Objective: to assess the possibility of using varying interval between intravenous infusions of tocilizumab (TCZ) as a tool for choosing the optimal treatment regimen in systemic juvenile arthritis (SJA).Subjects and methods. The observational retrospective study included 72 patients (29 boys and 43 girls) with a SJA fulfilled ILAR criteria, who received TCZ ≥12 months, in which previous therapy with various anti-rheumatic drugs was ineffective. We studied the changes of the main clinical and laboratory parameters of the SJA activity after correction of the interval between infusions.Results and discussion. In the studied group median age of onset was 3.8 [2.1; 5.9] years, duration of disease before the appointment of TCZ – 26.5 [9.25; 62.25] months. Therapy is continued by 70 patients, the median duration of therapy is 5.0 [2.75; 6.38] years. The initial interval between TCZ infusions was 2 weeks in 49 (group 1) and 4 weeks in 23 patients (group 2). After 6 months of therapy in group 2, the interval was reduced to 2 weeks in 15 (65.2%) patients due to decreased effectiveness. Prolongation of the period between the introduction of TCZ in patients of group 1 who did not reach the inactive status of the disease in the 1st year of the disease resulted in a significant increase of erythrocyte sedimentation rate, C-reactive protein level and exacerbation of systemic manifestations of SJA (p<0.01) in the absence of statistically significant changes of joint status parameters (p>0.05). 40% of these patients had involvement of «new» joints, including hip joints. «Harbingers» of exacerbation in the period of increasing intervals between infusions were: arthralgia (88%), myalgia (65%), sore throat (30%), dysphoria (50%, more often in preschool children), increase of ferritin level and number of leukocytes. In 90.3% of patients who have reached the inactive status of the disease, it was possible to gradually increase the interval between infusions. In 6 patients, TCZ was canceled by gradually increasing the intervals, in 4 of them, therapy was resumed at an initial interval of 2 weeks after 3, 6, 21 and 22 months, respectively, in two patients, a drug-free remission was maintained during 23 and 20 months. Reduction of intervals to the initial 2 weeks was performed in 13 (18.1%) patients. The development of exacerbations with the need to reduce the interval to the initial one was most often observed at 24–35 months of therapy, which chronologically coincided with the period of active growth. Currently, 15 patients receiving TCZ with an interval of 5–6 weeks, and 40 – with an interval of 4 weeks, 9 patients – 3 weeks, in 6 patients attempt to increase the interval to more than 2–2,5 weeks was unsuccessful.Conclusion. Experience suggests the need to comply with a two-week interval between infusions of TCZ at the initial stage of therapy in most patients with SJA until the inactive stage of the disease, followed by a smooth individual increase in the interval to 4 weeks (2–3 days under careful medical supervision). Appearance of initial signs of exacerbation, requires to reduce the interval to 2 weeks. Before deciding on the complete withdrawal of TCZ, it is advisable to increase the interval between infusions to 5–6 weeks under careful clinical and laboratory control.
Background It is known that Tocilizumab (TCZ) is effective option in systemic Juvenile idiopathic arthritis (sJIA). NNZ had “off label” status for children in Russia till December 2011, but with Ethics Committee approvement it used in clinical practice for most seriously affected sJIA patients (Pts). Objectives To analyzed effects of TCZ on activity and other disease features in Ptswith active sJIA, who were received TCZ in our clinic from Nov 2009 to Jan 2012. Methods TCZ was indicate to 23 Pts with sJIA (11 boys, 12 girls; mean age of 8.96, range 1.6–17.6 yrs; mean disease duration of 5.5, range 0.3–11,75 yrs) who had persistent disease activity in spite of adequate treatment, included NSAID, steroids, DMARDs (methotrexate (MTX) alone–7; MTX in combination with cyclosporine or leflunomide–16). After starting TCZ therapy second DMARD was cancelled andMTX therapy was continued in all children. 9 Pts were previously treated by biologics (7- TNF-inhibitors; 2-rituximab). Ongoing steroids was used in 19 Pts (meanprednisone dose - 0.35mg/kg/day, range 0,11–0.68), NSAIDs recievedall Pts. At baseline 22 Pts had active arthritis (mean number of active joints 14, range 3–30), 18 - systemic features, all Pts had high laboratory activity (mean CRP 108.25 mg/l, range 14.9-223 mg/l). We began TCZ use in a dose of 8 mg/kg intravenously every 4 weeks according to indications for adult RA patients. At 7 Pts the disease flare has developed for 15-20 day after infusion, therefore an interval have reduced till 2 weeks, the dose has been increased to 10-12 mg/kg. Results The ACR Pedi 30,50,70,90 responds were achieved by 96%,48%,9%,0% of Pts at Week 4 (n=23), by 87%,87%,40%,7% at Week 12 (n=12), by 100%,92%,75%,17% at Week 24 (n=12), by 100%,100%,70%,30% at Week 52 (n=10), by 100%,100%,100%,83% at Week 76 (n=6), by 100%,100%,100%,80% at Week 104 (n=5) respectively. Systemic features and CRP level responded rapidly within few days, the arthritis responded later. Steady improvemaent allowed to decrease prednisolone dose inall Pts. Neutropenia was observed in 2 children during 2-3 days after infusion, but it was recovered without treatment. Growth increasing reached 5.56±2.9 cm/year (range 3-11) in Pts receiving TCZ longer than 1 year. 4 Pts had worsening of hip damage by X-ray, however at 1 patient we found X-ray improvement similar to that described by other authors (ref.1). We have also observed some unexpected effects: allergic reaction (acute urticaria during 2nd infusion in 2 Pts, Quincke’s edema during 3rd infusion - 1); non-durable sore throat on the 2nd day after infusion - 3. 3 Pts had symptoms of dramatic disease flare on 2-3 days after infusion (increasing of poliarthritis, rash, leucocytosis to 36000), state improved without treatment during 1-2 days. 2 children put the weight on (+31% and +84% added during 2 years). Conclusions TCZ therapy is able to produce physical and emotional well-being of children with sJIA even in case of a very longstanding disease. In some Pts we have observed two types of disease flare - a ...
BackgroundBiological agents (BA) are high efficacy options for current therapy for patients (pts) with juvenile idiopathic arthritis (JIA). They are successfully used not only for the arthritis but also for uveitis, psoriasis and inflammatory bowel disease (IBD). However, paradoxical induction of these conditions in pts treated with BA is a well-established phenomenon.ObjectivesTo evaluate the frequency of new onset of uveitis, psoriasis or IBD occurring under BA therapy in JIA pts, to establish clinical features, which may be associated with development of such effects.MethodsRetrospective cohort study involved all JIA pts (740) who were treated with BA in our clinic from 2004 to 2016. All cases of new onset (no)-uveitis/psoriasis/IBD collected; clinical features of disease onset and course, activity level, JIA category, exposure to Methotrexate (MTX) and BA, presence of ANA, HLA B27 were studied.ResultsWe identified 20 (2.7%) pts (11 female/9 male) with no-uveitis under BA, mostly during etanercept (ETA) therapy (18 cases from 285 ETA courses, 6.3%), 1/112 - in abatacept (ABA) and 1/233 - in adalimumab (ADA); 2.46 events/100 patient-year (PY) vs 0.31 in ABA, and 0.15 in ADA), ETA exposure was 14.9±9.9 months (mo). JIA subtypes were as follows: RF-neg polyarthritis 5 (25%), persistent oligoarthritis 3 (15%), extended oligoarthritis 10 (50%) ERA - 2 (10%). JIA started in this group at the age of 4.5±3.9 yrs.18/20 patients had high laboratory activity (CRP 55±25 mg/l) and severe arthritis before BA initiation. Most of pts (16/20) achieved 90–100% ACRpedi-response by the uveitis development. 1 pt was treated by ADA for the 71 mo and switched to ABA. in 1 pt no-uveitis was obseved under ABA. 12/20 pts were ANA-positive, 10/20 pts had HLAB27, 1 pt did not have ANA or HLAB27. Uveitis was occurred earlier in ANA plus B27 positive pts (mean exposure - 10.7 mo vs 27.4 in ANA+ and 21.6 in B27+ pts). 17/20 (85%) of pts received MTX. In all cases of no-uveitis BA was switched. 5 pts from 740 (0.7%) developed no-psoriasis under BA: INF - 2 cases (0.62/100PY), ADA - 2 (0.15/100PY), ABA -1 (0.31/100PY). JIA subtypes were presented by RF-negative polyarthritis (1), extended oligoarthritis – 3. All received MTX. 1/5 pts was ANA+, 2/5 - HLAB27+. Average age of disease onset was 9.8±7.8 years; BA exposure before psoriasis was 25±11.5 mo. Therapy was continued in 3/5 pts; switched from INF to ADA in 2. Only 1 case of no-IBD was occurred in female patient fulfilled to systemic-onset JIA criteria years. She was treated by INF for the 62 months and switched to ADA due to secondary inefficiency presented by active polyarthritis and sacroiliitis (HLAB27neg), but 2 months later severe gastrointestinal symptoms appeared and diagnosis of Crohn's disease was established by endoscopy.ConclusionsOur study suggested that new onset of uveitis, psoriasis and IBD is rare adverse event during BA therapy in JiA. It seemes to be as delayed implication of disease natura. but not therapy complication. Uveitis observed mostly in pts receiving ETA, unlik...
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