sign in sign up
<<
Home , Band keratopathy, Cycloplegia, Retinitis, Uveitis

Annual Rheumatology & Therapeutics Review for Organizations & Societies Ocular Inflammatory Disease: Focus on

Learning Objectives

• Identify the challenges in recognizing the various forms of ocular inflammatory diseases, specifically uveitis • Construct a differential diagnosis for various forms of uveitis

• Lids • • • • • •

Uveitis – Lecture Goals

• Definitions & terminology • Examination • Diagnostic approach • Treatment Problems with Ophthalmologic Diseases for the Rheumatologist/Ophthalmologist

• Ophthalmologists are not trained nor comfortable with systemic diseases and immunosuppressive • Rheumatologists/Internist are not comfortable treating patients in whom they cannot monitor response

Ocular Inflammatory Diseases

• Uveitis • / • Orbital Inflammatory Disease • • • • Sicca www.picturesdepot.com;https://sp.yimg.com/ib/th?id=HN.608045044661423993&pid=15.1&P=0 Bernard et al Arthritis Rheum, January 2006 Ocular Immunology Basics

• The is an ‘immune privileged’ organ • Phenomenon: passive and active processes that disallow • Evolutionary basis: protection of vital structures in face of injury or infection (Eye, Brain, Pregnant uterus, Ovary, Testes)

Tolerance of Ocular Antigens

• Active mechanisms: – High expression of anti-inflammatory mediators1 – TGF-beta, A-MSH, VIP – High expression of FasL on ocular cells2 • Passive mechanisms: – Blood/ocular barrier (similar to blood/brain) – Lack of lymphatic drainage of the

1Streilein JW: Regional immunity and ocular immune privilege. Chem Immunol 1999;73:11-38. 2Caspi RR, Roberge FG, Nussenblatt RB: Organ-resident, nonlymphoid cells suppress proliferation of autoimmune T-helper lymphocytes. Science 1987;237:1029-32. • Uveitis related antigen, Specific autoreactive T-cells and Autoantibodies – Can occur in healthy individuals

Uveitogenic proteins: Retinal soluble antigen Immunology

Triggering event (s) in correct genetic environment

Failure of suppressive: Stimulation of active :

(clonal deletion, clonal anergy, active supression) (APC/CD4+ cell interaction)

Clonal expansion and pro -inflammatory cascade

Cytokine, Chemokines, Enz Experimental Models

• Experimental Autoimmune Uveitis (EAU) can be induced with a variety of retinal antigens and in a variety of species and strains of animals. – Varying these can result in differentiation between acute and chronic and location of uveitis.

Immune Mechanisms of Uveitis

Histopathology of endotoxin-induced uveitis in the C3H/HeN mouse

www.nei.nih.gov; Image of anterior segment of mouse with EIU Breakdown in Tolerance

• In humans, the mechanism of breakdown of tolerance is largely unknown •

Sympathetic Ophthalmia

incidence ranges from 0.2 to 0.5% after Injury 0.01% after intraocular surgery.

Louis Braille

http://www.immunopaedia.org.za GENETICS

• Behcet’s HLA – B51/B5 1 (Odds Ratio 5.78) • JIA 20% children with oligoarticular form HLA –DR5 • Vogt-Koyanagi-Harada Syndrome HLA – DR4. Bilateral panuveitis (vertigo, meningitis, encephalopathy, hearing loss, tinnitus, vitiligo, alopecia)2 • Acute Anterior Uveitis 50% HLA - B273 • Birdshot Retinochoridopathy – 80-93.1% HLA-A294

Arthritis & Rheumatism 2009 61:10, 1287-1296; Am J Ophthalmol. Dec 1996;122(6):889-91 J Korean Med Sci. 2009 August; 24(4): 722–728.; Am J Ophthalmol. Jan 15 1992;113(1):33-5 Anatomy

Posterior: choroid, retina Anterior : iris,

CILIARY BODY

POSTERIOR CHAMBER ANTERIOR CHAMBER

VITREOUS

AQUEOUS

CHOROID Anatomy of the Eye: Uveal Tract

• All are vascular tissues • Derived from neuroectoderm and neural crest • Function: blood supply, size, and formation of aqueous and vitreous humors

Uveitis - Epidemiology

• Estimated incidence of uveitis in a general population is 15 to 52 cases per 100,000 patient years • 350,000 to 2 million patients in the US with Uveitis

Gritz DC et al . Incidence and prevalence of uveitis in Northern California: The Northern California Epidemiology of Uveitis Study. 2004;111:491-500. Uveitis Epidemiology

• Despite its rarity, uveitis accounts for one of the top preventable causes of irreversible blindness • About 33% of “chronic” uveitic become blind • Accounts for as much as 10% of severe visual handicap in US

Classification

• Anatomy • Time Course • Etiology

Anatomy - Anterior Uveitis

• Inflammation primarily involving the anterior chamber. • Results in: – Iritis, Cyclitis, Iridocyclitis

Anatomy – Posterior Uveitis

• Inflammation primarily involving the choroid and/or retina • Results in: – Choroiditis, , Retinochoroiditis, Retinal

Anatomy Intermediate and Panuveitis

Intermediate Uveitis Panuveitis • Inflammation primarily • Inflammation involving the vitreous involving both the • Includes: anterior and posterior Vitritis, Pars segments planitis,Peripheral retinitis

Other terminology - Sclerouveitis Example:

Results - Distribution of Uveitis by Location

Intermediate 11.3% Anterior Anterior 65.0% Intermediate

Posterior Posterior 8.7% Panuveitis

Panuveitis 15.0% Classification – Time Course

• Acute uveitis – Inflammatory episodes lasting < 3 months • Chronic uveitis – Inflammation persisting >3 months Acute vs Chronic

• Acute or Recurrent • Chronic – HLA-B27+ – JIA – Fuchs’ – TB – Behcet’s – – Postsurgical – – White dot syndromes – Birdshot – ARN – Sympathetic Classification - Etiology

• Autoimmune • Infectious • Misc.

Etiology

Autoimmune

Systemic Illness Idiopathic

Over 50 different disease states

Etiology - Autoimmune

• HLA-B27 associated uveitis – – Reactive Arthritis – Psoriatic arthropathy – Inflammatory bowel disease • Sarcoidosis • Behcet’s disease • Juvenile Idiopathic Arthritis

Prevalence of Uveitis in

1. Literature review 957 articles identified, 126 used 2. Acute in 88.7% 3. Unilateral in 87.3%

Prevalence of Uveitis % (SD) All SpA 32.7 (0.5) AS 33.2 (0.8) PsA 25.1 (2.3) IBD associated Arthritis 36.9 (4.4) Reactive Arthritis 25.6 (3.8) Undifferentiated SpA 13.2 (2.9)

Zeboulon et Al, Ann Rheum Dis2008;67:955-959 Prevalence and Factors Associated with Uveitis in Spondylarthritis Patients in France

• September 2008 to January 2009, 202 rheumatologists participated in the survey characterizing patients with uveitis - recruited 902 patients • Uveitis prevalence was 32.2% • SpA diagnoses were ankylosing spondylitis (71%), PSA(18%), or other SpA (11%). HLA-B27 positivity rate was 76% • Factors independently associated with uveitis were: • HLA-B27 • Disease duration

Canouï-Poitrine FArthritis Care Res 2012 Jun;64(6):919-24. doi: 10.1002/acr.21616. Epub 2012 Jan 19. Etiology - Infectious

• Syphilis • • Lyme • virus • Herpes zoster virus • • • retinitis

Etiology - Misc

• Post-surgical uveitis • Malignancies • • Misc Ophthalmic Syndromes – Vogt-Koyanagi Harada syndrome – Sympathetic ophthalmia – Birdshot retinochoroidopathy – Serpiginous choroidopathy • Medicine induced - , rifabutin, bisphosphonates

Signs and Symptoms Acute Anterior Uveitis

• Rapid onset of , • Usually unilateral or asymmetrical • Redness in circumlimbal location

Ciliary Flush

• Conjunctival injection involving the perilimbal vessels • Occurs in acute or recurrent anterior uveitis

Ciliary Flush

www.iritis.org jujuslupus.blogspot.com Uveitis

• WBC layer in lower anterior chamber

http://imgbuddy.com/hypopyon.asp Standardization of Uveitis Nomenclature (SUN Criteria)

• Grading schema for anterior chamber cells • Anterior chamber flare • Vitreous haze • Structural complications of uveitis •

Am J Ophthalmol. 2005 Sep;140(3):509-16. Anterior Chamber Cells

• Grading cells: • 1 x 1 mm slit beam • Cells/hpf: 1-2 rare <10 trace 10-19 1+ 20-29 2+ 30+ 3+ 30+fibrin 4+ http://www.rootatlas.com/wordpress/our-videos Chronic Anterior Uveitis

• Presents with visual changes • Onset uncertain, advanced disease • Keratic precipitates, iris nodules • Synechiae • Complications: , ,

Chronic Anterior Uveitis: Cataract & Synechiae

Courtesy T. Flynn Keratic Precipitates

http://www.rootatlas.com/wordpress/our-videos Band Keratopathy

openi.nlm.nih.gov Granulomatous Uveitis

• Mutton-fat keratic precipitates • Iris nodules • Treated granulomatous uveitis may appear nongranulomatous

Granulomatous Uveitis: Synechiae and Iris Nodules

• Syphilis • Tuberculosis • Sarcoidosis • Sympathetic ophthalmia • Vogt-Koyanagi Harada syndrome • Vasculitis

Intermediate Uveitis

• Present with blurry vision, • Vitreous cells, snowballs • Peripheral retinal scarring: snowbank • Neovascularization • Uni - or bilateral • Vision loss: , glaucoma, cataract,

Snowbank and Macular Edema

Tasman, William; Jaeger, Edward A.Wills Eye Hospital Atlas of Clinical Ophthalmology , The, 2nd EditionCopyright ©2001 Lippincott Williams & Wilkins Posterior Uveitis

• Variety of Presentations: – Choroiditis: Focal, Multifocal, Diffuse – – Retinochoroiditis – Retinal Vasculitis – Neuroretinitis

Multifocal Choroiditis: Birdshot

http://www.lookfordiagnosis.com/mesh_info.php?term=Choroiditis&lang=1 Retinal Vascultis

• Presents as decreased vision, floaters • Vessel sheathing, obliteration, and neovascularization late • Retinal arterial occlusion, necrosis • Macular edema, optic nerve swelling • High risk of blindness if untreated

Retinal Vascuiltis

Differential Diagnosis:

Syphlis Behcet’s Herpes SLE TB APS Borrelia MS PAN Sarcoid Sarcoid Vasculitis: Vessel Sheathing and Neovascularization of the Retina

http://imagebank.asrs.org/file/1511/retinal-vasculitis-with-hemorrhages-and-cotton-wool-spots Panuveitis

• Inflammation of anterior, intermediate, and posterior parts of eye • Presents with symptoms of anterior and posterior uveitis • Risk of complications and blindness extremely high without treatment

Uveitis - Diagnostic Testing

• Comprehensive and detailed history and physical • Is Diagnostic Testing Required ? – Mild unilateral single-episode of acute anterior uveitis – In a patient with a known systemic Ds in which uveitis is common • Uveitis “screen” – false positives

Diagnostic Testing

• Uveitis screening questionnaires • Biopsy • GI work up • X-ray, MRI, CT, Nuclear Scans • Labs – ACE- Sarcoid, Leprosy, Histo – ANA – SLE, JA – ANCA – Toxo antibodies, PCR – Anti viral antibodies – HIV – Syphilis – HLA – Lyme

Diagnostic Testing

• PPD, Interferon assays • Syphilis Serologies • CXR • Routine Labs • Lyme Ds, ACE, HLA ?

Therapy

• Exclude malignant and infectious etiology !!

Therapeutic Approach

• Anterior Uveitis – Topical Steroids • Most common error – frequency • Toxicity – glaucoma and posterior sucapsular cataract – Mydriatic and Cycloplegic Agents • Mydriatic agents reduces contact between the iris and the and prevents synechiae • reduces pain and photophobia by relaxing the ciliary body • , ,

• Anterior Uveitis (cnt.) – NSAID’s – Flurbiprofen, Suprofen, Ketorolac, Diclofenac – Topical cyclosporin – no benefit – Periocular – Subconjunctival or Sub-Tenon injections

• Systemic Corticosteroids – Unresponsive chronic anterior and intermediate uveitis – Posterior and Panuveitis – Systemic Ds requiring corticosteroids – Usually initiated at 40 to 80mg /day and tapered after 1 month – IV Medrol

Remittive Medications

• • Mycophenolate mofetil • Cyclosporin, (FK506) • Azathioprine • Cyclophosphamide • Chlorambucil de Vries J et al. BMJ 1990;74:344-349. Sloper CM et al. Ophthalmology 1999;106:723-728 Yazici H et al. N Engl J Med 1990;322:281-285. Greenwood AJ et al. Eye 1998;12:783-788. Godfrey WA et al. Am J Ophthalmol 1974;78:415-428. Cunningham ET et al. Inter Ophthal Clinics 2000;205-220 Larkin G et al. Ohthalmology 1999;106:370-374. Schwartzman S, Flynn TE. Arthritis and Rheumatism 42: S 1527, 1999 Martens AC et al. Ophthalmologica 1976;172:106-115 Intraocular Drug Delivery of

• Bypasses ocular barriers to drug delivery • Available for short-term (weeks) and long-term (2 years) drug delivery • Ocular steroid side-effects

Retisert

http://www.retisert.com/ http://www.retisert.com/ http://www.retisert.com/ MUST - Multicenter Uveitis Steroid Treatment Study

• Randomized Parallel treatment design - 255 pts intermediate, posterior or pan uveitis – Systemic Corticosteroids – fluocinolone acetonide • Vision improved similarly in both groups at 2 years • Systemic treatment produced fewer side effects. Fluocinoloneimplant produced more side effects - glaucoma, and .

Ophthalmology. 2011 Oct;118(10):1916-26. Epub 2011 Aug 15. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Louis TA, Sugar EA, Thorne JE. Osurdex

http://www.ozurdex.com/

Cytokines

• TNF, IFN, IL-1, IL-2, IL-17 and IL6 have been detected in ocular fluid from patients with uveitis • These same induce uveitis when injected intraocularly in animals Table 1. Cytokines in ocular fluids or cells (aqueous humor, vitreous) in uveitis.

Cytokine Aqeous Humor Vitreous

IL-1 Sarcoid [9]*95 ↑Idiopathic [2/5]84

↑Idiopathic [7]86 ↑BD [3]86 ↓BD [4]13 IL-2 ↑Idiopathic [10]*91 ↑AS [5]86 ↑FHC [1]86 ↓FHC [5]13 ↑Idiopathic [7],112[23],13 [5]84 ↑BD [3],113 [4],13 [3]118 ↑Idiopathic [5],84 [11/19]92 ↑Sarcoid [1],*95 [8]118 IL-6 ↑BD [3]118 ↑VKH [2],*95 [2]‡151 ↑FHC [9/11]118 ↑AS [5]113 ↑FHC [2],113 [9/11]118 ↑Idiopathic [23],13 [7]86 Idiopathic < FHC [18],90 [10]90 ↑BD [3]86 IFN-γ ND ↑VKH [1],*95 ↑AS [5],86 ↑FHC [1],86 ↑Idiopathic [7],86 ↑BD [3],83 TNF-α ND ↑AS [5],83 ↑FHC [2],83 ↓Idiopathic [8],82 IL-10 ↓Idiopathic [4],*91 ↑FHC [4],90 ↓Idiopathic [23],13 TGF-β ND ↑BD [4],13 Ooi et al CM&R 2006 :. Daclizumab

• Treatment of Noninfectious Intermediate and Posterior Uveitis with the Humanized anti-Tac mAb1 - Daclizumab – Anti-IL2 receptor mAb – Q 4 weeks over a 1 yr period of time – 80% response

Nussenblatt RB et al. Proc Natl Acad Sci1999;96:7462-7466 Interferon

• Treatment of Ocular Symptoms of Behcet’s Disease with Interferon alpha1 – Improvement in 6/7 treated over a mean of 23.6 mo. (treated for 4 mo)

1 Kotter I et al. Br J Ophthalmol 1998;82:488-494. Anti-TNF Rx

• Differential Efficacy of Inhibition in the Management of Inflammatory and Associated Rheumatic Disease1 – 16 Pt (14 etanercept 2 ) – 9 Uveitis 7 Scleritis. 3 Pts had a primary ocular Ds – 38% experienced improvement

1 Smith JR et al. Arthritis Care & Research 2001;45:252-257 A Prospective Trial of Infliximab Therapy in Patients With Refractory Uveitis: Trials and Tribulations, Successes and Setbacks

• Prospective non- randomized or controlled open label • Of 31 enrolled, 28 reached 10 weeks, 18 reached 1yr and 5 reached 2 yrs • 22/28 and 9/18 have been characterized as treatment successes at 10 weeks and 1yr • Only 1 post 10 week study termination occurred due to lack of efficacy (the remainder were due to noncompliance, protocol violation loss to f/u or side effects) – 3 cases of drug induced SLE – 1 neoplasm – 1 CHF – 1 MI 2 PE’s – 1 Serious infection

E.B. Suhler Ophthalmol. 2005;123:903-912. Infliximab for Refractory Uveitis Due to Behcet’s

• Retrospective Evaluation 18 BD – Cyclosporin resistant – 5mg/kg induction and Q8wks – Mean follow up 15 mo (2-25) – Uveitis Attacks and Visual Acuity improved in all – No SAE’s

Ito, ARVO 2009 Therapy for Refractory Uveitis: A Pilot Study

• Prospective, noncomparative, nonrandomized • 19 patients (10 idiopathic), only 1 anterior • 40mg QOW for 1 yr

• VA improved in 31% worsened in 3% • 63% achieved control of inflammation • 55% resolution of CME • Reduction of 50% of concomitant immunosuppressive • 42% required at least 1 periocular steroid injection

Diaz-Llopis, L et al. JNL Ocular Pharmand Therapeutics.2008;24.351-361. • AbbVie Receives Orphan Drug Designation for Adalimumab from the U.S. Food and Drug Administration for the Investigational Treatment of Certain Forms of Non-infectious Uveitis • May 20, 2014 • About Orphan Drug Designation The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the United States, or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. • The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval for an investigational use. Sponsors must establish safety and efficacy of a compound in the treatment of a disease through adequate and well- controlled studies.

TNF Blocking Agents Preventing Uveitis Flares

• Retrospective Observational Study of 46 SpA Patients Who Had ≥ 1 Episode of Uveitis

Flares/100 Pt-Yrs Before With n anti-TNF anti-TNF P All anti-TNF 46 51.8 21.4 0.03 Etanercept 13 54.6 58.5 0.92 Monoclonals 33 50.6 6.8 0.0008 Infliximab 25 47.4 9.0 0.008 Adalimumab 8 60.5 0.0 0.04

Guignard S, et al. Ann Rheum Dis. 2006;65:1631–1634. Etanercept (Enbrel) Associated Inflammatory Eye Disease: Case Report and Review of the Literature

• 52 y/o F w/ bilat Anterior uveitis where periods of injections w/ etanercept were related to flaring of uveitis. Re-challenging was consistently associated with worsening of ds and de - challenging with rapid resolution. • 17 cases of inflammatory eye disease believed to be associated with etanercept therapy were found in recent literature – Definition of cases – Actual relationship to drug vs progression of underlying ds – Explanation?

M. Taban,A, W.J. Dupps, Jr B. Mandell,B and V.L. Perez© 2005 2849—B402 Do Tumor Necrosis Factor Inhibitors Cause Uveitis?

• 2 Databases – WHO adverse events database and National Registry of Drug Induced Ocular side effects • Excluded diseases with potential uveitis as a complication of the disease

Etanercept Infliximab Adalimumab Number of pts 400,000 700,000 160,000 treated P <0.001 Cases of Uveitis 43 14 2 P<0.01 Cases of Uveitis P<0.001 23 10 2 after exclusions P<0.5

Lim L, Fraunfelder F Rosenbaum J Arthritis & Rheumatim 2007 56:10 3248-3252 • Despite this finding, the authors concluded:

“Regardless of the mechanism, the number of uveitis cases reported in our series with both agents is small. It would be fair to say that if there were a clear propensity for etanercept to cause uveitis in comparison to infliximab, the number of cases should be far higher.”

“Our findings do not support the use of infliximab over etanercept in the treatment of patients with inflammatory diseases that may or may not be associated with uveitis”

Loss of Efficacy During Long-Term Infliximab Therapy for Sight-Threatening Childhood Uveitis

• Prospective observational study • 15 pts failed steroids and MTX +/- cyclosporin • 5mg/kg Q 6-8 wks with approx ½ of the group receiving Q 10wks once achieved remission • Median F/U 30 mo • 13/15 achieved remission, median 10 wks • 85% tapered steroids by at least 50% • Probability of relapse correlated with length of Rx • All eventually relapsed • Sample size, infliximab dose, MTX dose, tertiary care center, no placebo

Rheumatology 2008;47: 1510-1514. Simonini et al

• EAU Rat Model1 – Interphotoreceptor Retinoid Binding Protein Immunized – 50 ng of Rabbit anti Mouse TNF single eye compared to PBS control eye – Clinical Score 3.5 in control 1.45 in Rx (p<0.01) – In a rabbit model 1.5mg of infliximab has t 1/2 6-7 days and none detectable 35-40 days2 • MTX microsphere intravitreal injection3 • Tacrolimus Encapsulated Liposomes4

1. ARVO 2009 D841 Nitaichi 2. ARVO 2009 A625 Giasanti 3. ARVO 2009 A562 Lin JL 4. ARVO 2009 D705 Zhang Miscellaneous

• Rituximab Case Report1 • IL6 - Mouse IRBP induced uveitis2 – IL-6RmAb 8mg or Isotype control – Suppressed Day 0 – 1, however by day 5 lost effect despite Rx. At this point Th17 differentiated – Effect correlated with differentiation of Th 17 cells

Tappeiner et al Ophthalmic Res 2007;39:184-86 ARVO 2009 A406 Haruta Abatacept for Severe Anti-TNF Refractory Juvenile Idiopathic Arthritis-Related Uveitis

• Seven patients (6 females and 1 male) with a mean uveitis duration of 11.6 years • The mean frequency of uveitis flares during the 6 months before and after treatment decreased from 3.7 to 0.7 episodes • One patient withdrew from the study with oral mycosis and arthritis flare

Zulian F Arthritis Care Res 2010 Jun;62(6):821-5. New Therapies

• Gevokizumab - Monoclonal IL-1 beta Monoclonal – Orphan Drug Designation for non-infectious intermediate, posterior or pan uveitis1

1. Gul A .Ann Rheum Dis 2012 Apr;71(4):563-6. doi: 10.1136/annrheumdis-2011-155143. Epub 2011 Nov 14. Intravitreal Infliximab

• 1mg/0.05 ml 15 pts w/ Behcet’s at onset of unilateral posterior attack

• No side effects, no electroretinopgraphy, or antichimeric Ab assessment (dose important different study – diabetes with diabetic macular edema 8/19 eyes developed severe uveitis) • 1.5mg/ 0.15 ml 7 pts no response in previous 3 mo • Mean Best Corrected visual acuity, central macular thickness and Vitreous haze transiently changed

wks 0 4 12 24 Markomichelakis Am J Ophth In Press 2012Favardin J Ocular Pharm and Therap In Press 2012 Uveitis - Lecture Goals

• Definitions & terminology • Examination • Diagnostic approach • Treatment

Das S et al; Eye. 2006 Jul;21:276–278. Background

• Incomplete shell comprising approx 90% of the outer coat of the eye • Composed of collagen and elastin • Relatively avascular and acellular • Functions as a protective outer coat, stabilizes pressure and provides attachment for muscles

Scleritis

• Uncommon - 0.1% of presentations in emergency eye clinic • Classified according to which part of the sclera is affected – anterior (98%) or posterior (2%) • 4 subclasses – Diffuse anterior - most common (and benign) form characterized by widespread inflammation of the anterior sclera. 94% of scleritis cases. – Nodular - erythematous, tender, fixed nodules in 20% of cases, progress to necrotizing scleritis. – Necrotizing - extreme pain and marked scleral damage, usually associated with underlying systemic disease – Scleromalacia perforans - this is also known as necrotizing anterior scleritis without inflammation and is notable for its lack of symptoms. It is most frequently associated with RA Episcleritis

• Episclera - lies between the conjunctiva and the sclera. • Episcleritis – Tends to be idiopathic but may be associated with systemic diseases • Simple episcleritis - recurring, self-limiting inflammation affecting part (simple sectoral episcleritis) or all (simple diffuse episcleritis) of the episclera lasts 7-10 days – usually spontaneously resolves • Nodular episcleritis - more severe takes longer to resolve and more likely to be associated with systemic illness • Episcleritis does not progress to true scleritis.

Presentation

Episcleritis Scleritis

• Acute onset, recurrent • Subacute: usually gradual onset, recurrent

• Mild pain/discomfort • Severe boring eye pain often radiating to forehead, brow and jaw. Pain worse with movement of eye and at night (may wake patient)

• Localised or diffuse • Localised or diffuse red eye

• Uni or bilateral • Uni or bilateral

• No associated ocular symptoms • Associated watering, photophobia and other than watering and gradual decrease in vision occasional mild photophobia, vision normal • Occasional associated systemic symptoms (fever, vomiting, headache)

• Scleromalacia perforans may present with minimal/no symptoms Associated Diseases

Episcleritis Scleritis

• Most commonly idiopathic but • At least 50% of these patients have an 30% is associated with underlying underlying systemic disease and in 15% of systemic disease. cases, the scleritis is the first manifestation • The most commonly associated • ,Wegener's systemic disorders are inflammatory granulomatosis, , bowel diseases systemic erythematosus, Reactive Arhtritis, and ankylosing • Connective tissue disease such as spondylitis. rheumatoid arthritis, PAN, SLE Wegner’s • , Churg-Strauss syndrome and syphilis. • Infectious causes are less common but • TB and local infections (usually spreading known, including Herpes, Lyme Syphlis, from a ) - P. aeruginosa, Strep. Hepatitis B , pneumoniae, Staph. aureus and varicella • Misc associations - gout, rosacea, zoster, . , thyroid Disease, foreign body • Misc associations - sarcoidosis, parasitic or chemicals may also cause episcleritis. infestation, lymphoma, trauma, foreign body. Bisphosphonates ? • Differentiating between episcleral and scleral vessels – Episcleral vessels can be moved with a cotton bud. If you apply 2.5% - blanch – Scleral vessels appear darker, follow a radial pattern, are immobile and do not blanch

Work Up at Time of Dx

• General history and physical exam • Ophtho Evaluation – Snellen VA, Ocular HTN, Corneal Ds, Cataract, Uveitis • Labs – CBC, ANA, RPR, ACE, RF, ANCA, UA, CXR, CCP, ESR, CRP

Treatment of Scleritis

• Treat the underlying disease • Diffuse and Nodular - NSAIDs with or without corticosteroids • Necrotizing or scleromalacia - High dose corticosteroids and either cyclophosphamide or rituximab • Other agents that have been used dependent on circumstances include: • Methotrexate, azathioprine, mycophenolate, cyclosporin, Infliximab

Jabs, DA Am J Ophthalmol 2000:130:469 Orbital Inflammatory Disease

• Inflammation of the may diffusely involve multiple or all orbital structures or may be localized to a specific orbital tissue - lacrimal gland, , or optic nerve sheath.

L K Gordon Eye (2006) 20, 1196–1206. Orbital inflammatory disease: a diagnostic and therapeutic challenge Differential Diagnosis

• Idiopathic Inflammatory Disease • Systemic inflammatory disease – Autoimmune thyroid disease: endocrine – Sarcoidosis, Microscopic polyangitis, Crohn's , SLE, Churg-Strauss – Tolosa–Hunt syndrome is a painful ophthalmoplegia with variable cranial nerve involvement – Erdheim-Chester syndrome -systemic non Langerhans histiocytic xanthogranulomatous inflammatory disease – Histiocytosis X – Giant cell arteritis – Idiopathic fibrosclerotic disorders – Periarteritis nodosa – Scleroderma – Sclerosing cholangitis

• Neoplasm – Lymphoma – Lymphoproliferative disorders – Rhabdomyosarcoma – Choroidal malignant with extrascleral spread – Metastatic disease • Misc – Congenital malformation – Dermoid cyst – Lymphangioma – Infectious disease – Trauma

Diagnostic Work Up

• History and physical • Labs - complete blood count, ESR, CRP, anti-nuclear antibody screen, ANCA, rheumatoid factor, ACE, Immunoglobulins and TFTs , anti-thyroid antibodies protein electrophoresis • Imaging – CT, MR, Ultrasound • Biopsy

Therapy

• Treat Underlying Disease • Systemic • Methotrexate • Cyclophosphamide • Azathioprine • Cyclosporine • Mycophenolate mofetil • Anti-TNF-alpha • IFN-alpha Rituximab

• 6 pts with refractory scleritis (4 idiopathic, 2 relapsing polychondritis) • All disease activity decreased. 2 complete remission • 4 patients symptoms returned - 2,4,6 and 9 mo • 2 patients received a second rituximab cycle successfully • 4 cases that responded well to treatment with rituximab. 2 remained on corticosteroids

van Bilsen et al. Journal of Translational Medicine 2011, 9(Suppl 2):P12 Kurtz A, Suhler EB, Rosenbaum JTBr J Ophthalmol 2009 Apr;93(4):546-8 clinicaltrials.gov/ct2/show/NCT00415506 IgG4- Disease

• Syndrome of unknown etiology comprised of a collection of disorders that share specific pathologic, serologic, and clinical features • The commonly shared features include tumor-like swelling of involved organs, a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and variable degrees of fibrosis that has a characteristic “storiform” pattern • Elevated serum concentrations of IgG4 are found in 60 to 70 percent of patients with IgG4-RD.

Plaza JA. Arch Ophthalmol. 2011 Apr;129(4):421-8. Associated Diseases

• Type 1 autoimmune pancreatitis (IgG4-related pancreatitis) • IgG4-related sclerosing cholangitis • Mikulicz’s disease (IgG4-related and ) • Sclerosing sialadenitis (Küttner’s tumor, IgG4-related submandibular gland disease) • Inflammatory orbital pseudotumor (IgG4-related orbital inflammation or orbital inflammatory pseudotumor) • Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related dacryoadenitis) • A subset of patients with “idiopathic” retroperitoneal fibrosis (Ormond’s disease) and related disorders (IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis) • Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis) • Riedel’s thyroiditis (IgG4-related thyroid disease) • IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (IgG4-related lung disease) • IgG4-related kidney disease (including tubulointerstitial nephritis and membranous glomerulonephritis secondary to IgG4-RD) • IgG4-related hypophysitis • IgG4-related pachymeningitis

• Prednisone 40 mg/day. A response is frequently seen within two to four weeks. Taper over a two-month period • In patients who are resistant or unable to have their dose reduced Azathioprine (2 mg/kg/day) or Mycophenolate Mofetil (up to 2.5 g/day to 3 g/day) • B cell depletion therapy with Rituximab

Conclusions

• Interesting and Complex Immunological Models • Significant Practical Implications • Immunomodulation