Serum Interleukin 18 As a Biomarker for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome and Use of Recombinant Human IL-18 BP in a Patient with Refractory Disease

Shima Yasin¹, Rachel Brown¹, Ndate Fall², Krista Solomon¹, Scott Canna³, Charlotte Girard⁴, Cem Gabay⁵, Eduardo Schiffrin⁶, Andrew Sleight⁶, Alexei A. Grom⁷ and Grant Schulert⁸, ¹Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²Division of Rheumatology, Cincinnati Children's Hospital, Cincinnati, OH, ³NIAMS, National Institutes of Health, Bethesda, MD, ⁴Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland, ⁵SCQM, Geneva, Switzerland, Geneva, Switzerland, ⁶AB2 Bio, Lausanne, Switzerland, ⁷Division of Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States Minor Outlying Islands, ⁸Pediatric Rheumatology, Division of Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Cytokines and macrophage activation syndrome, IL-1/IL-18, Systemic JIA

Session Information

Date: Monday, November 6, 2017

Title: Pediatric Rheumatology – Clinical and Therapeutic Aspects I: Autoinflammatory Diseases

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Systemic juvenile idiopathic arthritis is an autoinflammatory childhood arthritis with prominent innate immune activity. Macrophage activation syndrome is a severe and potentially fatal complication of sJIA. IL-18 is felt to play a key role in pathogenesis of sJIA and in particular MAS; possibly through IFN-g activation. IL-18 binding protein (IL-18BP) is an endogenous inhibitor that binds IL-18 tightly. However, clinical effects of blocking IL-18 in sJIA are still unknown.

Objective: To examine serum IL-18 levels in sJIA patients with regards to disease activity, MAS features, and other novel MAS biomarkers. Additionally, we report the use of recombinant IL-18 BP (rIL-18BP) in a patient with severe, refractory sJIA and MAS.

Methods: Serum samples obtained from 20 established sJIA patients. Total IL-18, CXCL9 and S100 protein were measured. In addition, in one patient serial free IL-18 levels were determined. We compared IL-18 levels in patients with active vs inactive disease as well as with history of MAS vs no MAS.

Results:

Serum IL-18 levels were higher in patients with active sJIA (mean 52537 pg/ml ± 24442, N=10), but were still persistently elevated (2733 ± 889, N=10, upper limit of normal 540) in majority of patients with inactive disease (p=0.07). Patients with history of MAS had significantly higher IL-18 levels (63170 ± 29586, N=8) as compared to those without MAS history (3945 ± 1708, N=12, p=0.03). Only patients with fever had significantly higher IL-18 levels compared to their counter parts (P=0.03), while arthritis and elevated ESR or CRP showed no difference (p=0.1 and 0.08 respectively). We observed a weak but significant correlation between total IL-18 and CXCL9 (correlation coefficient of 0.4 (p=0.03) but not for S100A8/A9. Given these findings by us and others, we utilized Tadekinig alfa (rhIL-18BP) in a 5 year old male with sJIA and persistently elevated free IL-18 levels. His course was complicated by recurrent MAS, failure of all prior biologic treatments, chronic high dose steroids with flare of sJIA and MAS upon attempts to wean steroids. He was started on rhIL-18BP 2mg/kg/dose subcutaneous every 48h in addition to continuous IL-1 inhibition attempting to control disease and prevent MAS. His initial total and free serum IL-18 levels were high at 117356 pg/ml and 46.8 pg/ml respectively. Although his total IL-18 remained elevated after start of rhIL-18BP, free IL-18 was undetectable. In addition, since initiation of Tadekinig alfa, steroid dose was decreased by more than 50% with increase in linear growth. While on Tadekinig alfa, he developed two MAS episodes (triggered by parainfluenza and acute gastroenteritis), but both were mild and easily controlled.

Conclusion:

Total serum IL-18 levels were elevated in the majority of sJIA patients regardless of disease activity, with higher levels in patients with active disease and those with history of MAS. This indicates that IL-18 might be an important driver of sJIA and MAS. Use of rIL-18 BP improved patient disease course with less frequent and easily controlled MAS episodes. This response raises optimism about use of rIL-18 BP in patients with IL-18 driven disease preventing life-threatening MAS.

Disclosure: S. Yasin, None; R. Brown, None; N. Fall, None; K. Solomon, None; S. Canna, AB2Bio Ltd, 5; C. Girard, None; C. Gabay, Roche, Pfizer, AB2 Bio, 2,Sanofi, AB2 Bio, AbbVie, Pfizer, BMS, MSD, Roche, Novartis, 5; E. Schiffrin, AB2bio Ltd, 3; A. Sleight, Ab2 bio, 3; A. A. Grom, NovImmune, 2,Ab2 Bio, 2,Novartis Pharmaceutical Corporation, 5,Juno, 5; G. Schulert, Novartis Pharmaceutical Corporation, 5.

To cite this abstract in AMA style:

Yasin S, Brown R, Fall N, Solomon K, Canna S, Girard C, Gabay C, Schiffrin E, Sleight A, Grom AA, Schulert G. Serum Interleukin 18 As a Biomarker for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome and Use of Recombinant Human IL-18 BP in a Patient with Refractory Disease [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/serum-interleukin-18-as-a-biomarker-for-systemic-juvenile-idiopathic-arthritis-and-macrophage-activation-syndrome-and-use-of-recombinant-human-il-18-bp-in-a-patient-with-refractory-disease/. Accessed .

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