A87: Different Tocilizumab Therapeutic Protocols and Possibility Achieving Tocilizumab-Off Remission in Systemic Juvenile Idiopathic Arthritis
Authors: Mikhail Kostik, Margarita Dubko, Ludmila Snegireva, Vera Masalova, Tatyana Kornishina, Tatyana Likhacheva, Irina Chikova, Eugenia Isupova, Ekaterina Kuchinskaya, Natalya Glebova, Olga Kalashnikova, Vyacheslav Chasnyk
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

Systemic juvenile idiopathic arthritis (SJIA) is one of the most striking forms of juvenile arthritis, required biologics due to failure of corticosteroids (CS) and DMARDs. In Russia until March 2013 no Il-1 blockers were available. Since tocilizumab (TCZ) was approved in adults with rheumatoid arthritis we used it for treatment of SJIA.



The aim of our study was to evaluate outcomes and to find possible criteria, related with different treatment TCZ protocols and achievement TCZ-off remission.



Methods:

our retrospective study was included 33 active SJIA children who fall CS, methotrexate (MTX), cyclosporine A (CsA) and their combination. We used TCZ in 2 branches in standard doses: every 2 (Q2W) or every 4 weeks (Q4W). The randomization was based on efficacy which was evaluated in 14th day. If patient had no signs of TCZ inefficacy during next 2 weeks (days 15–29) the patient was referred to Q4W group (n=24), if any clinical or laboratorial signs of inefficacy during first 4 weeks were occurred the patient was treated Q2W (n=9). The protocol of this trial was approved by local Ethic Committee of our University. The term “efficacy” means at least ACR70 improvement and absence of systemic features.



Results:

The main demographic parameters (Me;IQR) included the age-10.2 (6.0–12.75) years and delay of TCZ-36.0 (11.2–97.0) months. Treatment before TCZ were CS-31 (93.9%), MTX-29 (87.9%), CsA-16 (48.5%) and their combination. The macrophage activation syndrome (MAS) before TCZ was in 8 (24.2%). During the trial CS successfully discontinued 19/31 (61.3), CsA 9/16 (56.3%), MTX 8/29 (27.6%) patients. In 5 children TCZ was discontinued due to stable remission with median duration 640 days (3/5 remission off-medication, 2/5 still on MTX). After TCZ initiation 4 children have experienced MAS, but all of them had MAS before TCZ, so no “new cases” were observed on TCZ. 3 children early withdrew during the trial due to adverse events (infusion reaction, MAS) and 1 child died (severe uncontrolled MAS). Patients which were treated every 4 weeks had milder SJIA course compare with Q2W (table 1). Factors, related with milder SJIA course and allowed to use Q4W TCZ were: Hb>10.3 g/dl (p=0.00001), WBC ≤12.6*109/l (p = 0.013), granulocytes ≤8556 cells/μl (p = 0.00037), CRP ≤82.2 mg/l (p = 0.002), ESR ≤26 mm/h (p = 0.02), ferritin ≤605 mg/ml (p = 0.0001) before start of TCZ and granulocytes in 1 week after 1st TCZ ≤8142 cells/μl (p = 0.014). Criteria, associated with TCZ-off remission were: absence of knee (p = 0.045) and cervical spine involvement (p = 0.03), number of active joints ≤12 (p = 0.05), ESR ≤40 mm/h (p = 0.05), total protein ≤6.6 g/dl (p = 0.04) at the moment of 1st TCZ infusion and granulocytes in 2 week ≤2907/μl (p = 0.038), WBC in 4 week ≤6300/μl (p = 0.026) after 1st TCZ.


Table 1. 	Parameters	Q2W (n = 9)	Q4W (n = 24)	p


a

Me (IQR), Fisher's exact test




	
Hemoglobin, g/dl	9.8 (9.6–10.3)	11,5 (10,9–13,1)	0,003	
Anemia, n (%)	8 (88.9)	10 (41,7)	0,02a	
WBC,a109/l	17.2 (13.6–20.8)	9,5 (7,65–13,2)	0,016	
Granulocytes, cells in 1 μl	13728 (11424–18382)	6318 (4822–8184)	0,005	
Granulocytes in 1 week, cells 1 μl	8944 (6560–12375)	3314 (1840–7240)	0,015	
CRP, mg/l	84.5 (20.6–104.8)	17.6 (6.7–74.5)	0.025	
ESR, mm/h	45.0 (42.0–61.0)	25.0 (10.5–47.5)	0.016	
Ferritin, mg/ml	858.0 (326.0–1859.0)	128.0 (48.5–238.0)	0.004	
LDH, U/l	714.0 (655.5–792.5)	464.0 (360.0–513.0)	0.02	
Total protein, g/dl	6.6 (6.2–6.9)	7.1 (6.8–7.7)	0.003	
Albumin, g/dl	2.1 (1.7–2.6)	3.1 (2.9–3.3)	0.002	
Hepatomegaly	8 (88.9)	9 (37.5)	0.017a	
Coagulopathy	3 (33.3)	0 (0.0)	0.015a	
Interstitial lung disease	4 (44.4)	1 (4.2)	0.013a	
CNS dysfunction	5 (55.6)	0 (0.0)	0.001a	
Knee arthritis	2.0 (2.0–2.0)	1.5 (0.0–2.0)	0.02	
Knee arthritis, n (%)	9 (100.0)	14 (58.3)	0.03a	
MAS before TCZ	4 (44.4)	4 (16.7)	0.17	
MAS during TCZ	4 (44.4)	0 (0.0)	0.003a	
TCZ efficacy, n (%)	6 (66.7)	23 (95.8)	0.05a	
SJIA relapses	4/9 (44.4)	1 (4.2)	0.013a	
TCZ discontinuation. due to:	3 (100.0)	6 (100.0)	0.038	
-remission	0/3 (0.0)	5/6 (83.3)	 	
-infusion reaction	0/0 (0.0)	1/6 (16.7)	 	
-MAS + infusion reaction	2/3 (66.7)	0/6 (0.0)	 	
-MAS death	1/3 (33.3)	0/6 (0.0)	 	



Conclusion:

We found clinical and laboratorial criteria for mild/moderate SJIA allowed to use TCZ Q4W and provisional criteria, related to achievement TCZ-off remission.