Adherence to methotrexate in juvenile idiopathic arthritis

Non-adherence to treatments for chronic diseases may jeopardize patients’ health, increase costs of care, and cause unnecessary clinic appointments and diagnostic studies, as well as additional treatments with potentially serious side effects. Little is known about adherence to methotrexate in pediatric rheumatology. Because this medication is commonly used in JIA, we assessed adherence among children receiving methotrexate in two countries. A total of 76 outpatients (M:F 21:55) with JIA seen in Rio de Janeiro (Brazil) and in Boston (US) taking methotrexate for >2 months were enrolled. Questionnaires were completed by the parents from both centers. Non-adherence was defined as omission of ≥3 prescribed doses in the previous 8 weeks. Patients’ ages ranged from 1 to 17 years. Mean time on methotrexate was 20.5 months (±25). Overall rate of non-adherence was 18%. The rate of reported non-adherence was 8% in Boston and 24% in Rio de Janeiro (P = 0.012). The main reason for non-adherence in Boston was “child refused”; in Rio de Janeiro, the main reason was inability to obtain medication. Age had a negative association with adherence (P < 0.0001). Sex, time on methotrexate, route of administration, or concomitant use of other medications were not associated with adherence. Eighteen percent of children with JIA prescribed methotrexate were non-compliant. The difference in reasons for poor adherence between patients in Rio de Janeiro and Boston suggests that different strategies may be needed to improve adherence in these 2 settings. The rate of non-adherence warrants further investigation.     

Low-dose methotrexate treatment for oligoarticular juvenile idiopathic arthritis nonresponsive to intra-articular corticosteroids

The objective of this study was to evaluate the efficacy of low-dose (0.2 mg/kg) methotrexate (MTX) in the treatment of children with oligoarticular juvenile idiopathic arthritis (JIA) who do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and repeated intra-articular corticosteroid (IA) injections. Nineteen consecutive patients (age: 2–14 years, 18 females) with oligoarticular JIA were studied prospectively. Sixteen had a persistent course and three had an extended course of the disease. Patients were defined as nonresponders to IA injections if the duration of improvement following two consecutive injections was less than 4 weeks. These patients were offered low-dose oral MTX, administered once a week for at least 6 months. Of the 19 patients in this series, 2 responded to NSAIDs alone. Forty-eight IA injections were given to 17 patients; 11 (64%) of them did not respond to this treatment. Nine of the nonresponders were treated with low-dose MTX for a median duration of 15±3.8 months. Except for one patient with an extended disease course, all responded very well to treatment and went into remission after a median of 6.4±2.9 months, and none required additional IA injections after initiation of MTX treatment. Low-dose oral MTX appears to be very effective in the management of children with oligoarticular JIA, who are unresponsive to IA injections.     

Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis

Objective

Methotrexate (MTX) is the most commonly used disease‐modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients.

Methods

A cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis.

Results

The time from diagnosis to start of MTX treatment, physician's global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physician's global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined.

Conclusion

In children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.     

Combination therapy with methotrexate and cyclosporine A in juvenile idiopathic arthritis

OBJECTIVE: To investigate the efficacy and safety of a combination therapy with methotrexate (MTX) and cyclosporine A (CyA) in patients with juvenile idiopathic arthritis (JIA) who were refractory to MTX as a single second-line agent. METHODS: Seventeen consecutive patients with JIA who had refractory polyarthritis despite a minimum of 6 months of MTX as a single second-line agent at the dose of 15 to 25 mg/m2/week were continued with MTX with the addition of CyA (4 mg/kg/day) for 6 to 30 months (median 10 months) were analyzed. The clinical response to therapy was assessed through the preliminary definition of improvement in JIA. RESULTS: At the end of the treatment, as compared to the time when CyA was added to MTX, 8 patients (47%) met the 30% definition of improvement; among them 5 (29%) met the 70% definition of improvement, and 2 (12%) achieved complete disease control. Seven patients (41%) experienced side effects: 4 gastrointestinal discomfort, 1 liver transaminase elevation, and 2 increase > or = 30% in the serum creatinine concentration. No patients was discontinued from combination therapy due to adverse events. CONCLUSION: In our JIA patients who were refractory to MTX as a single second-line agent, the addition of CyA was associated with a significant clinical improvement in roughly half of the patients.     

Hepatotoxicity in patients with juvenile idiopathic arthritis receiving longterm methotrexate therapy

OBJECTIVE: To evaluate hepatotoxicity in patients with juvenile idiopathic arthritis (JIA) receiving methotrexate (MTX) therapy with doses of 20-30 mg/m2 of body surface area. METHODS: We graded the histology of percutaneous liver biopsies from 34 patients with JIA receiving longterm (> 2.4 years) MTX therapy at the Rheumatism Foundation Hospital, Heinola, Finland, using the Roenigk classification scale. Medical records of the patients with JIA were retrospectively analyzed. RESULTS: Of 10 patients with MTX doses >/= 20 mg/m2, 4 had grade II, 5 had grade I histology, and one specimen with extensive steatosis as the only pathologic finding could not be classified. All 24 patients treated with low dose MTX had grade I histology. No specimen showed fibrosis or cirrhosis. In 2 patients with grade II histology, extensive portal tract inflammation resolved when MTX was discontinued for 6 months. CONCLUSION: Aggressive medical treatment of JIA with MTX at 20-30 mg/m2 with concomitant disease modifying antirheumatic drugs and corticosteroids may contribute to minor liver abnormalities that seem to be reversible.     

白芍总苷胶囊治疗儿童特发性关节炎的临床有效性和安全性观察

目的观察白芍总苷胶囊(帕夫林,TGP)治疗幼年型特发性关节炎(JIA)的疗效及安全性。方法2003—2004年在上海4个中心(上海仁济医院、复旦大学附属儿科医院、上海第二军医大学附属长海医院、上海第二医科大学附属儿童医学中心)选择诊断明确的JIA中少关节型、多关节型及全身型三种类型的患儿80例,随机分为治疗组和对照组(采用拆信封法),治疗组给予TGP(朗生医药公司)联合甲氨蝶吟(MTX)治疗,对照组单用MTX治疗,观察患者关节症状改善程度、血沉变化情况以及药物副作用。结果第4周时治疗组患儿关节症状改善50%,明显高于对照组的30%(P<0.05),并且第4周时治疗组有效率为60%,明显高于对照组的37.5%(P<0.05),此外,白芍总苷胶囊与MTX联合应用在治疗初期能较大幅度地降低血沉。在不良反应发生方面,治疗组仅出现轻度的腹泻,且发生率较低(10%),而对照组部分患儿出现了肝功能的异常。结论白芍总苷胶囊与MTX联合应用能较好地缓解JIA患儿的关节症状,缩短患儿症状改善的时间,且不良反应发生率低,患儿耐受性好。     

Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis

OBJECTIVE: To assess the utility of the American College of Rheumatology guidelines for monitoring methotrexate (MTX)-related toxicity in a cohort of children with juvenile idiopathic arthritis (JIA). METHODS: Eighty-nine patients with JIA treated with MTX were monitored prospectively: aspartate aminotransferase (AST), alanine aminotransferase (ALT), complete blood count (CBC), and differential blood count were measured prior to starting MTX, and then monthly. Significantly abnormal blood tests (SABT) were prospectively defined as (1) significantly elevated liver enzymes (SELE) greater than twice the upper limit of normal; (2) granulocyte count < 1.5 109/l; (3) lymphocyte count < 0.9 109/l; or (4) hemoglobin decreased by > 2 g/l from previous level. Clinical interventions, current and cumulative MTX dose, duration of treatment, comorbidity, and concurrent medications at the time of the first SABT identification were recorded. Independent t tests and chi-squared tests were used for comparisons, and the probability of developing a SABT was calculated by Kaplan-Meier survival analysis. RESULTS: Forty percent of patients had a SABT: 26% had hematological abnormalities and 14% had SELE. Ninety-five percent of patients with SABT had symptoms consistent with a viral infection when the SABT was drawn and MTX dose was withheld until results had normalized on repeat testing. SABT persisting beyond one month occurred in only 2 patients, and their abnormalities resolved by 6 months with no specific identified cause; they resumed MTX at a later time without recurrence of SABT. There were no differences between patients with and without SABT with respect to current or cumulative MTX dose, duration of treatment, and concurrent medications at the time of the SABT. The probability of developing a SABT was estimated to be 11% at 3 months, compared to 10% probability of having an abnormal blood test by chance alone. CONCLUSION: Routine blood tests every 4 to 8 weeks in children with JIA are unnecessarily frequent.     

Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the efficacy of folinic acid in reducing the side effects associated with methotrexate (MTX) therapy in children with juvenile idiopathic arthritis (JIA) and to determine whether folate supplementation may reduce the benefit of MTX administration. METHODS: This was a retrospective, non-controlled study. Inclusion criteria were: 1) diagnosis of JIA according to the Durban 1997 criteria; 2) treatment with low to intermediate doses of MTX (10-20 mg/m2/week) as the sole second-line agent for at least 6 mos.; and 3) supplementation with folinic acid (2.5-7.5 mg) in a single weekly dose 24 hrs after MTX administration. All patients were started on folinic acid only after the development of a side effect. Exclusion criteria were: treatment with higher doses of MTX (> 20 mg/m2/week). The outcomes investigated were: hepatotoxicity (liver transaminase increase), gastrointestinal toxicity, disease flare, and clinical remission. The number of episodes per patient-year of MTX treatment of each outcome before and after folinic acid supplementation was compared by the Wilcoxon matched pairs test. RESULTS: A total of 43 children with JIA were included in the study. The mean duration of treatment before and after folinic acid supplementation was 1.1 years and 1.8 years, respectively. After the start of folinic acid supplementation, the mean number of episodes per patient-year of hepatotoxicity and gastrointestinal toxicity decreased from 2.30 to 0.32 (p < 0.001) and from 1.09 to 0.29 (p = 0.002), respectively. The mean number of disease flares and clinical remissions per patient-year did not change significantly. CONCLUSION: In our JIA patients, folinic acid supplementation resulted in a significant reduction in the most common side effects of MTX, without affecting the clinical efficacy of the drug.     

Protocol for clinical monitoring of juvenile idiopathic arthritis

The development of new and more efficacious therapeutic agents, though expensive and potentially toxic, helped to implement objective measures to quantify the improvement and to monitor the evolution of inflammatory rheumatic diseases. The aim of our protocol (PMAIJ) is to supply rheumatologists and paediatricians with a useful tool for follow-up of juvenile arthritis patients using validated instruments for the evaluation of activity, functional capacity and response to treatment. PMAIJ has 2 pages. The first page is filled only at the initial evaluation; the second page is filled at first and in all the appointments after that. The application of this protocol would contribute to the standardization of procedures in different Paediatric Rheumatology Centres and would help to obtain useful information on the clinical evolution of JIA patients followed in Portugal.     

Quality of randomized clinical trials in juvenile idiopathic arthritis

Objectives. We evaluated the quality of randomized clinicaltrials (RCTs) of therapy for juvenile idiopathic arthritis (JIA)using an individual component approach and assessed temporalchanges. Methods. A systematic review of the literature was performedto identify all RCTs involving exclusively JIA patients. Twoinvestigators independently assessed the identified articlesfor six quality indicators: generation of allocation sequence,allocation concealment, masking, intention-to-treat (ITT) analysis,dropout rates and clearly stated primary outcome. Results. Fifty-two RCTs involving JIA patients were assessed.Generation of allocation sequence was unclear in 79% of thestudies. Reporting of allocation concealment was adequate inonly one-third of the studies. Masking was adequate in 73%,inadequate in 19% and unclear in 8% of the reports. ITT analysiswas employed in 37% of the reports. Per-protocol analysis wasused in 40% and in 23% the method was unclear. Most of the reports(67%) had dropout rates     

Pulmonary function in children with juvenile idiopathic arthritis and effects of methotrexate therapy

Summary Objective To evaluate impairment of lung function as an adverse effect associated with methotrexate therapy in patients with juvenile idiopathic arthritis (JIA). Methods We performed pulmonary function testing including diffusion capacity for carbon monoxide as measured by the single breath method (DLCO-SB) in 89 children with juvenile idiopathic arthritis. Forty (45%) were treated with methotrexate for a median of 24 months (range 3 to 120 months). Except for the presence of asthma in two children, there was no clinical or radiological evidence of pulmonary disease. Results Pulmonary function testing demonstrated moderate airway obstruction in two children with known bronchial asthma. Neither obstructive nor restrictive alteration of ventilation was found in any other patient. Two juvenile idiopathic arthritis patients showed a reduced CO diffusion capacity of 64 and 67%. One of them was treated with methotrexate. Conclusions With regard to lung function impairment treatment with low dose methotrexate appears to be safe even when performed for several years reaching a total amount of up to 3.5 g. In contrast to studies performed in adult rheumatoid arthritis patients, in children with juvenile idiopathic arthritis impairment of lung function is a rare event. Received: 23 February 2001 Accepted: 16 May 2001     

Measuring clinical response and remission in juvenile idiopathic arthritis

PURPOSE OF REVIEW: The increasing availability of new medications for the treatment of juvenile idiopathic arthritis has made the accurate assessment of treatment outcomes critically important. The purpose of this review is to describe recent investigations focused on the development of new outcome measures in the domains of disease activity and joint damage, and to summarize recently published data within the area of health-related quality of life. RECENT FINDINGS: Since the development of the preliminary definition of disease improvement in 1997, the American College of Rheumatology pediatric response criteria have become the primary outcome measures in therapeutic trials in juvenile idiopathic arthritis. Additional definitions, including preliminary definitions of flare and remission have subsequently been added. Investigations have also sought to determine whether measures currently in use in adult rheumatoid arthritis might have utility in juvenile idiopathic arthritis. As the pathogenesis of juvenile idiopathic arthritis becomes better understood, biomarkers have significant potential as outcome measures. Lastly, recent reports regarding the health-related quality of life in large cohorts of children with juvenile idiopathic arthritis are important in guiding investigators towards areas most in need of improved treatment. SUMMARY: Significant progress has been made in the measurement of outcomes in juvenile idiopathic arthritis. Outcome measures will continue to be designed and tested to keep pace with the development of new therapies and the improved understanding of the disease pathogenesis.     

应关注幼年特发性关节炎的正确用药

近年来,对幼年特发性关节炎(juvenile idio-pathic arthritis,JIA)治疗理念和方法的认识有不少重要进展.停止或减缓关节破坏,缓解关节症状,改善关节功能,防止并发症的发生,帮助儿童尽可能正常的生长发育是治疗的主要目的,而早期、积极的治疗是停止或缓解疾病进展的唯一方法.     

Caregiver recall of treatment recommendations in juvenile idiopathic arthritis

OBJECTIVE: Health care providers in juvenile idiopathic arthritis (JIA) might refer to caregivers' self-report of children's treatment-related behaviors to assist in clinical decisions. However, caregivers may believe that they are adhering to treatment even though they have a different understanding of recommendations than that intended by the medical team. We examined whether caregiver recall of children's JIA treatment matched actual recommendations at baseline and 3, 6, 9, and 12 months. METHODS: A total of 235 primary caregivers were recruited from rheumatology clinics at 2 pediatric university-based teaching hospitals in Canada. Using the Parent Adherence Report Questionnaire, caregivers indicated whether their child was prescribed medications and/or exercises. Medical charts were reviewed to determine the prescribed treatment. Level of agreement between both sets of data was then examined. RESULTS: A total of 175 caregivers provided complete data. Mean age of the children was 10.2 years (68.6% girls); 44.6% were diagnosed with oligoarthritis. Kappa coefficients for medication represented substantial to almost perfect agreement beyond chance, with better levels of agreement at 12 months (kappa = 0.81, 95% confidence interval [95% CI] 0.68, 0.94) than at baseline (kappa = 0.61, 95% CI 0.47, 0.76). Kappa coefficients for exercise represented slight to moderate agreement beyond chance, with better agreement at 12 months (kappa = 0.44, 95% CI 0.24, 0.63) than at baseline (kappa = 0.27, 95% CI 0.08, 0.47). CONCLUSION: Weaker agreement for the exercise regimen raises concern that caregivers may pay less attention to exercise recommendations or that these recommendations may not be easily understood.