Objective
Wegener's granulomatosis (WG) is a predominantly small‐vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). There are few reports describing its clinical ...features and outcome in children. We report on the experience at a single tertiary referral center over 21 years.
Methods
We conducted a retrospective chart review of all patients diagnosed with WG at The Hospital for Sick Children between 1984 and 2005.
Results
Twenty‐five patients were identified. Median age at diagnosis and median followup were 14.5 years and 32.7 months, respectively. Male‐to‐female ratio was 1:4. Median duration of symptoms before diagnosis was 2 months. Of 22 patients, 21 were ANCA positive during their disease course (classic ANCA 78.9%). Constitutional symptoms were the most common clinical feature at presentation (24 of 25). Glomerulonephritis was present in 22 patients at presentation. Only 1 of 11 patients who presented with or developed renal impairment had normalization of serum creatinine. Upper airway involvement occurred in 21 patients at presentation and 24 over followup; only 1 had subglottic stenosis. Twenty patients had initial pulmonary involvement, most commonly nodules (44%) and pulmonary hemorrhage (44%). Five patients required ventilation for pulmonary hemorrhage. Four patients (16%) had venous thrombotic events (VTEs). Treatment included prednisone (100%), cyclophosphamide (76%), azathioprine (40%), and methotrexate (32%).
Conclusion
Pediatric WG typically presents in adolescence and has a female predominance. Glomerulonephritis and pulmonary disease are common at diagnosis and frequently present as a pulmonary‐renal syndrome. Loss of renal function is common and rarely completely reversible. As in adults, children with WG are at risk of VTEs.
A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may ...be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.
The daily start‐up and shut‐down operations were carried out for the 1 kW‐class solid oxide fuel cell stack composed of 46 electrolyte‐supported disk‐type planar cells made by Mitsubishi Materials ...Corporation and Kansai Electric Power Company. The representative Ni–gadolinia doped ceria cermet anodes in the deteriorated cells were analyzed by the dual‐beam focused ion beam‐scanning electron microscope. The anode microstructures were reconstructed and the microstructural parameters such as triple phase boundary (TPB) length were quantified. The surface area of nickel phase decreased with an increase in the deterioration rate, leading to a reduction in the TPB length. Furthermore, the TPB length had a strong correlation with the voltage deterioration rate.
BackgroundA preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic ...risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes.ObjectivesWe sought to determine whether PTPN22 rs2476601 exhibits a female-specific association with JIA.MethodsThe discovery sample was drawn from the Australian CLARITY JIA biobank. rs2476601 was genotyped in 413 cases (67% female, mean age 9.1 years) and 690 healthy controls (42% female, mean age 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype x sex interaction analysis. Sensitivity analyses were performed by restricting to individuals of European descent, subtypes of oligoarticular and polyarticular RF negative disease course, and exclusion of systemic JIA. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia. Analyses were performed using Stata or PLINK.ResultsThe outcomes of analyses are shown in the Table. rs2476601 was associated with all JIA in both the discovery and replication samples, and the association remained when adjusted for sex. When stratified by sex, a strong association was observed for females, but not for males. There was evidence for genotype-by-sex interaction (p=0.0087). Similar patterns were observed in all sensitivity analyses. In the replication sample, we also observed association of rs2476601 with JIA in females, but not in males.SampleNumber of cases/controlsMinor allele frequency case/controlAnalysisOR (95% CI)P valueDiscovery413/6900.12/0.07Total sample1.71 (1.26, 2.33)0.00066Sex adjusted1.63 (1.18, 2.24)0.0028Female only2.35 (1.52, 3.63)0.00011Male only0.91 (0.52, 1.60)0.75Replication1008/92870.13/0.09Total sample1.30 (1.09, 1.55)0.0039Sex adjusted1.30 (1.08, 1.56)0.0051Female only1.38 (1.09, 1.73)0.0068Male only1.19 (0.88, 1.63)0.26ConclusionsWe have demonstrated, in both a discovery and replication sample, that the association between PTPN22 rs2476601 and JIA appears restricted to females, helping to explain the greater number of females that develop this disease.Disclosure of InterestNone declared
Scurvy: Forgotten but not gone Akikusa, JD; Garrick, D; Nash, MC
Journal of paediatrics and child health,
January 2003, 2003, 2003 Jan-Feb, 2003-01-00, 20030101, Letnik:
39, Številka:
1
Journal Article
Recenzirano
:
Scurvy is still seen sporadically in the developed world. At a time when subclinical vitamin C deficiency in the general population is being recognized increasingly, the need for clinicians to be ...aware of this disease remains. We present the case of a 9‐year‐old boy admitted to hospital with musculoskeletal pain, weakness and changes in the skin and gums. After extensive investigation, he was found to have vitamin C deficiency resulting from a restricted eating pattern. Musculoskeletal complaints are a common mode of presentation of scurvy in children. Failure to appreciate this fact and the risk factors for poor vitamin C intake in the paediatric age group can result in unnecessary and invasive investigations for apparent ‘multisystem’ disease.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
Background
CLIPPER2 was an 8-year, open-label extension of the phase 3b, multicenter, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in the treatment of patients (pts) with ...juvenile idiopathic arthritis (JIA) categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).
Objectives
The objective of this analysis was to describe the safety of ETN in this population after 10 years of follow up.
Methods
Pts (n=127) with eoJIA (2-17 years), ERA, or PsA (each 12-17 years) who received ≥1 ETN dose (0.8 mg/kg once weekly max, 50 mg) in CLIPPER were eligible to enter CLIPPER2. The primary outcome measure was the occurrence of malignancy. Long-term safety was assessed as the total incidence of events from CLIPPER baseline (BL) to month (mth) 120, frequency of events per 100 patient-years (EP100PY), and frequency of events in each study year.
Results
A total of 109/127 (86%) pts entered CLIPPER2; 99 (78%) continued in the active treatment period. At mth 120, 84 (66%) pts had completed the study; 27 (21%) while actively taking ETN; 7 (6%) had withdrawn from treatment due to low/inactive disease; 5 (4%) had re-started ETN following an earlier withdrawal from treatment; and 45 (35%) had stopped ETN (but remained under observation); 25 (20%) pts permanently discontinued from the CLIPPER2 study. In CLIPPER/CLIPPER2, 1 case of malignancy (Hodgkin’s disease) was reported (1 pt with eoJIA in Year 3). There was 1 case of uveitis (1 pt with eoJIA in Year 8) and 3 of Crohn’s disease (2 pts with ERA, Year 1/Year 6; 1 pt with eoJIA, Year 5). There were 2 cases of opportunistic infections (both herpes zoster), and no deaths. Overall, there were 559 (81.82 EP100PY) treatment-emergent adverse events (TEAEs) excluding infections and injection-site reactions (ISRs). The overall rate of TE serious infections was low (N=14; 2.05 EP100PY) (Table 1), with the most common TE serious infection being gastroenteritis (N=2; 0.29 EP100PY). The most frequently reported TEAEs (N EP100PY) were headache (28 4.10), arthralgia (24 3.51), pyrexia (21 3.07), diarrhea (14 2.05), and leukopenia (12 1.76). Overall, 39 patients reported serious AEs (excluding infections/ISRs). The number and frequency (N EP100PY) of TEAEs (excluding infections/ISRs) decreased over the 10-year study period from 193 173.81 in Year 1 to 9 27.15 in Year 10. The number and frequency of TE infections and TE serious infections also decreased over the 10-year study period. There was no clear trend of a decrease over time for the incidence of TE serious AEs (Figure 1).
Table 1.
ETN Safety Summary (from CLIPPER BL to mth 120), N (EP100PY) (FAS)*
eoJIA, n=60(EXP=313.667 PY)
ERA, n=38(EXP=206.971 PY)
PsA, n=29(EXP=162.576 PY)
Total, n=12(EXP=683.214 PY)
TEAEs†
269 (85.76)
176 (85.04)
114 (70.12)
559 (81.82)
TE serious AEs†
16 (5.10)
17 (8.21)
7 (4.31)
40 (5.85)
TE ISRs
23 (7.33)
29 (14.01)
12 (7.38)
64 (9.37)
TE infections
418 (133.26)
99 (47.83)
155 (95.34)
672 (98.36)
TE serious infectionsǂ
5 (1.59)
4 (1.93)
5 (3.08)
14 (2.05)
Opportunistic infections§
0
1 (0.48)
1 (0.62)
2 (0.29)
TEAEs causing withdrawal†
7 (2.23)
9 (4.35)
2 (1.23)
18 (2.63)
TE infections causing withdrawal
2 (0.64)
0
1 (0.62)
3 (0.44)
*While on active ETN treatment or within 30 days of last dose
†Excluding infections/ISRs
ǂGastroenteritis, 2 (0.29); acute tonsillitis, anal abscess, bronchopneumonia, gastrointestinal infection, helicobacter gastritis, influenza, peritonitis, pharyngitis, pyelocystitis, sepsis, urinary tract infection, viral infection, all 1 (0.15)
§Both herpes zoster
EXP, exposure to ETN; FAS, full analysis set; n, number of patients; N, number of events
Conclusion
ETN treatment to mth 120 was well tolerated in this patient population and consistent with the known safety profile. Frequency of TEAEs and TE infections decreased over time. Over 10 years, there was 1 reported event of malignancy and the overall rate of TE serious infections was low.
References
1
NCT00962741
/NCT01421069
Acknowledgements
Medical writing support was provided by Iain McDonald, PhD, of Engage Scientific Solutions and was funded by Pfizer.
Disclosure of Interests
Jelena Vojinovic Speakers bureau: Abbvie, Roche, Sandoz, Joke Dehoorne Speakers bureau: Abbvie, Roche, Consultant of: Abbvie, Roche, Violeta Panaviene: None declared, Gordana Susic: None declared, Gerd Horneff Speakers bureau: Chugai, Eli-Lilly, Glaxo Smith and Kline, Janssen, Novartis, Pfizer, Roche and Sobi, Grant/research support from: Novartis, Janssen, Roche, Valda Stanevicha Speakers bureau: Sandoz, Abbvie, Roche, Katarzyna Kobusinska: None declared, Zbigniew Żuber: None declared, Bogna Dobrzyniecka: None declared, Jonathan Akikusa: None declared, Tadej Avcin Speakers bureau: AbbVie, Octapharma, and Takeda, Consultant of: AbbVie, Alexion, Octapharma, and Takeda, Alberto Martini Speakers bureau: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Consultant of: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Cecilia Borlenghi Shareholder of: Pfizer, Employee of: Pfizer, Edmund Arthur Employee of: Pfizer, Svitlana Y Tatulych Shareholder of: Pfizer, Employee of: Pfizer, Chuanbo Zang Shareholder of: Pfizer, Employee of: Pfizer, Bonnie Vlahos Shareholder of: Pfizer, Employee of: Pfizer, Nicolino Ruperto Speakers bureau: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB., Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB.
Background
CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in patients (pts) with juvenile idiopathic arthritis ...(JIA), categorized as extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).
Objectives
Evaluation of the efficacy of ETN and its effect on health outcomes over 10 years of follow-up were secondary objectives and are reported here.
Methods
Pts (n=127) with eoJIA (n=60; 2-17 years of age), ERA (n=38; 12-17), or PsA (n=29; 12-17) who received ≥1 ETN dose (0.8 mg/kg once weekly max, 50 mg) in CLIPPER were eligible to enter CLIPPER2. The study design has been reported previously.
1
Efficacy endpoints included proportions of pts achieving JIA American College of Rheumatology (ACR) 30/50/70/90/100 criteria, Juvenile Arthritis Disease Activity Score (JADAS) inactive disease and clinical remission criteria, and sustained clinical remission (ACR criteria) or JADAS ≤1 for 12 continuous months (mths). Exploratory efficacy endpoints included time to flare following ETN withdrawal (based on ≥30% worsening in ≥3/6 ACR Pedi components, with ≥30% improvement in <2/6 remaining components and ≥2 active joints), and time to re-treatment with ETN.
Observed Cases were used (i.e., there was no imputation for missing data) for pts who were in the Active Treatment Period.
Results
A total of 109/127 (86%) CLIPPER participants entered CLIPPER2 (n=55 eoJIA, n=31 ERA, n=23 PsA), with 99 (78%) pts continuing in the Active Treatment Period. Overall, 84 (66%) pts completed 120 mths of follow-up; 27 (21%) while actively taking ETN. Thirty (24%) pts entered the Withdrawal Period from the Active Treatment Period (i.e., they discontinued ETN, either by meeting the Wallace definition for clinically inactive disease for at least 6 months on ETN, or by having had a good clinical response and being deemed to benefit from withdrawal in the investigator’s judgment). Of the pts in the Active Treatment Period, over 90% achieved JIA ACR 50 response at all study time points. Sustained JADAS and ACR remission was achieved by 42 (33%) pts and 17 (13%) pts, respectively. The mean improvements from baseline in JADAS disease activity at mth 24 of CLIPPER were largely maintained through CLIPPER2 A total of 109/127 (86%) CLIPPER participants entered CLIPPER2 (n=55 eoJIA, n=31 ERA, n=23 PsA), with 99 (78%) pts continuing in the Active Treatment Period. Overall, 84 (66%) pts completed 120 mths of follow-up; 27 (21%) while actively taking ETN. Thirty (24%) pts entered the Withdrawal Period from the Active Treatment Period (i.e., they discontinued ETN, either by meeting the Wallace definition for clinically inactive disease for at least 6 months on ETN, or by having had a good clinical response and being deemed to benefit from withdrawal in the investigator’s judgment). Of the pts in the Active Treatment Period, over 90% achieved JIA ACR 50 response at all study time points. Sustained JADAS and ACR remission was achieved by 42 (33%) pts and 17 (13%) pts, respectively. The mean improvements from baseline in JADAS disease activity at mth 24 of CLIPPER were largely maintained through CLIPPER2.
Conclusion
The low numbers of evaluable pts notwithstanding, efficacy results were consistent with the profile of ETN, and treatment responses were considered clinically meaningful and durable with long-term treatment.
References
1Foeldvari I, et al.
Arthritis Res Ther
2019;21:125.
2Trincianti C, et al.
Arthritis Rheumatol
2021:73;1966-75.
Trial Registration:
NCT00962741
/NCT01421069
Acknowledgements
Medical writing support was provided by Iain McDonald, PhD, of Engage Scientific Solutions and was funded by Pfizer.
Disclosure of Interests
Jelena Vojinovic Speakers bureau: Abbvie, Roche, Sandoz, Joke Dehoorne Speakers bureau: Abbvie, Roche, Consultant of: Abbvie, Roche, Violeta Panaviene: None declared, Gordana Susic: None declared, Gerd Horneff Speakers bureau: Chugai, Eli-Lilly, Glaxo Smith and Kline, Janssen, Novartis, Pfizer, Roche and Sobi, Grant/research support from: Novartis, Janssen, Roche, Valda Stanevicha Speakers bureau: Sandoz, Abbvie, Roche, Katarzyna Kobusinska: None declared, Zbigniew Żuber: None declared, Bogna Dobrzyniecka: None declared, Jonathan Akikusa: None declared, Tadej Avcin Speakers bureau: AbbVie, Octapharma and Takeda, Consultant of: AbbVie, Octapharma and Takeda, Alberto Martini Speakers bureau: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Consultant of: Aurinia, Bristol Myers and Squibb, Eli-Lilly, EMD Serono, Janssen, Pfizer, Roche, Cecilia Borlenghi Shareholder of: Pfizer, Employee of: Pfizer, Edmund Arthur Employee of: Pfizer, Svitlana Y Tatulych Shareholder of: Pfizer, Employee of: Pfizer, Chuanbo Zang Shareholder of: Pfizer, Employee of: Pfizer, Vasileios TSEKOURAS Shareholder of: Pfizer, Employee of: Pfizer, Bonnie Vlahos Shareholder of: Pfizer, Employee of: Pfizer, Nicolino Ruperto Speakers bureau: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB., Consultant of: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB.
PDF
