Systemic Juvenile Adiopathic Arthritis: Treatment Options 15. Alexei A. Grom, MD Cincinnati Children s Hospital Medical Center

Transcription

1 Systemic Juvenile Adiopathic Arthritis: Treatment Options 15 Alexei A. Grom, MD Cincinnati Children s Hospital Medical Center

2 Disclosures NIH grants AR059049, AR Consulting fees Novartis, Roche, Merck Research collaboration Novartis, NovImmune

3 Systemic Juvenile Idiopathic Arthritis In 1897, Frederick Still highlighted the unique clinical features of systemic arthritis in children and differentiated it from both rheumatoid arthritis of adults and other forms of juvenile arthritis Still F. On a form of chronic joint disease in children. Medical-Chirurgical Transactions 1897;80:47-59 Painting by Gerald Kelly

4 Systemic Juvenile Idiopathic Arthritis ILAR Classification Criteria Arthritis in at least one joint may not be present initially Fever for at least 2 weeks with or preceding arthritis documented daily ( quotidian ) for at least three days At least one of the following Evanescent erythematous rash Generalized lymph node enlargement Hepatomegaly and/or splenomegaly Serositis ILAR criteria, 2001

5 Arthritis About 80% of patients have arthritis in >1 joint at presentation wrist, knees, and ankles are most common sites Behrens, et al. J Rheumatol 2008;35: Schneider, et al. J Ped 1992;120:200-5

6 SJIA Course Over time, systemic features tend to subside in most patients Overall outcome depends on the evolution of arthritis About 50-60% of the patients develop severe destructive polyarthritis early appearance of erosive changes in the joints is common hips involved in about 50-60% approximately 1/3 will progress to total arthroplasty bony ankylosis is common particularly in C-spine, carpal and tarsal bones Hagem et al. Revue du Rheumatisme 1994 Schneider R, Laxer RM. Baillieres Clin Rheumatol 1998, 9

7 Growth Delay

8 Acute Complications Macrophage Activation Syndrome

9 MAS Disease Definition MAS is caused by excessive, uncontrolled activation and proliferation of T cells and well differentiated non-neoplastic macrophages Macrophages exhibit hemophagocytic activity Hadchouel M, Prieur AM, Griscelli C. J Pediatr 1985;106: Silverman ED, et al. J Pediatr 1983;103:872. Grom AA, Passo MH. J Pediatr 1996;106:561-6.

10 MAS Definition - continued Massive systemic inflammatory response associated with cytopenias liver disfunction coagulopathy consistent with DIC extreme hyperferritinemia Hadchouel et al. J Pediatr 1985;106: Silverman et al. J Pediatr 1983;103; Clinically similar to Hemophagocytic Lymphohistiocytosis Major source of mortality in pediatric rheumatology

11 Treatment of Juvenile Idiopathic Arthritis Pre-biologic Era 1950s-2000s Biologic Era JIA Then NSAIDs Corticosteroids Methotrexate Anti-TNF agents Abatacept (sctla4) now JIA Now Dramatic improvement in the outcome of non-systemic subtypes of JIA

12 In contrast Introduction of the TNF-inhibiting agents and abatacept did not have a major impact on the outcome of systemic JIA Focus on translational research in SJIA

13 Biologic properties of IL-1 and IL-6 may explain many clinical features of SJIA Dinarello C. J Exp Med 2005;201:1355

14 Attention: IL-6 and Growth IL-6 transgenic mice are much smaller; the bones are shorter normal levels of Growth Hormone decreased levels of Insulin-like Growth Factor 1 Growth Hormone exerts its effects through IGF1 De Benedetti et al. JCI 1997;99:643

15 Growth hormone acts on liver cells, causing the release into the blood stream a hormone called Insulin-like Growth Factor (IGF-1)

16 Administration of IL-6 in Healthy Mice Leads to Decreased Levels of IGF-1 De Benedetti et al. JCI 1997;99:643

17 Growth Delay As in IL-6 transgenic mice, in SJIA patients growth delays may be due to IL-6 induced decrease in IGF-1 Since growth hormone exerts its effects through IGF1, this may explain why growth hormone therapy is not effective in SJIA patients with active disease De Benedetti et al. JCI 1997;99:643

18 Old Treatment Algorithm for SJIA Woo P. Nature Clinical Practice Rheumatology 2:28-34, 2005

19 SJIA Medication Use (CARRA Registry) Current Medications at Baseline Percent current use Methotrexate GC IL1 inhibitor TNF inhibitor IL6 inhibitor Kimura Y. ACR 2012

20 STRATEGIES TO BLOCK IL-6 ACTIVITY

21 Anti-IL-6 blockade - Tocilizumab TCZ IL-6 sil-6r IL-6R gp130 gp130 Phase III trials in SJIA completed, approved by FDA

22 STRATEGIES TO BLOCK IL-1 ACTIVITY

23 Anti-IL-1 blockade - Anakinra IL-1 receptor antagonist IL-1 type I receptor IL-1 receptor accessory protein No FDA approval, but widely used by pediatric rheumatologists based on small studies

24 Anti-IL-1 blockade - Canakinumab Phase III trials in SJIA completed, approved by FDA

25 Anti-IL-1 blockade - Rilonacept Phase III clinical trial completed, data not published yet

26 Anakinra in Systemic JIA Several early reports of anakinra benefit in SJIA have heralded usage in many cases; especially in lieu of inadequate response to TNF inhibiting agents and methotrexate: - 2 pts, case reports, excellent response Verbsky & White. J Rheumatol 31:2071-5, pts, case reports, excellent response Henrickson M, et al. ACR 2004, abstr /14 pts improved with complete resolution of systemic signs, 10/14 complete resolution of arthritis Irogoyen P, et al. ACR 2004, abstr 438.

27 Anakinra in Systemic JIA Later reports, however, were somewhat less optimistic for sustained benefit of Anakinra in SJIA Lequerre T, Quartier P, Rosellini D. Ann Rheum Dis 2008;67:302 Diminishing response may be related to the choice of strategy to block cytokine activity? hard to occupy the large number of IL-1 receptors receptors are expressed on all cells except RBCs IL-1 receptors are readily generated each day anakinra rapidly excreted by the kidney blood levels low after 24 hours Dinarello C. Current Opinion in Pharmacology 2004

28 Increasing interest in long acting monoclonal antibodies directed against IL-1β (canakinumab) IL6R (tocilizumab) IL1-trap (rilonacept)

29 New Engl J Med, December 2012

30 TOCILIZUMAB IN SJIA PHASE III TRIAL

31 Patients, % JIA ACR Responses Over Time JIA ACR30 JIA ACR70 JIA ACR50 JIA ACR Weeks n = De Benedetti et el. New Engl J Med, 2012

32 Safety De Benedetti et el. New Engl J Med, 2012

33 CANAKINUMAB IN SJIA PHASE 3 TRIALS

34 Patients, % Patients, % Canakinumab: Clinical Response at Day TRIAL 1 84 * 67 * 61 * * * 33 Weeks JIA COMPARE: Tocilizumab Adapted JIA ACR 30 Adapted JIA ACR 50 Adapted JIA ACR 70 Adapted JIA ACR 90 Adapted JIA ACR 100 Inactive disease Canakinumab Placebo n= * P < P value not determined for comparison of inactive disease. Adapted JIA ACR criteria include absence of fever. Ruperto N, et al. N Engl J Med. 2012;367:

35 Kaplan-Meier Estimate: Probability to Remain Flare Free, % Trial 2, Part II: Time to flare 100 The response is sustained in the vast majority of patients Canakinumab/Canakinumab Canakinumab/Placebo Canakinumab Placebo Days in Part II Patients were also allowed to take concomitant medications during this period. Ruperto N, et al. N Engl J Med. 2012;367:

36 Canakinumab: Safety Summary Open-label Part I Randomized withdrawal Part II Canakinumab n=177 Placebo n=50 Canakinumab n=50 Patients with AEs, n (%) 138 (78) 35 (70) 40 (80) Number of AEs Rate of AEs/100 patient days NA Patients with serious AEs, n (%) 15 (8) 6 (12) 6 (12) AEs leading to discontinuation, n (%) 5 (3) 6 (12) 0 Infections, n (%) 97 (55) 19 (38) 27 (54) Rate of Infections/100 patient-days NA Serious Infections, n (%) 7 (4.0) 2 (4.0) 2 (4.0) MAS, n (%) 4 (2) 1 (2) 0 Death, n (%) 1* (1) 1** (2) 0 *A 13-year-old boy, previously treated with anakinra and tocilizumab, died during study participation. The child was hospitalized for an episode of adenovirus gastroenteritis, which resolved within 14 days. Four days later, after receiving the third dose of canakinumab, he was rehospitalized for the MAS; severe pulmonary hypertension developed, and he died 3 weeks later. **A 16-year-old girl received eight doses of canakinumab, followed by placebo for 164 days (six doses); she then had progressive clinical worsening and urosepsis. Clinical, laboratory, and bone marrow findings suggested the MAS. She had cardiac arrest requiring resuscitation and intubation while in tertiary care. Chest radiography was consistent with the acute respiratory distress syndrome. The patient died 7 days after the transfer to the tertiary care hospital (2 days after withdrawal from the study). Ruperto N, et al. N Engl J Med. 2012;367:

37 Summary In SJIA with active systemic features, short-acting IL-1 inhibiting agent anakinra provides marked response in many patients, but the response is not always sustained Long-acting anti-il-1b mab canakinumab and anti IL6R mab tocilizumab provide clinically meaningful response rates In Phase III trials, rapid response with marked improvement at ACR 90 level in almost half of patients, clinical remission in 1/3 Sustained therapeutic effect Efficacious on arthritic as well as systemic components Infections are the most common adverse event No cases of malignancy, tuberculosis, or opportunistic infections, so far Risk for MAS is not increased, but no full protection, even in patients whose underlying SJIA is well controlled

38 TREATMENT ALGORITHMS

39 Systemic JIA Still high variability in treatment approaches among pediatric rheumatologists in the US The main points of disagreement: When to start DMARDs/biologics? What biologic to use first? Is methotrexate beneficial? Should patients in the systemic and arthritic phases be approached differently?

40 When to start DMARDs or biologics? Monocyclic course in many patients These patients may need just a relatively short course of steroids (4-6 months duration) If steroid taper leads to a flare of SJIA then start biologics or DMARDS What is the proportion of patients with monocyclic course?

41 Systemic JIA Disease Course (%) Lomater (2000) Singh-Grewal (2006) Monocyclic Polycyclic 34 7 Persistent 55 51

42 When to start biologics? IL-1 inhibition may be more effective at early stages of the disease before systemic inflammatory response settles down in the joints Delayed start of IL-1-inhibiting agents may lead to decreased responsiveness Nigrovic et al, Arthritis&Rheum 2011;63:545

43 Old Treatment Algorithm for SJIA Anti-IL1 and IL-6? Woo P. Nature Clinical Practice Rheumatology 2:28-34, 2006

44 Biologics as Initial Treatment? Anakinra as First-Line Disease Modifying Therapy in Systemic Juvenile Idiopathic Arthritis 46 patients from 11 centers In this study, the long-term outcome was better compared to historic numbers, but it is not clear how many patients in this group were bound to have a monocyclic course and go into remission regardless of the initial treatment Nigrovic et al, Arthritis&Rheum 2011;63:545-55

45 METHOTREXATE IN SJIA

46 MTX in JIA USA/USSR clinical trial 114 JIA patients with polyarticular course included in the final analysis 58 polyarticular onset 33 systemic onset 23 oligoarticular onset No effect on systemic features Arthritis: the frequency of response did not appear to be influenced by type of onset But the numbers were small Giannini et al NEJM 1992

47 Role of Methotrexate in SJIA? Better response rate during the arthritic stage (without systemic features)? Giannini et al NEJM 1992

48 Methotrexate in sjia Randomized, placebo-controlled, crossover trial of lowdose oral methotrexate in children with extended oligoarticular or systemic juvenile idiopathic arthritis (Woo et al, A&R 2000) ACR30 responders Placebo MTX p Systemic JIA (n=45) 16% 25% 0.35 Extended Oligo JIA (n=43) 18% 58%

49 Background Methotrexate in Phase III Clinical Trials in SJIA TOCILIZUMAB: 1 year CANAKINUMAB: 3 months De Benedetti, ACR no fever Novartis, data on file 49

50 Role for MTX in SJIA MTX is still used in SJIA by many physicians It is appropriate to initiate MTX during the arthritic phase of the disease Beukelman et al, ACR Recommendations for JIA management. Arthritis Rheum 2011;63:465-82

51 What biologic to use first?

52 Systemic JIA Still no clear answers: When to start DMARDs/biologics? What biologic to use first? Is methotrexate beneficial? Should patients in the systemic and arthritic phases be approached differently? Not surprizingly, the most current ACR recommendations provide full flexibility in terms of possible choices:

53 Ringold S, et al. Arthritis Rheum ;65:2499

54 Systemic Juvenile Adiopathic Arthritis: Treatment Options 15 Alexei A. Grom, MD Cincinnati Children s Hospital Medical Center