Blindsided by Arthritis

Transcription

1 Blindsided by Arthritis Melissa A. Lerman, MD, PhD, MSCE Division of Rheumatology The Children s Hospital of Philadelphia The Perelman SOM at the University of PA No financial disclosures. 1

2 Case yo female with altered gait, intermittently, for 2 months. She moves less well in the morning and after naps. She does not complain of pain. Synechiae sign of eye inflammation 2

3 Eye inflammation Uveitis, scleritis, episcleritis, optic neuritis Uvea = grape (Greek) Iris, ciliary body, choroid Causes of Uveitis Trauma Infection Genetic Leukemia Idiopathic (unknown) Autoimmune/rheumatic disease 3

4 Infectious Causes Bartonella Brucella CMV EBV Histoplasmosis Lyme Syphilis Toxocara Toxoplasma Tuberculosis HIV HSV Uveitis in Rheumatic Disease Juvenile idiopathic arthritis Tubulo interstitial nephritis and uveitis (TINU) Sarcoidosis/Blau Syndrome Psoriasis Ankylosing Spondylitis Inflammatory Bowel Disease Vasculitides (Behçet Disease, Cogan s, AAV, SLE) Multiple Sclerosis Idiopathic 4

5 Non Infectious Uveitis 10 15% blindness in developed world Prevalence (Optum Database, 2012) Adult: 121/100,000 Pediatric: 29/100,000 (26% JIA associated) In the 2015 US population (estimated): 298, 801 adults 21, 879 children Thorne JE, et al. JAMA Ophthalmol 2016, Sep 8. Juvenile Idiopathic Arthritis 26% Non infectious pediatric uveitis Arthritis > 6 weeks Oligoarticular 4 joints first 6 mo (40%) Polyarticular 5 joints first 6 mo (20% RF, 5% RF+) Enthesitis Related (ERA)(5 10%) Psoriatic (5 10%) Systemic (10%) Undifferentiated (5 10%) ILAR Classifications (1997, 2001) (Intl League of Associations for Rheum) 5

6 Uveitis in JIA 13 23% of JIA Anterior, chronic, bilateral Bilateral over time 65% asymptomatic* F>M (4.4:4)* 30% Oligo> 15% Poly RF neg >10% PsA * exceptions Case 2 5 yo girl with oligojia since she was 22 mo is in the office. She is growing well, has no active arthritis, and feels great. When did you last see the eye doctor? We ve been busy, so it has been probably about a year. Vision 20/80 6

7 Timing of Uveitis Activity Joint eye Uveitis can develop at any time 12% incidentally on eye exam JIA diagnosis Can be present at the diagnosis of JIA Can develop years after the JIA Regular SCREENING eye exams are crucial (more detail later) Risk Factors for JIA U Female, young age, ANA positive, subtype (oligo) 1,2 Age of onset and ANA 3,4 Screening guidelines depend on: age onset, ANA, subtype Highest risk 1 st 2 years (up to 5 7 years) 2,4 1. Saurenmann, RK et al. Arthritis Rheum. 2007; 56(2): Heiligenhaus A, et al. Rheumatology (Oxford). 2007;46: Saurenmann, RK et al. Arthritis Rheum. 2010; 62(6): Calandra, S et al. J Rheumatol. 2014; 41(7):

8 Case 3 13 year old boy with Enthesitis related arthritis: He wears glasses so he waits until his vision check at the optometrist. He is given antibiotic drops no improvement. Uveitis in ERA and AS Different from other JIA associated uveitis Anterior (same) Unilateral Acute (sudden onset and limited duration) Reportedly SYMPTOMATIC Boys>girls Fewer complications 8

9 Classification of Uveitis Location Course of uveitis Degree of inflammation Other: granulomatous Anterior (80%) Iritis Iridocyclitis Intermediate Vitirits Pars planitis Posterior Pan Optic nerve Vasculitis Choroid lesion 9

10 Classification of Uveitis Location Course of uveitis Degree of inflammation Other: granulomatous Jabs, DA et al. AJO 140(3):

11 Standardization of Uveitis Nomenclature (SUN) Working Group Jabs, DA et al. AJO 140(3): Classification of Uveitis Location Course of uveitis Onset Course Duration Degree of inflammation 11

12 SUN Working Group Criteria AU* * AU: Anterior Uveitis Granulomatous Uveitis Nodules in the iris, mutton fat KP, large vitreous snowballs, or choroidal granulomas TB Syphilis Vogt Koyanagi Harada (VKH) Sarcoid 12

13 Presentation of Disease Anterior Uveitis (AU) 60 80% pediatric uveitis Largest percentage of JIA associated uveitis? Red eye, blurry vision, photophobia JIA often painless What can your rheumatologist see in the office? New scarring of pupil since last visit Otherwise a slit lamp exam is necessary to see uveitis 13

14 Synechiae Iris Scarring Anterior to cornea Posterior to lens Glaucoma Treat: Dilating drops if new Slit Lamp Exam 14

15 Anterior Chamber (AC) Cells Hypopyon 15

16 Flare Blood/aqueous barrier broke down from inflammation Extra protein in the anterior chamber Flare in AC disease reactivation Keratitic Precipitates Clusters of cells on cornea (inferior) Marker of quite active disease Less common with JIA 16

17 Case 4 12 year old girl with bilateral knee pain and swelling for 2 months Moves around like an old man in the morning No signs of pubertal maturation Poor weight gain for 2 years No linear growth for 1 year Uveitis in Inflammatory Bowel Disease Posterior uveitis (can be intermediate) Bilateral Insidious in onset Chronic in duration Girls>boys Macular edema More complications Episcleritis, scleritis, and glaucoma (> than ERA) 17

18 Intermediate Posterior 15% uveitis Cells in vitreous 10 15% Uveitis Chorioretinitis Optic neuritis (pain,vision) Macular edema MS, Sarcoid, IBD, infection (Lyme) Sarcoid, Behçet, VKH, Infection Differential Diagnosis Is it sudden or insidious? Laterality? Which part of the eye is affected? Acute or chronic? Associated symptoms? 18

19 Tests to Consider CBC CMP ESR, CRP Urinalysis ANA HLA B27 ACE, Lysozyme, U Ca /U Cr ANCA RPR Toxoplasma, Toxocara ELISA CMV Ab (serum, urine) Lyme PPD Uveitis Complications Visual deficits (<20/50), blindness (<20/200) Synechiae Cataracts (posterior subcapsular) * Band keratopathy Increased intraocular pressure glaucoma * Cystoid macular edema Need for surgery 19

20 Cataracts pedsinreview.aappublications.org Band Keratopathy Calcific band across middle of cornea (under epithelium) 20

21 Increased Intraocular Pressure Blocked flow: Synechiae, trabecular scarring Corticosteroids Pressure checks at EACH visit Cystoid Macular Edema 21

22 Complications in JIA 45% at initial visit 37 56% overall 1,2 Cataracts > synechiae > glaucoma Predictors 1 Complication at presentation Uveitis pre arthritis ANA negative 3 1. Heiligenhaus A. Rheumatology (Oxford). 2007; 46: Saurenmann, RK. Arthritis Rheum. 2007; 56(2): Chalom, E. J Rheumatol 1997;24(10):2031. Cataracts in JIA U Incidence 0.04/eye yr, prevalence 80% (adult JIA) 1 Risk factors: Active, ongoing inflammation Posterior synechiae at onset Systemic CS 87% risk reduction risk 3 gtt/d vs. 4 gtt/d 2 Worse post surgery visual outcomes in JIA U Control inflammation peri op better outcomes 1. Angeles-Han, S. Curr Rheumatol Rep. 2011, Dec Thorne, JE. Ophthalmology. 2010; 117(7):

23 Visual Loss in JIA U 10 30% Mean F/u 20/50 20/200 Review of Smith ( years 30% 24% 2004) 2 Germany % 15% (2002) 3 Toronto ( ) % 9% 1. Cabral DA. J Rheumatol. 1994; 21: Thorne JE. Am J Ophthalmol. 2007;143: Heiligenhaus A. Rheumatology (Oxford). 2007;46: Saurenmann, RK. Arthritis Rheum. 2007; 56(2):647. What can we do to prevent this? Dx: Screening w/in 1 2 wk Ophthalmologist Ensure regular screenings 23

24 AAP Screening Guidelines Cassidy J, et al. Pediatrics 2006;117(5): German Uveitis Study Group Heiligenhaus A. Rheumatology (Oxford) 2007;46(6):

25 We ve identified it what now? Dilating drops (atropine) Limit development/breakup synechiae Use only in acute phase Anti inflammatory drugs Anti inflammatory Players Steroids Conventional immunosuppression Biologic immunomodulators 25

26 Steroids Immunomodulators Methotrexate Conventional Mycophenolate Mofetil Azathioprine Cyclosporine Biological TNFα Inhibition and others Effectiveness? Toxicity? Corticosteroids Topical (drops, gels) Injections/instillations Intraocular, periocular, long acting depot No role for systemic CS in JIA U (anterior) Can same complications as disease itself 26

27 Goals of uveitis control Decrease inflammation (<0.5+) Shortest possible time to control Maintain control Spare steroid exposure Limit topical steroids (<2 drops/day) Outcome measures vary by study 27

28 Anti metabolites Methotrexate Mycophenolate Mofetil Weiss, A et al. The Journal of pediatrics :

29 Methotrexate Mechanism: folate antagonist, limits neutrophil adherence (increase adenosine release) Administration: mg/kg or 15 mg/m 2 Up to 25 mg weekly (1 ml) Oral or subcutaneous, weekly 2 3 months to build up and become effective Meta analysis: 73% respond (95% CI 66%, 81%) Simonini, G. Rheumatology. 2013; 52: Other immunosuppressants 29

30 Mycophenolate Mofetil (Cell Cept) 55-88% (vary by outcome measure) Other immunosuppressants Azathioprine Cyclosporine/tacrolimus Cyclophosphamide 30

31 Biologics TNFα Inhibition Role in murine uveitis models Levels increased in aqueous humor & serum 2001 first inflammatory eye disease report Used for those failing steroids + methotrexate OR with severe/vision threatening disease at onset ADD do not switch Not FDA approved for AU (New: Adalimumab for IU/PU) Reiff, Aet al. Arthritis Rheum 2001; 44(6). Smith, JR et al. Arthritis Rheum. 2001; 45(3). 31

32 Efficacy of TNFα Inhibition in Pediatric Uveitis Etanercept ineffective for uveitis monoclonals Infliximab (Remicade): 40 80% response in those resistant to topical steroids + Methotrexate Higher dose than for arthritis ( 10 mg/kg) Adalimumab (Humira): 20 80% response Weekly? Time to treatment success under anti TNFα Proportion of children form 6 sites achieving success within: # mo % (95% CI) 3 47% (35, 60) 6 59% (46, 72) 12 75% (62, 87) Median = 3.4 months JIA AU most successful Lerman, MA et al. J Rheumatol. 2013; 40(8)

33 Safety Infections, reactivation TB, low blood counts, site reactions, anaphylaxis, PML 8% treatment episodes discontinued w/in 12 mo for adverse effects 1 8.8% minor adverse reactions (no major) 2 IFX: 18.8/100 pt yr vs. ADA: 4.7/100 pt yr No live virus vaccines FDA black box warning malignancy 1. Lerman, MA. J Rheumatol Zannin, M. J Rheumatol Jan;40(1):74-9. Which anti TNFα? Comparative effectiveness still under exploration Higher likelihood achieve remission ADA vs. IFX log rank, Mantel Cox , P< Using very low dose infliximab Other studies do not agree Burden on patient and families Financial burden 1. Simonini, G et al. Arthritis Care Res. 2011;63(4):

34 Reactivation Following Achievement of Quiescence under anti TNFα 28% relapse within 12 mo While on anti TNF: 21.6% After stop anti TNF: 63.8% Relapse higher ADA vs. IFX (HR 13.4, 95% CI: ) Vs. At 40 mo still in remission on medication: ADA 9/15 (60%) of vs. 3/16 (18.8%) IFX (p<0.02) 1. Lerman, MA et al. Am J Ophthalmol. 2015; 160(1): Simonini, G et al. Arthritis Care Res. 2011;63(4): What if anti TNFα is not enough? What if disease if uveitis remains active despite anti TNFα? What if disease re activates WHILE on anti TNFα? 34

35 JIA U Is a Chronic Disease 46 57% reactivate within 12 mo after d/c MTX Relapse free survival associated with: Longer duration disease inactivity before stop (>2 yrs) 1 Lower levels of S100A8/S100A9 (calprotectin) Of those quiet on anti TNFα, 28% relapse within 12 mo While on anti TNF: 21.6% After stop anti TNF: 63.8% 1. Kalinina Ayuso, V et al. Am J Ophthalmol. 2011; 151(2): Foell D, et al. JAMA. 2010; 303(13): Lerman, MA et al. Am J Ophthalmol. 2015; 160(1):

36 JIA U Reactivate after stop MTX Affected by duration of control? Biomarkers? Study 1: 46% reactivate within 12 mo after d/c 1 Factors associated with relapse free survival after d/c: Study 2 Included: inactive uveitis >2 yrs pre d/c (p=0.033) 56 57% reactivate 6 and 12 mo 2 Reactivation: Higher levels of S100A8/S100A9) 1. Kalinina Ayuso, V et al. Am J Ophthalmol. 2011; 151(2): Foell D, et al. JAMA. 2010; 303(13): Other open questions Chronic uveitis often reactivates after stopping drug. Is this driven by duration of disease control on drug or other biomarkers? Clinical question: How long to treat once uveitis is quiet? 36

37 High risk of uveitis in JIA Key Points Uveitis is often painless BUT vision threatening Regular screening by an ophthalmologist is imperative Uveitis is often chronic and should not be treated long term with steroids Immunomodulators & biologics helpful and safe Immunization recommendations Uveitis Coordinated Care Clinic at the Children s Hospital of Philadelphia Ophthalmology: Dr. Stefanie Davidson ( ) Rheumatology: Dr. Melissa Lerman ( ) 37

38 Acknowledgements Division of Rheumatology The Children s Hospital of Philadelphia (CHOP) David D. Sherry, MD Division of Rheumatology, CHOP John Kempen, MD, MPH, MHS, PhD Division of Ophthalmologist, University of Pennsylvania & Discovery Eye Institute, Addis Ababa, Ethiopia Stefanie Davidson, MD Division of Ophthalmology, CHOP 1. Angeles Han S, Yeh S. Curr Rheumatol Rep 2011, Dec Cabral DA, Uribe AG, Benseler S, O'Neil KM, Hashkes PJ, Higgins G, et al. Arthritis Rheum 2009, Nov;60(11): Calandra S, Gallo MC, Consolaro A, Pistorio A, Lattanzi B, Bovis F, et al. J Rheumatol 2014, Jul;41(7): Cassidy J, Kivlin J, Lindsley C, Nocton J. Pediatrics 2006, May;117(5): Chalom EC, Goldsmith DP, Koehler MA, Bittar B, Rose CD, Ostrov BE, Keenan GF. J Rheumatol 1997;24(10): Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K, German Uveitis in Childhood Study Group. Rheumatology (Oxford) 2007, Jun;46(6): Lerman MA, Burnham JM, Chang PY, Daniel E, Foster CS, Hennessy S, et al. J Rheumatol 2013, Aug;40(8): Petty RE Southwood TR Baum J References Rheumatol 1998, Oct;25(10): Saurenmann RK, Levin AV, Feldman BM, Rose JB, Laxer RM, Schneider R, Silverman ED. Arthritis Rheum 2007, Feb;56(2): Saurenmann RK, Levin AV, Feldman BM, Laxer RM, Schneider R, Silverman ED. Arthritis Rheum 2010, Feb 22;62(6): Simonini G, Paudyal P, Jones GT, Cimaz R, Macfarlane GJ. Rheumatology (Oxford) 2013, May;52(5): Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Am J Ophthalmol 2007, May;143(5): Thorne JE, Woreta FA, Dunn JP, Jabs DA. Ophthalmology 2010, Jul;117(7): Zannin ME, Birolo C, Gerloni VM, Miserocchi E, Pontikaki I, Paroli MP, et al. J Rheumatol 2012, Nov 1. 38

39 Wilmer Eye Institute Caveats: On Oral CS, mostly adults, 20% scleritis, MTX likely oral Galor, A et al. Ophthalmology (10): Black Box warning Food and Drug Administration based decision on review of 48 cases of malignancies (worldwide) in children with IBD, Sarcoid, and JIA Combined different diseases Combined TNF inhibitor classes Combined different co treatment profiles (MTX vs AZA) Diak, Pet al. A. administration. Arthritis Rheum 2010;62(8):