In recent years, newly developed therapeutic agents have brought clinical, structural, and functional remission to many pediatric patients with rheumatic diseases that were refractory to conventional ...therapy. However, achieving these remissions alone is insufficient as a treatment goal, especially for adolescent patients, because advanced therapies have not always encouraged their psychosocial stability and mental maturity. Consequently, various problems have arisen during the puberty and transition period from pediatrics to adult medical care. "Dreams come true remission" is a state of remission that allows patients to have clear dreams for the future in childhood and to increase the potential that their dreams will be realized in adulthood. This new treatment goal may empower children with chronic diseases such as PRDs to overcome the problems occurred during puberty and transition period.
Interleukin (IL)-18 is a pleiotropic, pro-inflammatory cytokine involved in the regulation of innate and adaptive immune responses. IL-18 has attracted increasing attention as a key mediator in ...autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS) including systemic juvenile idiopathic arthritis and adult-onset Still’s disease. In these diseases, dysregulation of inflammasome activity and overproduction of IL-18 might be associated with the development of MAS by inducing natural killer cell dysfunction. Serum IL-18 levels are high in patients with these diseases and therefore are useful for the diagnosis and monitoring of disease activity. In contrast, a recent study revealed the overproduction of IL-18 was present in cases of autoinflammation without susceptibility to MAS such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. The pathogenic and causative roles of IL-18 remain unclear in these autoinflammatory diseases. Further investigations are necessary to clarify the role of IL-18 and its importance as a therapeutic target in the pathogenesis of autoinflammatory diseases.
Abstract To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting ...macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76 s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18-dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750 pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels > 47750 pg/ml might be useful to predict MAS development.
Abstract
Objective
To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).
Methods
Patients completing the randomized, ...double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety.
Results
All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference –0.120 mg/kg/day; 95% CI −0.154, −0.087). Imaging evaluations indicated that most patients’ disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported.
Conclusion
These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns.
Trial registration
JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.
Background: Regular assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is essential for detecting glucocorticoid-induced osteoporosis in juvenile-onset autoimmune ...diseases. Z-score is used to standardize osteoporosis assessment in children and is evaluated with only one of three devices in Japan. The purpose of this study was to determine how many Japanese medical facilities for pediatric rheumatic diseases were unable to use Z-scores to evaluate osteoporosis. Methods: Electronic questionnaires were distributed between 2017 and 2019 to hospitals belonging to the Pediatric Rheumatology Association of Japan and to university hospitals and public children's hospitals that provide medical care for pediatric rheumatic diseases. The questionnaire inquired about the location of DXA measurement, manufacturer (Hologic, GE healthcare, Hitachi), and measurement site, and the answers were collected using Google Forms. Statcel 4 was used for analysis. Results: Overall, 120 facilities responded to the survey, of which 117 had DXA. In the remaining three facilities, DXA was not installed in two and was out of order in one. Bone loss in childhood was evaluated using a Z-score calculated from age-based reference values; however, 30% of hospitals without HOLOGIC DXA could not evaluate osteoporosis by Z-score in Japanese childhood. The characteristics of the hospitals enrolled in this study did not bias the selection of Hologic DXA. Conclusions: Neighboring institutions should consider sharing access to Hologic DXA equipment, to ensure use of uniform reference values. GE BMD reference values should be established for Japanese children.
► MAS could develop even during TCZ therapy. ► TCZ masks the clinical symptoms of s-JIA-associated MAS. ► We should be careful for persistent increase of serum IL-18.
Macrophage-activation syndrome ...(MAS) is a potentially life-threatening complication of systemic juvenile idiopathic arthritis (s-JIA). Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, is an effective cytokine inhibitor for the treatment of s-JIA. We described the clinical courses of five cases of MAS during TCZ therapy and demonstrated the need for monitoring serum interleukin (IL)-18 and IL-6 concentrations. Clinical symptoms of patients with s-JIA receiving TCZ were apparently mild compared to those not receiving TCZ. Furthermore, serum CRP concentrations never increased during TCZ therapy, even in MAS. Serum IL-6 concentrations increased during s-JIA flare-up and with the complication of infection. Serum IL-18 concentrations increased persistently before the other measures of disease activity. The clinical symptoms of MAS and s-JIA could be masked during TCZ therapy; hence, monitoring serum concentrations of IL-18 and IL-6 is recommended for the evaluation of disease activity in s-JIA and to detect the complication of infection.
To collect clinical information and
mutation data on patients with Blau syndrome and to evaluate their prognosis.
Fifty patients with
mutations were analysed. The activity of each
mutant was ...evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians.
The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in
were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment.
In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.
Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (
NOD2
) gene. NOD2 is an intracellular pathogen recognition ...receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an
ex vivo
study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in
NOD2
lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.
To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX).
Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) ...patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein.
Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment.
Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients.
To describe the pre-conception status, pregnancy outcomes, and medication prevalence in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease (CD), and ulcerative colitis ...(UC).
E-mail-based questionnaire survey for the Japan Maternal Fetal Intensive Care Unit Network hospitals inquiring prevalence and clinical features of SLE, RA, CD and UC complicated pregnancies for 2 years.
The number of SLE, RA, CD and UC among 69,810 deliveries was 184, 139, 27 and 178, respectively. Less than half of pregnancies were planned. Assisted reproductive technology (ART) pregnancy rates were higher in SLE, RA and UC than in the general population (11.4, 23.0 and 7.4 vs 5.1%,
< .001 each). Preterm delivery, preeclampsia, and fetal growth restriction (FGR) were more frequent in SLE than in the general population (39.4 vs. 5.6%
< .001, 15.0 vs. 6.0%
< .001, 12.9 vs 4.2%
< .001). Prevalence of preterm delivery in RA and UC (27.5 vs. 5.6%
< .001, 11.3 vs. 5.6%
< .05) and FGR in CD (28.6 vs. 4.2%
< .001) was also higher than that in the general population.
SLE, RA, CD, and UC complicated pregnancies were at high risks of obstetric adverse outcome. High ART rates necessitate pre-conception counseling in SLE, RA, and UC pregnancies.
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