Abstract Objectives The purpose of our study was to detect early clinical and laboratory signs that help to discriminate macrophage activation syndrome (MAS) from active systemic juvenile idiopathic ...arthritis (SJIA) without MAS. Methods Our retrospective study was based on reviewing the medical charts of the children admitted to the rheumatology department with active SJIA and definite MAS ( n = 18) and without MAS ( n = 40). We evaluated the data related to SJIA and MAS at the moment of the patient׳s admission. If the patient had signs of MAS since admission or developed definite MAS later during this flare, he was referred to the main group. The children who did not have MAS during the flare episode and did not have MAS in the past medical history were in the control group. We calculated the cutoff points for MAS parameters, performed the analysis of sensitivity and specificity, identified the predictors, and provided the preliminary diagnostic rule through “the-number-of-criteria-present” approach. Results The clinical signs were relevant to MAS in SJIA: oligoarticular disease course (OR = 5.6), splenomegaly (OR = 67.6), hemorrhages (OR = 33.0), and respiratory failure (OR = 11.3). The involvement of wrist (OR = 0.2), MCP (OR = 0.1), and PIP joints (OR = 0.1) was protective against MAS development. The best cutoffs for laboratory parameters were PLT ≤ 211 × 109 /l, WBC ≤ 9.9 × 109 /l, AST > 59.7 U/l, LDH > 882 U/l, albumin ≤ 2.9 g/dl, ferritin > 400 μg/l, fibrinogen ≤ 1.8 g/l, and proteinuria. The laboratory variables were more precise in the discrimination of early MAS than clinical: any 3 or more laboratory criteria provided the highest specificity (1.0) and sensitivity (1.0) and OR = 2997. Conclusions We detected clinical and laboratory markers and created preliminary diagnostic (laboratory) guidelines for early discrimination of MAS in active SJIA.
Objectives:
To describe the clinical characteristics of hip involvement in juvenile idiopathic arthritis (JIA) from arthritis to hip osteoarthritis (HOA) and total hip arthroplasty (THA).
Study ...Design:
Seven hundred fifty-three patients aged 2–17 years with JIA were included in the study. The comparison analysis was performed between the following subgroups: (i) JIA without hip involvement (
n
= 600; 79.7%) vs. JIA with hip involvement without HOA (
n
= 105; 13.9%), (ii) JIA with hip involvement with HOA, but without THA (
n
= 32; 4.3%) and JIA with hip involvement with HOA and with THA (
n
= 16; 2.1%). Clinical, laboratory characteristics and treatment regimens compared.
Results:
Hip involvement was present in 20.3% of patients. HOA was present in 6.4% (12
*
1,000 patient-years) of the entire JIA group and 31.4% of patients with hip involvement. Sixteen patients (2.1%; 4.0
*
1,000 patient-years) required THA. The following factors were associated with HOA: sJIA (OR = 3.6,
p
= 0.008; HR = 3.0,
p
= 0.002), delayed remission (OR = 4.2,
p
= 0.004; HR = 1.4,
p
= 0.538), delay in biologic therapy initiation (OR = 7.5,
p
= 0.00001; HR = 6.7,
p
= 0.002), alkaline phosphatase <165 U\l (OR = 4.1,
p
= 0.0003; HR = 5.2,
p
= 0.000004), treatment with corticosteroids (CS) (OR = 2.6,
p
= 0.008; HR = 1.2,
p
= 0.670), cumulative corticosteroids >2,700 mg (OR = 4.3,
p
= 0.032; HR = 1.4,
p
= 0.527). The following factors were associated with THA: delay in biologic treatment initiation (OR = 1.04,
p
= 0.0001; HR = 9.1,
p
= 0.034), delayed hip involvement (OR = 5.2,
p
= 0.002; HR = 3.0,
p
= 0.044), and methylprednisolone pulse therapy (OR = 10.8,
p
= 0.0000001; HR = 5.6,
p
= 0.002).
Conclusion:
Both sJIA and systemic CS, impaired calcium-phosphorus metabolism, and delayed hip arthritis are associated with HOA development in JIA. HOA is considered to be a severe adverse event of CS treatment, especially delayed hip involvement.
JAK-inhibitors are small molecules blocking the JAK-STAT pathway that have proven effective in the treatment of different immune-mediated diseases in adults and juvenile idiopathic arthritis (JIA).
...To evaluate the safety and efficacy of tofacitinib in children with different rheumatic diseases.
We extracted information from 24 children with the following diagnosis: JIA (
= 15), undifferentiated systemic autoinflammatory diseases (SAIDs) (
= 7), and juvenile dermatomyositis (JDM) (
= 2) who have been treated with tofacitinib for a period of longer than 6 months. The treatment outcomes were classified according to the opinion of the attending physicians as having a complete response (CR), i.e., the absence of disease activity, or a partial response (PR)-a significant improvement of symptoms and disease activity, or no response (NR)-no changes in disease activity.
CR was achieved in 10/24 patients; 7/15 among JIA patients, 1/2 among JDM patients, 4/7 among SAID patients, and PR in 5/15 of JIA, 1/2 of JDM, and 3/7 of SAID patients. Three non-responders with JIA discontinued tofacitinib. Corticosteroids were successfully tapered off in 11/14 patients and discontinued in 2/14 patients. Four patients had side effects not requiring treatment discontinuation: liver enzyme elevation (
= 2), hypercholesterolemia (
= 1), lymphadenitis (
= 1).
JAK-inhibitors are effective new therapies for the treatment of multiple immune-mediated diseases. Our experience has shown the best results in patients with JIA and JIA-associated alopecia, and type I interferonopathies. More data from randomized controlled clinical trials are needed to use JAK-inhibitors safely in pediatric rheumatic diseases.
Chronic nonbacterial osteomyelitis (CNО) and tuberculous osteomyelitis (TBO) are both primarily chronic inflammatory bone diseases with similar clinical and radiological findings, but entirely ...different in aetiology, pathogenesis, treatment, and outcomes. Our study aimed to evaluate the clinical and laboratory features which could discriminate the CNO and TBO. The study included 124 patients—91 with CNO and 33 with TBO. All patients underwent routine blood tests: WBC, platelets, ESR, C-reactive protein, haemoglobin, and imaging. The ability of each variable to discriminate CNO from TBO was evaluated with sensitivity and specificity analysis, AUC-ROC analysis, and calculating the odds ratio. Patients with TBO had less number of bone foci (
p
= 0.0000001), onset age (
p
= 0.00001), rarely articular involvement (
p
= 0.01), lower haemoglobin level (
p
= 0.02), higher incidence of TBO in the male subjects (
p
= 0.002), and higher leukocyte bands (
p
= 0.0000001). TBO is rarely characterized by spine (
p
= 0.0009), foot (
p
= 0.01), and clavicula (
p
= 0.047) involvement. The diagnostic rule: criteria allowing to differentiate NBO from TBO are negative bone microbiota tests (sensitivity—100.0%, specificity—100.0%) or major discriminative criteria or clavicula involvement alone (sensitivity—11.0%, specificity—100.0%) and at least four from the five additional criteria: number of foci > 1.0 (
p
= 0.00002), WBC ≤ 11.0 (
p
= 0.004), neutrophil bands ≤ 120.0 × 106/l (
p
= 0.002), lymphocytes ≤ 52% (
p
= 0.0005), and CRP > 0.2 mg/l (
p
= 0.003). All patients with monofocal CNO required bone biopsy with microbiology assessment. The created provisional criteria may help to discriminate TBO and CNO and should be used only with other known diagnostic tools.
Key Points
•
Nonbacterial osteomyelitis and tuberculous osteomyelitis are both primarily chronic inflammatory bone diseases with similar presentations.
•
Nonbacterial osteomyelitis and tuberculous osteomyelitis may be associated with other immune-mediated diseases.
•
Only bone biopsy can confirm and discriminate both conditions. All patients with monofocal CNO required bone biopsy with microbiology assessment.
Objective
Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal condition associated with systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) is a key cytokine ...in the pathogenesis of sJIA MAS. Many cases of MAS are medically refractory to traditional doses of biologic cytokine inhibitors and may require increased dosing. When MAS occurs in the setting of sJIA treated with the IL-1 receptor antagonist (IL-1Ra), anakinra, increased anakinra dosing may be beneficial. Increased dosing of another IL-1 inhibitor, canakinumab, a monoclonal antibody to IL-1β, has not been reported to treat refractory MAS in the setting of sJIA.
Methods
Retrospective data collection extracted from the electronic medical record focused on canakinumab usage and dosing in 8 children with sJIA who developed MAS at a single academic center from 2011 to 2020.
Results
Eight sJIA children (five girls) with median age 8.5 years (range, 0.9–14.2 years) were included in the present study. Five children developed MAS at disease onset and three during ongoing canakinumab therapy. MAS resolved in all eight children with canakinumab treatment. When the canakinumab dosing was insufficient or MAS developed during canakinumab therapy, the dosing was temporally up-titrated (four patients, maximum 300 mg per dose) without observed side effects.
Conclusion
This report provides evidence for the efficacy and safety of short-term increased doses (2–3-times normal) of canakinumab in treating sJIA associated MAS. Further study of the efficacy and safety of increased doses of canakinumab for treatment of MAS in children with sJIA is warranted.
Multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) is a life-threatening condition that often requires intensive care unit (ICU) admission. The aim of this study was to ...determine risk factors for severe/life-threatening course of MIS-C. The study included 166 patients (99 boys, 67 girls) aged 4 months–17 years (median 8.2 years). The criterion of severity was the fact of ICU admission. To conduct a comparative analysis, MIS-C patients were divided into two groups: patients hospitalized in the ICU (n = 84, 50.6%) and those who did not need ICU admission (n = 82, 49.4%). Patients with a more severe course of MIS-C were significantly older. They had a higher frequency of signs such as rash, swelling, hepatomegaly, splenomegaly, and neurological and respiratory symptoms. Hypotension/shock and myocardial involvement were much more common in patients with severe MIS-C. These patients had a more significant increase in CRP, creatinine, troponin, and D-dimer levels. Additionally, the presence of macrophage activation syndrome was higher in patients admitted to the ICU. Conclusion: Nineteen predictors of severe course of MIS-C were found, out of which hepatomegaly, splenomegaly, D-dimer > 2568 ng/mL, troponin > 10 pg/mL were mainly associated with the probability of being classified as early predictors of severe MIS-C requiring ICU admission.
The aim of our study was to evaluate disease courses and outcomes of sJIA children undergoing tocilizumab (TCZ) treatment, and to establish the predictors which distinguish inactive disease and ...disease flares.
Our retrospective study included 48 active sJIA children who were refractory to different anti-rheumatic drugs and who were then started on TCZ. The effectiveness of TCZ was assessed by the changes of sJIA attributed signs and symptoms and the remission was judged according to the Wallace (2004) criteria.
The main demographic parameters (Me; IQR) were shown; mean age: 9.9 (5-12.7) years and mean duration of TCZ administration: 27.0 (5.9-89.7) months. During the TCZ treatment 40 cases (83.3%) achieved remission in 138.5 (56.0; 255.0) days. Patients who achieved remission had milder disease course, and presented less frequent epatosplenomegaly, lung, heart involvement and MAS. They had higher Hb and lower WBC, granulocytes, ESR, CRP, LDH, ferritin. The main predictors of achievement of inactive disease, calculated with Cox-regression models, were CRP≤82.0 mg/l (OR=7.9, HR=1.17), ESR≤32 mm/h (OR=17.0, HR=0.85), ferritin ≤273 ng/ml (OR=56.5, HR=2.6), Hb>113 g/l (OR=17.0, HR=1.33), LDH≤676 U/l (OR=113.6, HR=3.2), PLT>335*109/l (OR=5.0, HR=2.5), and intensive depression of WBC in 2 weeks after the 1st TCZ infusion>11% (OR=13.0, HR=6.0) and granulocytes>12% (OR=14.0, HR=4.7).
sJIA children with milder disease course have more posssibilty of achieving disease remission during TCZ treatment. Male sex, signs of high disease activity, previous CS treatment, the long time needed to achieve inactive disease and treatment protocol deviations increased the risk of sJIA flare.
Hemophagocytic syndrome is a key point in the pathogenesis of severe forms of multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C). The factors associated with ...hemophagocytosis in patients with MIS-C were assessed in the present study of 94 boys and 64 girls ranging in age from 4 months to 17 years, each of whose HScore was calculated. In accordance with a previous analysis, patients with HScore ≤ 91 (
= 79) and HScore > 91 (
= 79) were compared. Patients with HScore > 91 had a higher frequency of symptoms such as cervical lymphadenopathy, dry cracked lips, bright mucous, erythema/swelling of hands and feet, peeling of fingers, edematous syndrome, hepatomegaly, splenomegaly, and hypotension/shock. They also had a higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and D-dimer levels, and a tendency to anemia, thrombocytopenia, and hypofibrinogenemia. They more often needed acetylsalicylic acid and biological treatment and were admitted to ICU in 70.9% of cases. Conclusion: The following signs of severe MIS-C were associated with HScore > 91: myocardial involvement, pericarditis, hypotension/shock, and ICU admission.
Lung damage in systemic juvenile arthritis (sJIA) is one of the contemporary topics in pediatric rheumatology. Several previous studies showed the severe course and fatal outcomes in some patients. ...The information about interstitial lung disease (ILD) in the sJIA is scarce and limited to a total of 100 cases.
To describe the features of sJIA patients with ILD in detail.
In the present retrospective cohort study, information about 5 patients less than 18-years-old with sJIA and ILD were included. The diagnosis of sJIA was made according to the current 2004 and new provisional International League of Associations for Rheumatology criteria 2019. ILD was diagnosed with chest computed tomography with the exclusion of other possible reasons for concurrent lung involvement. Macrophage activation syndrome (MAS) was diagnosed with HLH-2004 and 2016 EULAR/ACR/PRINTO Classification Criteria and hScores were calculated during the lung involvement.
The onset age of sJIA ranged from 1 year to 10 years. The time interval before ILD ranged from 1 mo to 3 years. The disease course was characterized by the prevalence of the systemic features above articular involvement, intensive rash (100%), persistent and very active MAS (hScore range: 194-220) with transaminitis (100%), and respiratory symptoms (100%). Only 3 patients (60%) developed a clubbing phenomenon. All patients (100%) had pleural effusion and 4 patients (80%) had pericardial effusion at the disease onset. Two patients (40%) developed pulmonary arterial hypertension. Infusion-related reactions to tocilizumab were observed in 3 (60%) of the patients. One patient with trisomy 21 had a fatal disease course. Half of the remaining patients had sJIA remission and 2 patients had improvement. Lung disease improved in 3 patients (75%), but 1 of them had initial deterioration of lung involvement. One patient who has not achieved the sJIA remission had the progressed course of ILD. No cases of hyper-eosinophilia were noted. Four patients (80%) received canakinumab and one (20%) tocilizumab at the last follow-up visit.
ILD is a severe life-threatening complication of sJIA that may affect children of different ages with different time intervals since the disease onset. Extensive rash, serositis (especially pleuritis), full-blown MAS with transaminitis, lymphopenia, trisomy 21, eosinophilia, and biologic infusion reaction are the main predictors of ILD. The following studies are needed to find the predictors, pathogenesis, and treatment options, for preventing and treating the ILD in sJIA patients.
Background: The causative agent of the new coronavirus infection SARS-CoV-2 has unique properties causing hyperinflammatory syndrome and cytokine storm, as well as widespread endotheliitis and ...thrombotic microangiopathy, initially detected in the lungs of adult patients who died from a severe form of the disease. Venous and arterial thrombosis in adults were identified as common causes of severe complications and deaths in new coronavirus infections. There are very few reports of thrombotic events in children with COVID-19 in the literature. Methods: We conducted a retrospective analysis of the histories of 60 patients in the Irkutsk Regional Children’s Clinical Hospital from November 2020 to November 2022 with a MIS-C diagnosis established according to WHO criteria, of which 8 (13.3%) were diagnosed with venous and/or arterial thrombosis, confirmed by laboratory and ultrasound and/or X-ray methods. Results: The average age of children with thrombosis (Me) was 7.5 years (min 4 months, max 17 years), with a M:F ratio of 3.0. Venous thrombosis was detected in six of the eight patients, including in the deep veins of the lower extremities in four. Pulmonary embolism occurred in two (one of them was fatal), and cerebral venous sinus thrombosis and thrombosis of the branches of the upper and lower vena cava were found in one patient. Extensive bilateral stroke due to thrombosis of the large cerebral arteries occurred in two patients, including one in combination with distal gangrene. Secondary thrombotic renal microangiopathy took place in three of the eight patients. Among these three, atypical HUS was diagnosed in one case. Multiple thrombosis involving the venous and arterial bed was detected in four of the eight patients. High levels of D-dimer, thrombocytopenia, increased NT-proBNP, cerebral coma, and aseptic meningitis were the events most often associated with thrombosis. All patients received immunomodulatory therapy (immunoglobulin, dexamethasone/methylprednisolone), pathogenetic therapy for multiorgan failure, anticoagulant therapy with heparin/LMWH, and acetylsalicylic acid. Biologics were used in two patients. Conclusions: The main predictors of thrombosis in children with MIS-C were increased D-dimer, thrombocytopenia, hospitalization in the ICU, and noncardiogenic pulmonary edema. Thrombosis of the deep veins of the lower extremities, large cerebral arteries, and secondary thrombotic microangiopathy was common. There was a single death (12.5% of the eight patients), associated with PE.
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