Biologic Therapy Modifies Clinical and Laboratory Features of Macrophage Activation Syndrome Associated with Systemic Juvenile Idiopathic Arthritis

Grant Schulert¹, Francesca Minoia², John F. Bohnsack³, Randy Q. Cron⁴, Soah Hashad⁵, Isabelle Koné-Paut⁶, Mikhail Kostik⁷, Daniel J Lovell⁸, Despoina Maritsi⁹, Peter A. Nigrovic¹⁰, Priyankar Pal¹¹, Angelo Ravelli², Masaki Shimizu¹², Valda Stanevicha¹³, Bas Vastert¹⁴, Fabrizio De Benedetti¹⁵ and Alexei Grom¹⁶, ¹Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²Istituto Giannina Gaslini, Genoa, Italy, ³Division of Allergy, Immunology and Pediatric Rheumatology, University of Utah, Salt Lake City, UT, ⁴Pediatric Rheumatology, Children's Hospital of Alabama, Birmingham, AL, ⁵Tripoli Children's Hospital, Tripoli, Libya, ⁶Hopital Kremlin Bicetre, University of Paris SUD, Paris, France, ⁷Hospital Pediatrics, State Pediatric Medical University, Saint-Petersburg, Russia, ⁸PRCSG Cincinnati Children's Hospital Medical Center, Cinncinnati, OH, ⁹2nd Department of Academic Pediatrics, Athens Medical School, university of Athens, Athens, Greece, ¹⁰Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, ¹¹Institute of Child Health, Kolkata, India, ¹²Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan, ¹³Pediatric cathedra, Riga Stradiņš University, Riga, Latvia, ¹⁴Wilhelmina Children's Hospital / UMC Utrecht, Utrecht, Netherlands, ¹⁵Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy, Rome, Italy, ¹⁶Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Biologic agents, Systemic JIA and macrophage activation syndrome

Session Information

Date: Tuesday, November 15, 2016

Title: Pediatric Rheumatology – Clinical and Therapeutic Aspects - Poster III: Systemic JIA, Autoinflammatory Syndromes, Scleroderma, Vasculitis, Miscellaneous

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation and a substantial cause of morbidity and mortality in pediatric rheumatology. It occurs most often as a complication of systemic juvenile idiopathic arthritis (SJIA). Despite highly efficacious treatments for SJIA with biologic agents blocking IL-1 and IL-6, patients remain at risk for MAS. Additionally, it is unclear whether treatment with biologic agents alters the clinical presentation of MAS.

Methods: We performed a comprehensive literature review to identify published cases of MAS in SJIA patients which occurred while being treated with biologic agents. Where necessary, authors were contacted directly to obtain further demographic, clinical or laboratory information. These accumulated cases were then compared to the large database of MAS cases collected as part of the 2016 MAS classification criteria project, which we used as a historical cohort.

Results: Together, sixteen published manuscripts or abstracts were identified, describing 138 episodes of MAS occurring while patients were treated with biologic agents. Further data collection and removal of duplicates led to 85 cases of MAS where clinical and laboratory information was available for analysis. Of these, 34 cases occurred while on canakinumab and 46 while on tocilizumab. Patients who developed MAS while treated with canakinumab had no significant differences in their reported clinical features. These patients did have a lower median white blood cell count (3.4 x10⁹/L vs 9.9 x10⁹/L, p<0.0001) and serum ferritin level (2170 ng/ml vs 5353 ng/ml, p<0.05) at MAS onset than the historical cohort; all other laboratory features of MAS were not significantly different. In contrast, patients who developed MAS while treated with tocilizumab were less likely to present with fever or hepatomegaly than patients in the historical cohort. In addition, patients treated with tocilizumab had significantly lower white blood cell counts (3.6 vs 9.9, p<0.0001), serum ferritin levels (983 vs 5353, p<0.0001), and less severe anemia (12.0 g/dl vs 9.8 g/dl, p=0.01) than patients in the historical cohort. Additionally, other laboratory features of MAS were more pronounced in patients treated with tocilizumab, with lower platelet counts (96 x10⁹/L vs 144 x10⁹/L, p<0.0001) and fibrinogen levels (113 g/l vs 267 g/l, p<0.0001), and higher aspartate aminotransferase levels (244 U/l vs 134 U/L, p<0.05). Due to these differences, the 2016 MAS classification criteria only categorized 53-55%% of tocilizumab treated patients as having MAS, compared to 76-83% of patients treated with canakinumab and 78% of the historical cohort.

Conclusion: This represents the largest reported analysis of MAS cases occurring during treatment with biologic therapy, and reveals important differences in clinical and laboratory features when MAS occurs during treatment with canakinumab and tocilizumab. Taken together, these findings support the need for increased clinical vigilance for signs of developing MAS in these patients, as well as the use of supporting laboratory features such as platelet count, AST and fibrinogen in MAS surveillance.

Disclosure: G. Schulert, Novartis Pharmaceutical Corporation, 5; F. Minoia, None; J. F. Bohnsack, None; R. Q. Cron, MedacPHARMA, 5,SOBI, 5,SOBI, 2; S. Hashad, None; I. Koné-Paut, Novartis, SOBI and Roche, 2,Novartis, SOBI, Pfizer, Abbvie, Roche, 5; M. Kostik, None; D. J. Lovell, National Institutes of Health, 2,Astra-Zeneca, Bristol Meyers Squibb, AbbVee, Pfizer, Roche, Novartis, UCB, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, Glaxo Smith Kline, Boehringer Ingelheim, Celgene and Jannsen, 5; D. Maritsi, None; P. A. Nigrovic, None; P. Pal, None; A. Ravelli, AbbVie, BMS, Pfizer, Hoffman LaRoche, Novartis, Centocor, 8; M. Shimizu, None; V. Stanevicha, Pfzer, 2,AbbVie, Roche, 5; B. Vastert, None; F. De Benedetti, Pfizer, Abbvie, Roche, Novartis, Novimmune and BMS and SOBI, 2; A. Grom, Novartis Pharmaceutical Corporation, 5,novimmune, 5.

To cite this abstract in AMA style:

Schulert G, Minoia F, Bohnsack JF, Cron RQ, Hashad S, Koné-Paut I, Kostik M, Lovell DJ, Maritsi D, Nigrovic PA, Pal P, Ravelli A, Shimizu M, Stanevicha V, Vastert B, De Benedetti F, Grom A. Biologic Therapy Modifies Clinical and Laboratory Features of Macrophage Activation Syndrome Associated with Systemic Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/biologic-therapy-modifies-clinical-and-laboratory-features-of-macrophage-activation-syndrome-associated-with-systemic-juvenile-idiopathic-arthritis/. Accessed .

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