Guideline Update: 2013 ACR Recommendations Norman T. Ilowite, MD
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5 Guideline Update: 2013 ACR Recommendations Norman T. Ilowite, MD Professor of Pediatrics Albert Einstein College of Medicine Bronx, NY
6 Introduction Recommendations always intended to be reviewed annually and updated IL-1 and IL-6 inhibition in systemic JIA supported by level A evidence Address macrophage activation syndrome (MAS) a major complication of systemic JIA Repeat TB screening for all categories of JIA Long-term exposure False positive results associated with annual screening
7 Methods RAND/UCLA Appropriateness Method Goal was to identify agreement where it existed, not to force consensus Systematic literature review, development of evidence report PIs, Core Expert Panel: Develop clinical scenarios Disease activity, threshold Task Force Panel: Rate appropriateness of interventions Recommended, inappropriate, uncertain Level of evidence assigned (A,B,C,D) Typical dose of DMARDs, biologics Ringold S, et al. Arthritis Rheum. 2013;65(10):
8 Reprinted with Permission from Ringold S, et al. Arthritis Rheum. 2013;65(10):
9 Initial Therapy: Systemic JIA with Active Systemic Features and Varying Degrees of Synovitis Assume with or without glucocorticoids, intra-articular glucocorticoids MD global 5 or MD global <5 and AJC >4 Anakinra Glucocorticoid monotherapy NSAIDs MD global <5 and AJC 1-4 Anakinra NSAIDs MD global <5 and AJC = 0 NSAIDs AJC: active joint count; 0 joints, 1 4 joints, or >4 joints MD global: physician global assessment; <5 or 5 on a 10-point scale (0 10 visual analog scale, where 0=no disease activity and 10= the most severe) Ringold S, et al. Arthritis Rheum. 2013;65(10):
10 Continued Disease Activity: Systemic JIA with Active Systemic Features and Varying Degrees of Synovitis Following 1 month of anakinra AJC 0-4 Canakinumab Tocilizumab Methotrexate or leflunomide AJC > 4 Canakinumab Tocilizumab Methotrexate or leflunomide TNF-α inhibitor AJC: active joint count; 0 joints, 1 4 joints, or >4 joints Ringold S, et al. Arthritis Rheum. 2013;65(10):
11 Continued Disease Activity: Systemic JIA with Active Systemic Features and Varying Degrees of Synovitis Following 2 weeks glucocorticoid monotherapy MD global 5, MD global <5 and AJC = 0 Anakinra Canakinumab Tocilizumab MD global <5, AJC > 0 Anakinra Canakinumab Methotrexate or leflunomide Tocilizumab AJC: active joint count; 0 joints, 1 4 joints, or >4 joints. MD global: physician global assessment: <5 or 5 on a 10-point scale (0 10 visual analog scale, where 0=no disease activity and 10= the most severe) Ringold S, et al. Arthritis Rheum. 2013;65(10):
12 Continued Disease Activity: Systemic JIA with Active Systemic Features and Varying Degrees of Synovitis Following 1 month of NSAIDs MD global <5, AJC = 0 Anakinra MD global <5, AJC > 0 Anakinra Glucocorticoid monotherapy MD global 5 Canakinumab Tocilizumab AJC: active joint count; 0 joints, 1 4 joints, or >4 joints. MD global: physician global assessment; <5 or 5 on a 10-point scale (0 10 visual analog scale, where 0=no disease activity and 10= the most severe Ringold S, et al. Arthritis Rheum. 2013;65(10):
13 Continued Disease Activity: Systemic JIA with Active Systemic Features and Varying Degrees of Synovitis For continued disease activity after 2nd treatment, the same recommendations were made post anakinra or post glucocorticoid monotherapy as after 1st treatment Abatacept After trial of both an IL-1 inhibitor and tocilizumab Calcineurin inhibitor After trial of both an IL-1 inhibitor and tocilizumab Ringold S, et al. Arthritis Rheum. 2013;65(10):
14 Reprinted with Permission from Ringold S, et al. Arthritis Rheum. 2013;65(10):
15 Initial Therapy: Without Active Systemic Features and Varying Degrees of Synovitis AJC > 4 Methotrexate or leflunomide NSAID monotherapy AJC > 0 and 4 NSAID monotherapy Intra-articular glucocorticoid AJC: active joint count; 0 joints, 1 4 joints, or >4 joints Ringold S, et al. Arthritis Rheum. 2013;65(10):
16 Continued Disease Activity: Without Active Systemic Features and Varying Degrees of Synovitis Following 3 months of methotrexate or leflunomide AJC > 0 Abatacept Anakinra TNF-α inhibitor Tocilizumab AJC: active joint count; 0 joints, 1 4 joints, or >4 joints Ringold S, et al. Arthritis Rheum. 2013;65(10):
17 Continued Disease Activity: Without Active Systemic Features and Varying Degrees of Synovitis Following 1 month of NSAID monotherapy AJC > 4 Anakinra Methotrexate or leflunomide AJC > 0 and 4 Methotrexate or leflunomide AJC: active joint count; 0 joints, 1 4 joints, or >4 joints Ringold S, et al. Arthritis Rheum. 2013;65(10):
18 Continued Disease Activity: Without Active Systemic Features and Varying Degrees of Synovitis Following initial joint injection AJC > 4 Anakinra Methotrexate or leflunomide AJC > 0 and 4 Methotrexate or leflunomide AJC: active joint count; 0 joints, 1 4 joints, or >4 joints Ringold S, et al. Arthritis Rheum. 2013;65(10):
19 Continued Disease Activity: Without Active Systemic Features and Varying Degrees of Synovitis If any active arthritis after these therapies, any of the below are recommended if not previously given Abatacept Anakinra Methotrexate or leflunomide TNF-α inhibitor Tocilizumab Ringold S, et al. Arthritis Rheum. 2013;65(10):
20 For Features Concerning MAS* Monotherapy Anakinra Calcineurin inhibitor Systemic glucocorticoids (oral or IV)? Rilonacept?TNF-α inhibitor after trial of calcineurin inhibitor + anakinra?tocilizumab Ringold S, et al. Arthritis Rheum. 2013;65(10): *Defined as any combination of disease manifestations: Persistent fever, cytopenias or falling cell line counts, falling erythrocyte sedimentation rate, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, transaminitis, coagulopathy, organomegaly, low or absent natural killer cell activity, hyperferritinemia, or CNS dysfunction
21 Repeat Testing for Latent TB Inappropriate if low risk Recommended if risk was or changed to moderate or high as determined by regional disease guidelines Ringold S, et al. Arthritis Rheum. 2013;65(10):
22 Limitations/Caveats Not all phenotypes of systemic JIA addressed Lack of a standardized disease activity score Thresholds for MD global, AJC determined by consensus Many recommendations not supported by high levels of evidence Lack of MAS diagnostic criteria Recommendations not intended to replace physician judgment, shared decision making with families, nor unusual complex cases
23 Take Home Points Different recommendations for systemic JIA patients with and without systemic symptoms The period of time to wait until changing therapy for continued disease activity depends on the specific treatment (eg,nsaids, glucocorticoid monotherapy, anakinra, other biologics) Anakinra has joined glucocorticoids and calcineurin inhibitors for treatment of MAS Recommendations for repeated TB testing are different from other published recommendations Lovell DJ, et al. Arthritis Care Res. 2011;63(1):10-16.
24 Advancing Science: Incorporating New Options in Systemic Juvenile Idiopathic Arthritis Treatment Fabrizio De Benedetti, MD, PhD Head, Division of Rheumatology Ospedale Pediatrico Bambino Gesù Rome, Italy
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26 Anemia Lancet 1995 Blood 1996 Thrombocytosis Arthritis Rheum 1991 Fever Arthritis Rheum 1991 Prominent Interleukin-6 production in systemic JIA Joint Inflammation J Exp Med 1998 Growth Impairment J Clin Invest 1997 Endocrinol 2001 Osteoporosis Arthritis Rheum 2006 IL6/soluble IL6R and CRP J Clin Invest 1994 MAS Arthritis Rheum 2012
27 Reverse Translation Identifying the Role of IL-1β in Systemic JIA Using IL-1 Inhibitors Sera from patients induce IL-1b production from normal PBMC Increased expression of IL-1b related genes Pascual V, et al. J Exp Med. 2005; 209:
28 Incorporating Advancing Science in the Treatment of Systemic JIA Forward translation: IL-6 in systemic JIA Reverse translation: IL-1 in systemic JIA Guidelines from available clinical evidence 47 references on systemic JIA treatment 5 out of 47 are level A based on trials in systemic JIA 2 out of 47 are level A based on trials in JIA 40 out of 47 are case series or expert opinions
29 A New Patient with Systemic JIA Making a quick diagnosis Diagnosis might be difficult in the absence of overt arthritis
30 Possible Biomarkers for Early Diagnosis S100A12 Data shows a very high level of this protein in SJIA as well as in FMF but not in a number of other autoinflammatory or inflammatory or hematological diseases, suggesting that really S100 might be an early biomarker for the diagnosis of SJIA Wittkowski H, et al. Arthritis Rheum. 2008;58(12):
31 A New Patient with Systemic JIA Making a quick diagnosis Diagnosis might be difficult in the absence of overt arthritis Lack of a validated laboratory test: S100A12 Predicting disease course
32 SJIA: Natural Disease Course Monocyclic course (30%-40%) Remission within 2 4 years Relapsing course (5%-10%) Flares of systemic features and mild arthritis Persistent course (40%-60%) Systemic flares with persistence of arthritis Persistence of both systemic features and arthritis Lomater C, et al. J Rheumatol. 2000;27(2): Singh-Grewal D, et al. Arthritis Rheum. 2006;54(5):
33 Predictors of Persistent/Severe Disease Clinical At 6 months from onset 1 Active systemic features + PLT > /mm 3 At 3 months from onset 2,3 Active systemic features + active arthritis Active joints >13 + PLT > /mm 3 Laboratory 4,5 Elevated d-dimers Carriage of the MIF -173 C allele 1. Spiegel LR, et al. Arthritis Rheum. 2000;43: Singh-Grewal D, et al. Arthritis Rheum. 2006;54: Sandborg C, et al. J Rheumatol. 2006;33: Bloom BJ, et al. J Rheumatol. 2009;36: De Benedetti F, et al. Arthritis Rheum. 2003;48:
34 A New Patient with Systemic JIA Making a quick diagnosis Diagnosis might be difficult in the absence of overt arthritis Lack of a validated laboratory test: S100A12 Predicting disease course Monocyclic versus persistent Lack of validated predictors
35 A New Patient with Systemic JIA: A Window of Opportunity to Change the Disease Course?
36 A New Patient with Systemic JIA: A Window of Opportunity to Change the Disease Course? Clinical trials: No data available on early treatment Tocilizumab trial Mean disease duration: 5 years Minimal disease duration: 6 months Canakinumab trial Median disease duration: 2 years Minimal disease duration: 2 months Observational studies De Benedetti F, et al. New Engl J Med. 2012;367(25): Ruperto N, et al. New Engl J Med. 2012;367(25):
37 International Collection of Cases with Early Treatment with Anakinra in Systemic JIA Inclusion criteria: Treatment with anakinra as part of the initial DMARD regimen Time from disease onset to anakinra treatment Complete Response (n=27) Partial/Absent Response (n=19) P value Median (IQR), days 90 (44-150) 75 (30-225) 0.84 Nigrovich PA, et al. Arthritis Rheum. 2011;63:
38 Effectiveness of First-line Use of Recombinant IL-1RA Treatment in Steroid-naïve Systemic JIA Results of a Prospective Cohort Study 20 patients Disease duration at time of initiation of treatment is not provided Treated with 2 mg/kg escalated to 4 mg/kg if fever present at day 3 7/20 patients needed additional treatments (glucocorticoids, methotrexate, tocilizumab, canakinumab) At 12 months 17/20 (85%) had JIA ACR90 + absence of fever Possibly affected by inclusion of patients with monocyclic disease Vastert SJ, et al Arthritis Rheum :
39 A New Patient with Systemic JIA: A Window of Opportunity to Change the Disease Course? Clinical trials: No data available on early treatment Tocilizumab trial Mean disease duration: 5 years Minimal disease duration: 6 months Canakinumab trial Median disease duration: 2 years Minimal disease duration: 2 months Observational studies: Available data do not suggest a clear advantage De Benedetti F, et al. New Engl J Med. 2012;367(25): Ruperto N, et al. New Engl J Med. 2012;367(25):
40 A New Patient with Systemic JIA Conventional therapy (NSAIDs + glucocorticoids) Many children do well Inexpensive Risks are known and can be significant (bone density, growth, infections, avascular necrosis) Early cytokine blockade (anakinra) Expensive Uncomfortable Short-term risk appears acceptable Long-term risks not yet fully known Severe disease, pericarditis, impending macrophage activation syndrome
41 Appropriate Dosing Based on Pharmacokinetic Studies Anakinra Tocilizumab Canakinumab
42 Appropriate Dosing Based on Pharmacokinetic Studies: Anakinra Body weight significantly affected anakinra pharmacokinetics Daily dose of anakinra changed as a function of body weight in order to reach a mean steady state concentration of 0.4 mg/l Reprinted with permission from Urien S, et al. BMC Pharm Toxicol. 2013;14(1):40.
43 Japanese Randomized Withdrawal Study in Systemic JIA Lower body weight associated with lower probability to obtain clinical response Body weight Patients NOT achieving JIA ACR30 and CRP <0.5mg/dL BW <30 kg (n=29) BW 30 kg (n=21) 6/29 (21%) 0/21 (0%) JIA ACR50 5/29 (17%) 0/21 (0%) JIA ACR70 11/29 (37%) 3/21 (15%) Yokota S, et al. Lancet. 2008;371(9617): Roche and Chugai: data on file
44 TENDER: Dosing Regimen Based on: Efficacy data Pharmacokinetic analysis and modeling Children <30 kg body weight 12 mg/kg every 2 weeks Children >30 kg body weight 8 mg/kg every 2 weeks Lu P, et al. Arthritis & Rheumatology. 2014;66:S222-S223.
45 TENDER: Serum Tocilizumab Concentration Time Profile by Dosing Regimen Roche: Data on file
46 Appropriate Dosing Based on Pharmacokinetic Studies Anakinra Body weight >50 kg: 100 mg/day Body weight <50 and >10 kg: 2 mg/kg/day Body weight <10 kg: 3 mg/kg/day Tocilizumab Body weight >30 kg: 8 mg/kg every 2 weeks Body weight <30 kg: 12 mg/kg every 2 weeks Canakinumab No published data available
47 Background Methotrexate in Systemic JIA
48 Background Methotrexate in Systemic JIA Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis ACR30 responders Placebo MTX P Systemic JIA (n=45) Extended oligoarticular JIA (n=43) 16% 25% % 58% Woo P, et al. Arthritis Rheum. 2000;43(8):
49 Patients, % Patients, % Background Methotrexate in Systemic JIA: Results from Clinical Trials Tocilizumab: 1 year Canakinumab: 3 months Background MTX Use Background MTX use Yes (n=78) No (n=34) YES (n=97) No (n=81) JIA ACR30 + fever absent JIA ACR70 JIA ACR90 0 JIA ACR30 + no fever JIA ACR90 De Benedetti F. Presented at American College of Rheumatology Scientfic Meeting. Nov Chicago. De Benedetti F. Presented at Pediatric Rheumatology European Society Meeting.
50 Background Methotrexate in Systemic JIA Randomized, placebo-controlled, trials do not show significant difference in ACR30 No apparent difference in response rate with or without background methotrexate in canakinumab and tocilizumab trials No apparent differences in maintaining inactive disease while tapering tocilizumab with or without background methotrexate
51 Clinically Relevant Outcomes: Evidence from Randomized Clinical Trials never compare a clinical trial Tocilizumab 1 Canakinumab 2 1 year OUTCOME Variable (Median 113 days) 59% ACR90 + absence of fever 51% 28% Clinically inactive disease 31% 48% Absence of active arthritis Not reported 52% Stopped glucocorticoids 33% 1 De Benedetti F, et al. New Engl J Med. 2012;367(25): Ruperto N, et al. New Engl J Med. 2012;367(25):
52 Somatic Growth as an Outcome in Systemic JIA: Results from TENDER De Benedetti et al submitted
53 Height Velocity, cm/yr Somatic Growth as an Outcome in Systemic JIA Results from TENDER: Catch-up Growth ** ** 0 Pre-Tx Year 1 Year 2 dashed lines mean normal expected height velocities De Benedetti et al submitted Pre-Tx, n=36; Year 1, n=81; Year 2, n=71 Patients with 1 year of TCZ who had Tanner stage <4 at baseline (**) Comparisons made between pre-tx and year 1 and year 2 using paired t-tests; all P<0.0001
54 Radiologic Progression an Outcome in Systemic JIA: Results from TENDER Week 52 Week 104 Adapted Sharp/van der Heijde (n=47), median (IQR) Poznanski (n=33), median (IQR) 0.00 ( 8.70, 4.00) 0.50 ( 7.50, 12.00) 0.29 ( 0.05, 1.05) 0.16 ( 0.01, 1.04) The great majority of patients showed no progression over 2 years of treatment with tocilizumab (Sharp/van der Heijde 45/47; Poznaski 30/33) Limitation: Small population size because of difficulties in performing radiography and in obtaining evaluable data from the readings Malattia C, et al. Arthritis & Rheumatology. 2014;66:S222-S223.
55 Clinically Relevant Outcomes: Evidence from Randomized Clinical Trials never compare a clinical trial Tocilizumab 1 Canakinumab 2 1 year OUTCOME Variable (Median 113 days) 59% ACR90 + absence of fever 51% 28% Clinically inactive disease 31% 48% Absence of active arthritis Not reported 52% Stopped glucocorticoids 33% 1 De Benedetti F, et al. New Engl J Med. 2012;367(25): Ruperto N, et al. New Engl J Med. 2012;367(25):
56 Tapering and Withdrawing Glucocorticoids Guidelines from clinical trials: canakinumab Tapering was permitted starting from week 8 Tapering may occur if the patient has achieved at least a JIA ACR50 response and no fever Prednisone equivalent dose Maximum permitted amount of reduction >0.1 mg/kg/day 0.1 mg/kg/day 0.05 mg/kg/day 0.1 mg/kg/week until at dose of 0.1 mg/kg/day 0.05 mg/kg/day and bring to 24 hours for 1 week Bring to alternate dosing days for 2 weeks and then discontinue Ruperto N, et al. New Engl J Med. 2012;367(25): supplementary material: protocol
57 Tapering and Withdrawing Glucocorticoids Guidelines from clinical trials: tocilizumab Tapering was allowed from Week 6 if a patient attained a JIA ACR 70 and normal ESR and absence of fever Tapering was allowed from Week 16 if a patient attained a JIA ACR 50 and normal ESR and absence of fever Prednisone equivalent dose Maximum permitted amount of reduction (every 2 weeks) 30 mg/day 10 mg 15 but <30 mg 5 mg >7.5 and <15 mg/day 2.5 mg <7.5 mg/day 1.25 mg De Benedetti F, et al. New Engl J Med. 2012;367(25): supplementary material: protocol
58 Tapering and Withdrawing Treatment in Patients in Inactive Disease To qualify for the optional tapering schedule, patients had to be in the study for 2 years and have achieved inactive disease status and have stopped glucocorticoids Rules for tocilizumab tapering Tocilizumab trial Maintaining inactive disease for at least 12 weeks can switch to infusion every 3 weeks Maintaining inactive disease for at least 12 weeks can switch to infusion every 4 weeks Maintaining inactive disease for at least 12 weeks can stop methotrexate and NSAIDs (if used) Maintaining inactive disease for at least 12 weeks can stop tocilizumab De Benedetti F, et al. Pediatric Rheumatology 2013,11(Suppl 2):P151.
59 Take Home Points Diagnosis and predictors of disease severity Clinical and laboratory predictors of persistent disease Clinical practice Early treatment Tapering glucocorticoids Background MTX Clinically relevant outcomes ACR90, clinically inactive disease, no active arthritis, off glucocorticoids... growth, radiological progression Future issues Predictors of response, withdrawing therapies, MAS and other unusual long-term complications Long-term safety
60 Reducing Complications in Systemic Juvenile Idiopathic Arthritis Alexei A. Grom, MD Professor of Pediatrics Cincinnati Children s Hospital Medical Center Cincinnati, OH
61 Outline Macrophage activation syndrome (MAS) Pulmonary hypertension
62 scd8 sil2rα CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ TNF-α IL-6 IL-1 IL-18 M-CSF CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ MΦ IFN-γ M-CSF scd163 MΦ MΦ Mo MΦ Hemostatic TF MΦ MΦ Cassidy JT, et al. Textbook of Pediatric Rheumatology, 6th Edition.
63 Impact IL-1/IL-6 Inhibiting Agents on MAS
64 Impact IL-1/IL-6 Inhibiting Agents Highly effective in systemic JIA 1,2 Since MAS episodes are often triggered by systemic JIA flare, it is reasonable to expect some response to IL-1/IL-6 inhibition due to a better control of the underlying disease Mice transgenic for IL-6 show exaggerated inflammatory response to TLR ligands 3 On the other hand, although linked, MAS and systemic JIA differ in terms of the underlying pathophysiology As an example, MAS responds to cyclosporine A, while a conventional systemic JIA flare would not 1. Ruperto N, et al. N Engl J Med. 2012;367(25): DeBenedetti F, et al. N Engl J Med. 2012;367(25): Strippoli R, et al. Arthritis Rheum. 2012;64(5):
65 IL-1 Inhibiting Agents and MAS: Anakinra Conflicting reports in MAS: MAS responded to Anakinra Kelly A, et al. Nat Clin Pract Rheumatol. 2008;4(11): Behrens EM, et al. J Rheumatol. 2006;33(10): Miettunen PM, et al. Rheumatology (Oxford). 2011;50(2): Patients developed MAS while on Anakinra but some patients improved on a higher dose Zeft A, et al. J Clin Rheumatol. 2009;15(4): Nigrovic PA, et al. Arthritis Rheum. 2011;63(2):
66 MAS in Systemic JIA Patients Treated with Canakinumab Entire systemic JIA clinical program, including extension phase All suspected cases adjudicated by an independent panel of experts Clinical Systemic JIA program Canakinumab Placebo Difference (95% CI) Cincinnati experience Patient-years exposure, years Number of MAS events reported Rate of reported MAS events/100 patient years (-15.0, 6.8) 4-6 Grom A, et al. Manuscript in preparation
67 Canakinumab and MAS For systemic JIA patients treated with canakinumab MAS risk not increased But no full protection, even in patients whose underlying systemic JIA is well controlled An infectious trigger was identified in almost all cases Clinical presentation of MAS was not modified by canakinumab treatment Diagnostic approaches should remain the same Treatment responses to steroids and cyclosporine A did not appear to be modified Grom A, et al. Manuscript in preparation
68 IL-6 Inhibiting Agents and MAS: Tocilizumab 3 MAS cases in TENDER trial of tocilizumab in systemic JIA (1.5 cases per 100 patients/year) De Benedetti F, et al. New Engl J Med. 2012;367(25): One case report describing a patient with severe adult-onset Still's disease who showed a very good initial response to tocilizumab, but then rapidly progressed to develop MAS Kobayashi M, et al. Mod Rheumatol. 2011;21: MAS clinical presentation may be modified No CRP increase Shimizu M, et al. Cytokine. 2012;58:
69 Tocilizumab Post-marketing surveillance conducted by Chugai Pharmaceuticals Co, Ltd 394 systemic JIA patients registered between 2008 and patients develop MAS based on reports provided by managing physicians All cases reviewed by Safety Evaluation Committee Definite MAS in 5 patients 2 triggered by Epstein Barr virus Probable MAS in 11 patients Possible MAS in 7 patients About 4% Yokota S, et al. Arthritis Rheum. 2013;65(10):S114.
70 Tocilizumab and MAS For systemic JIA patients treated with tocilizumab MAS risk not increased But no full protection, even in patients whose underlying systemic JIA is well controlled 1,2 Clinical presentation of MAS may be modified CRP may remain within normal range 3 Treatment responses to steroids and cyclosporine A did not appear to be modified 1. De Benedetti F, et al. New Engl J Med. 2012;367(25): Yokota S, et al. Arthritis Rheum. 2013;65(10):S Shimizu M, et al. Cytokine. 2012;58:
71 Pulmonary Complications
72 Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic JIA 25 systemic JIA patients who developed pulmonary artery hypertension, interstitial lung disease or alveolar proteinosis identified through Listserv Compared with a cohort of systemic JIA patients enrolled in CARRA registry Kimura Y, et al. Arthritis Care Res. 2013;65(5):
73 CARRA Registry: Clinical Features at Pulmonary Disease Diagnosis Kimura Y, et al. Arthritis Care Res. 2013;65(5):
74 CARRA Registry: Patient Demographics and SJIA Disease Characteristics Kimura Y, et al. Arthritis Care Res. 2013;65(5):
75 Pulmonary Artery Hypertension in Systemic JIA The increase in the number of systemic JIA patients diagnosed with pulmonary artery hypertension coincided with the introduction of IL-1 and IL-6 inhibiting agents WHY? Increased awareness and better diagnostic tools, and increased survival or Adverse effect of the new biologics?
76 CARRA Registry: Medications During Disease Course Kimura Y, et al. Arthritis Care Res. 2013;65(5):
77 Pulmonary Artery Hypertension Reprinted with permission from Rabinovitch M. J Clin Invest. 2012:122:4306. Kherbeck N, et al. Clin Rev Allergy Immunol. 2013;44:31.
78 Idiopathic Pulmonary Artery Hypertension Germline mutations in BMPR2 In >80% of patients with familial idiopathic pulmonary artery hypertension About 20% of patients with sporadic idiopathic pulmonary artery hypertension Deng Z, et al. Am J Hum Genet. 2000;67:737. Thomson JR, et al. J Med Genet. 2000;37:741. BMPR2 signaling leads to suppression of the growth of pulmonary artery smooth muscle cells Davies RJ, et al. Am J Physiol Lung Cell Mol Physiol.2012;302:L604. Reduced BMPR2 expression is seen in patients with acquired pulmonary artery hypertension Can be induced by inflammatory cytokines Brock M, et al. Circ Res. 2009;104:
79 Inflammation in Idiopathic Pulmonary Artery Hypertension mononuclear cells in vessels of idiopathic pulmonary artery hypertension lungs compared with control subjects Tissue sections were stained with antibodies specific for the marker of macrophage CB68. Brown staining identifies macrophages. Quite a few macrophages in the lung tissue in general, but there are quite a few of them also in the blood vessel wall. Savai R, et al. Am J Resp Critical Care Med. 2012;186:
80 Circulating IL-1 and IL-6 in Idiopathic Pulmonary Artery Hypertension Patients with primary pulmonary artery hypertension have extremely high levels of IL-1-beta and IL-6 Humbert M, et al. Am J Resp Critical Care Med. 1995;151:
81 IL-6 in Idiopathic Pulmonary Artery Hypertension IL-6 can reduce BMPR2 expression via STAT3-mir17/92 expression Brock M, et al. Circ Res. 2009;104: Reprinted with permission from Furuya Y, et al. Int J Rheumatol. 2010:
82 IL-1 and IL-6 in Idiopathic Pulmonary Artery Hypertension IL-6 as a potential therapeutic target for pulmonary artery hypertension Pulmonary artery hypertension in patients with mixed connective tissue disease dramatically improved in response to tocilizumab Furuya Y, et al. Int J Rheumatol. 2010: Pulmonary artery hypertension in adult-onset Still s disease: rapid response to Anakinra Campos M, et al. Case Rep Rheumatol. 2012;2012:
83 Pulmonary Artery Hypertension in Systemic JIA Pulmonary artery hypertension develops in response to inflammation-driven vasculopathy rather than biologics?
84 CARRA Registry: Medications During Disease Course Kimura Y, et al. Arthritis Care Res. 2013;65(5):
85 Cyclosporine A and Endothelial Injury Cyclosporine A, a calcineurin inhibitor, has been implicated in the development of pulmonary artery hypertension in bone marrow transplant patients Mathew R, et al. J Pediatr Hematol Oncol. 2011;33: FK506 (tacrolimus) may be better A calcineurin inhibitor, but also binds FKBP12 (a repressor of BMPR2 signaling) as a result, increases BMPR2 signaling Spiekerkoetter E, et al. J Clin Invest. 2013;123:
86 Take Home Points Macrophage activation syndrome In systemic JIA patients treated with canakinumab or tocilizumab, MAS risk is not increased, but no full protection, even in patients whose underlying systemic JIA is well controlled Anakinra may be beneficial in some patients Pulmonary hypertension Most likely, pulmonary artery hypertension develops in response to inflammation-driven vasculopathy rather than biologics Increasing concern that Cyclosporine A may cause endothelial injury in the lung vasculature and contribute to the development of pulmonary artery hypertension
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