Extra-articular manifestations of rheumatic disease - inflammatory eye disease
The three complaints that matter
- *Anatomy dictates the symptoms, and the symptoms dictate the urgency*
- The three complaints that matter in rheumatology practice
| Conjunctivitis | SCLERITIS | ANTERIOR UVEITIS (iritis) | |
|---|---|---|---|
| Pain | Gritty, not truly painful | *SEVERE, BORING, wakes from sleep, radiates to jaw/brow* | Aching, moderate |
| Photophobia | Mild | Yes | Marked |
| Pupil | *Normal* | *Normal* | *CONSTRICTED, irregular (posterior synechiae)* |
| Vision | Normal | May be reduced | Usually reduced |
| Redness | Diffuse, superficial, mobile vessels | Deep, violaceous, does NOT blanch with phenylephrine, vessels immobile | Ciliary flush (perilimbal) |
| Discharge | Yes | No | No |
| Tenderness | No | *Globe tender to palpation* | No |
| Associations | Reactive arthritis, bacterial, viral | RA, SLE, GPA, PAN, relapsing polychondritis, herpes zoster | HLA-B27 disease, sarcoidosis, Behcet, vasculitis, JIA |
- *EPISCLERITIS vs SCLERITIS is the discrimination that matters*
- Episcleritis: mild or no pain, sectoral, BLANCHES with topical phenylephrine 2.5%, benign, self-limiting
- Scleritis: severe pain, does NOT blanch, threatens the globe, signals systemic disease
Epidemiology
- Anterior uveitis: ~50% of all uveitis; incidence ~12-25 per 100,000/yr
- HLA-B27 is positive in ~50% of acute anterior uveitis - the single commonest identifiable association
- Uveitis occurs in ~25-40% of ankylosing spondylitis over the disease course
- Scleritis complicates ~0.2-6% of RA - and marks severe, extra-articular, seropositive disease
- Keratoconjunctivitis sicca: ~10-20% of RA; >90% of Sjogren syndrome
- JIA-associated uveitis - *chronic, ANTERIOR, ASYMPTOMATIC and WHITE* - the reason for mandatory slit-lamp screening
Mechanisms
- Anterior uveitis - HLA-B27-restricted, IL-23/IL-17-driven inflammation of the iris and ciliary body; shares its immunology with the spondyloarthropathies
- Scleritis - immune complex deposition and small-vessel VASCULITIS of the scleral vessels -> ischaemia, collagen destruction, scleral necrosis and perforation
- This is why it behaves as a vasculitic manifestation and needs systemic immunosuppression
- Keratoconjunctivitis sicca - lymphocytic destruction of lacrimal glands
- Retinal vasculitis (Behcet, sarcoid, SLE) - occlusive or non-occlusive; sight-threatening
- Drug-induced: bisphosphonates (uveitis, scleritis), rifabutin (hypopyon uveitis), cidofovir, checkpoint inhibitors, topiramate (acute angle closure)
Red eye - the emergencies to exclude first
- *Acute angle-closure glaucoma - severe pain, nausea, haloes, FIXED MID-DILATED pupil, hard globe, hazy cornea*
- *Corneal ulcer / keratitis - fluorescein uptake; contact lens wear*
- *Necrotising scleritis* - globe perforation
- *Orbital cellulitis - proptosis, restricted eye movements, pain on movement, systemic upset*
- *Giant cell arteritis - sudden painless visual loss, amaurosis fugax, jaw claudication (an emergency even with a normal eye*)
Uveitis by anatomical site and the disease it points to
| Site | Pattern | Associations |
|---|---|---|
| Anterior (iritis/iridocyclitis) | Acute, unilateral, recurrent, alternating, PAINFUL and RED | *HLA-B27: ankylosing spondylitis, psoriatic arthritis, IBD, reactive arthritis*; herpes; syphilis |
| Anterior | Chronic, bilateral, ASYMPTOMATIC, WHITE eye | *JIA (oligoarticular, ANA-positive girls)*, sarcoidosis, TINU |
| Intermediate (pars planitis) | Floaters, vitreous "snowballs" | Multiple sclerosis, sarcoidosis, Lyme |
| Posterior (choroiditis/retinitis) | Visual loss, floaters | Toxoplasmosis, CMV (HIV), syphilis, TB, sarcoidosis, Behcet |
| Panuveitis | All layers | *BEHCET, sarcoidosis, VKH, sympathetic ophthalmia, syphilis, TB* |
- Hypopyon (layered pus in the anterior chamber) -> *BEHCET disease, HLA-B27 uveitis, endophthalmitis, rifabutin*
- Keratic precipitates - "mutton fat" granulomatous precipitates suggest sarcoidosis, TB or syphilis
Other rheumatological eye manifestations
- Keratoconjunctivitis sicca - Schirmer test <5 mm in 5 min; Sjogren, RA
- PERIPHERAL ULCERATIVE KERATITIS ("corneal melt") - *RA and GPA; a sign of systemic vasculitis requiring urgent systemic immunosuppression*
- Scleromalacia perforans - painless scleral thinning with visible uvea; long-standing seropositive RA
- Retinal vaso-occlusive disease - SLE, antiphospholipid syndrome (cotton wool spots, arterial/venous occlusion)
- Orbital inflammation/proptosis - GPA, IgG4-related disease, thyroid eye disease
- Optic neuritis - MS, NMOSD, sarcoidosis, GCA (anterior ischaemic optic neuropathy - pale swollen disc)
- Drug toxicity
- *HYDROXYCHLOROQUINE retinopathy - keep to <=5 mg/kg actual body weight; baseline then annual screening from 5 years* (OCT + automated visual fields)
- Corticosteroid - cataract and raised intraocular pressure
- Ethambutol - optic neuropathy
Systemic work-up for uveitis
- Targeted, not shotgun: HLA-B27, CXR/HRCT and serum ACE or soluble IL-2R (sarcoid), syphilis serology, QuantiFERON, HIV, ANA (JIA), ANCA, FBE/UEC/urinalysis, toxoplasma serology
- Directed by the anatomical pattern and the systemic history - a first episode of typical acute unilateral anterior uveitis in an otherwise well adult needs little beyond HLA-B27 and a syphilis/TB screen
1. Get the eye seen
- *Acute anterior uveitis, scleritis, painful red eye with reduced vision, or any visual loss -> SAME-DAY ophthalmology*
- *Never prescribe topical corticosteroid without a slit-lamp examination - a herpes simplex dendritic ulcer treated with steroid can perforate the cornea*
2. Anterior uveitis
- Topical corticosteroid (prednisolone acetate 1%), frequently at first, then tapered
- CYCLOPLEGIC/mydriatic (atropine, cyclopentolate, homatropine) - relieves ciliary spasm and prevents/breaks POSTERIOR SYNECHIAE
- Monitor intraocular pressure (steroid response, and inflammation itself)
- Recurrent or bilateral disease -> treat the underlying systemic disease
- *Sulfasalazine reduces the frequency of recurrent anterior uveitis in spondyloarthritis*
- MONOCLONAL TNF inhibitors (adalimumab, infliximab) prevent uveitis flares; ETANERCEPT does NOT and may be associated with new-onset uveitis - a favourite exam point
- Methotrexate, mycophenolate, azathioprine as steroid-sparing agents
3. Scleritis
- *Treat as a systemic vasculitic manifestation*
- Oral NSAID for mild non-necrotising disease
- Systemic corticosteroid + steroid-sparing immunosuppression (methotrexate, mycophenolate) for severe or necrotising disease
- Necrotising scleritis or peripheral ulcerative keratitis -> CYCLOPHOSPHAMIDE or RITUXIMAB - these signal active systemic vasculitis with high mortality if untreated
- *Topical steroid alone is inadequate; avoid topical steroid in necrotising disease* (impairs scleral healing)
- Investigate for GPA, RA, PAN, relapsing polychondritis, and herpes zoster
4. Episcleritis
- Reassurance, lubricants, topical or oral NSAID - self-limiting over 1-2 weeks; no systemic work-up needed for a first isolated episode
5. Sicca
- Preservative-free artificial tears, ointment at night, punctal plugs, ciclosporin drops, pilocarpine
- Review anticholinergic drugs
6. Screening obligations
- *JIA - slit-lamp screening 3-monthly in high-risk children (young, oligoarticular, ANA-positive); the eye is white and the child asymptomatic until vision is lost*
- Hydroxychloroquine - baseline and annual screening from 5 years
- Corticosteroid - periodic IOP and cataract assessment
- Ethambutol - visual acuity and colour vision monitoring
Associations
- *HLA-B27 spondyloarthropathies - ankylosing spondylitis, psoriatic arthritis, IBD-related, reactive arthritis -> acute anterior uveitis*
- Juvenile idiopathic arthritis - chronic asymptomatic anterior uveitis (ANA-positive oligoarticular girls)
- Sarcoidosis - any uveitis pattern; Heerfordt syndrome (uveoparotid fever + facial palsy)
- Behcet disease - panuveitis, retinal vasculitis, HYPOPYON (a leading cause of blindness in endemic regions)
- Rheumatoid arthritis - sicca, scleritis, scleromalacia perforans, peripheral ulcerative keratitis
- GPA - scleritis, orbital pseudotumour, nasolacrimal obstruction, peripheral ulcerative keratitis
- SLE / antiphospholipid syndrome - retinal vasculopathy, occlusion
- Giant cell arteritis - anterior ischaemic optic neuropathy, amaurosis fugax, diplopia
- Relapsing polychondritis, PAN, Cogan syndrome (interstitial keratitis + vestibuloauditory dysfunction)
- Infection - syphilis, TB, HSV/VZV, toxoplasmosis, CMV (HIV), Lyme, Whipple
- Drugs - bisphosphonates, rifabutin, checkpoint inhibitors, cidofovir, topiramate
Course and complications
- Acute anterior uveitis - resolves over 4-6 weeks with topical treatment; *recurs in ~50%*, often in the other eye
- Complications of recurrent or inadequately treated uveitis
- Posterior synechiae -> irregular pupil -> pupil block -> SECONDARY GLAUCOMA
- Cataract (disease and steroid), band keratopathy, cystoid macular oedema (the commonest cause of visual loss), hypotony, phthisis
- *Uveitis accounts for ~10% of legal blindness in developed countries* - most of it preventable
- Scleritis - necrotising disease threatens the globe and signals systemic vasculitis with significant mortality; up to 40% of scleritis patients have or develop a systemic disease
- Episcleritis - benign, recurrent, no sequelae
- JIA uveitis - the worst visual prognosis of all, because it is silent; band keratopathy, cataract, glaucoma, amblyopia
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