Maria Trachana

Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis : a randomised trial

BACKGROUND Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedmans test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

The effect of anti-TNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis.

Our aim was to study the effect of anti-TNF treatment on immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Thirty-one children (mean age:12.9+/-4.6 years) treated with anti-TNFs plus Disease Modifying Anti-Rheumatic Drugs (DMARDs) and 32 age-matched children treated only with DMARDs were vaccinated with two doses of PCV7. After the first vaccine dose geometric mean titers (GMTs) were significantly increased for all vaccine serotypes (p<0.0001) in both groups and were found to be protective (>0.35microg/ml) in 87-100% of all children, depending on the serotype. Children receiving anti-TNFs achieved a significantly lower GMTs against serotypes 4, 14 and 23F (p<0.05). A >or=4-fold increase of the baseline titers to >or=5 vaccine serotypes was observed in 50% and 75% of the anti-TNF and control patients, respectively (p=0.0697). No patient developed vaccine-associated serious adverse events or disease flares.

Safety and efficacy of adalimumab treatment in Greek children with juvenile idiopathic arthritis

Objectives: To evaluate the safety and efficacy of adalimumab (AD) administration in patients with juvenile idiopathic arthritis (JIA). Methods: Twenty-six patients were enrolled from January 2004 to January 2008 in this prospective observational study. Inclusion criteria were either unresponsiveness to disease-modifying anti-rheumatic drugs (DMARDs; n = 17) or to other anti-tumour necrosis factor (anti-TNF) agents (n = 9) or development of uveitis under other anti-TNFs (n = 2 of the 9). Efficacy was estimated using the American College of Rheumatology Pediatric (ACR Pedi) criteria. Results: After 1–5 years of AD exposure, nine different adverse events (AEs) were recorded (12.6 AEs/100 patient-years), mainly mild respiratory tract infections and injection site-related reactions. Serious AEs (SAEs, 2.8/100 patient-years) were the development of abscess at the site of injection (n = 1) and lethal sepsis (n = 1). The ACR Pedi ≥ 30 responses for the first to the fifth year of treatment were 88.5, 57.7, 50.0, 34.6, and 11.5%, respectively. In total, 17 of the 26 (65.4%) patients responded to AD. Five of the 11 patients under steroids discontinued them 6 months post-treatment. Seven patients required weekly AD treatment to maintain remission and four of them benefited from this policy. Recurrent uveitis was hindered in three of the six patients, no new cases were recorded, and radiological regression was observed in two of the four patients with lesions. Conclusions: AD was safe and efficacious during the study period in the majority of patients. However, vigilance is required for the early detection of severe and potentially fatal infections. AD may control recurrent uveitis and radiological progression.

Case Report. Hepatic abscesses due to Aspergillus terreus in an immunodeficient child

Summary. We report the first case of hepatitis due to Aspergillus terreus in a 13‐year‐old boy with common variable immunodeficiency that occurred while the patient was receiving secondary prophylaxis with fluconazole after an episode of pulmonary candidosis. The infection subsided after the addition of itraconazole to the combination of liposomal amphotericin B and granulocyte‐macrophage colony‐stimulating factor that he was receiving.

The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment

OBJECTIVE To study the significance of persistent (12 months) new autoantibodies, in Juvenile Idiopathic Arthritis (JIA) patients treated with either Infliximab (INFL) or Etanercept (ET) for 2 years. PATIENTS-METHODS 26 children under INFL (n=12) or ET (n=14) were prospectively studied. A large panel of autoantibodies was tested using indirect immunofluorescence (ANA, anti-dsDNA, anti-ENA, SMA, LKM, AMA, PCA, anti-R1, ATA), ELISA (ANA, anti-ENA, anti-cardiolipin, ANCA), immunoblotting assay (anti-ENA: anti-Ro, anti-La, anti-Sm, anti-URNP, anti-Jo, anti-Scl70, anti-centromere, anti-ribosomal and anti-histone) and rate nephelometry (RF). RESULTS Apart from the positive patients for ANA (13/26) and RF (2/26) prior to anti-TNF treatment, 6/26 patients (23%) developed new autoantibodies (SMA, anti-R1, ATA) which persisted for 12-50 months. None developed antibodies to nuclear antigens. In only one case, ATA was associated with the development of Hashimotos thyroiditis. CONCLUSIONS These findings indicate that in JIA patients in contrast to adult RA patients, development of new autoantibodies to various nuclear antigens is rare. Other non relevant to rheumatic diseases autoantibodies, may appear and persist for >12 months, but very rarely they may be related to clinical entities, especially in the presence of a positive family history of autoimmunity.

Investigation of juvenile idiopathic arthritis susceptibility loci: results from a Greek population.

The strategy of studying the putative role of RA susceptibility genetic factors in the development of juvenile idiopathic arthritis (JIA), an autoimmune disease characterized by persistent chronic arthritis, has been proven highly successful so far. Moreover, accumulated evidence indicates that an ethnic heterogeneity of genetic factors exists for rheumatic disorders. We investigated whether five single nucleotide polymorphisms (SNPs), previously found to be associated with JIA in various populations so far, are also associated with JIA in Greece. The sample set consisted of 128 Caucasian JIA patients and 221 healthy controls from Northern Greece. Five Single Nucleotide Polymorphisms (SNPs) markers, namely TRAF1/C5 rs10818488, PTPN22 rs2476601, STAT4 rs7574865, CD247 rs1773560 and PTPN2 rs7234029 SNPs were genotyped in a case-control study with Restriction Fragment Length Polymorphisms (RFLPs) or Taqman primer-probe sets. This study demonstrated for the first time in a Greek population that the PTPN22, TRAF1/C5 and CD247 polymorphisms examined are associated with an increased susceptibility to JIA, thus suggesting that the respective risk alleles may confer susceptibility to clinically distinct disorders. However, our results did not demonstrate any association of STAT4 and PTPN2 SNPs with the disease in our population, thus highlighting the importance of comparative studies in different ethnic populations.

Simultaneous changes in serum HMGB1 and IFN-α levels and in LAIR-1 expression on plasmatoid dendritic cells of patients with juvenile SLE.. New therapeutic options?

We investigated the simultaneous changes in serum levels of HMGB1 and IFN-α as well as in LAIR-1 expression on plasmatoid dendritic cells (pDCs) of juvenile systemic lupus erythematosus (jSLE) patients in order to explore their involvement in the disease pathogenesis and their correlation with disease activity and other characteristics. In total, 62 blood samples were studied from 26 jSLE patients (18 girls), aged 8–16 years. Twenty healthy subjects (16 girls) of comparable age were included as healthy controls (HCs). Concentrations of serum HMGB1 and IFN-α were assessed by ELISA and LAIR-1 expression on pDCs by five-color flow cytometry. The disease activity index was assessed by SLEDAI and ECLAM scores. It was found that mean serum levels both of HMGB1 and IFN-α were significantly increased in jSLE patients compared to HCs and in jSLE patients with active disease with or without active nephritis compared to those with inactive disease. Mean serum levels of HMGB1 were positively correlated with levels of IFN-α and both were positively correlated with the SLEDAI and ECLAM scores. The expression of LAIR -1 on pDCs of jSLE patients was significantly lower than that of HCs. In conclusion, our findings indicate that serum HMGB1 not only represents a potential marker of disease activity but together with the lack of LAIR-1 inhibitory function may contribute to the sustained inflammatory action of IFN-α in jSLE. In this regard, blocking the action of HMGB1 and its receptors or enhancing the expression/inhibitory function of LAIR-1 on pDCs should be included in future immune interventions for controlling jSLE.

Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti-tumor necrosis factor treatment and disease activity

Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non-anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P < .001, confidence interval [CI] = -101 to -331). Analysis according to anti-TNF treatment and disease activity showed that ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research.

Development of the autoinflammatory disease damage index (ADDI)

Objectives Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency. Methods We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds. Results More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain. Conclusions An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.

Chemical synoviorthesis with rifampicine and hyaluronic acid in haemophilic children

In response to the excellent work presented in a previous issue regarding synoviorthesis [1], we would like to report our own brief experience on synoviorthesis in haemophilic children. It is well known that intra-articular haemorrhage is very commonly seen in haemophilics, with a reported incidence that exceeds 80% [2]. Repeated episodes lead to hypertrophy and hypervascularity of the synovial membrane, thus predisposing to further bleeding and progressively resulting in the development of haemophilic arthropathy [3]. Standard conservative methods including factor replacement and physiotherapy do not always break this vicious cycle and continuous prophylaxis may be required. In chronic synovitis unresponsive to conventional treatment, synovectomy either surgical or preferably medical (synoviorthesis) is indicated. Radiation synovectomy (mainly with Yttrium or Phosphorous) is considered the method of choice, with demonstrated safety and efficacy, however, chemical synoviorthesis with rifampicine may be an effective alternative when radioactive materials are unavailable [4–8]. Hyaluronic acid, widely used in the treatment of osteoarthritis of the knee, has also shown promising results in hamophilic arthropathy, however, published data is limited and restricted to adult patients [2,9]. Hyaluronic acid is a natural substance from the group of saccharide bipolymers that are the building blocks of cartilage and synovial fluid. Although the exact mechanisms of its intervention in the complex pathogenesis of haemophilic arhtropathy are not yet entirely clear, it is considered to protect the cartilage by improving the functional characteristics of the joint fluid and hyaluronic acid layer on the surface of the articular cartilage [9]. In addition, it offers the great advantage of fewer and less painful injections compared with rifampicine synoviorthesis. In the present report, eight children aged 8–16 years (mean age 11 years), out of 23 children attending the haemophilic centre of the First Department of Pediatrics of Aristotle University of Thessaloniki, underwent synoviorthesis. All patients were suffering from haemophilia A presenting with grade I–III arthropathy as classified according to the Arnold–Hilgartner scale [10]. Chemical synoviorthesis, as a more readily available method, was performed using either rifampicine or hyaluronic acid. Indication for rifampicine injection was grade I or II arthropathy involving small joints (ankles and elbows), and for hyaluronic injection, grade III arthropathy or arthropathy affecting big joints (knee, shoulder), regardless of grade [2,6,9,11]. The technique of synoviorthesis included injection of 250 mg of rifampicine along with lidocaine once a week for five consecutive weeks or injection of 20 mg of hyaluronic acid once a week for a 3-week period. In all cases, patients were covered on the day of injection with antihaemophilic factor at a dose of 15 IU kg. In total, 11 joints were treated: five ankles, four elbows, one knee and one shoulder. All patients were evaluated by physical examination conducted by the same physician before synoviorthesis and during the follow-up period, which ranged from 6 to 12 months. Results were classified as excellent, good, fair or poor, both on a subjective and an objective basis (parent/patient assessment of functional ability as well as physician evaluation of presence of synovitis and haemarthrosis, clinical improvement and recovery of function) [2]. The results obtained are seen in Table 1. Out of 11 joints treated, synoviorthesis was completed in eight cases. In patient 2, treatment was interrupted after the first rifampicine injection due to persistent haemarthrosis confirmed by ultrasound, laboratory examination revealing the presence of factor VIII Correspondence: M. Athanassiou-Metaxa MD PhD., Ag. Sofias 30, Thessaloniki 546 22, Greece. Tel.: + 30 310857 111; fax: + 30 310857 111; e-mail: marina@med.auth.gr