The issue of a therapy of children with juvenile idiopathic arthritis (JIA) with intolerance or insufficient effectiveness of methotrexate remains actual. Objective: Our aim was to study the efficacy and safety of tocilizumab in patients with polyarticular JIA. Methods. In a retrospective study, we studied the results of the use of tocilizumab in patients with active polyarticular JIA ( 5 active joints) resistant to prior therapy with methotrexate or a combination of methotrexate with other nonbiologic disease-modifying antiinflammatory drugs. Results. The data of 40 children (83% girls) with the onset median of polyarticular JIA of 4.8 (2.9, 8.1) years and the interval between the disease onset and the initiation of tocilizumab therapy of 5.7 (1.8, 8.5) years was analyzed. Tocilizumab was used as an intravenous infusion of 8 mg/kg (with a weight 30 kg) or 10 mg/kg (with a weight < 30 kg) every 4 weeks. The duration of tocilizumab monotherapy in 5 (13%) children was 1,109 days (452; 1,542). The stages of inactive disease (according to the criteria of C. Wallace, 2004) in 6 months of tocilizumab therapy reached 6 (15%) patients, in 42 months — 32 (80%) patients. In 3 patients, tocilizumab was canceled due to persistent remission. After 6 months of treatment, there was a marked decrease in erythrocyte sedimentation rate, C-reactive protein concentration, number of leukocytes and platelets (in all cases, p < 0.001) to normal values, which persisted throughout the whole period of drug administration. Predictors for achieving inactive disease were the initial (at the onset of tocilizumab therapy) number of peripheral blood leukocytes < 9.0X109/l [relative risk (RR) 1.92; 95% confidence interval (CI) 0.9–4.6)] and the absence of prior biological therapy (RR 1.92, 95% CI 0.9–4.6). The most frequent side effects of tocilizumab therapy were transient hypercholesterolemia (in 13), hypertriglyceridemia (in 4), transient grade II neutropenia (in 1). Conclusion. The long-term efficacy and relative safety of tocilizumab in children with polyarticular JIA have been showed.
Hepcidin - 25-amino acid peptide - is known to be a key regulator of systemic iron metabolism [Ganz T., Nemeth E., 2012]. Hepcidin acts indirectly through ferroportin, which is both a receptor for hepcidin and the only known exporter of iron in the human body [De Falco L. et. al., 2013]. Hyperproduction of hepcidin due to the influence of pro-inflammatory cytokines, especially IL-6, triggers to transport of iron from circulation to the storage, consequently, limiting iron accessibility for erythropoiesis [Weiss G., Goodnought T., 2005]. Thus, overproduction of hepcidin seems to be the leading mechanism of development of anemia in children with Juvenile Idiopathic Arthritis (JIA). A set of negative factors of a chronic disease, particularly disbalance of vitamins, proteins, amino acids and minerals, which are also the known causes, of anemia can weaken control of iron metabolism by hepcidin.
Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) appears in non-remitted fever, cytopenia, coagulopathy, liver and CNS dysfunctions. Triggers of MAS could be disease activity, infections and medications. Known IL-1 is the key cytokine in pathogenesis of MAS and SJIA, and disease flare associated with increased amounts of different cytokines, especially IL-1β. Many cases of MAS are medically-refractory to traditional doses of cytokine inhibition and may require increased dosing of biologic cytokine blockade. Interleukin-1 (IL-1) is typically a key cytokine in the pathogenesis of sJIA and associated MAS. When MAS occurs in the setting of sJIA treated with IL-1 inhibitors, then increased dosing of IL-1 blockers may be beneficial. This has been shown for anakinra, an IL-1 receptor antagonist, but this drug is currently not available worldwide. Another IL-1 blocker, canakinumbab (CKB), is a monoclonal antibody that blocks IL-1β, but does not also block IL-1α like anakinra. Herein, we describe 2 sJIA patients who developed MAS on standard doses of CKB (4 mg/kg). Both patients received an increased dose of CKB: 150 mg (7.5 and 12.5 mg/kg, respectively) with rapid and complete resolution of MAS. Later the CKB doses was tapered to normal regimen. No side effects or adverse events were noticed during usage of increased CKB doses. Increased dosing of CKB should be considered for CKB-treated sJIA patients who develop MAS on standard dosing.
Macrophage activation syndrome (MAS) – is a severe life-threatening hematological condition, mostly complicated systemic juvenile idiopathic arthritis (SJIA). Early detection of MAS can lead to appropriate therapeutic interventions and change the outcomes. There are no strict criteria for early MAS detection in SJIA. Currently applied HLH criteria can determinate only advanced stage of MAS, which lead to delay diagnosis, late start of specific treatment and associated with poor outcomes. There are several sets of preliminary criteria of MAS in SJIA.
Background: Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA). Usually uveitis developed during first two years after arthritis occurred [1]. In the previous studies was shown the shorter time interval between arthritis and uveitis the severe uveitis course was observed [2]. Information about course of uveitis developed before arthritis is scarce. Objectives: We aimed to evaluate the clinical features and therapy of JIA-associated uveitis, which developed before and after joint manifestation. Methods: In the retrospective study 191 pediatric autoimmune uveitis included. The onset age ranged from 1 to 17 years. We evaluated differences in clinical, laboratorial and treatment differences between groups, i) where uveitis developed before (n=58) and ii) after (n=133) arthritis. Chronic autoimmune uveitis without joint manifestations was excluded. Results: Uveitits before arthritis developed in 58 (30.4%) cases. Patients whom uveitis developed before arthritis had were elder and characterized equal gender involvement, rare ANA positivity, and rare use of immunosupression, e.g. corticosteroids, biologics and methotrexate, due to treatment by ophthalmologist predominantly. Patients developed uveitis before arthritis received biologics earlier due to severity of uveitis (LogRank test, p=0.016, HR=1.97 (95%CI: 1.3; 3.1, p=0.004). Data are in the Table 1 and Figure 1. Conclusion: Patients with JIA associated uveitis with initial ocular presentation demonstrated more severe course and delayed diagnostics and treatment due to lack of contacts with pediatric rheumatologist. Cooperation between ophthalmologist and pediatric rheumatologist is strictly required in all cases with chronic anterior uveitis. Table 1. Table 1. Parameter Uveitis before arthritis (n=58) Uveitis after arthritis (n=133) p Sex, female 32 (55,2) 97 (72,9) 0.016 Onset age, years 6.7 (4.6; 10.2) 3.2 (2; 6.1) 0.000001 JIA category Oligoarthritis 41 (70.7) 84 (63.6) 0.174 Polyarthritis 9 (15.5) 36 (27.3) Enthesytis-related arthritis 8 (13.8) 12 (9.1) Type of uveitis Anterior 44 (75.9) 111 (84.1) 0.315 Peripheral 3 (5.2) 2 (1.5) Posterior 3 (5.2) 3 (2.3) Panuveitis 8 (13.8) 16 (12.1) Unilateral uveitis, n (%) 19 (32.8) 48 (36.1) 0.632 ANA posititivity, n (%) 25/54 (46.3) 72/110 (65.5) 0.019 HLA B27 positivity, n (%) 8/35 (22.9) 13/62 (21.0) 0.828 Methotrexate, n (%) 3 (5.2) 57/132 (43.2) 0.0000001 Systemic corticosteroids, n (%) 3 (5.2) 44/131 (33.6) 0.00003 Biologic, n (%) 26 (44.8) 88 (66.2) 0.006 ESR, mm/h 19.0 (4.0; 25.0) 23 (15.0; 32.0) 0.095 CRP, mg/l 97.0 (0.1; 107.5) 8.1 (0.9; 57.4) 0.493 Time between arthritis and uveitis, years 2.7 (0.9; 4.3) 4.0 (2.0; 7.1) 0.016 Time before biologic, years 2.5 (0.9; 3.5) 1.3 (0.5; 5.0) 0.462 This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001). References: [1]Verazza S, et al. Pediatr Rheumatol Online J 2008;6(Suppl 1):77. [2]Zannin ME, et al. Acta Ophthalmol 2012;90:91-5. Disclosure of Interests: None declared Figure 1.
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.
Systemic corticosteroids are continued to be administered in juvenile idiopathic arthritis (JIA) patients, especially in systemic JIA (sJIA), despite the ability of biologic therapy. One of the complications of long-term CS treatment is delayed hip arthritis development with risk of secondary hip osteoarthritis formation and total hip arthroplasty (THA).We compared different types of hip joint lesions in JIA, especially, secondary hip osteoarthritis development and THA rates in systemic and non-systemic JIA, and evaluate systemic corticosteroids contribution to those complications.The study included 753 JIA patients. They were divided into 2 groups: patients with sJIA and non-systemic JIA (nsJIA). Clinical and demographic characteristics, CS treatment regimens were compared. Results. Hip arthritis was found equally often in both groups, but both secondary hip osteoarthritis (19% vs 5,3%) and THA (8.6% vs 1.6%) prevailed in the sJIA. Patients with sJIA had delayed hip involvement (57.9% vs 30.6%; p=0.019), earlier secondary hip osteoarthritis development (4.5 vs 5.1 years after the JIA onset) with younger age of secondary hip osteoarthritis achievement (13.7 vs 15.2 years; р=0.045), they also had higher inflammatory activity, greater systemic corticosteroids administration (94.8% vs 56.1%; р=0.0000001) and higher cumulative systemic corticosteroids dose (3085 mg vs 2000 mg; p=0,005). More than half patients (56.1%) with nsJIA had systemic corticosteroids treatment and impaired calcium-phosphorus metabolism. Conclusion. Systemic corticosteroid treatment and delayed hip involvement are independent predictors of secondary hip osteoarthritis in all JIA categories. Calcium and phosphate metabolism disturbances are additional predictor for secondary hip osteoarthritis in non-systemic JIA categories
