● ● ● ● ● ● Gum hyperplasia ● Endocrine system Diabetes ● ● ● Adrenal suppression ● Integumentary system Hirsutism ● Immune system Infection ● ● ● ● ● ● ● Bone marrow ● ● ● ● ● ● Musculoskeletal system Osteoporosis ● Nervous system Mood disorder

●

Tremor ● ● Reproductive system Infertility ● Teratogenic

● ● ●

Respiratory system ● Urinary system

Renal impairment ● ● Cystitis ● Risk of malignancy ●


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http://en.wikipedia.org/wiki/Circulatory_system

http://en.wikipedia.org/wiki/Gastrointestinal_tract

http://en.wikipedia.org/wiki/Endocrine_system

http://en.wikipedia.org/wiki/Integumentary_system

http://en.wikipedia.org/wiki/Immune_system

http://en.wikipedia.org/wiki/Musculoskeletal_system

http://en.wikipedia.org/wiki/Nervous_system

http://en.wikipedia.org/wiki/Reproductive_system

http://en.wikipedia.org/wiki/Respiratory_system

http://en.wikipedia.org/wiki/Urinary_system

Summary of side effect profiles Immunomodulatory agent Infliximab Adalimumab Interferon α Rituximab Anakinra Campath Circulatory system Hypotension ● ● ● Hypercholesterolaemia ● Heart failure ● ● ● ● Arrhythmias ● ● Digestive System Liver dysfunction ● Endocrine system Irreversible thyroid dysfunction

●

Immune system Hypersensitivity reaction

● ● ● ● ● ●

Infection ● ● ● ● ● ● Bone marrow suppression

● ● ● ●

Reactivation of TB ● ● Nervous system Demyelination ● ● Lower seizure threshold

●

Lethargy ● ● Reproductive system Infertility ● Urinary system Renal impairment ● Risk of malignancy ● ● ●


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http://en.wikipedia.org/wiki/Circulatory_system

http://en.wikipedia.org/wiki/Gastrointestinal_tract

http://en.wikipedia.org/wiki/Endocrine_system

http://en.wikipedia.org/wiki/Immune_system

http://en.wikipedia.org/wiki/Nervous_system

http://en.wikipedia.org/wiki/Reproductive_system

http://en.wikipedia.org/wiki/Urinary_system

Immunosuppressive Therapy

• Immunosuppressive therapy may be effective in the longer term management of

inflammatory eye disease for some patients. The aim of therapy is to allow a

reduction in the steroid dosage while maintaining disease control. Most drugs are

well tolerated but all carry a small risk of severe side effects which may be

potentially life-threatening.

• As most immunosuppressive drugs take several weeks to be effective, reduction of

the oral prednisolone, even in patients with controlled ocular inflammation may need

to be deferred for several weeks after commencement of the immunosuppressive

agent.

• In active disease, high dose prednisolone is often required at the same time as

commencing immunosuppressive therapy.

• Pregnancy and breast feeding are relatively contraindicated while on

immunosuppressive therapy.

• It is important to ensure adequate contraception being used. See appendix for

teratogic risks.

• To minimize the risk of skin cancer, exposure to sunlight and UV light should be

limited by wearing protective clothing and using sunscreen with a high protection

factor.

• Once a treatment plan is agreed this should be actioned as promptly as possible.

• If an agent is not effective, provided an adequate period of treatment has been

adhered to, then there should not be unnecessary delay ( max 2 Weeks) in either

switching or adding further therapy.

• When a decision is made to commence biologic therapies, treatment should begin

within 2 weeks of that decision.

This document does not replace the advice given by the British National Formularly, nor the advice given my manufacturers.


12

Prednisolone

Indications

Corticosteroids are the initial mainstay of treatment in inflammatory eye disease. Almost all

patients with sight-threatening uveitis will require systemic steroids at some point.

Systemic steroids are effective in the short and longer term management of inflammatory

eye disease. They are usually well tolerated, but do have a number of side-effects, most of

which are predictable .

What to do

• Consult BNF.

• Ensure no potential interaction with other medications.

• Check baseline U+E, LFTs, FBC, serum glucose, urinalysis and blood pressure.

• Consider what is the most appropriate route of administration (Steroids may be

administered topically, intra-orbitally, intra-vitreally or systemically).

• Initial treatment may depend on consultant and patient preference.

• Many authors would advocate initial dosing of prednisolone at 1mg/kg, however it is

our experience that a starting dose between 40mg and 60mg is usually required for

patients with uveitis, depending on severity and type of uveitis.

• If rapid disease control is required then methylprednisolone may be given at a dose

of 1g pulses per day over 3 consecutive days. This would be followed by high-dose

oral prednisolone.

• High dose oral steroid therapy does not increase the risk of ulcer disease(3,4) and

therefore the routine use of proton pump inhibitors (PPI) or histamine H2 blockers is

not necessary. However many patients complain of dyspepsia when commenced on

steroids and PPIs or H2 blockers may have a role in these patients. Patients should

be started on a PPI if they are also taking non-steroidal anti-inflammatory drugs

(NSAIDS) as this combination of therapy has been associated with a fourfold

increased risk of gastric ulceration.(4)


13

• Bone densiometry should be considered for any patient on any dose of oral

prednisolone for longer than three months or where the patient is likely to require

prednisolone for at least three months due to the risk of osteoporosis. The college of

physicians guidelines are summarized on the following website

http://www.rcplondon.ac.uk/pubs/books/glucocorticoid/

• Patients on corticosteroid for longer than 3 weeks, treatment must not be stopped

abruptly. Adrenal suppression can last for a year or more after stopping treatment

and the patient must mention the course of corticosteroid when receiving treatment

for any illness or injury

• Unless patients have had chickenpox, patients receiving oral or parenteral

corticosteroids should be regarded as being at risk of severe chickenpox.

Manifestations of fulminant illness include pneumonia, hepatitis and disseminated

intravascular coagulation; rash is not necessarily a prominent feature.

Passive immunisation with varicella–zoster immunoglobulin is needed for exposed

non-immune patients receiving systemic corticosteroids or for those who have used

them within the previous 3 months. Confirmed chickenpox warrants specialist care

and urgent treatment. Corticosteroids should not be stopped and dosage may need

to be increased.

• Mood and behaviour changes. Corticosteroid treatment, especially with high doses,

can alter mood and behaviour early in treatment—the patient can become confused,

irritable and suffer from delusion and suicidal thoughts. These effects can also occur

when corticosteroid treatment is being withdrawn. Medical advice should be sought if

worrying psychological changes occur.

• Steroid Treament Cards should be issued to all patients.

Side Effects

Side effects include acne, atherosclerosis, avascular necrosis of femoral head, cataract,

delay in pubertal growth, diabetes mellitus (up to 30%)(5), dyslipidemia (up to 30%)(6,7), heart

failure, hypertension (up to 85%) (6), infection, osteporosis, raised intraocular pressure

(IOP), serious psychosis (up to 5%) (8,9), sleep disturbance.


14

http://www.rcplondon.ac.uk/pubs/books/glucocorticoid/

Antimetabolites

Azathioprine

Indications

Azathioprine may be used as a steroid sparing agent.

Evidence in Inflammatory Eye Disease

• A recently published retrospective cohort study found 69% of patients with

intermediate uveitis, 44% of patients with posterior or panuveitis and 24% of patients

with anterior uveitis patients had control of their ocular inflammation within 6 months

of treatment with azathioprine(10).

• The only randomized, placebo-controlled, double-blind trial of azathioprine was in

patients with Behcet disease. This trial found azathioprine to be effective in the

treatment of chronic uveitis and in reducing incidence of second eye involvement

when used in combination with prednisolone(11).

• Azathioprine has also been shown to provide effective long-term control of uveitis

associated with Behcet disease (12,13) but newer drugs are likely to be more effective.

See section on interferon alpha and tumour necrosis factor alpha inhibitors.

• There are a number of case series illustrating the efficacy of azathioprine in the

treatment of chronic uveitis in patients with eye disease (13,14,15).

• Azathioprine has been shown in case series to be useful in the treatment of

serpiginous choroiditis, multifocal choroiditis tubulointerstitial nephritis and panuveitis

when combined with prednisolone or ciclosporin A(16,17,18,19).

What to do

• Consult BNF.


• U&E, LFT and FBC should be checked before commencing therapy, then weekly for

the first month of therapy and at least three monthly thereafter.


15

• The enzyme thiopurine methyltransferase (TPMT) metabolises azathioprine; the risk

of myelosuppression is increased in those with a low activity of the enzyme,

particularly in the very few individuals who are homozygous for low TPMT activity.

Normal levels: normal dose. Medium levels (heterozygous for TPMT mutation):

reduce dose. Very low levels (homozygous for TPMT mutation): low dose or avoid

use.

• If Allopurinol is co-prescribed the dose of Azathioprine should be reduced by 75%.

• If on warfarin then close monitoring of INR is advised as azathioprine may alter

anticoagulant effect.

• Azathioprine may be started at a dose of 50mg/day and if tolerated increased to

100mg after a week.

• Dosing usually needs to be adjusted based on the clinical response and side effects.

• Dose may be increased to a maximum of 2.5mg/kg/day.

• In practice, this will rarely exceed 150mg/day.

Side effects

Side effects are common and in one study 24% patients stopped azathioprine due to

side effects (10). These include generalised muscle aches, fatigue and headache. Slow

titration of the dose reduces the chance of these side effects and if they do occur then

dose reduction is often enough for symptoms to resolve. Regular blood monitoring is

required to identify liver dysfunction and bone marrow suppression. These effects

usually resolve on stopping the azathioprine. Gastrointestinal upset is relatively

common. A recent retrospective review would suggest that there is no increased cancer-

related mortality in patients treated with azathioprine for ocular inflammatory disease(20).


16

Methotrexate

Indications

• Most frequently used in disease in association with connective tissue disorders as a

steroid sparing agent.

• May be used in combination with infliximab for idiopathic inflammatory eye disease.


• Methotrexate has been show in several large studies to be effective in the treatment

of uveitis(18,22,23,24,25,26,27) with one large study showing remission in 76% patients (22).

• A recently published retrospective cohort study found 55.6% of patients with anterior

uveitis, 47.4% of patients with intermediate uveitis and 24% of patients with posterior

or panuveitis had control of their ocular inflammation within 6 months of treatment

with methotrexate (21).

• This however appears not to be the case in Scottish clinical practice and

methotrexate is rarely used except in patients requiring some form of

immunosuppression while on infliximab and all other immunosuppressants have

been either ineffective or not tolerated.

What to do

• Consult BNF.


• Full blood count and renal and liver function tests before starting treatment and

repeated weekly until therapy stabilised, thereafter patients should be monitored

every 2–3 months.

• A baseline CXR is required.

• Patients should be advised to report all symptoms and signs suggestive of infection,

especially sore throat

• Not suitable for patients with either significant renal or liver disease.


17

• 16% patients (21) are intolerant of this drug.

• Commence at 7.5mg/week (as single dose).

• Dose may be increased by 2.5mg increments every 6-8 weeks (available in strengths

of 2.5mg and 10mg).

• The maximum dose is usually 15-25mg/week.

• Nausea, diarrhoea and mouth ulcers may respond to folic acid 5mg once a week 3

days after methotrexate.

• Respiratory symptoms should be investigated with a CXR and pulmonary function

tests as there is a risk of pulomary fibrosis.

• Side effects

• Regular blood monitoring is important as hepatoxicity and bone marrow suppression

may occur. These usually resolve on stopping the methotrexate. Nausea, diarrhoea

and mouth ulcers are relatively common but usually respond to treatment.

Conception must be avoided for at least 3 months after administration has ceased for

both males and females. May cause reversible sterility in males. Hair loss or rash

may occur. It is important to get medical review urgently if a rash develops. Hair loss

generally improves on stopping methotrexate. Irreversible lung changes may occur

(interstitial disease).


18

Mycophenolate mofetil

Indications

Used as a steroid sparing agent.


• In a number of published case series mycophenolate mofetil appears to be effective

in the treatment of ocular inflammatory disease (28,29,30).

• In one retrospective case series 64.3% patients achieved long term disease control

with mycophenolate mofetil (31).

• A recently published retrospective cohort study showed mycophenolate was

associated with a greater level of treatment success at six months than azathioprine

and methotrexate (70%, 58%, 42% respectively)(32) .

What to do

• Consult BNF


• U&E, LFT, lipid profile and FBC should be checked before commencing therapy.

• FBC should be checked weekly for the first month, then twice a month for the second

and third months, then every month in the first year. Thereafter monitoring every two

to three months may be appropriate.

• U&E, LFTs and blood pressure should also be monitored regularly.

• Avoid clozapine and mycophenolate together as there is an increased risk of

agranulocytosis.

• Use cautiously in renal impairment or gastrointestinal disorders.

• Commence orally at 1g twice a day.

• May be increased up to 1.5g twice daily if clinically indicated.

• A negative pregnancy test is essential prior to commencement of therapy.


19

• Patients should be warned to report immediately any signs or symptoms of bone

marrow suppression e.g. infection or inexplicable bruising or bleeding

• Mycophenolate should not be prescribed concomitantly with azathioprine.

Side effects

Side effects include generalised muscle aches, fatigue and headache and

gastrointestinal upset. May be reduced by titrating the dose slowly. If side effects do

occur then dose reduction is often enough for symptoms to resolve. Regular blood

monitoring is important to identify liver dysfunction and bone marrow suppression.

These effects usually resolve on stopping the drug. A recent retrospective review would

suggest that there is no increased cancer-related mortality in patients treated with

mycophenolate for ocular inflammatory disease (20) .


20

T-cell inhibitors/Calcineurin Inhibitors

Ciclosporin

Indications

Ciclosporin may be used as a steroid sparing agent.


• Case series have suggested that cyclosporin is an effective monotherapy for the

treatment of uveitis at a dose of 10 mg kg/day (33). This is much higher dose than that

currently used.

• Several studies in uveitis have shown its efficacy and safety (34,35,36,37,38,39,40).

• In a randomized controlled trial involving 56 patients with uveitis, ciclosporin had

similar efficacy to oral steroids (41), though greater efficacy was noted in combination.

What to do

• Consult BNF.


• Baseline FBC, LFTs, U&E (x2), lipids, urinalysis and blood pressure.

• U&E, LFTs and FBC should then be checked fortnightly until dose stable for 3

months, then monthly thereafter.

• Lipids should be checked every six months.

• BP should be checked at each monitoring visit.

• There is no indication for routine monitoring of serum concentrations of the drug as

they do not correlate well with efficacy. May be useful if compliance in question.

• Because of differences in bioavailability, the brand of oral ciclosporin to be dispensed

should be specified by the prescriber

• Doses given for Neoral.


21

• Commence at 2mg/kg twice a day (4mg/kg/day) orally.

• Dose adjusted dependent upon clinical response and side effects.

• Nephrotoxicity is relatively uncommon on doses of 2-5mg/kg/day. Treatment

contraindicated in patients with evidence of moderate or severe renal impairment.

• Do not prescribe concomitantly with tacrolimus.

• The concomitant use of nifedipine or colchicine should be avoided.

• Potassium sparing diuretics, ACE inhibitors, Angiotensin-II receptor antagonists and

potassium salts should be used with caution.

• Grapefruit juice should not be taken at the same time as ciclosporin.

Side effects

• Frequently causes hirsutism and therefore less favoured in women. Not generally a

problem in men

• Gum overgrowth may occur. Does not generally resolve on stopping ciclosporin and

may require surgery to correct.

• Regular blood monitoring usually allows early identification of liver or kidney

impairment. These effects may resolve on stopping the ciclosporin.

• High blood pressure and high cholesterol may result in an increased risk for stroke

and heart disease. Both of these side effects are monitored for and are potentially

treatable with further medication.

• Low magnesium levels may occur with ciclosporin. Occasionally these may cause

muscle aches or numbness. If these are problematic then the magnesium levels

usually return to normal on stopping the ciclosporin.

• Pregnancy and breast feeding relatively contraindicated while on ciclosporin.

• Tremor if not well tolerated may require cessation of treatment.

• Mild nephrotoxicity often responds to dose reduction. Ciclosporin should be stopped

if nephrotoxicity moderate or worse. Nephrotoxicity (42). All patients on 10mg/kg/day


22

will develop evidence of nephrotoxicity. This is significantly reduced on doses of 2-

5mg/kg/day.

Tacrolimus

Indications

Used as a steroid sparing agent.


• Small case series have suggested tacrolimus is effective in the treatment of uveitis,

achieving between 62% to 76% control (43,44,45,46).

• One prospective randomized controlled trial has shown tacrolimus to be as

efficacious as ciclosporin but with a better side effect profile (47).

What to do

• Consult BNF


• Baseline FBC, LFTs, U&E and creatinine, lipid profile, blood glucose, coagulation

screen and ECG.

• Once on treatment U&E, creatinine, LFTs, FBC and blood pressure, should be

checked weekly for 4 weeks then fortnightly for 2 months then monthly.

• Lipid profile and blood glucose should checked regularly.

• Monitoring the blood concentration of tacrolimus is not essential when using low

doses. However, trough tacrolimus levels are useful when considering increasing the

tacrolimus dose, for ensuring that maintenance doses are not toxic and as a

measure of compliance.

Recommended doses given for Prograf

• An initial dosage of 0.05 mg per kg per day may be effective for uveitis.

• Usual effective dose 1-2mg twice daily.


23

• Dosing should be based on achieving disease control with minimal side effects.

• Do not prescribe concomitantly with ciclosporin.

• Grapefruit juice should not be taken at the same time as tacrolimus.

• Potassium sparing diuretics and potassium salts should be used with caution.

Side effects

• Regular blood monitoring usually allows early identification of liver or kidney

impairment. These effects may resolve on stopping the tacrolimus.

• May cause hypertension and hypercholesterolaemia which potentially may result in

an increased risk of stroke and ischaemic heart disease. Both of these side effects

are monitored for and are potentially treatable with further medication.

• Tacrolimus is associated with diabetes.

• Low magnesium levels may occur with tacrolimus and may result in muscular aches.

If these are problematic then magnesium supplements may be tried. The magnesium

levels usually return to normal on stopping the tacrolimus.

• Gastrointestinal upset including abdominal pain, nausea, vomiting, and diarrhoea

may occur. Slow dose increase reduces the chance of these side effects and if they

do occur then dose reduction is often enough for symptoms to resolve.

• Tremor occurs in some patients but stops with treatment cessation.

• Due to reports of reversible cardiomyopathy in children receiving tacrolimus following

cardiac transplant, it is recommended that children have regular echocardiograms

(reference to BNF). However, screening is generally not undertaken in adults.

• Occasionally headache can be a problem.

• Pregnancy and breast feeding relatively contraindicated while on tacrolimus. Avoid

steroid based contraceptive agents as tacrolimus may alter their metabolism.

• Adverse effects generally resolve or improve when tacrolimus is stopped or when the

dosage is reduced.


24

Alkylating Agents

Cyclophosphamide

Indications

Essential therapy in some forms of inflammatory disease especially if systemic disease

involvement. Used as an induction therapy.


• The majority of data on cyclophosphamide use in ocular inflammatory disease

comes from uncontrolled case series (50,51,52,53).

Intravenous pulsed cyclophosphamide has fewer side effects, but is less efficacious than

the preferred oral route (52).

What to do

• Consult BNF


• U&E, LFT, FBC and urinalysis and pregnancy test (if appropriate) before

commencing treatment.

• Once treatment commenced, U&E, LFT, FBC and urinalysis weekly for the first

month, two weekly for the second and third month and then monthly thereafter.

• Doses given for oral route of administration.

• Starting dose orally, 1 to 3 mg/kg/day.

• Usual starting dose 100-150mg/day.

• Use with caution in elderly population (start at 50mg/day).

• Dose may be adjusted depending on response and toxicity.

• If toxicity occurs, dose may be decreased by 25 to 50 mg.

• Dosage reduction may be necessary in renal impairment.


25

• Should not be given concurrently with allopurinol as this increases bone marrow

suppression, or sulphonylureas due to the increased risk of hypoglycaemia.

• Opportunistic infections are more common with oral daily cyclophosphamide

compared to intravenous “pulse”, with 30% of patients on oral regimen developing

Pneumocystis carinii pneumonia in one study (48). Intermittent intravenous

administration is increasingly favoured by rheumatologists (49).

• Pneumocystitis carinii pneumonia prophylaxis should be considered for all patients

commencing cyclophosphamide. Septrin 960mg three times a week is

recommended. (see BSR guidelines)

• Patients should be asked about the presence of sore throat, rash, abnormal bruising

or oral ulceration at each visit.

• If a patients has haematuria on a urine dipstick they should be advised to increased

fluid intake. Monitor closely.

• If a patient develops macroscopic haematuria or haematuria with dysuria the drug

should be stopped.

Side effects

• Bone marrow suppression is dose dependent, reversible and more common in the

elderly.

• It is important that the patient is aware of signs and symptoms of bone marrow

suppression. They should be instructed to stop the cyclophopsphamide and to seek

urgent medical advice if they develop a sore throat, rash, abnormal bruising or oral

ulceration.

• Relative increased risk of cancer (especially bladder and bone cancer), however

most patients receiving this treatment do not develop cancer.

• Hair loss, usually recovers.

• Cystitis due to cyclophosphamide irritating bladder (high fluid intake reduces risk).

• Blood in urine, may be microscopic or macroscopic and is more common in patients

with inadequate fluid intake. Patients should stop treatment and seek medical advice

immediately if macroscopic haematuria occurs.


26

• Nausea and vomiting.

• Cyclophosphamide is contraindicated during pregnancy and lactation and should be

withdrawn at least 3 months prior to conception.

• Amenorrhoea and azoospermia may occur in patients taking cyclophosphamide.

• May result in primary ovarian failure in over 70% patients (53,54,55,56).

• Patients should be offered sperm banking/ cryopreservation of oocytes.


27

Biological therapies

Biologic therapies currently have a role in treating sight threatening uveitis refractory to

conventional immunosuppression. They may be used as steroid sparing agents or where

other immunosuppressive agents are poorly tolerated as well as when ocular inflammation

remains uncontrolled. There remains some uncertainty about the long term consequences of

biologic therapy and so they should not be used as first-line treatment at present. There are

considerable cost implications to these therapies, but they may be sight-saving, and in

patients where the more ‘traditional’ approaches have failed, expense should not prevent

appropriate treatment. Common and important side effects of medication are discussed here

but please consult the British National Formulary and product datasheets for more complete

information.

The aim of biological immunosuppressive therapy is to control ocular inflammation and allow

the oral prednisolone dosage to be reduced below 7.5mg. The overall duration of treatment

is dependent on the individual and their disease. At present there are no large studies

comparing biological treatments in inflammatory eye disease. The use of biological therapy

for treating inflammatory conditions is changing rapidly and as our understanding of immune

mechanisms contributing to ocular inflammation improves we should aim to target our

therapies more precisely.


28

Tumour necrosis factor (TNF) alpha inhibitors

The tumour necrosis factor (TNF) alpha inhibitors comprise adalimumab, infliximab and

etanercept. Adalimumab and infliximab are being used for the short and long term treatment

of refractory ocular inflammatory disease and are discussed below but etanercept appears

to be ineffective. Adalimumab offers the advantage of being delivered via a subcutaneous

injection whereas infliximab is given as an infusion. However, there is currently more

experience with infliximab than with adalimumab in treating uveitis.

The anti-TNF therapies can:

• Can unmask previously unidentified multiple sclerosis.

• May reactivate tuberculosis.

• Allergic-like reaction may occur during infusion (infliximab). Slowing infusion or pre-

treating with hydrocortisone often effective in preventing this during further infusions.

• Sudden death has been reported in patients with known heart problems.

• Pregnancy and breast feeding relatively contraindicated.

• Injection site reactions may occur. It has been reported that cooling the site prior to

administering the injection reduces pain associated with the injection.

• Infection including histoplasmosis and other invasive fungal infections.

• SLE and lupus like syndrome.

• Hepatitis B reactivation has been reported in patients on infliximab.

• Patients with hepatitis B should be referred to a gastroenterologist to consider

antiviral prophylaxis prior to starting anti TNF alpha therapy.

• Lymphoma has been reported but the incidence was not higher than would be

expected for that population.

• Haematologic reactions including pancytopenia and aplastic anaemia are rare.

• Although adverse effects may be severe, they are relatively rare and should be

compared with those associated with other immunosuppressive agents.


29

Adalimumab

Indications

• It is recommended that adalimumab should be used as an adjunctive therapy for

refractory cases of uveitis rather than as a first-line treatment.

• Can be used as either a steroid sparing agent or an inducing agent.

• Adalimumab has not been licensed for use in inflammatory eye disease


• There are a number of moderate sized case series, and one open label prospective

trial looking at adalimumab in paediatric uveitis. These have reported an

improvement in ocular inflammation (57,58,59,60), reduction in the use of topical and

systemic medication (57,59) and a low rate of uveitis flares (61) in children, the majority

of whom had juvenile idiopathic arthritis associated uveitis.

• There is one open label prospective trial of patients with uveitis refractory to therapy

treated with adalimumab for 12 months. This reported a reduction in macular

oedema, ocular inflammation and immunosuppression but 42% of patients had

relapses requiring periocular steroid injections (62).

• There is one small case series showing maintenance of remission of Bechet’s uveitis

in patients on adalimumab (63).

Practical Considerations

Prior to commencing therapy:

• Consult BNF.


• Medical history and examination looking for evidence of infection or malignancy.

• Full blood count (FBC), urea and electrolytes (U+E), liver function tests (LFTs), C-

reactive protein (CRP), erythrocyte sedimentation rate (ESR), antinuclear antibodies

(ANA), double stranded DNA (dsDNA).

• Consider testing for hepatitis B.


30

• Consider investigating for central nervous system (CNS) demyelination in patients

with intermediate uveitis or a history of optic neuritis.

• Chest X-ray (CXR) to exclude tuberculosis (TB). Patients with an abnormal CXR,

history of TB or TB treatment should be referred to a TB specialist.

• Patients at high risk of TB eg. black African aged over 15 years and all South Asians

born outside the UK should be considered for TB chemoprophylaxis.

• Urinary pregnancy test as appropriate.

Short and longer term

• Usual adult dose is 40mg subcutaneous administered 2 weekly. May be increased to

40mg weekly if required. There is no data looking at the optimum dose of

adalimumab in uveitis.

• Dose for child ≤30kg is 20mg 2 weekly. Child ≥30kg is 40mg 2 weekly.

• Patients may be taught to self-administer adalimumab.

• Blood monitoring (FBC, U+E, LFT, CRP and ESR) should be performed 4 to 8

weekly.

Adalimumab as a monotherapy

• Adalimumab has been successfully used as a monotherapy in patients with ocular

inflammatory disease (59,61) although in the majority of reported cases it has been

used in combination with systemic steroids and/ or other immunosuppressive agents.

• In rheumatoid arthritis, a combination of methotrexate and adalimumab has been

found to be superior to adalimumab alone (64).

• There is currently no data on anti-adalimumab antibody formation in patients with

uveitis.

Contra-Indications/drug interactions

• Avoid concomitant use of adalimumab with other biological therapies.

• Avoid live vaccines (www.humira.com)


31

• Breast feeding. It is not known whether adalimumab is excreted in breast

milk (www.humira.com)

• Pregnancy. The effect of adalimumab on the fetus is unknown. (www.humira.com)

• Active infection including tuberculosis (www.humira.com)

• Demyelinating CNS disorders (65).

Side Effects

• Injection site reactions (10.6%). It has been reported that cooling the site prior to

administering the injection reduces pain associated with the injection (61).

• Infection including histoplasmosis and other invasive fungal infections (65,66) .

• Reactivation of tuberculosis (61).

• Demyelinating disease (61).

• SLE and lupus like syndrome (61) .

• Hepatitis B reactivation has been reported in patients on infliximab (66,67). Patients

with hepatitis B should be referred to a gastroenterologist to consider antiviral

prophylaxis prior to starting anti TNF alpha therapy (68).

• Lymphoma has been reported but the incidence was not higher than would be

expected for that population (65).

• Congestive cardiac failure (65). Use with caution in patients with known cardiac failure

(www.humira.com).

• Haematologic reactions including pancytopenia and aplastic anaemia are rare

(www.humira.com).


32

Infliximab

Indications

• It is recommended that infliximab should be used as an adjunctive therapy for

refractory cases of uveitis rather than as a first-line treatment.



• In one prospective open label trial infliximab in patients with refractory uveitis, clinical

success was achieved in the majority of patients (17 out of 23 patients) at 10 weeks

although by one year the numbers of patients considered a success had fallen to 7

out of 14 patients (69).

• There are a number of prospective open label trials of patients with refractory

Behcet’s uveitis showing rapid control of inflammation with infliximab (70,71,72), a

significant reduction in uveitis flares (72,73) and of systemic steroid dose in patients

treated with infliximab compared with the pre-treatment period (73).

• There are case series reporting success in controlling ocular inflammation in

childhood uveitis (60,74,75,76).


• Consult BNF.


• Hepatotoxicity has been reported. Infliximab should be stopped if liver function tests

become elevated to >5 times normal levels.

• Haematologic reactions including pancytopenia and aplastic anaemia are rare.

• Infusion hypersensitivity reaction – 10% of patients. May be severe and delayed.

• Although adverse effects may be severe, they are relatively rare and should be

compared with those associated with other immunosuppressive agents.


33


• Medical history and examination looking for evidence of infection or malignancy .

• FBC, U+E, LFTs, CRP, ESR, ANA, dsDNA.

• CXR to exclude tuberculosis (TB). Patients with an abnormal CXR, history of TB or

TB treatment should be referred to a TB specialist.

• Patients at high risk of TB eg. black African aged over 15 years and all South Asians

born outside the UK should be considered for TB chemoprophylaxis.

• Consider testing for hepatitis B

• Consider investigating for CNS demyelination in patients with intermediate uveitis or

a history of optic neuritis.


• Usual dose is 5mg/kg administered as an intravenous infusion but doses of up to 20

mg/kg may be given.

• After the initial dose a second dose may be given after two weeks and then at 6

weeks.

• Further doses may be given up to 6 to 8 weekly dependent upon clinical response.


weekly.

Infliximab as a monotherapy

• Infliximab has been used successfully as a monotherapy in uveitis (71,72), although in

the majority of reported cases it has been used in combination with systemic steroids

and/ or other immunosuppressive agents.

• Studies of patients with rheumatoid arthritis have shown that the formation of anti-

infliximab antibodies is greater in patients on infliximab alone compared with those

on infliximab combined with methotrexate (77). The formation of anti-infliximab

antibodies has been associated with a loss of clinical response and an increased

rate of infusion reactions (78).


34

• There is currently no data on anti-infliximab antibody formation in patients with

uveitis. However, it is recommended that infliximab is used in combination with

another immunosuppressive agent where this is tolerated.

Side Effects

• Infusion hypersensitivity reaction – 10% of patients (79). May be severe and delayed.

• Infection, including histoplasmosis and other invasive fungal infections.

• Reactivation of tuberculosis (80).

• Demyelinating disease (81) .

• Optic neuropathy (82).

• SLE and lupus like syndrome (83).

• Hepatitis B reactivation (66,67). Patients with hepatitis B should be referred to a

gastroenterologist to consider antiviral prophylaxis prior to starting infliximab (68).

• Lymphoma has been reported but it is unclear whether the incidence is higher than

that in the general population (84).

• Congestive cardiac failure. Both exacerbation of existing heart failure and new-onset

heart failure reported (85,86) .

• Hepatotoxicity has been reported. Infliximab should be stopped if liver function tests

become elevated to >5 times normal levels (www.remicaide.com).

• Rare reports of haematologic disorders including leucopenia, neutropenia,

thrombocytopenia and pancytopenia (www.remicaide.com).


35

http://www.remicaide.com/

Interferon α

Indications

• It is currently recommended that Interferon-α is used only in cases of uveitis

refractory to conventional immunosuppressive therapy.



• Both interferon alpha 2a (Roferon A®) and interferon alpha 2b (Intron A®,

Viraferon®) have been used in uveitis.

• A large prospective case series of patients with Behcet’s disease reported that 92%

patients responded to treatment. This effect appears to be prolonged with 40%

remaining inactive for 7 to 58 (mean 29.5) months after stopping treatment (87).

• Interferon alpha has been used to treat children with uveitis associated with Behcet’s

disease, and a corticosteroid sparing effect has been reported in one case series (88).

• Case series of patients with idiopathic uveitis, predominantly posterior and

panuveitis, refractory to conventional immunosuppression have demonstrated a

beneficial effect of interferon-α on uveitis in 59 to 83% of patients (89,90).

• Refractory uveitic cystoid macular oedema responded to interferon alpha with

complete resolution in 6 out of 8 patients in a prospective pilot study (91).

What to do

Pre-treatment

• Consult BNF.


• Medical history and examination, including history of mental illness.

• Prior to administration of the first dose, the following investigations should be

performed: FBC, U+E, LFTs, CRP, ESR, thyroid function tests (TFT), autoantibodies


36

including dsDNA and thyroid autoantibodies, coagulation screen, lipid profile, urinary

pregnancy test as appropriate.

• The patient’s weight should be recorded.

• Base line ECG for patients with cardiovascular disease.

• Chest X-ray.

• Steroid dose should be no greater than 15 mg prednisolone daily when interferon

treatment commenced, and ideally reduced to 10mg or less.

• Other immunosuppressive drugs should be stopped prior to starting interferon

therapy.


• Starting dose 3 million units once daily for Intron A.

• Maximum dose of Intron A used in ocular inflammatory disease is nine million units

daily.

• Administered as a subcutaneous injection daily before bed as patients may feel tired

after the injection.

• Paracetamol should be given 500mg tds for days 1-3.

• The following blood tests should be monitored during treatment at weeks 1, 2, 4, 8

and every month thereafter: FBC, U+E, LFTs, CRP, ESR, TFT and lipid profile

• Weight should be recorded at each clinic visit.


• Avoid concomitant use of interferon alpha with other immunosuppressive agents.

Low doses of steroids may be used in combination with interferon alpha.

• Avoid live vaccines.

• Breast feeding. It is not known whether interferon alpha is excreted in breast milk.

(http://www.introna.com).


37

http://www.introna.com/

• Pregnancy. The effect of interferon alpha on the fetus is unknown.


• History of severe depression.

• Hypersensitivity to interferon alpha (http://www.introna.com).

• Autoimmune hepatitis (http://www.introna.com).

• Decompensated liver disease (http://www.introna.com).

• Uncontrolled thyroid disease (http://www.introna.com).

Side Effects

• Flu-like illness (fatigue, headache, arthralgia, fever) occurs in almost all patients(87,88)

( http://www.introna.com). It is most predominant in the first two weeks of therapy

and may be improved by taking regular paracetamol (http://www.introna.com).

• Fatigue may persist during therapy (90).

• Anorexia and weight loss - 33% (90).

• Bone marrow toxicity resulting in myelosupression (87,89) and rarely aplastic anaemia


• Injection site reaction. 25% (90) - 100% (87).

• Alopecia. 24% (96). Hair growth returns when interferon alpha is stopped


• Hepatotoxicity (91). If the ALT rises to greater than 5 times normal, interferon should

be withheld. It may be later re-introduced at 50% of the initial dose. If the ALT rises

to greater than 10 times normal, interferon should be stopped and not re-started


• Regular blood monitoring usually allows early identification of liver disturbance and

bone marrow suppression. These effects should resolve on stopping the interferon.

• Depression may be dose related and improve as the dose is reduced (89). Selective

serotonin re-uptake inhibitors have been used to treat interferon-induced depression

in a case series of patients (92). Depression may be severe and suicidal ideation has


38











been reported (88,90). Patients with severe or worsening depression should have their

therapy stopped (92).

• Pruritis 24% (87)

• Diarrhoea

• Hypertriglyceridaemia, which may cause pancreatitis (http://www.introna.com).

• Cardiovascular problems – Hypotension, hypertension and arrhythmias. Use

cautiously in patients with known cardiovascular disease (http://www.introna.com).

• Retinopathy manifesting as cotton wool spots and retinal haemorrhages (90) .

• Acute hypersensitivity reactions. Drug should be stopped if an acute reaction

develops (http://www.introna.com). The risk of development of hypersensitivity

reactions may be greater with second and subsequent treatments

• Thyroid dysfunction, which may not be reversible when the drug is stopped


• Psoriasiform rash (90)

• Seizures (87)

• Interferon alpha may impair fertility (http://www.introna.com).

• The patient should be made aware of the possibility of delayed adverse reactions

and should be advised to report any symptoms which may give them cause for

concern.

• Not recommended in pregnancy or breast feeding.

• Women of childbearing age should use effective contraception during treatment and

for four months after.


39






Daclizumab

Indications

• It is recommended that Daclizumab is used only in cases of uveitis refractory to

conventional immunosuppressive therapy.

• Humanised IgG monoclonal antibody that binds CD25 of the human IL-2 receptor.

• Mechanism of action may be via induction of natural killer (CD56bright) cells.


• Daclizumab has been found to be effective in the treatment of intermediate and

posterior uveitis in a small open label study. Eight out of ten patients maintained

remission of uveitis over 4 years and were able to withdraw concomitant

immunosppressive medications with 2 to 4 weekly infusions of daclizumab (94).

• High dose intravenous daclizumab has been used successfully as an induction

therapy for active sight-threatening uveitis in a small open label study with control of

uveitis in 4 out of 5 patients at 4 weeks (95). Standard dose daclizumab (1mg/kg)

improved ocular inflammation in 59% of eyes in one case series (96).

• Two-weekly subcutaneous administration of daclizumab has also been shown to be

effective in maintaining remission of uveitis in a small 26 week open label trial (61,97).

• A retrospective case series of patients with birdshot retinochoroidopathy showed an

improvement in clinically observed ocular inflammation with daclizumab, but

electroretinography parameters declined in some patients (98).

• Three out of five children with ocular inflammatory disease responded to daclizumab

in one series but there were a number of adverse events with three children

developing transient leukopenia, one nausea, and one myalgia and fatigue (60).

• A small randomised controlled trial of daclizumab use in patients with Behcets

disease did not show any benefit of intravenous daclizumab over placebo in

preventing ocular attacks of Behcet’s disease (99).


40


• Consult BNF.


• Infusion hypersensitivity reaction. If a severe reaction occurs, daclizumab should be

discontinued.

• Fatigue may occur.

• Infection. An increased risk of death from sepsis was observed in a trial using

daclizumab for cardiac transplantation but these patients were on up to 5

immunosuppressive agents (93).

• Skin rash, liver disturbance, painful muscles, lymphadenopathy and leucopenia have

been reported.

• An increased risk of malignancy has not been found in studies of renal transplant

patients, but there is a theoretical increased risk of malignancy with

immunosuppression.

• Side effect profile should be discussed explaining that although adverse effects may

be severe, they are relatively rare and should be compared with those associated

with other immunosuppressive agents.

• Prior to commencing therapy:

• Medical history and examination looking for evidence of infection or malignancy .

• U+E, LFTs, CRP, FBC, ESR






weekly prior to administering infusion.


41

Daclizumab as a monotherapy

• Daclizumab has been used effectively as a monotherapy for uveitis. In a four year

open label study, patients were tapered off other immunosuppressive agents and

maintained on daclizumab alone (94).

Side Effects

• Infusion hypersensitivity reaction. If a severe reaction occurs, daclizumab should be

discontinued (http://www.rocheusa.com/products/zenapax/)

• Infection. An increased risk of death from sepsis was observed in a trial using

daclizumab for cardiac transplantation but these patients were on up to 5

immunosuppressive agents (93).

• Skin rash (100).

• Hepatic dysfunction (98).

• Leucopenia (96,98).

• Lymphadenopathy (94).

• Fatigue (60).

• Myalgia (60).

• An increased risk of malignancy has not been found in studies of renal transplant

patients (101), but there is a theoretical increased risk of malignancy with

immunosuppression (http://www.rocheusa.com/products/zenapax/)


• The dose regime for transplantation is an intravenous infusion of 1mg/kg two weekly

for 5 doses.

• In uveitis, induction doses of 8mg/kg have been used intravenously with a second

dose of 5mg per kg at 14 days (95).

• Maintenance intravenous dose is 1mg per kg (up to 100mg). Administer 2-4 weekly (94).


42

http://www.rocheusa.com/products/zenapax/

http://www.rocheusa.com/products/zenapax/

• Although subcutaneous daclizumab has been used in trials at a dose of 1 to 2mg/kg,

2 to 4 weekly (maximum 200mg) (94,96) there is not currently a commercial product for

subcutaneous use.

Campath (Alemtuzumab)

Indications

• It is currently recommended that Alemtuzumab is used only in cases of uveitis

refractory to conventional immunosuppressive therapy.


• Is a humanised mAb which binds to CD52, the pan-lymphocyte antigen.


• One case series of ten patients showed Campath-1H to be effective in the treatment

of refractory ocular inflammatory disease with initial improvement in all patients.

Eight patients had control of ocular inflammation lasting 5 months or longer (102).

• Campath-1H has also been used effectively in the treatment of a Mooren’s ulcer (103).

• A case series of patients with Behcet’s syndrome were treated with Campath using a

total of 134mg administered over 5 days. Details of eye involvement is limited in the

paper but there were four patients with active ocular disease prior to receiving

Campath, and at 6 months two were in remission and two in ‘partial remission’ (104).


What to do

Pre-treatment


• Consult BNF.



43

• Medical history and examination looking for evidence of infection or malignancy.

• FBC, U+E, LFTs, CRP, ESR

• Baseline cytomegalovirus serology.



• Consider HIV test.


• Ensure adequate contraception is used for at least 6 months following the infusions.

Short and longer term.

• Patients should be pre-treated with steroid, paracetamol and anti-histamine e.g. 1g

oral paracetamol, 100mg hydrocortisone and 10ml chlorpheniramine 30 minutes

prior to the infusion.

• Patients should receive anti-infective prophylaxis against Pneumocystis jiroveci

pneumonia (e.g. trimethoprim/ sulfamethazole 1 tablet twice daily, 3 times weekly)

and an oral anti-herpes agent such as famiciclovir 250mg bd while on therapy and

following treatment for a minimum of two months after treatment or until the CD4+

count has recovered to 200 cells/μl (whichever occurs later). (www.campath.com).

• Patients should have daily monitoring of full blood count and platelet count during

therapy with Campath and at 1, 2 and 4 weeks post therapy and at intervals

thereafter until haematological indices have recovered. Thyroid function should be

monitored.


• Breast feeding. It is not known whether Campath is excreted in breast milk

(http://emc.medicines.org.uk/).

• Pregnancy (http://emc.medicines.org.uk/).

• Active infection (http://emc.medicines.org.uk/).

• HIV (http://emc.medicines.org.uk/).


44

http://www.campath.com/

http://emc.medicines.org.uk/




• Use with caution in patients with ischaemic heart disease, angina and patients on

antihypertensives. (http://emc.medicines.org.uk/). Mycocardial infarction following

a Campath infusion has been reported (104).

• Avoid live vaccines (www.campath.com)

Side Effects

• Infusion reactions due to cytokine release causing rigors, fever, nausea, vomiting

and skin rashes are common. Severe reactions with bronchospasm, syncope, acute

respiratory distress syndrome, myocardial infarction and death have been reported.

Infusion reactions may be minimised by dose-escalation and by pretreatment with

oral antihistamines, paracetamol, and corticosteroids

(http://emc.medicines.org.uk/).

• Haematological toxicity. Lymphopenia occurs in all patients. Neutropenia,

thrombocytopenia (106), anaemia (www.campath.com), and coagulopathy (107) may

occur.

• Severe infections, some resulting in death, have been reported in patients with

haematological malignancies treated with Campath, although these patients received

higher doses than are used for ocular disease and had received other

immunosuppressive agents. Opportunistic infections included cytalomegalovirus,

aspergillosis, cerebral toxoplasmosis and progressive multifocal leukencephalopathy (108). There have been no reports of significant opportunistic infections in patients

treated with Campath for ocular inflammatory disease but experience of Campath

treatment in ocular disease is limited (109). Patients should be advised to report

symptoms of infection e.g. pyrexia (www.campath.com).

• Myocardial infarction post-infusion has been reported in the oncology literature (105).

• Hypothyroidism developed in 2 out of 18 patients with Behcet’s disease following

Campath infusions (http://emc.medicines.org.uk/). Thyroid dysfunction, usually

associated with thyroid autoantibodies, developed in 22% of patients with multiple

sclerosis and occurred up to 30 months after the last infusion. Some patients

required long term treatment for thyroid disease (110).


45







• Campath is administered as an intravenous infusion over 2 hours

(www.campath.com). The reported regimen for ocular inflammatory disease is daily

infusions for five days (102).

• The initial dose is 3mg. If tolerated this may be increased to 5 mg on the second day

and then up to 10mg. The maximum reported dose for treating ocular inflammatory

disease is 10-12 mg daily (102).

• One paper on Campath use in systemic Behcet’s disease, which included patients

with ocular disease, used an escalating regimen of 4mg,10mg, 40mg, 40mg and

40mg infusions on consecutive days (104). Doses of up to 30mg daily or 90mg weekly

are used for B cell chronic lymphocytic leukaemia (www.campath.com).

• If blood products are required following Campath therapy, these should be irradiated

while the patient remains lymphopenic because of the risk of graft versus host

disease (http://emc.medicines.org.uk/).

Rituximab

Indications


• Is a monoclonal antibody that binds to CD20 on mature B lymphocytes.

• Depletes CD20+ B cells by antibody-dependent cellular cytotoxicity, complement-

dependent cytotoxicity and apoptosis.

• Significant reduction in peripheral blood B lymphocytes occurs for 6 to 12 months.


• There are isolated case reports showing a benefit in anterior uveitis(112), scleritis

associated with Sjögrens syndrome (113), and scleritis (114) and peripheral ulcerative

keratitis (115) associated with Wegener’s granulomatosis. Rituximab has been used in

the treatment of retinal vasculitis (116).

• A number of small uncontrolled studies and case reports suggest that rituximab may

be effective in systemic lupus erythematosus (117) and systemic vasculitis (118).


46





What to do

Pre-treatment

• Consult BNF.


• U&E, LFT, FBC before commencing treatment.

• Four rituximab infusions (375mg/m2) intravenously at 4 weekly intervals effective in

treatment of anterior scleritis. So far no information or data for its use in uveitis. It

may be that this could be reduced further.

• Administration of IV administration of corticosteroids prior to the first dose of

rituximab reduces the incidence of infusion reactions. Infusion reactions less

common after the second rituximab dose, compared with the first.

• It may be that this could be reduced even further as an on-going dose-ranging trial

for the use of Rituximab in RA suggests dosing at day 1 and 15 at either 500mg or

1000mg proved efficacious (111) .


• U&E, LFT, FBC weekly for the first 2 months and 4 weekly thereafter.

• Human antichimaeric antibodies against rituximab have been detected, although

despite these patients were successfully retreated.

• Regular blood monitoring usually allows early identification of liver impairment and

bone marrow suppression with increased risk of infection and bleeding.


• Breastfeeding.

• Recent MI.

• Severe arrhythmias.


47

• Uncontrolled CCF.

• Women of childbearing age should use effective contraception during treatment and

for twelve months after.

Side Effects

• Up to 94% patients have reported adverse events during clinical trials for Rituximab (119).

Infusion related reactions

• Transient flu-like symptoms during first infusion (50-87%). Normally resolves within 3

hours. May require paracetamol and/or antihistamine (120,121,122,123,124,125).

• Up to 10% patients also experienced bronchospasm, hypotension or severe cytokine

release syndrome during first infusion.

• Generally treatment can be completed after symptoms resolved.

• Administration of IV corticosteroids prior to the first dose of rituximab reduced the

incidence of infusion reactions. Infusion reactions less common after the second

rituximab dose, compared with the first (121,123).

• Fatalities following severe cytokine release syndrome (characterised by severe

dyspnoea) and associated with features of tumour lysis syndrome have occurred 1–2

hours after infusion of rituximab (0.04–0.07% of patients) in patients treated for AML

and CLL.

• In the vast majority of cases these adverse effects are reversible with interruption or

discontinuation of rituximab along with supportive care severe consequences of

infusion-related reactions have been reported, including pulmonary infiltrates, acute

respiratory distress syndrome and cardiovascular events. Multi-organ failure can

occur. Infusion- related fatalities with rituximab have been rare (126).

• Transient hypotension frequent during infusion. Recommend withholding

antihypertensives for 12 hours prior to infusion.

• Cardiac arrhythmias (2%) (121) .

• Angina pectoris.


48

• Syncope.

• Anaphylaxis.

• Urticaria (127).

• Stevens-Johnson syndrome (127).

• Human antichimaeric antibodies (HACA) against rituximab were detected in <1%

and patients were successfully re-treated with the drug after developing HACA (124).

• Anaemia (Hb<10 g/dl) (10%) (121).

• Thrombocytopenia (2%) (121).

• Leucopenia (121).

• Neutropenia (0.5-1.5x109 cells/L) (10%) (121).

• These mild haematological abnormalities resolved spontaneously in 4 to 8 days

(relationship to treatment not reported) (121).

• All side effect information available is for use in AML and CLL therapy where dosing

regimens more aggressive and therefore we would hope the type and severity of

adverse reactions would be much less with this dosing regimen.

• Two dose-ranging studies have shown no relationship between side effects and

administered dose (120,122).

Anakinra

Indications

• May be used as a steroid sparing agent or an inducing agent.


• Anakinra is an anti-IL-1 agent.

• There is one case report of successful treatment of a child with uveitis associated

with the CINCA syndrome using anakinra (128). There is also a report of scleritis

responding to anakinra in two patients with rheumatoid arthritis (129).


49

• Although anakinra has been shown in several randomized, controlled, double-blind

clinical trials to be effective in the treatment of rheumatoid arthritis, there are no

human studies for its use in ocular inflammatory disease (130,131).


What to do

• Consult BNF.


• Monitor neutrophil count before treatment, then every month for 6 months, then

every 3 months—discontinue if neutropenia develops.

• Dose 100mg subcutaneous once a day.

• Alternating injection site recommended.

• Supplied in pre-filled syringe.

• Use cautiously in patients with a history of asthma (risk of serious infection).

• Patients should be instructed to seek medical advice if symptoms suggestive of

neutropenia (such as fever, sore throat, infection) develop.


• Predisposition to infections.

• History of asthma (risk of serious infection).

• Renal impairment. Manufacturer advises caution if creatinine clearance 30–

50 mL/minute; avoid if creatinine clearance less than 30 mL/minute.

• Despite animal model studies suggesting a benefit of combination therapy with

anakinra and anti-TNF-α in inflammatory arthritis, a safety study, though showing

increased efficacy, identified a high rate of adverse effects(132). A further study looked

at the additional benefit of anakinra and etanercept versus etanercept alone in

patients with rheumatoid arthritis but didn’t show any additional clinical benefit (133).

Combination therapy is therefore not recommended.


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Side Effects

• Injection site reactions (70%) (http://www.kineretrx.com/#).

• Serious infection (mainly bacterial) (http://www.kineretrx.com/#).

• Neutropaenia (<1 x109/L) (0.4%) (http://www.kineretrx.com/#).

• Increased lymphoma (3.6 fold increase) and melanoma rates (3 fold increase)

(http://www.kineretrx.com/#).

• Unlike anti-TNF-α therapies, there has been no report of increased incidence of

tuberculosis or opportunistic infections in patients treated with anakinra.

• Regular blood monitoring usually allows early identification of bone marrow

suppression with increased risk of infection.

• Patients should be instructed to seek medical advice if symptoms suggestive of

neutropenia (such as fever, sore throat, infection) develop.

• Relative increased risk of cancer (especially lymphoma and melanoma), however

most patients receiving this treatment do not develop cancer.

Other biological therapies

Etanercept

Etanercept appears to be ineffective as an agent for the treatment of uveitis. While an early

report suggested a benefit in children with uveitis (134) the majority of these patients had an

incomplete treatment response and small randomised controlled trials looking at the role of

etanercept in preventing relapse of uveitis (135), controlling juvenile idiopathic arthritis

associated uveitis (136) and ocular sarcoidosis (137) have shown no benefit over a placebo.

Retrospective comparison of infliximab and etanercept in controlling uveitis have found the

former to be superior (138,57). There are also case reports of new onset uveitis occurring in

patients on etanercept for other conditions (139,140). Etanercept is not currently recommended

for use as treatment for eye disease.


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http://www.kineretrx.com/




Summary of use of second line and biologic agents

• The aim of immunosuppressive therapy is to control disease and allow the oral

prednisolone dosage to be reduced to 7.5mg or less.

• Cystoid macular oedema is the leading cause of visual loss in uveitis and systemic

treatment should be considered in ALL patients with cystoid macular oedema.

• Having achieved disease control, immunosuppressive therapy is usually continued

for at least 6 months.

• The overall duration of treatment is dependent on the individual and disease activity

• Treatment may be required in the long-term or possibly even life-long depending on

the underlying condition.

• Once the prednisolone dose below 7.5mg and provided ocular inflammation remains

controlled then immunosuppressive therapy is slowly withdrawn.

• Dosage reductions are usually made every 4 to 6 weeks. and complete withdrawal of

therapy may take up to 12 months.

• At present there are no large studies comparing treatment efficacies.

• Individual treatment plans often initially the result of a patients preferred side effects

rather than on evidence-based decisions.

• Mycophenolate or tacrolimus are often the first choice agents with the choice of

agent based on likely efficacy and tolerability.

• T-cell inhibitors (ciclosporin or tacrolimus) are often the first choice agent for T-cell

mediated disease (retinal vasculitis, Vogt-Koyangi-Harada disease, sympathetic

ophthalmitis).

• Frequent review and early identification of treatment failure is important to allow

appropriate therapeutic changes to reduce morbidity and improve long-term visual

outcomes.

• The aim of biological immunosuppressive therapy is to control ocular inflammation

and allow the oral prednisolone dosage to be reduced below 7.5mg.


52

• Biological therapies are associated with significant systemic side effects. The long

term effects of biological therapies are still unknown and so these drugs should not

be used as first line agents.

• The overall duration of treatment is dependent on the individual and their disease.

• At present there are no large studies comparing biological treatments.

• The use of biological therapy for treating inflammatory conditions is changing rapidly

and as our understanding of immune mechanisms contributing to ocular

inflammation improves we should aim to target our therapies more precisely.


53

Combination Therapy

• As with all treatments for inflammatory eye disease, the concept of combination

therapy was adopted from allied specialities.

• This strategy has a long and proven history in the treatment of cancer.

• Due to the many pathways involved, a ‘two-pronged’ approach affecting different

parts of the immune system may be more effective than individual therapies.

• As the drugs have different side effect profiles, combination therapy may allow lower

individual doses to be used and so may be better tolerated than monotherapy.

• Alhough in other specialities large randomized controlled trials have been

undertaken to show the benefits of combination immunosuppressive therapy over

monotherapy (141,142,143), there are currently no randomized clinical trials making such

comparisons (1).

• In practice, immunosuppressive therapy is usually prescribed in combination with

oral prednisolone, the exception being interferon, where it is felt that combination

therapy actually reduces its efficacy. If prednisolone is used in combination with

interferon then the dose of prednisolone should be 10mg or less.

• In one case series combining methotrexate, ciclosporin and corticosteroid was

shown to be beneficial (144).

• Triple therapy in the form of azathioprine, cyclosporine and corticosteroid appears to

be more effective than monotherapy in the treatment of serpiginous choroidopathy (16).


54

Appendices

Appendix 1: Posterior Uveitis requiring early immunosuppressive therapy

Immunosuppression is recommended at the outset in a number of inflammatory eye

diseases due to the chronicity and potentially poor prognosis that these conditions have if

untreated. These conditions include ocular Behçet’s disease, birdshot retinochoroidopathy,

multifocal choroiditis with panuveitis, serpiginous choroidopathy, Vogt-Koyangi-Harada

disease and Sympathetic ophthalmitis

A number of these specific conditions and their treatment guidelines are presented below.

Where possible evidence for the efficacy of therapy is provided but due to the relative

scarcity of some of these conditions the evidence base is limited. It is important to realise

that many of these conditions have been treated under the blanket of sight-threatening

uveits, the individual conditions being lost within the study’s statistics. In practice therefore

where evidence doesn’t exist for specific disease-directed therapy then the therapy should

be directed by the disease activity.

Behçet’s disease

Treatment guidelines

• The acute presentation should be controlled with high dose oral prednisolone (1 to

1.5 mg/kg/ day).

• Sight-threatening disease may warrant urgent high dose pulsed methylprednisolone

of 1g per day for 3 days.

• Corticosteroids rarely prevent recurrences and are therefore used in combination

with immunosuppressive agents (145,146,147).

• Second line immunosuppresion should be started as soon as the diagnosis is

confirmed.

• Treatment choice will depend on the individual patient circumstances and disease

activity, both ocular and systemic.

• Chlorambucil and cyclophosphamide are effective in disease control in this condition (148) (case series). Chlorambucil is usually commenced at 0.1 mg/kg/day (149) and it

may take up to 3 months to be effective.


55

• Both ciclosporin and tacrolimus have been used widely for the treatment of uveitis in

patients with Behçet’s disease (34,150,44,46). Ciclosporin has been shown to be more

effective than colchicine and cyclophosphamide in the treatment of ocular Behçet’s

disease (151,52,36).

• Tacrolimus may be effective in patients with posterior uveitis refractory to ciclosporin (151) .

• Ciclosporin and tacrolimus are not recommended in patients with central nervous

system involvement as they may potentiate this (152).

• Azathioprine (dose of 2.5 mg per kg per day), has been shown to be effective

(controlled trial), although 22% patients developed disease while on azathioprine (11).

Other groups have also reported favourable results (153).

• Biologic agents, specifically interferon α and infliximab have recently been shown to

be effective in the treatment of ocular Behcet’s disease (154,155,156,157,70,96).

• Interferon α has been shown to produce remission, even in previously refractory

disease (96). In one study 92% patients with previously refractory disease responded

to treatment. This effect appears to be prolonged with 40% remaining inactive 14

months after stopping treatment (96).

• The results of infliximab in ocular Behcet’s disease appear very promising. In one

study, 24 of 25 patients had went immediate remission after a single treatment (70)

and remission was attained for over six months in 60% patients who had further

dosing. Numerous other studies have shown favourable results for the use of

infliximab in ocular Behcet’s disease (155,156,158,159).

• Infliximab should be used as an adjunctive therapy for refractory cases rather than

as a first-line treatment (70,159). Etanercept has not been shown to be effective (135).

• For refractory ocular disease biologic agents should be considered.

Birdshot Retinochoroidopathy


• Ciclosporin may be effective in the treatment of birdshot retinochoroidopathy (36,160,161)

(case series, no controlled trials).


56

• Ciclosporin is more efficacious than corticosteroid therapy alone. Disease control

was achieved in 85% patients compared to 46% respectively over a follow up period

of between 24 and 48 months (160).

• Another case series has shown in individual patients ciclosporin, mycophenolate

mofetil, azathioprine, methotrexate, and daclizumab to be effective (162).

Multifocal Choroiditis with panuveitis


• Oral corticosteroids are effective in up to 50% patients (163) in treatment of cystoid

macular oedema, dense vitritis or macular choroidal neovascular membrane (164).

• Consider immunosuppressive therapy, although there is no evidence at present to

suggest the efficacy of this (165).

Serpiginous Choroidopathy


• Ciclosporin in combination with oral prednisolone has been advocated for early

treatment of this condition (166,167).(Case series, no controlled trials)

• Other authors have found this treatment ineffective (168) and some have

recommended a triple therapy regimen (16,17) involving concurrent administration of

prednisone, ciclosporin and azathioprine.

• Alkylating agents have been shown to be effective in an uncontrolled case series (169)

.


57

Appendix 2: Treatment of Inflammatory choroidal neovascularization (CNV)

Inflammatory choroidal neovascularization (CNV) is a comparatively rare complication of

uveitis, occurring in 1.9% of patients with uveitis (12 of 648) in one large retrospective

review (170) . However, inflammation is the third most common cause of choroidal

neovascularization, after age related macular degeneration (AMD) and pathological myopia,

and CNV of any aetiology can lead to severe visual loss (170).

Inflammatory conditions with a high incidence of CNV include punctate inner choroidopathy

(PIC), multifocal choroiditis with panuveitis, ocular histoplasmosis, serpiginous choroiditis,

Vogt-Koyanagi-Harada disease and ocular toxoplasmosis. CNV can develop during an

episode of active uveitis or in eyes with signs of previous uveitis but no active inflammation

at the time of visual loss from the CNV. In a recent multicentre treatment study of

inflammatory ocular neovascularization, 26% of eyes (26 of 99) had signs of active uveitis,

whereas in 74% of eyes (73 of 99) the uveitis was inactive (171).

The following treatments for inflammatory CNV have been used either as monotherapy or in

combination: argon laser photocoagulation, surgical excision, corticosteroids (local injections

or systemic), second line immunosuppressive agents, photodynamic therapy (PDT) and

intravitrel anti-vascular endothelial growth factor (VEGF) agents.

Laser photocoagulation of subfoveal CNV causes immediate loss of vision and is therefore

counterproductive. In cases of juxtafoveal or extrafoveal CNV, laser photocoagulation can

reduce the risk of severe loss of vision; however, enlargement of the subsequent scar, and

recurrence of neovascularization at the edge of the scar, often causes late visual loss (172).

The Submacular Surgery Trials Research Group presented a randomized comparison of

surgery vs observation for subfoveal CNV in eyes with ocular histoplasmosis or idiopathic

cause (173). At the 24-month follow-up, median BCVA was 6/75 (20/250) in the observation

arm and 6/48 (20/160) in the surgery arm. CNV recurred in 58% of surgically treated eyes.

Overall this study did not show a significant benefit for surgical excision.

A tapering course of high dose oral prednisolone monotherapy has been shown to stabilize

or improve vision, in the short term, in the majority of patients with inflammatory CNV due to

PIC or multifocal choroiditis (174). However, some patients fail to respond to systemic

immunosuppression (175), or develop recurrences when immunosuppression is reduced.

The Verteporfin in Ocular Histoplasmosis Study treated 22 patients showing subfoveal CNV

with an average of 3.9 sessions of PDT (176). At the 24-month examination, the median


58

improvement was 1.2 lines. PDT has been used to reduce CNV activity and improve vision

when initial treatment with systemic immunosuppression has failed. In a small study of 5

patients with CNV secondary to PIC, combination therapy with PDT and systemic

corticosteroids, led to an average improvement of 9 ETDRS letters at 12 months follow up (177).

Multiple recent studies have reported a beneficial effect with intravitreal bevacizumab

(Avastin) for inflammatory CNV (171,178) . A large multicentre retrospective study of 99 eyes

with inflammatory ocular neovascularization treated with intravitreal bevacizumab has

recently reported 12 month and 24 month results (171) . (6 out of 99 eyes had new vessels at

the disc or elsewhere rather than CNV). Forty-one patients (44 eyes) were also taking oral,

periocular, or intraocular corticosteroids or other immunosuppressive agents. Thirty-three

eyes received 0.1ml (2.5 mg) of intravitreal bevacizumab and 66 eyes received 0.05 ml

(1.25 mg). The majority of centres treated with single intravitreal injections as required,

although some centres gave a monthly injection for 3 visits and then subsequent injections

as required. Ninety-five eyes completed the 12-month follow-up with a mean gain of 2.5

lines and an average of 2.3 (+/- 1.8) bevacizumab injections (range 1–12). Best corrected

visual acuity (BCVA) worsened in 14 eyes (14.7%). So far 27 eyes have completed the 24-

month follow-up with a mean gain of 2.2 lines and an average of 3.6 (+/- 4.2) bevacizumab

injections (range 1–21). BCVA worsened in 5 eyes (18.5%).

In summary, recent evidence suggests that anti-VEGF therapy provides superior results at 2

years than previous therapies. The most commonly used protocol is to give single injections

of 0.05ml (1.25mg) of bevacizumab (Avastin) on an as required basis depending on activity

of the CNV. If there is active uveitis then concurrent treatment with systemic steroids or

other immunosuppressive agents should be included in the regime. If there is no active

uveitis then monotherapy with intravitreal bevacizumab is reasonable. There have been no

reports of intravitreal ranibizumab (Lucentis) therapy for inflammatory CNV, but on the basis

of the wet AMD trials there is likely to be a similar treatment effect. For patients who decline,

are not suitable for, or fail to respond to anti-VEGF therapy, PDT is a reasonable alternative.

It must be remembered no drug treatments have been licensed for the treatment of

inflammatory CNV and patients should be counseled to this effect. Many patients with

inflammatory CNV are young women and all of the above drug treatments should be

avoided, if possible, in pregnancy or when breast-feeding.


59

Appendix 3: Management of uveitis-associated glaucoma

Glaucoma in association with uveitis is relatively common. One retrospective study

identified a prevalence of 22.3% in patients with chronic uveitis at 10 year follow up (179).

Glaucoma is commoner in specific uveitic syndromes including Fuchs’ heterochromic cyclitis (180) , sarcoidosis, herpes simplex keratouveitis (181), and herpes zoster associated uveitis (181).

Most of the ocular hypotensive agents can be used for the treatment of uveitis-associated

glaucoma, in some patients topical carbonic anhydrase inhibitors appear be very effective (182). Prostaglandin analogues are relatively safe and appear to increase the uveitis activity in

only a minority of patients (183,184,185). They should however be used with caution in patients

with a history of cystoid macular oedema (186,187,188) or herpetic disease (189,190). Cyclodiode

laser has a high rate of hypotony in uveitis (19%) (191).

Laser iridotomy may provide temporary relief in secondary angle closure glaucoma,

although longer term failure rate is relatively high due to on-going inflammation. Surgical

iridectomy may be necessary. Filtration surgery is appropriate if intraocular pressure

remains high despite maximum medical therapy (192,193,194,195) .

Ideally, ocular inflammation should be controlled prior to any surgery. Anti-proliferative

agents should be used with trabeculectomy. Good results have been obtained with

glaucoma drainage implant devices (196,197,198,199).


60

Appendix 4: Management of uveitis in the perioperative period

Ideally ocular surgery should only be performed when the inflammation has been controlled

for a period of at least 3 months. Control may mean 1+ cells in the anterior chamber. Ensure

intraocular pressure is adequately controlled prior to surgery.

Although most uveitis specialists would agree that the use of steroid perioperatively is

efficacious, there currently doesn’t appear to be any consensus as to what this should entail.

Whether this should be oral or intravenous, pre, peri, or post-operative and if oral steroids

should be continued for a prolonged post-operative period.

One study involving 40 patients found that a two week course of oral prednisolone prior to

surgery resulted in less blood aqueous barrier break down than a single dose of intravenous

methylprednisolone in the perioperative period (200) .

One author recommends 2 hourly steroid drops for the 2 weeks preceeding surgery for

patients with relatively inactive anterior segment disease. In patients with chronic

inflammation whether or not they are already on systemic immunosuppression, he

recommends intensive topical corticosteroids as above plus a pulse of iv methylprednisolone

500mg in the immediate pre-operative period. Post-operatively 2 hourly topical

corticosteroids for a minimum of 4 weeks before considering a slow reduction. Early regular

review is important (201).

Another opinion is that in general old anterior uveitis that has been quiet for years requires

no treatment. If quiet posterior/intermediate uveitis off immunosuppression, give one dose of

500mg IV methylprednisolone intraoperatively. Patients with uveitis on immunosuppression

give 3 doses of IV methylprednisolone 500mg day before, day of and day after surgery.


61

Appendix 5: Immunosuppression during pregnancy

As the highest incidence of uveitis occurs in the working population (202), a large proportion of

women with sight-threatening uveitis will be of child-bearing age. Conception, pregnancy,

foetal development, and lactation may all be affected by the medications used to treat

inflammatory eye disease. It is important that the physician caring for these women is aware

of the potential side effects of these treatments. The risk of impaired fertility and congenital

abnormality should be explained to any woman of childbearing age prior to commencing

immunosuppressive therapy. Effective contraceptive measures should be used by all

patients on immunosuppressive therapy.

Pregnancy itself may have an immunosuppressive effect and it may be possible to lower

immunosuppression without relapse during this period. If immunosuppression is required

during pregnancy then it should be explained to the mother that although there can be no

guarantee that the foetus will be unharmed the risk to the baby is probably small. It is also

important to remember immunosuppressive agents may cause infertility and potentially

teratogenetic in men (203,204) .

Azathioprine and ciclosporin appear to be safe for men wishing to father children on therapy

(205). Methotrexate may cause reversible sterility in men (206,207) .

The U.S Food and Drug Administration (FDA) utilises a rating system for ranking pregnancy

risks associated with medications as outlined below.

FDA pregnancy category

Interpretation

A Well controlled studies have failed to demonstrate a risk to the foetus.

B Lack of well controlled studies in human but animal studies so far demonstrate no risks to the foetus.

C Animal studies had shown adverse outcome on the foetus OR animal studies are lacking and no well controlled human studies exist; hence foetal risk cannot be ruled out.

D Evidence of human foetal risk but potential benefits may warrant the use of this medication in pregnant women.

X Use contraindicated as studies in animals, human or both have shown foetal abnormalities and the foetal risk clearly outweigh the benefits of its usage in pregnant women.


62

NSAIDS

• Can be used during pregnancy until the last 6 weeks of gestation (208,209).

• Felt to be safe while breast feeding (210,211).

Prednisolone

• FDA pregnancy category B.

• Increased risk of cleft lip and cleft palate (212).

• Important to limit to the lowest effective dosage or if possible, avoid during the first

trimester while hard palate is forming.

• After the first trimester, can be used for sight-threatening disease.

• Require “stress doses” of hydrocortisone for any emergency surgery, caesarean

section or prolonged labour.

• Monitor babies in the neonatal periods for infection or possible adrenal insufficiency

(213).

• Not contraindicated in breast feeding (214).

• Avoid breast feeding for 4 hours immediately following maternal ingestion will reduce

the amount of glucocorticoid in the milk (214).

Antimetabolites

Azathioprine

• FDA pregnancy category D.

• No significant teratogenic effect on the foetus (215).

• Prematurity, foetal growth restriction, adrenal hypoplasia and reduced serum

immunoglobulin levels have been reported (216,217,218).

• Transient neonatal leucopenia and thrombocytopenia. Reduction of dosage at 32

weeks’ gestation may decrease the risk.


63

• Felt to be safe in breast feeding (219,220,221,222).

Methotrexate

• FDA pregnancy category X.

• Teratogenic and therefore absolutely contraindicated in pregnancy (223,224,225)

• Reversible sterility in males.

• Discontinue at least 3 months prior to conception (214).

• If conception occurs while on treatment, methotrexate should be stopped

immediately and patient given folic acid to reduce risk of neural tube defects.

• Contraindicated in breast feeding.

Mycophenolate mofetil


• Associated with congenital malformations and spontaneous abortions (226,227).

• Contraindicated in pregnancy.

• A negative pregnancy test is essential prior to commencement of therapy.

• FDA recommends the use of 2 reliable forms of contraception 4 weeks prior to

treatment, during treatment and 6 weeks after discontinuation of treatment.

• Contraindicated in breastfeeding.

T-cell inhibitors/Calcineurin inhibitors

Ciclosporin

• FDA pregnancy category C.

• No specific pattern of congenital malformations detected (205).

• No significant increased risk of foetal malformations (228).

• Acceptable immunosuppressant in pregnancy (229).


64

• The American Association of Paediatrics warns against breast feeding while on

treatment.

Tacrolimus


• Small increase in foetal malformations but no consistent pattern (230).

• Incidence of gestational diabetes and transient neonatal hyperkalaemia reported (231).

• Transient neonatal immunosuppression.

• Safe to be used during pregnancy at therapeutic level (232).

• Secreted in breast milk and no adequate studies to determine the safety of breast

feeding, therefore breast feeding not recommended.

Alkylating agents

Cyclophosphamide


• Teratogenic therefore contraindicated in pregnancy (233).

• Discontinue at least 3 months prior to conception.

• May result in primary ovarian failure in over 70% patients (53,56).

• Cryopreservation of oocytes should be considered.

• Contraindicated in breast feeding (234).

Biologics

Knowledge of the safety of these agents in human pregnancy is very limited and therefore

only consider these agents if benefits outweigh the potential risks.

Infliximab



65

• Felt to be safe in pregnancy based on limited data.

• No increased risk of teratogenicity (TREAT registry and Infliximab Safety Database) (235).

• Should be stopped during the 3rd trimester when transplacental transfer is at its

greatest (237).

• Reports of decreased sperm motility and morphology (235).

• Infliximab is undetectable in breast milk of nursing mother, felt to be safe in breast

feeding (236,237).

Adalimumab


• Limited data but the OTIS registry and published case reports do not suggest an

increased risk for adverse pregnancy outcomes during the 1st trimester exposure (238,239,240).

• Limited data on breast feeding, but case report shows no adverse effects to infant

whose nursing mother was on medication during pregnancy and post delivery (239).

Rituximab


• Few case reports show low levels of B lymphocytes during the first 6 months of life,

but no reported adverse pregnancy outcome (241).

• Should only be used if benefits outweigh risks.

• Limited data on breast feeding, therefore breast feeding not recommended.

Interferon alpha


• Limited human case reports which demonstrate no increased risk of teratogenicity (242).


66

• Reported cases of neonatal lupus and intrauterine growth restriction (243).

• Compatible with breast feeding (214).

Campath


• Contraindicated in pregnancy.

• FDA suggests that women and men should use effective birth control during

treatment with Campath and for 6 months after stopping treatment.

• FDA warns against breast feeding during treatment and 3 months after stopping

treatment.

Anakinra


• Animal studies show no evidence of foetal harms but no controlled data in human

pregnancy, therefore only recommended when benefits outweigh risks.


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Appendix 6: Paediatric guidelines

Scottish Uveitis Network and Scottish Paediatric and Adolescent Rheumatology Network Joint Management and Screening Guideline for Juvenile Idiopathic Arthritis associated Uveitis, Idiopathic Paediatric Uveitis and other rare causes of uveitis in children.

This document gives guidance on the screening for Juvenile Idiopathic Arthritis associated

Chronic Anterior Uveitis (JIA CAU), and the management of JIA CAU and idiopathic

paediatric uveitis (IPU).

Very rarely uveitis occurs in children with other disease associations, such as Behcet’s

disease, sarcoid, inflammatory bowel disease, and other rare causes. The management of

these conditions is poorly evidence based, and is best done by experts with the greatest

possible knowledge of these conditions, but it is expected the management should adhere to

the principles of good uveitis and paediatric care and care pathways inherent in this

document.

Rationale

Asymptomatic CAU associated with JIA has long been recognised as an important cause of

visual loss in childhood (244,245) with high levels of complications compared to other forms of

anterior uveitis. The incidence of bilateral disease is between 67-85% (246,247,248,249) , and

complications are reported in 20-40% of children at presentation and steadily accumulate

over the first two decades of life, especially in those with persistently active disease (247,248,249,250,251,252) . In order to reduce the ocular complications early, regular, screening by

slit lamp examination has been recommended for many years, but the incidence of a poor

visual outcome remains high (16-38%) (246,247,253,254) . The current screening advice (255) ,

albeit based on limited evidence is the basis for the current screening guidance in this

document, and is in line with other guidance (256) . It has not been possible to demonstrate

unequivocally that screening programmes have reduced the frequency of either

complications at presentation, or long-term visual loss (257,258,259) , but it is becoming clearer

that early diagnosis, and early immunosuppression with an aggressive approach to removal

of inflammation are important (1, 246, 251, 253, 260, 261, 262, 263, 264, 265, 266) . Some medication choices

may be important risk factors for developing uveitis (61, 57, 134, 135, 136, 137, 138, 139, 140, 267, 268, 269, 270)

. Other risk factors are not yet clearly elucidated, poorly controlled uveitis and chronicity of

inflammation themselves presents a significant risk of cataract and glaucoma in 10- 50% of

patients in many series, and are increasingly common with longer follow-up (47, 251, 253, 261, 263,


68

266, 271, 272, 273, 274, 275) . Persistent ongoing application of topical steroid is also associated with

cataract and glaucoma (246, 251, 253, 261, 263, 264, 265) . There is growing evidence for the value of

early introduction of disease modifying anti-rheumatic therapies (DMARD), particularly

methotrexate (276, 277) and mycophenolate (278, 279, 280, 281) , and for early introduction of

biologic therapies, namely infliximab (57, 74, 75, 76, 282, 283, 284) or adalimumab (58, 59, 60, 62, 269) . The

majority of children with uveitis have JIA, and paediatric rheumatology services in Scotland

already manage and prescribe these drugs for the other organ manifestations of JIA. This

includes access to specialist paediatric nurses with a remit to manage and educate about

these drugs for children and parents.

These guidelines are based on an agreement between SPARN and the Uveitis Network that

joint working between these teams is a useful way forward, and that paediatric rheumatology

services are happy to support the use of these complex drugs in all children with uveitis,

including those who do not have JIA, including providing paediatric nurse specialist support

for ophthalmology services. Whilst the networks accept this guidance is not fully evidence

based they are current best practise and are adopted by both networks until more definitive,

evidence based guideline is developed.

Core principles:

Communication

In each region key personnel caring for paediatric uveitis and providing screening should

be clearly identified through both SPARN and the uveitis network.

• For eye screening identified paediatric ophthalmologists would usually be the key

lead for each region.

• The management of paediatric uveitis is expected to be undertaken by an

ophthalmologist who has expertise in the management of uveitis, but who should

be properly supported by paediatric services, including specialist paediatric

nursing support in line with current standards of care (286, 287,288) . This will usually

be through the local paediatric rheumatology service. In some regions the same

individuals may provide both screening and uveitis care. It is essential that all

children are seen in an appropriate paediatric environment supported by

appropriately trained paediatric staff, even where occasional component of care

takes place unavoidably in an adult setting. In many regions paediatric


69

ophthalmologists may do the screening, day to day uveitis care, liasing with

uveitis experts as required.

• Rapid, consistent and complete two way communication between the

ophthalmologist and the paediatric rheumatologist / paediatric rheumatology services

is key to an effective screening service. Both services will need to have good

knowledge of the screening guidelines, with awareness of decisions that alter the

screening requirements for an individual patient.

• Uveitis care requires the same high level of communication.

• Planned transition to adult services aims to involve both adult rheumatology and

ophthalmology services (285) .

• The following is considered a core set of information to be included in all

correspondence, or immediately accessible from shared clinical notes, from both

ophthalmologists and rheumatologist includes:

o Next planned appointment

o All systemic and topical medication, whether or not given for eyes. Systemic

treatment given for JIA or other systemic disease association should be

recorded in the ophthalmology notes whether or not it is given for eye

complications.

o All changes in systemic and topical medication particularly cessation of

treatments.

o Ophthalmologists should record at each visit in the clinical notes, and where

the clinical notes are not shared with the rheumatology team, communicate

the following to the rheumatology team in numerical values, vague or

descriptive terms should be avoided: visual acuity, the presence and absence

of uveitis, and the severity of uveitis using the SUN criteria (289) recording the

actual number of cells using a 1mm circular beam set at 45 degrees, bright

light and high magnification. Flare should be recorded. For the

measurement of intraocular pressures proxymetacaine should be used and a

gentle examination performed. Goldman is preferred (290) . This may be

difficult in the very young and the failure to record pressures should be

documented. The appearance of the optic disc, and the macular if the vision


70

o Those providing screening should be able to provide rapid access to

examination under anaesthetic where examination is difficult in line with

current standards of care (255) . To minimise the number of general

anaesthetics ideally a shared general anaesthetic with rheumatology services

providing joint injections wherever possible.

o Rheumatologists should urgently highlight to the ophthalmologist any

changes in medication or diagnostic details that materially alter the screening

programme required (255) . The paediatric rheumatologist should be aware of

the implication to the management of the eyes that changes in treatment for

other aspects of JIA care will make, and where this is unclear should make

this decision in conjunction with the ophthalmologist.

o It should be avoided that ophthalmologists and rheumatologists are both

prescribing disease modifying drugs (DMARDS) or biologics for different

aspects of JIA care. The lead clinician for prescribing should be formally

identified, and should normally be the paediatric rheumatologist unless

otherwise agreed in writing, and appropriate paediatric nursing support

provided.

o All communication should be sent within two weeks of clinical review in line

with current guidance.

Uveitis Screening

JIA CAU Screening guidelines have been produced jointly by BSPAR and the RCPOphth in

2006 (255) (appendix 7). Whilst these are not fully evidence based they are current best

practise and are adopted by both networks until more definitive, evidence based guideline is

developed. Both rheumatology and ophthalmology services should be aware of these

guidelines, and ensure changes in diagnosis or management are effectively communicated

to the other services to facilitate adherence to these guideline. In Scotland geographical

issues are not an acceptable barrier to meeting screening needs. Where screening is

provided by training ophthalmology doctors they should be aware of their responsibilities

under the screening guidelines, and should not deviate from the screening guideline unless

this is a consultant led decision and communicated to the paediatric rheumatology team.


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Management of JIA CAU and IPU

The management of paediatric uveitis differs from adult uveitis in that an earlier and more

aggressive approach to the introduction of DMARDS and biologics is found (47, 57, 58, 59, 60, 62, 74,

75, 76, 140, 259, 269, 271, 272, 273, 276, 277, 278, 280, 281, 282, 283, 284) . The algorithm demonstrates the key

pathways agreed includes time lines for rapid progression through treatment regimes but

acknowledges the lack of evidence base for this (1, 246, 251, 253, 261, 262, 263, 264, 265, 266, 271) . Key

red flags for concern are considered to be:

o Persistent requirement of topical steroids after 4 months, with or without a DMARD

o Presence of macular oedema or posterior involvement.

Detailed discussion points from the algorithm:

Differences between the management of uveitis in adults and children include:

1) Steroids

a. In children a very cautious approach to even low dose topical steroid is

usually taken (because of the risk of glaucoma and cataract) (135, 246, 251, 253, 261,

263, 264, 291, 292) . In severe inflammation where high dose frequent application

of topical prednisolone is required earlier introduction of DMARDS or more

rapid progression through the algorithm is appropriate.

b. Once control is achieved it is expected that low dose topical and systemic

steroid will be withdrawn before weaning off the second line agent. The

second line agents are usually given for a longer time period than is usual in

adult uveitis, and may be required indefinitely.

2) Biologics: In children progress to a biologic agent is usual after the first second-line

agent has failed.

Paediatric Nursing Care

Children receiving DMARDS or biologic agents are expected to have

o Access to identified trained paediatric nursing care with expertise in the management

of these drugs including skills in education, monitoring and training of families

appropriate for the care of children (286, 287, 288) .


72

o The paediatric nurse has a key role in coordinating both the PR and ophthalmology

teams. One team (usually paediatric rheumatology because of their role in prescribing

immunosuppression for other organ involvement) is formally responsible for the

monitoring and prescribing of these drugs.

Drug Monitoring

DMARDs and biologics are expected to be formally monitored. The BSPAR and RCN

guidelines on the use of these drugs, including doses and monitoring guidelines, are

appropriate guidance to follow for these patients (287, 288, 293) .

Choice of DMARD

The usual choices of DMARD would be methotrexate or mycophenolate (259, 276, 277, 278, 279, 280,

281) . The rationale for the choice may be influenced by the other features of JIA, such as

joint involvement where methotrexate is usually the preferred choice, mycophenolate has

poorer efficacy for synovitis (281) , whereas where eye features predominate mycophenolate

may be the preferred choice. Whichever is chosen first if the response to DMARD treatment

is unacceptable a biologic would usually be the next choice rather than the other DMARD.

Methotrexate is also used as the first choice in conjunction with the biologic agents

infliximab and adalimumab to reduce allergic reactions, and may improve the efficacy of

these drugs for JIA and uveitis (57, 61, 269) although adalimumab is licensed for use on it’s own.

Choice of Biologic

The current first choices for which there is evidence of efficacy are of an anti-TNF. The

choice is between infliximab (75, 76, 282, 283, 284) or adalimumab (57, 58, 59, 60, 61, 62, 76, 269, 282, 283) .

There is a current lack of evidence base to guide choice between either of these, and

practical or patient related issues around administration often influence the choice. The

licences suggest these should be given with a DMARD, usually methotrexate. Where the

response to one is inadequate or significant side-effects occur the other may be tried. The

anti-TNF etanercept should be avoided in uveitis because of lack of efficacy and some

suggestion that it might worsen inflammation in uveitis (57, 61, 135, 136, 137, 138, 139, 140, 252, 267, 268, 269,

270) .

Macular oedema

The assessment of macular oedema is difficult in children. If the vision is reduced it is

appropriate to assume that macular oedema is present, until proven otherwise. Initially oral

steroid can be given, but in severe cases intravenous pulsed methylprednisolone may be


73

most appropriate. Concurrent commencement or escalation of DMARDS or biologics is

appropriate.

Time lines for moving through the algorithm

These are the longest time periods felt acceptable before moving through the algorithm.

Where severe disease persists, vision is threatened, glaucoma has developed, or

unacceptable doses of topical or systemic steroids are required it is appropriate to move

more rapidly to the next stage of the algorithm.


74

JIA associated chronic anterior uveitis or

idiopathic paediatric uveitis

Introduce corticosteroid

treatment

Communication between named

personnel in rheumatology

and ophthalmology

services

Failure to wean topical or systemic corticosteroids to zero over 12

weeks despite optimisation of dose and route of DMARD progress to

biologic therapies

BIOLOGICS usually adalimumab or infliximab

DMARD and biologic use requires the support of a

trained paediatric nurse

Wean topical prednisolone to

zero over 4 months.

If activity

recurs or is not controlled add

DMARD

Macular oedema start steroids and a

DMARD +/- topical steroids

DMARD usually methotrexate or

mycophenolate

Anterior Chamber involvement only

Topical prednisolone


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Appendix 7: Guidelines for Screening for Uveitis in Juvenile Idiopathic Arthritis (JIA)

Produced jointly by BSPAR and the RCPOphth 2006

Aim of the screening programme

To reduce the incidence of visual impairment among children and young people with juvenile

idiopathic arthritis (JIA) by early detection through screening allowing for early intervention.

Background

The prevalence of uveitis in JIA overall is approximately 8-30%, but in young oligoarticular

onset group (ie arthritis in which up to 4 joints are involved) it may be as high as 45-57%.

The annual incidence of JIA in the UK is 1:10,000 with a prevalence of 1:1000. The type of

arthritis and age at onset dictates the risk of developing uveitis. Only the highest risk groups

are included in the regular screening recommendations below. However, late onset of first

uveitis can occur even in young adults and cases have been reported in systemic JIA so it is

important to make clinical referrals for ophthalmology assessment in patients where there

are clinical concerns even if the patient is not specifically covered by these screening

guidelines.

The uveitis in JIA is asymptomatic and therefore screening by slit-lamp is essential for

diagnosis. Visual impairment arises mainly from complications of the uveitis including

cataract, glaucoma, macular oedema and hypotony. Once complications have arisen they

are often irreversible. Early detection and treatment can prevent the development of

complications and can prevent permanent visual impairment. These complications are more

frequent and more severe in younger children and are often asymptomatic. The most

frequent cause of avoidable morbidity remains missed or inadequate examinations in the first year of disease and all efforts must be made to achieve early and thorough early examinations.

Principles

1) Initial screening examination Uveitis often starts soon after onset of arthritis but may

also start before the arthritis. The initial screening examination is therefore a clinical priority and should occur as soon as possible and no later than 6 weeks from referral. (

Reference the BSPAR Standards of Care.)

2) Symptomatic patients or patients suspected of cataracts or synechiae should be seen

within a week of referral.


76

3) Difficult examinations If the patient is uncooperative at initial screening or for an urgent

symptomatic examination in a young child an examination under anaesthetic should be

considered.

4) Parent information Parents and carers of children with JIA need to be fully informed

about the possibility of uveitis and that this is usually an asymptomatic condition until

complications arise. They need to be told that a high street optician assessment is not an

adequate examination to exclude uveitis. They should be instructed to seek medical

assessment urgently if their child develops visual symptoms or signs. These include red

eyes, photophobia, abnormal pupils, corneal clouding, or visual impairment. In younger

children this may be manifest by unusual blinking, eye rubbing, visual inattention or

preferential attention on auditory signals, or a new onset squint.

5) Missed appointments Parents and carers must be fully informed about the method of

screening and the need to attend for specific uveitis screening examinations on a regular

basis. Arrangements need to be in place to give priority to rebooking of any missed

appointments in this group with a system of contacting non-attenders.

6) Training Ophthalmologists and other health professionals carrying out uveitis screening

should be appropriately trained and experienced. They should have facilities to audit the

outcomes of their screening program.

7) Older patients Older teenage patients need to be told to return quickly should they

become symptomatic. If there is concern about their reliability, e.g. in developmental delay,

then they should be considered for longer term less frequent screening. After discharge from

the screening programme an annual check by an optometrist is a useful adjunct to self-

monitoring for symptoms.

8) On stopping immunosuppressant treatment such as Methotrexate

Patients who have been treated with methotrexate for their arthritis may not have developed

uveitis due to drug suppression. However after methotrexate is stopped uveitis may flare.

Screening should therefore restart at 2 monthly intervals after stopping Methotrexate or any

other immunosuppressant therapy during the period of maximum risk for 6 months before

reverting to the previous screening arrangements.

Scottish addition: Where a child is started on etanercept alone in the absence of

methotrexate the ophthalmologist should be aware of the possible increased risk in


77

developing uveitis, or worsening severity of pre-existing uveitis and return to 2 monthly

screening for 6 months.

Specific Screening Schedules

These schedules are the best recommendation possible with current data and are focused on the highest risk groups.

First screening within 6 weeks of referral

Two monthly intervals from onset of arthritis for 6 months

Scottish simplification: Then 3-4 monthly screening until their 12th birthday.

Older patients presenting for the first time after the age of 11, should undergo one year of

screening.

When a patient is discharged from the regular screening program it is vital to stress to

them that they and the family are now deemed able to detect any changes in their vision

which may signify a new onset or flare of uveitis. It does NOT mean that their risk of uveitis

has gone completely. A tip for family self monitoring is to remind the young person to check

his or her vision uniocularly- eg by reading small print with each eye once a week.

Monitoring may need to continue indefinitely if there are other reasons such as learning

difficulties or treatment non-compliance when the young person may be unable to detect a

change in vision or unwilling to seek re-referral.

Systemic onset JIA and definite rheumatoid factor positive polyarticular JIA patients are at

very low risk of uveitis. However, there may be delay in being certain about the diagnosis or

exact category of JIA, and overlaps between groups do occur. For this reason an initial

screening examination may be indicated.

Some important facts about uveitis in JIA

Boys do get severe uveitis

ANA negative patients get significant uveitis

Uveitis does occur in young patients with psoriatic arthritis

Patients with polyarticular JIA do get uveitis.


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Patients with enthesitis related arthritis may get chronic as well as acute iritis.

Scottish modification Nov 2009


79

Appendix 8: Membership of NMCN treatment guideline development group and stakeholders group

Uveitis national managed clinical network treatment guideline development group

Dr Graeme Williams Consultant Ophthalmic Physician, Gartnavel General Hospital,

Glasgow

(Chair)

Dr John Olson Consultant Ophthalmic Physician, Aberdeen Royal Infirmary

(NMCN Lead Clinician)

Ms Frances Philip, MCN Support Manager, Woolmanhill Hospital, Aberdeen

(NMCN Support Manager)

Dr Neil Basu Honorary Consultant Rheumatologist, Aberdeen Royal Infirmary

Dr Chee Peng Cheng Medical Ophthalmology Specialty Registrar, Gartnavel General

Hospital, Glasgow

Dr Nicholas Fluck Consultant Nephrologist, Aberdeen Royal Infirmary

Dr Janet Gardner-Medwin Senior Lecturer in Paediatric Rheumatology, Royal Hospital

for Sick Children, Glasgow

Dr Catherine Guly Medical Ophthalmology Specialty Registrar, Aberdeen Royal

Infirmary

Dr Fraser Imrie Consultant Ophthalmologist, Gartnavel General Hospital, Glasgow

Uveitis national managed clinical network stakeholders group

Dr Stuart Roxburgh Consultant Ophthalmologist, Ninewells Hospital Dundee

(Chair)

Dr John Olson Consultant Ophthalmic Physician, Aberdeen Royal Infirmary

(NMCN Lead Clinician)

Mrs Lorraine Urquhart, Managed Clinical Network Manager, Woolmanhill Hospital,

Aberdeen

(NMCN Manager)


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Ms Frances Philip, MCN Support Manager, Woolmanhill Hospital, Aberdeen

(NMCN Support Manager)

Dr Neil Basu Honorary Consultant Rheumatologist, Aberdeen Royal Infirmary

Mr Donald Cameron Independent Optometrist, Optometry Scotland

Professor Bal Dhillon Consultant Ophthalmologist, Princess Alexandra Eye Pavilion,

Edinburgh

Dr Suzanne Brannan Consultant Ophthalmologist, Queen Margaret Hospital,

Dunfermline

Dr Brian Fleck Consultant Ophthalmologist, Princess Alexandra Eye Pavilion,

Edinburgh

Professor Forrester Professor of Ophthalmology, University of Aberdeen

Dr Janet Gardner-Medwin Senior Lecturer in Paediatric Rheumatology, Royal Hospital

for Sick Children, Glasgow

Dr Catherine Guly Medical Ophthalmology Specialty Registrar, Aberdeen Royal

Infirmary

Mr Phil Hibbert Founder, Uveitis Information Group

Dr Simon Hewick Consultant Ophthalmologist, Raigmore Hospital, Inverness

Dr Fraser Imrie Consultant Ophthalmologist, Gartnavel General Hospital, Glasgow

Ms Angela James Ophthalmology Pharmacist, Princess Alexandra Eye Pavilion,

Edinburgh

Mr Allan Jones Edinburgh & The Lothians Operations Manager, RNIB Scotland

Dr Lucia Kuffova Senior Lecturer in Ophthalmology, University of Aberdeen

Mr John Legg Director of RNIB Scotland

Mrs Ali McAllister Project Office Standards Development Team, NHS Quality

Improvement Scotland

Mrs Gill Ogden Uveitis Nurse Specialist, Queen Margaret Hospital, Dunfermline


81

Dr Sheila Paterson-Brown Associate Specialist in Ophthalmology, Princess Alexandra

Eye Pavilion, Edinburgh

Miss Vanessa Sandison Clinic Nurse Manager, Aberdeen Royal Infirmary

Dr Angus Scott Consultant Ophthalmologist, Stirling Royal Infirmary

Miss Caroline Smith Patient Representative

Mrs Fiona Smith Patient Representative

Mr James Stephen Programme Manager, National Services Division, NHS National

Services Scotland

Dr Mohan Varikkara Consultant Ophthalmologist, Ayr Hospital

Dr Meena Virdi Consultant Ophthalmologist, Hairmyres Hospital, East Kilbride

Mrs Carri-Anne Walker Director of Fundraising, Uveitis Information Group

Dr Graeme Williams Consultant Ophthalmic Physician, Gartnavel General Hospital,

Glasgow

Dr Imran Zaheer Consultant Ophthalmologist, Dumfries Infirmary


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