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Treatment approach of patients with juvenile idiopathic arthritis
Source publication
Juvenile idiopathic arthritis is the most common chronic rheumatic disease of childhood resulting in disability in untreated cases. Disease modifying anti-rheumatic drugs form the first-line treatment in JIA. However, the data about leflunomide (LFN) in treatment of JIA is limited. We reviewed the medical files of JIA patients who were followed-up...
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Introduction
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Background
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Methods
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Objective
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Citations
... Ayaz et al., demonstrated that leflunomide could offer a viable treatment option for patients who cannot tolerate MTX, and in cases of low disease activity, it may reduce the need for biologic medications. Leflunomide can serve as an alternative DMARD for psoriatic JIA when there is intolerance to MTX [23]. Side effects may consist of diarrhoea, skin rashes, cytopenia, abnormal liver function test results, and teratogenicity. ...
Juvenile idiopathic arthritis (JIA) is the most widespread rheumatic disease and main cause of disability in children. The disorder includes various classified forms depending on the affected joints’ location and number, as well as the presence or absence of various inflammatory markers. The specific cause is not known but is believed to involve a combination of genetic, humoral, and environmental factors. The aims of treating JIA are to reduce inflammation, reach remission, alleviate pain, sustain function, and do so with minimal side effects. Nonsteroidal anti-inflammatory drugs are still beneficial in mild cases, while intra-articular steroid injections remain the most common treatment for patients with oligoarticular juvenile idiopathic arthritis. Disease-modifying drugs like methotrexate and leflunomide have shown to be effective and safe, but in numerous patients, the disease continues to be active even with this therapy. These patients are given more specific medical care like tumour necrosis factor -alpha (TNF-α) inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, selective costimulation modulators, and selective B-cell blockade. Treatment comes with risks, as several medications necessitate monitoring and patient education to manage potential complications. If left untreated, the disease can progress and become chronic, leading to significant illness and potentially having a devastating impact on the child’s quality of life. Despite the advancements in modern therapies improving patient outcomes, a significant portion of individuals still do not respond to treatment. This underscores the necessity for a deeper comprehension of disease development and recovery in order to properly categorize patients for appropriate treatment options.
... Le unomide, an isoxazole derivative with antiproliferative activity, has been studied to inhibit the entire biosynthesis of pyrimidines by inhibiting DHODH and thus ultimately inhibiting the proliferation of lymphocytes and B cells [44,45] . Le unomide is currently effective in the treatment of juvenile rheumatoid arthritis, juvenile idiopathic arthritis and cutaneous small vessel vasculitis [46][47][48] . Le unomide in the treatment of lumbar intervertebral disc herniation in the speci c mechanism is unclear, still need further research. ...
Objective: To explore mitochondrial metabolism-related genes as potential hub genes in lumbar disc herniation (LDH) and their associated molecular regulatory mechanisms, and to predict potential drug targets.
Methods: Based on the mRNA-Seq data of mitochondrial metabolism genes and LDH from public databases, the hub genes were screened and their biological functions were investigated using LASSO regression analysis, support vector machine (SVM) algorithm and random forest (RF). Then, the immune profile of osteoporosis was detected based on the CIBERSORT algorithm to study the immune cell infiltration of the hub genes. The diagnostic model Nomogram risk prediction model is constructed and the effect is evaluated. Finally, potential drug targets were obtained and validated by molecular docking through drug database.
Results: 4 hub genes were obtained:DHODH,BAK1,TIMM17B and TIMM23. The results of GO analysis mainly include mitochondrial function and composition,macromolecular transport such as Bcl-2 family proteins,heat shock protein binding,etc. KEGG pathway is mainly involved in multi-species apoptosis pathway,thyroid cancer,pyrimidine metabolism,etc. These four hub genes have correlation with a variety of immune cells, as well as constructing a diagnostic model with good diagnostic efficacy. Finally, through drug database screening and molecular docking validation, DHODH was found to have a potential role in the treatment of LDH by affecting pyrimidine metabolism.
CONCLUSION: DHODH, BAK1, TIMM17B, and TIMM23 are hub genes associated with mitochondrial metabolism in LDH. They act on LDH through multiple pathways and may be hub genes for LDH diagnostic biomarkers. Finally, DHODH was found to be a potential drug target for the treatment of LDH.
... In the study by Ayaz [20], 36 patients with JIA, who were unable to receive MTX due to complications, were given LFN. In this study, unlike our study, there was no simultaneous administration of the two mentioned drugs. ...
Objectives
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children. Alt-hough methotrexate (MTX) is the first line disease-modifying antirheumatic drug for JIA, many pa-tients do not respond well or cannot tolerate MTX. The aim of this study was to compare the effect of combination therapy of MTX and leflunomide (LFN) with MTX in patients who do not respond to MTX.
Material and methods
Eighteen patients (2–20 years old) with polyarticular, oligoarticular or extended oligoarticular sub-types of JIA who did not respond to conventional JIA therapy participated in this double-blind, pla-cebo-controlled, randomized trial. The intervention group received LFN and MTX for 3 months while the control group received oral placebo and MTX at a similar dose to the intervention group. Re-sponse to treatment was assessed every 4 weeks using the American College of Rheumatology Pe-diatric criteria (ACRPed) scale.
Results
Clinical criteria, including number of active joints and restricted joints, physician and patient global assessment, Childhood Health Assessment Questionnaire (CHAQ38) score, and serum erythrocyte sedimentation ratelevel, did not differ significantly between groups at baseline and at the end of the 4th and 8th weeks of treatment. Only the CHAQ38 score was significantly higher in the intervention group at the end of the 12th week of treatment. Analysis of the effect of treatment on study parameters revealed that only the global patient assessment score differed significantly between groups (p = 0.003).
Conclusions
The results of this study showed that combining LFN with MTX does not improve clinical outcomes of JIA and may increase side effects in patients who do not respond to MTX.
... Abdominal pain, gastritis, dyspepsia, diarrhea, nausea, vomiting, anorexia, alopecia, weight loss, rash, elevated liver transaminases, can be seen as side effects of LFN therapy (7,8,12). Aktay Ayaz et al. (11) reported side effects in 2/38 (lymphopenia in 1 patient and elevated liver enzymes in 1 patient) patients in their study. Alcântara et al. (10) reported the intolerance with LFN in 7/43 patients (nausea and abdominal pain in 3 patients, elevated liver enzymes in 4 patients). ...
... LFN, isolated or combined with MTX, has been found to be safe and effective in patients with JIA unresponsive to MTX (10). Aktay Ayaz et al. (11) demonstrated in their study involving 38 patients that LFN is an effective treatment in patients with MTX intolerance and low disease activity. Our results also suggest that LFN therapy can be used in JIA patients with low disease activity in the presence of MTX intolerance. ...
Amaç: Juvenil idiyopatik artrit (JİA), çocukluk çağının en sık görülen kronik romatizmal hastalığıdır. Metotreksat (MTX), leflunomid (LFN) gibi hastalık modifiye edici antiromatizmal ilaçlar (DMARD) JİA'da birinci basamak tedavilerdir. MTX en sık reçete edilen ilaçtır ve çalışmalar ağırlıklı olarak MTX etkinliğini ve güvenliğini ele almaktadır. Ancak LFN ile ilgili veriler sınırlıdır. Bu çalışmada, JİA hastalarında LFN tedavisi ile ilgili kliniğimizin deneyimlerini sunmayı amaçladık. Gereç ve Yöntem: Bu retrospektif çalışmaya hastanemiz çocuk romatoloji polikliniğinde düzenli olarak takip edilen ve LFN tedavisi verilmiş JİA hastaları dahil edildi. Hasta demografik bilgileri, klinik ve laboratuvar özellikleri ile ilgili veriler tıbbi dosyalardan elde edildi. Bulgular: Çalışmaya ortanca (çeyrekler arası aralık) hastalık başlangıç yaşı 7,3 (3,1-12,0) yıl olan 18 hasta (15 kadın ve 3 erkek) dahil edildi. 8 hastada oligoartiküler JİA, 7 hastada poliartiküler JİA, 2 hastada sistemik JİA ve 1 hastada entezitle ilişkili artrit (ERA) vardı. Tüm hastalara başlangıç tedavisi olarak MTX verildi (ERA tanısı konan bir hasta sulfasalazin ile tedavi edildi hariç). Gastrointestinal sistem (GİS) intoleransı nedeniyle başlangıçta MTX alan tüm hastalarda MTX kesildi ve LFN tedavisi başlandı. Daha önce MTX alırken GİS intoleransı gelişen hastalık aktivitesi düşük olan yedi hastadan altısına LFN tedavisi verildi. Bu hastalarda LFN ile tam remisyon sağlandı. MTX ile remisyonda izlenen dört hastada hastalık aktivasyonu görüldü. Daha önce MTX intoleransı olan bu hastalara LFN tedavisi verildi. Dört hastanın üçünde LFN ile remisyon sağlandı. MTX ile remisyon sağlanamayan orta ve yüksek hastalık aktivitesine sahip altı hastaya biyolojik tedavi başlandı. Yeterli yanıt alınamayan bu hastalarda MTX kesilerek LFN tedavisi başlandı. LFN ve biyolojik ajan kombinasyonu ile sadece bir hastada inaktif hastalık elde edildi. ERA tanılı bir hastada sulfasalazin tedavisine yetersiz yanıt alması üzerine LFN tedavisine geçildi ve LFN ile tam remisyon elde edildi. Sonuçlar: LFN tedavisi, diğer DMARD'larla düşük hastalık aktivitesi ve/veya remisyonu olan ve ilaç kesildikten sonra nüks olan hastalarda faydalı olabilir.
... Systemic administration of corticosteroids can have a positive short-term effect, but its prolonged administration is associated with severe side effects such as osteoporosis, growth suppression or immunosuppression (213)(214)(215). The American College of Rheumatology (ACR) recommends early use of DMARDs in JIA patients, specifically methotrexate (MTX) (214,(216)(217)(218). Furthermore, biological drugs have also been approved for JIA treatment, including TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab) (219)(220)(221)(222)(223); the T-cell modulator abatacept (224,225); the humanized monoclonal antibody against the IL-6 receptor (IL-6R) tocilizumab (226)(227)(228) and the IL-1 inhibitor canakinumab (for sJIA) (229)(230)(231). ...
Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.
... MTX is also considered to be effective in children with PsJIA, though the axial manifestations limits prescription of MTX and so TNF inhibitors are typically required in these cases [5]. Leflunomide may be used as an alternative DMARD for pJIA in cases of MTX intolerance [52,53]. Sulfasalazine is recommended for patients with moderate activity of ERA with active peripheral arthritis, but is inefficient in case of sacroiliitis [18,54]. ...
Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways.
... Methotrexate is a commonly chosen DMARD that has been shown to be effective in clinical trials [70,72,73]. Other considerations are sulfasalazine and leflunomide [74,75]. Sulfasalazine is effective for peripheral joint arthritis in ERA [71]. ...
Joint pain is a common symptom in children and adolescents. While there are many causes of joint pain in children, most of these are acute or not related to underlying joint inflammation. Chronic arthritis, however, can be one of the reasons behind the joint pain. The most common causes of chronic arthritis in children are categorized under juvenile idiopathic arthritis (JIA). The purpose of this review is to highlight the most important clinical features, work-up, and medical management of the different subtypes of JIA.
Objectives
Intra-articular corticosteroid injection (IACI) is a safe first-line or adjunct therapy used in any subtype of juvenile idiopathic arthritis (JIA). Limited studies evaluated the effect of IACI on cartilage. Our study aimed to examine the femoral cartilage thickness of patients with JIA who received IACI to the knee joint using ultrasound.
Methods
We randomly selected JIA patients who performed IACI in the knee joint. Baseline bilateral joint cartilage and tendon thicknesses were measured. The articular fluid was aspirated, and applied IACI at the same period. Six months after injection, the exact measurements were repeated. Distal femoral cartilage, quadriceps tendon, and distal and proximal patellar tendon thicknesses were compared at the baseline (before IACI) and 6 months after IACI.
Results
Thirty patients with JIA were included, and 23 (76.7%) were female. The median age was 11 years (interquartile range, 6 to 14), and the median disease duration was 3.3 years (interquartile range, 5 months to 5 years). The subtypes of JIA were oligoarticular in 25 (83.3%), polyarticular in 2 (6.7%), enthesitis-related arthritis in 2 (6.7%), and juvenile psoriatic arthritis in 1 (3.3%). Distal femoral cartilage thickness was 2.96 ± 0.79 mm at baseline and 2.85 ± 0.70 mm at 6 months after IACI (P = .35). The tendon thicknesses were similar at 6 months after baseline measurements.
Conclusions
Our findings reveal that knee IACI in patients with JIA did not significantly change cartilage and tendon thicknesses. This observation could indicate that IACIs have no detrimental effects on the cartilage and the tendons.
Purpose:
To describe the effectiveness of leflunomide as adjunctive therapy with anti-tumor necrosis factor (anti-TNF) agents in pediatric patients with uveitis who are not able to tolerate methotrexate.
Methods:
A retrospective case series was performed of pediatric patients who were receiving leflunomide in conjunction with anti-TNF agent therapy after intolerance to a combination of methotrexate with anti-TNF therapy. Dose and duration of methotrexate, leflunomide, and anti-TNF therapy were recorded. Extensive history, demographics, laboratory data, and uveitis flare rate were obtained.
Results:
A total of five children were included in the study. Most patients were initially receiving methotrexate and an anti-TNF agent was added subsequently due to inadequate response to monotherapy. After discontinuation of methotrexate, leflunomide was initiated with anti-TNF therapy. The replacement of methotrexate with leflunomide showed decreased side effects and was associated with lower flare rates and steroid-free remission.
Conclusions:
Leflunomide was found to be well tolerated and effective at maintaining uveitis quiescence in conjunction with anti-TNF agents in pediatric patients who do not tolerate methotrexate. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XX-XX.].
Immunmodulierende Substanzen und Zytostatika spielen als „disease modifying drugs“ eine herausgehobene Rolle in der Rheumatologie. Die evidenzbasierte Medizin hat hierbei die Entwicklung von Gold und Penicillamin, die therapeutisch heute keine Rolle mehr spielen, hin zu neueren Substanzen getrieben. Viele dieser Substanzen haben sich in kontrollierten Studien im Kindesalter als effektiv erwiesen. In diesem Kapitel werden Wirkmechanismen, Pharmakokinetik, unerwünschte Wirkungen und der praktische Einsatz der folgenden immunmodulierenden Substanzen und Zytostatika im Einzelnen dargestellt: Sulfasalazin, Antimalariamittel, Methotrexat, Leflunomid, Azathioprin, Cyclophosphamid, Ciclosporin, Mycophenolatmofetil.
