Dr Pramod K Sharma

Retina , Uvea & ocular immunology service

VSS Medical College, Burla

Example

A 58 years lady preseneted with recurrent severe pain & redness which is alternating to both eyes since last year. Her VA in right eye is reduced this time.

She is having joint pain for which she is on Aceclofenac 100mg SR OD, Salazopyrin 1g BID since 2 years by her rheumatologist.

Her hands showed typical z deformity with subcutaneous nodule on fingers. She is dyspneic at little work.

Her ocular exam shows fiery red superior bulbar congestion, tender to touch as well as to ocular movement. VA – OD -6/12, OS- 6/6. OD Fundus shows choroidalfold

Investigation – Microcytic hypochromic anemia, Leukocytosis with raised neutrophil count, ESR raised, High +ve titre Rh factor,

B Scan showed thickened RCS complex OD

Her old radiograph of hand suggestive of RA

What is the Diagnosis and how we will approach ?

Scleritis

Eighty % of exterior of eye ball is sclera

Most of the ophthalmologist give less importance as it takes no active part in visual function like cornea, lens, retina, uvea and optic nerve but carries infinite visual significance as it encompasses these visual vital structures.

But this rarity significant scleral issues at times coupled with profound systemic life threatening diseases.

Watson & Hazleman pointed out in their text book “The Sclera & Systemic Disorders “ that 27% of patients with Necrotizing Scleritis are dead with in 5 years from systemic vasculitic lesion.

Similarly Maza & Foster in their text “ The Sclera “ found scleritis may be a harbinger of severe immune mediated vasculitidis.

Special anatomic consideration Divided into 3 layers- episclera, scleral stroma, lamina

fusca. Has profuse sensory innervation through ophthalmic

division of trigeminal ( long anterior & short posterior ciliary nerve). That is Why scleral inflammation is very painful.

Episcleral vessels has no muscular layer but has endothelium with its basement membrane and discontinuous layer of pericytes. Here artery to artery anastomosis exists where blood oscillates and sites for immune complex deposit. That is why microangiopathydisorders ( e.g. RA, SLE, PAN etc. ) affects sclera.

Etiology Exogenous agents-

Viruses- HSV, VZV, EBV etc have direct cytopathic effect and they or

their components induce antigens that invoke an immune response* Bacteria & mycobacteria Fungi Protozoa- acanthemoeba

*Lider M et al. The infectious etiology of Vasculitis. Autoimmunity .2009;42(5):432-8.

Endogenous Substances-

Immunological cross reactivity of glycosaminoglycan,collagen between sclera and other organ suggest auto immunity*.

*Coster L et al. The Dermatan sulfate proteoglycans of bovine sclera and their

relationship to those of articular cartilage. J biol chem.1987:262:3809

Pathogenesis Interaction of genetically controlled mechanisms with

environmental factors such as viruses or trauma gives rise to an autoimmune process that damages the vessels through immune complex mediated type III hypersensitivity.

Persistent immunological injury leads to granulomatous response via type IV hypersensitivity

Classification* Episcleritis-

- Simple- Nodular

Scleritis- Anterior

- Diffuse- Nodular- Necrotizing

-with inflammation- without inflammation ( scleromalacia perforancs)

-Posterior Scleritis

* Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. 1976;60(3):163–91

Diagnostic Approach 5 phases of approach

1. Investigation 0f the illness

Interview Major complaints- pain, redness ,photophobia, tenderness, decreased VA History of present illness- Past history-any systemic illness that can cause scleritis, any illness that might

eventually modify future therapy Family history- Genetic relation frequently seen in RA,SLE, AS, ReA, Behcet’s

disease,atopy etc Past & present therapy history- type, route,dosage, response, side effects,

related complication , concomitant Rx for other condition and reason for discontinuation of therapy

Review of the system-

Physical Examination

systemic exam- head & Extremities

Ocular Exam- 1. Day light exam, SL exam-diffuse, Slit, red free light exam

2. General eye exam- VA, pupil & EOM, Cornea, Ant Uvea, Lens, fundus, IOP

2. Diagnostic tests

Blood & Urine tests

Unless the cause is infectious blood, urine lab test rarely establish a diagnosis of systemic disorder. So blanket testing is expensive & wasteful.

a. Rh factor- though 80% of RA patient is +ve for Rh factor but it is not specific test for RA. It’s high titre signifies severity of disease with extra articular manifestation.

b.Anti-CCP test – a better specificity test for RA than Rh factor.

c.ANA test – Ab to ds-DNA, ss-DNA, nRNP,sm RNP etc are indicative of autoimmune disease. Pattern of IF positivity has diagnostic significance.

d. ANCA test- PR-3 ( c-ANCA) specific for GPA, MPO( p-ANCA) specific for Microscopic polyangitis.

e. CICs- it’s detection is not essential of diagnosis but helps to support specific disorder. Also it’s level interpreted as response to therapy

f. Complement- Level of complement components decreased during complement activation. Ag-Ab reaction activates this pathway and consume complements as in auto-immune disorder. Quantification of C3, C4 and CH50

g. HLA typing- Presence of certain HLA type increases the probability of presumptive diagnosis when clinical & radiological findings are equivocal. B27 for AS,ReA, B5 for Behcet’s, DR4 for RA

h .Ab against infectious agents- FTA-ABS for syphilis, Lyme’s titre for Borreliosis, Ab for HSV,VZV etc

i. IGRAs- QuantiFERON-TB gold test, T-SPOT TB test

PCRSmears & CulturesSkin TestingRadiologic Studies-

Chest x-ray, Sinus film, Sacro-illiac joint, limb joints

Other Imaging studiesA Scan, B-Scan, CT scan, MRI

3.Biopsy-detection of inflammatory microangiopathy in scleral or conjunctiva supports diagnosis of systemic vasculitis- detection of infectious agents

4. Data integration

ExampleA 58 years lady preseneted with recurrent severe pain & redness which is alternating to both eyes since last year. Her VA in right eye is reduced this time.She is having joint pain for which she is on Aceclofenac 100mg SR OD, Salazopyrin 1g BID since 2 years by her rheumatologist. Her hands showed typical z deformity with subcutaneous nodule on fingers. She is dyspneicat little work.Her ocular exam shows fiery red superior bulbar congestion, tender to touch as well as to ocular movement. VA – OD -6/12, OS- 6/6. OD Fundus shows choroidal fold Investigation – Microcytic hypochromic anemia, Leukocytosis with raised neutrophil count, ESR raised, High +ve titre Rh factor,B Scan showed thickened RCS complex ODHer old radiograph of hand suggestive of RAWhat is the Diagnosis and how we will approach ?

Diffuse Anterior Scleritis & posterior Scleritis with Rheumatoid arthritis

Therapeutic PlanEpiscleritis does not require any treament. Regrettably

many physician prescribe steroid preparations which has not only have rebound effect but also side effects.

If patient demand Rx or if his occupation demands as in actors ,systemic NSAID may be instituted like scleritis for 6months with taper.

Episcleritis with systemic disorders requires specific therapy e.g. SLE– HCQ, Gout-allopurinol, Rosacea- Tetracycline etc.

Otherwise we recommend refrigerated tear substitute for idiopathic episcleritis.

Infectious Scleritis

With anti-microbial therapy ancillary anti-inflammatory agents may be required e.g. Scleritisassociated with syphilis.

Any patient with fungal etiology must not be under corticosteroid.

Rx for Scleritis Systemic NSAID almost invariable effective. Sequential trials of

several NSAIDs may be required before one that is completely effective found.

We treat scleritis who responded NSAIDs, at least for 1 year before attempting to taper and discontinue.

Patients with associated disease require specific treatment e.g. Rosacea, gout, atopy

Patients with connective tissue or collagen vascular diseases requires special consideration. Scleritis with GPA, PAN, RP require aggressive therapy with cytotoxic agents like cyclophosphamide.

Scleritis with RADiffuse scleritis

Our first choice is NSAIDs. Before concluding for additional systemic medications we go through 3 different NSAIDs .

Our next step is additional short course of systemic prednisolone typically 1mg/kg, taper when scleritis has resolved totally and then switch to alternate day therapy once dose down to 20mg/day.

If no recurrence with topical steroid discontinuation and 20mg/day prednisone, next approach is 40mg on every other day for 2 weeks, then 30mg, 20mg,15mg,10mg,7.5mg,5mg and finally discontinued.

Those who do not respond require low dose MTX weekly.

Nodular scleritis

Majority respond to systemic steroid program but some require once a week MTX 15mg/week ( < 50kg, start 10mg ) as starting dose, which can be increased upto35mg/week depending upon response.

Necrotizing scleritis It must be treated with systemic immunosuppressant. Systemic

prednisone with immunosuppressant works well.

If unilateral and not severe, systemic prednisone and weekly MTX is of choice.

In bilateral and severe, not responding to MTX , Azathioprine 2mg/kg is prefered. Other options available are Mycophenolate, Cyclosporine-A& Biologic agents ( Infliximab, Adalimumab, Rituximab etc.).

Cyclophosphamide is considered in severe or rapidly progressive cases.

Surgical treatment Virtually necessary for scleral reinforcement in necrotizing scleritis

where globe is threaten to perforate.

Donor Sclera, periosteum, fascia lata are the graft material.

However graft can not solve the problem. Essential ingredient is to

control or cure the underlying immunoregulatory dysfunction.

Take home message

Non infectious Scleritis may be an ocular manifestation of severe life threatening systemic disease.

Timely and judicious use of IMT can save visual morbidity and life of the patient.