Safety profiles of agents used in the treatment of JIA

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2 Safety profiles of agents used in the treatment of JIA Sampath Prahalad, MD, MSc Marcus Professor of Pediatric Rheumatology Chief, Division of Pediatric Rheumatology Emory University School Of Medicine July 25, 2015

3 Disclosure statement I have served on an advisory board for Novartis.

4 Poly JIA Five joints in first six months Few teens have RF Polyarticular Oligoarticular Oligo JA No more than 4 joints first One third may extend Poly RF +ve Poly RF -ve

5 Systemic Fever rash swelling Makes systemic JIA Can have Heartache too Boys with heel, back pain Most have B twenty seven Can have eye pain too ERA

6 When you can t sort, use undifferentiated. More or less than one. Psoriatic Rash, pits, sausages Makes psoriatic JA Has arthritis too

7 Remission and disability in JIA Systemic Poly RF + Poly RF - All poly Oligo From Prahalad S, Current Medical Literature 2006

8 What is a joint like this. doing in a nice girl like her?

9 MR image of a knee in a 6 year old girl

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11 Pathogenesis of inflammatory arthritis

12 Active disease for long time can cause joint erosions

13 Untreated synovitis can lead to erosion and ankyosis

14 JIA can also result in bony fusions

15 The Role of medications in JIA MTX, Steroids X X Abatacept Etanercept Infliximab Adalimumab Golimumab Certolizumab X X X Prostaglandins etc COX X Arachidonic acid NSAIDS Anakinra Rilonacept Canakinumab Rituximab tocilizumab

16 Non-steroidal anti inflammatory drugs Serious toxicity is rare in children Cardiac: No differences in children taking Celebrex vs. others Liver: mild enzyme elevation can occur Renal: 0.2 to 0.4% with abnormalities CNS: Headache, fatigue, tinnitus Reyes Syndrome: Aspirin. Petty et al: Textbook of Pediatric Rheumatology 2015

17 NSAIDS: GI side effects Common in adults (5-fold risk). 702 children on NSAID for > 1 year; 0.7% with gastritis, esophagitis, ulcer Another study: 4% had ulcer/erosions Take with food; Use Omeprazole Anti-acids / misoprostol Petty et al: Textbook of Pediatric Rheumatology 2015

18 NSAIDs side effects Cutaneous: Pseudoporphyria; Can occur with naproxen 3-fold higher risk in fair, blue-eyed children Schäd et al. Arthritis Research & Therapy :R10 Petty et al: Textbook of Pediatric Rheumatology 2015

19 Methotrexate: safety Overall frequency and severity of AEs in children with JIA is low Most side effects are reversible Occur within hours. GI: Abdominal discomfort, nausea in 12-20% Intolerance: Anticipatory nausea (up to 50%) Oral ulcers: 3% of children Folic acid supplementation helps.

20 Methotrexate & the liver Mild toxicity with enzyme elevation in 9-17% of children. Most are less than twice normal values. Studies of liver biopsies in children on MTX have not found fibrosis or cirrhosis. Mostly transient or resolve with lower dose May stop or lower NSAID to help. Check LFTs every 3 months on stable dose

21 Methotrexate & blood May lower blood cell counts especially white blood cell counts. Less common in children compared to adults. Infections Rate is same in MTX vs no MTX. Hold MTX during course of antibiotics. Surgery Hold for 1 week before, 2 weeks after Dental work: Can continue MTX.

22 Methotrexate: special precautions Spontaneous abortions /congenital anomalies Adult women should practice contraception Discontinue at least one cycle before trying to conceive Does not appear to affect male fertility Can be excreted in breast milk

23 LEFLUNOMIDE GI: Abdominal pain, anorexia, gastritis Rash, hair loss, weight loss Symptoms tend to be dose related. Teratogenic: Cholestyramine to absorb drug Check drug levels prior attempt to conceive Breast feeding contra-indicated. CBC, CMP at baseline, and 3 monthly

24 Sulfasalazine Intolerance in 30% of children in 1 study Rashes in 1 to 5% of children Oral ulcers / Stevens-Johnson syndrome rare but serious complication Avoid in patients with allergy to SULFA CBC, CMP baseline and after dose change. Monitor every 3 months when stable

25 Use < 6 mg/kg/day Hydroxychloroquine Major side effect is retinal toxicity Eye exam at baseline and annually Skin pigmentation rare side effect GI intolerance in some CNS: headache, insomnia

26 Steroids: necessary evil Weight gain Striae Hypertension Diabetes Cataracts Osteoporosis Infections Behavior changes

27 Steroids: caution Dose reduction when feasible Alternate day regimens Vitamin D and calcium supplementation Eye exam to look for cataracts Stress doses (surgeries)

28 IA corticosteroids in JIA Complications: infection subcutaneous atrophy periarticular calcification thepainsource.com Hashkes, P. J. et al. JAMA 2005

29 Anti TNF agents are the first line of biological agents in IA

30 Anti TNF agents are the first line of biological agents in IA Agent Type /Route Uses Etanercept (Enbrel) Adalimumab (Humira) Infliximab (Remicade) Golimumab (Simponi) Certolizumab (Cimzia) Humanized SC Humanized SC Chimeric IV Humanized SC Humanized SC RA, JA, PsA, AS, PS RA, JA, PsA, AS, PS, CD, Uv RA, JA, PsA, AS, PS, CD, Uv RA, PsA, AS, UC CD, RA, PsA

31 Reported risks of TNF inhibitors Injection site reactions Infusion reactions (Infliximab) Reactivation of tuberculosis Malignancy and serious infections Demyelination (MS) Petty et al: Textbook of pediatric rheumatology

32 Anti IL1 agents Injection site reactions; Liver enzyme elevation Neutropenia High lipid levels Agent Type /Route Uses Anakinra (Kineret) Canakinumab (Ilaris) Rilonacept (Arcalyst) Humanized SC Humanized SC Humanized SC RA, sjia, CAPS CAPS, SJIA CAPS, SJIA

33 Infections TB reactivation Malignancy GI perforation Adverse effects of tocilizumab Hypersensitivity reaction Anaphylaxis MS or demyelination With or without MTX Monitor WBC, liver enzymes and lipid profile 33

34 Co-stimulation blockade in RA/JIA/Uveitis Injection site reactions Headaches Has been used in combination with anakinra IV and SC forms available Infections: 1.3 /100 PY 34

35 Adverse reactions reported with Rituximab Anti CD-20 monoclonal antibody Given as 2 or 4 IV infusions Results in low B cell counts and low IgG Infusion reactions Progressive multifocal leukencephalopathy Infection Premed: steroids, Tylenol, benadryl

36 Biological agents Safe and well tolerated Injection site reactions URI symptoms Infections should be treated early and seriously PPD/Quantiferon gold test before starting and annually. FDA warning about the potential for malignancies and life threatening infections. Combination therapy not recommended. 36

37 Infections associated with JIA and its treatment Medicaid Database from Identify children with JIA (n = 8503) Treatment history Steroids (n=3098) MTX ( n = 3491); TNF inhibitors (n = 1392) 15 opportunistic infections identified Calculate incidence rate ratios compared to children with ADHD (360,362) Beukelman et al; Arthritis Rheum

38 Rates of infections in JIA compared to ADHD per 100,000- patient years All infections Herpes zoster All - zoster Salmonella Beukelman et al; Arthritis Rheum 2013

39 Rates of coccidiodes infection 100 fold increased in JIA vs ADHD Coccidoides 101 ADHD JIA Beukelman et al; Arthritis Rheum 2013

40 Rates of zoster per 100,000 patient years exposed to JIA drugs JIA alone MTX only TNF (+/-) MTX NO GC GC Swart JF; Arth Res Ther 2013

41 Rates of infections per 100 patient years exposed to JIA drugs Normal JIA alone JIA+MTX INFL ETN ADAL ABT TOCI RTX 0 Swart JF; Arth Res Ther 2013

42 Malignancy associated with JIA and its treatment Medicaid Database from Identify children with JIA (n = 7812) Treatment history MTX ( n = 3243); TNF inhibitors (n = 1484) Malignancies identified (possible, probable or highly probable) Calculate standardized incidence ratios compared to children with ADHD (321,821) Also compared to children with Asthma (652,234) Beukelman et al; Arthritis Rheum

43 Rates of malignancies per 100,000 patient years of exposure to JIA drugs in a National database JIA no exposure MTX alone TNFI Asthma ADHD 60 External controls Beukelman et al; Arthritis Rheum 2012

44 Rates of malignancies per 100 patient years exposed to JIA drugs; A systematic review Normal JIA alone JIA+MTX ETN Swart JF; Arth Res Ther 2013

45 Relative risk of malignancies in RA Author Number Risk or incidence ratio Askling 22, ( ) Gottlieb 13, ( ) Burmester 14, ( ) BSRBR 15, ( ) DANBIO 9, ( ) SABER 29, ( ) Mariette >40, ( ) NA Database 7, ( ) RABBIT 5, ( ) Taiwan Nat DB 22, ( ) ARTIS 4, ( ) Lebrec et al; Current Medical Research & Opinion; 2015

46 Malignancy associated with JIA and its treatment: summary Studies in RA and IBD suggest that the underlying disease might increase risk of malignancy Several pediatric studies suggest a 2 fold increase in rate of malignancy in JIA TNF inhibitors do not seem to increase the risk of malignancy in RA or JIA. Other agents are less well studied. Still the numbers of children with malignancies are small. 46

47 Registries may allow for better monitoring 47

48 Pharmacovigilance efforts underway will help provide more definitive answers FDA issues changes to drug labels and black box warning with safety concerns CARRA CoRe Registry for monitoring European database of suspect ADRs Yellow Card in the UK

49 Christiaan Barnard Born 1922, Beaufort west, South Africa Completed medical school at 23 Dxed with RA at U of Minnesota at 34 Performed first heart transplant at 45 What was the use of continuing, if my hands would soon fumble in the tying of a simple overhand knot, or even tremble with a scalpel? One life

50 JA Camp in the early 1980s. Slide courtesy of Dr. Daniel Lovell 50

51 Camp Acheaway Slide courtesy of AF 51

52 Acknowledgments The children with rheumatic diseases and their Families The American College of Rheumatology The National Institutes of Arthritis, Musculoskeletal and Skin Diseases, The Marcus Foundation, The Arthritis Foundation.