Тоцилизумаб в лечении детей с системным вариантом ювенильного артрита: анализ факторов, влияющих на эффективность терапии в долгосрочном периоде

BackgroundInterleukin-1 inhibitor Canakinumab (a humanized anti- Il-1β monoclonal antibody) is gaining wider use in Russian clinical practice recently for treatment of auto-inflammatory diseases (AIDs). Experience with Canakinumab for systemic juvenile idiopathic arthritis (SoJIA), considered as AIDs, is being accumulated as first and second line biologic agents therapy. In Russia Canakinumab was initially marketed in 2011 for cryopyrin-associated periodic syndromes (CAPS), in 2013 – for SoJIA.ObjectivesTo assess efficacy and tolerability of Canakinumab in AIDs and SoJIA patients in clinical practice.MethodsUse Canakinumab at our Institute was commenced in 2012 y. The study included 19 pts, among them 12 had AIDs (including CAPS – in 8 pts: MWS – in 6, and CINCA/NOMID- in 2 pts; TRAPS - in 3 pts; Schnitzler syndrome – in 1), 7 pts had SoJIA. Among AIDs pts there were 7 females and 5 males, 9 pediatric and 3 adult pts, 2 pts from pediatric population getting adult by the time of analysis. Mean AIDs pts age at inclusion was 18,6 y (3–44), infantile disease onset was recorded in 9 pts, in 6 out of them – it was a neonatal onset from the moment of birth. Two familial MWS cases were included. Disease duration ranged from 3 to 44 years. Genetic mutations were established in 9 pts, including: gene NLRP3- 6 (Thr436Ile, Thr438Ile, Thr350Met – in 4 pts (two familial cases)), gene TNFRSF1A - 3 (His51Tyr, Cys59Arg, Cys99Arg). All AIDs pts presented with rash, fever, conjunctivitis or uveitis (8), neurosensory deafness (4), arthritis symptoms (9), lymphadenopathy (7), CNS involvement in 2, abdominal pain (5), stomatitis (4), physical retardation in CINCA/NOMID pts, intellectual retardation and cognitive impairment in 1 patient. SoJIA pts were aged 3,5 -17,5 y.o. predominantly males (5), with disease duration 1 - 16 y. All pts presented with systemic manifestations, 4 pts had severe polyarthritis. Increased levels of acute phase markers were documented in all pts. Canakinumab efficacy was estimated based on changes in ESR, CRP and WBC count vs baseline.ResultsCanakinumab was administered s/c at 2–4mg/kg (max 150 mg) once every 8 weeks in AIDs pts, and at 4–6mg/kg (max 300mg) once in every 4 weeks in SoJIA pts. Canakinumab therapy duration in AIDs pts varied from 3mo to 2,5y, in SoJIA pts – from 9mo to 4y. Rapid clinical improvement was documented in all pts, with resolution of systemic manifestations and normalizing levels of acute phase markers. Prolonged ESR and CRP normalization was observed in one CINCA/NOMID patient. In 4 SoJIA pts arthritis manifestations were not sufficiently controlled. Canakinumab tolerability was satisfactory in all AIDs and SoJIA pts. No serious adverse reactions were documented. Canakinumab discontinuation in one SJIA patient was associated with secondary drug failure and onset of macrophages activation syndrome (MAS).ConclusionsThe single Federal Center experience with Canakinumab in clinical practice in AIDs and SoJIA pts demonstrated high efficacy and good tolerability of this medication. No seri...

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Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a significant genetic predisposition. Recent studies have identified STAT4 (signal transducers and transcription activators 4) as a susceptibility gene for SLE.Objectives:To investigate the hypothesis of the association of STAT4 rs7574865 G/T polymorphism with the predisposition to SLE in children and its relationship with some of SLE manifestations.Methods:The case-control pilot study included 143 children (39 with SLE and 103 healthy unrelated volunteers as a control group). Diagnosis of SLE was based on 2012 SLICC criteria. STAT4 rs7574865 G/T polymorphism was investigated using allele-specific real-time polymerase chain reaction (RT-PCR).Results:The group of pts with SLE consisted of 29 girls and 10 boys, with an average age of 11.8±3.7 years (from 3 to 17 years) and an average disease duration of 4.1±2.4 years. 79.5% pts had acute cutaneous lupus at the onset, 46.1% - nonscarring alopecia, 71.8% - arthritis, 23.1% - oral and nasal ulcers, 23.1% - serositis, 43.6% - renal involvement, 35.9% –neuropsychiatric disorders. Leucopenia/lymphopenia was found in 71.8% of pts, thrombocytopenia – in 23,1%. ANA were detected in 100% pts, anti-dsDNA – in 79.5%, anti-Sm – in 31.6%, antiphospholipid antibodies - in 7,3%, hypocomplementemia – in 61.5%, positive direct Coombs test – in 35.9 %. Macrophage activation syndrome at the onset was documented in 15.4 % of pts. The distribution of rs7574865 genotypes in the control group showed no significant deviations from the Hardy-Weinberg equilibrium. The distribution of genotype frequencies among pts had statistically significant differences compared to the control (χ2=12.95, p=0.0015): GG-30.8% and 63.1% (p=0.001), GT-56.4% and 33.0% (p=0.018), TT-12.8% and 3.9% (p=0.114), GT+TT - 69.2% and 36.9% (p=0.0005). The frequency of the mutant STAT 4 allele T (polymorphism), was significantly higher in the SLE group than in the control group (41% and 20.4%, respectively; p=0.0007). We identified an association of the T allele with some clinical, laboratory, and immunological disorders in SLE: arthritis (OR 3.9, p=0.0002), acute cutaneous lupus (OR 2.47, p=0.003), nonscarring alopecia (OR 3.12, p=0.002), renal involvement (OR 2.42, p=0.022), leucopenia (OR 2.72, p=0.003), thrombocytopenia (OR 4.88, p=0.002), anti-dsDNA (OR 2.82, p=0.0006), hypocomplementemia (OR 2.34, p=0.012), positive direct Coombs test (OR 3.38, p=0.002).Conclusion:Our pilot study confirmed that the STAT4 rs7574865 G/T polymorphism was associated with the risk of SLE in children and some of SLE manifestations.Disclosure of Interests:None declared