M. Gattinara

Focus on adverse events of tumour necrosis factor α blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients

Objective: To report adverse events (AEs) seen in a large cohort of patients with juvenile idiopathic arthritis (JIA) treated with tumour necrosis factor (TNF)α blockers (infliximab and etanercept). Methods: All patients with JIA treated with infliximab or etanercept at the Paediatric Rheumatologic Centre of the G Pini Institute (Milan, Italy) from November 1999 to February 2006, were enrolled in an open, single-centre, long-term prospective study Results: In all, 163 patients (68 infliximab, 95 etanercept) were enrolled. Mean (SD) age of onset was 6.4 (4.8) years, mean age 17.1 (9.2) years, mean therapy duration 22.9 (17.6) months. A total of 45 patients (32 infliximab, 13 etanercept) failed to respond to or did not tolerate the first therapy and switched to a second one. In all, 208 treatments (81 infliximab, 127 etanercept) were performed. A total of 71 AEs occurred in 51 (62.9%) patients on infliximab and led to discontinuation in 26 (32.1%); 133 AEs occurred in 69 (54.3%) patients on etanercept and led to discontinuation in 18 (14.2%). Some AEs, such as thrombocytopoenia, neuropsychiatric disorders, new onset of Crohn disease and new onset or flare-up of chronic iridocyclitis (CIC), are unusual and have rarely been described before, yet proved to be significant in frequency and/or clinically noteworthy in the large population we followed. Conclusions: In our 6-year study, anti-TNFα agents infliximab and etanercept were well tolerated and safe, and were associated with only few serious, but all reversible, AEs. However, such inhibitors are associated with various and numerous AEs. Children and young adults affected by JIA should be carefully monitored so as to limit the risk of AEs during anti-TNFα therapy as much as possible.

Anti-CD 20 monoclonal antibody (rituximab) treatment for inflammatory ocular diseases

Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B cells and widely used in the treatment of non-Hodgkins lymphoma and rheumatoid arthritis. There is a growing amount of literature which suggests that rituximab may be useful for inflammatory ocular diseases and intraocular lymphoma. Few cases have been reported on treatment of refractory scleritis, peripherative ulcerative keratitis, uveitis and ocular surface inflammatory disorders. Rituximab may be effective in the treatment of ocular inflammatory diseases in particular the most aggressive, recalcitrant and sight-threatening forms of inflammation such as uveitis associated to juvenile idiopathic arthritis. We review the literature covering the use of Rituximab in these conditions and report our results on the efficacy of Rituximab in the treatment of 8 children with very severe and long-standing uveitis who failed to respond to one or more TNF blockers. Our patients showed improvement in activity of uveitis, reduction of concomitant corticosteroids and immunosuppressants after a mean follow-up time of 14.87 months on rituximab. No serious adverse events were encountered in our treated patients. Although further studies are needed for assessing the efficacy of rituximab and the exact dosing regimen, rituximab may be considered as a treatment alternative in patients with the most aggressive forms of inflammatory ocular diseases who fail to respond to conventional and anti-TNF immunosuppressive agents.

Accuracy of Wallace Criteria for Clinical Remission in Juvenile Idiopathic Arthritis: a Cohort Study of 761 Consecutive Cases

Objective. To evaluate disease course and clinical usefulness in some categories of juvenile idiopathic arthritis (JIA) by applying newly developed Wallace definitions of remission off drugs. Methods. In a retrospective study, charts of patients with chronic form of primary (idiopathic) arthritis followed from our center since 1970 were reviewed and clinical/laboratory variables were collected for further analysis. Results. The cohort included 761 eligible patients [516 (67.8%) female, 245 (32.2%) male] with JIA. Mean disease onset age (± standard deviation) was 6.25 ± 4.4 years (range 0.5–15.9). Disease mean duration to last visit was 10.02 ± 4.31 years. Followup mean period was 7.6 ± 6.4 years (range 1.5–35 yrs). A total of 247 (32.46%) patients achieved remission according to criteria [persistent oligoarthritis 153 (42.9%); extended oligoarthritis 15 (13.1%); seronegative polyarthritis 21 (22.4%); systemic arthritis 33 (33.7%); enthesitis related arthritis (ERA) plus juvenile psoriatic arthritis (JPsA) 25 (33.4%)]. No patients with seropositive polyarthritis achieved remission status (p < 0.001). In remitted patients the mean survival function (± standard error of the mean) before relapse calculated by Kaplan-Meier was of 20.9 (± 1.3) months overall: 21.7 (± 0.46) in persistent oligoarthritis, 25.0 (± 6.6) in extended oligoarthritis, 26.7 (± 13.2) in seronegative polyarthritis, and 17.6 (± 2.44) in ERA+JPsA (p > 0.1). Conclusion. In our cohort about one-third of cases obtained a remission episode in 4 decades of observation, with a significant difference between oligoarthritis and other categories (p < 0.001) using the Kaplan-Meier method; the remission status duration before a relapse has been about 20 months, without a significant difference between JIA categories.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial

BACKGROUND Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING Italian Agency of Drug Evaluation.

Drug survival and reasons for discontinuation of the first course of biological therapy in 301 juvenile idiopathic arthritis patients

The objective of this study was to determine long-term effectiveness and safety of 1st biological treatment (BT) in a cohort of 301 juvenile idiopathic arthritis (JIA) patients (pts), non-responders to disease-modifying antirheumatic drugs (DMARDs), in terms of drug survival (continuation rate on therapy) and to identify the baseline predictors of treatment discontinuation. Each JIA pt enrolled in BT is prospectively assessed at the start of treatment and then every 2 months for the evaluation of safety and efficacy according to ACR-Pedi30 criteria. All clinical charts of pts who started a BT between November 1999 and July 2010 have been reviewed. Survival analysis methods suitable for competing risks were used to study time to drug discontinuation due to disease control (defined according to Wallace criteria) or failure [adverse event (AE), lack of efficacy (LaE) or loss of efficacy (LoE) according ACR-Pedi30]. A number of 301 JIA pts, non-responders or intolerant to DMARDs and treated with one or more cycles of BT, were identified. Median disease duration, from onset to the beginning of 1st BT, was 7.8 years (interquartil range 2.21-15.1). In total, there were 294 1st corses with anti-TNF agents, 5 with abatacept and 2 with anakinra. A number of 298 pts were included in the analysis for drug discontinuation (3 pts with no follow-up data after their first dose of BT were excluded). The median follow-up on treatment, before discontinuation due to every cause, was 53.7 months (range 0.45-124.45). One hundred and sixty-five pts discontinued BT: 27 due to disease control, 135 because of failure (78 AEs, 12 LaE and 45 LoE), 3 pts temporarily stopped for pregnancy. Among 135 pts who discontinued for failure, 117 switched to a 2nd BT. Among 27 pts who discontinued due to remission, 13 pts restarted on BT for relapse of disease activity (10 pts restarted with the same BT, 3 switched to a different one). Predictors of discontinuation due to AE were female gender (P=0.01) and longer disease duration (P=0.02). Predictors of discontinuation due to LaE or LoE were systemic onset and polyarthritis FR positive (vs other JIA subtypes) (P<0.05) and use of mAb-anti-TNF (vs sTNFR) (P=0.02). Predictors of discontinuation due to inactive disease were male gender and shorter disease duration (P<0.05). Although only few pts discontinued BT due to a complete and persistent disease control, the majority of them remained on BT for a long time, suggesting that in our cohort of JIA pts, affected by a severe long lasting refractory disease, BT was globally well tolerate and efficacious in controlling the disease.

Anakinra in systemic juvenile idiopathic arthritis (soJIA) non responsive to antiTNF.

TNF-inhibitors have demonstrated a favourable benefit-to-risk profile. Intolerance, lost of efficacy or adverse events led to other options as the antagonist of the IL-1 receptor (Anakinra), in SoJIA. 206 pts were treated with TNF inhibitors; 45 patients (22%) were affected by SoJIA.

Baseline ultrasound examination as possible predictor of relapse in patients affected by juvenile idiopathic arthritis (JIA)

Objectives To define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares. Methods 88 consecutive patients with JIA—46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months—underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years. Results US was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US-negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18). Conclusions US abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories.

A controlled trial of intra-articular corticosteroids with or without methotrexate in oligoarticular juvenile idiopathic arthritis

In contrast with the numerous controlled trials conducted in polyarticular or systemic juvenile idiopathic arthritis (JIA), little evidence-based information is available for oligoarticular JIA. As a result, the management of children with this subtype, which is the most prevalent in Western countries, is largely empiric. Intra-articular corticosteroid (IAC) injection is the therapy of first choice for oligoarthritis in many pediatric rheumatology centers. However, although IAC injections are usually highly efficacious, relapses of synovitis are common and sometimes occur only a few months after the procedure. It is still unclear whether concomitant administration of methotrexate (MTX) may increase and prolong the effectiveness of IAC injections.

Relationship between delayed menarche and bone density in patients affected by juvenile idiopathic arthritis

The aim of our study was to prospectively evaluate bone density in adolescents females with JIA, and to correlate the results with puberty. Lumbar spine (L2–L4) areal bone mineral density (aBMD) (assessed by Dual X-ray Absorbiometry, DXA) was monitored every 6–12 months in a group of 38 girls with JIA. The evaluated bone density accrual during the peripubertal time as well as absolute and relative (Z-score) aBMD in relationship with age at menarche, JIA subset, disease activity, corticosteroid and methotrexate treatment was assessed. Height, body mass index, Bone Mass Content values were also collected. Volumetric BMD evaluated with a geometric correction formula has been calculated and compared to aBMD. Patients were divided into two groups: - group I included girls with menarche age within normal limits for italian standards; - group II included girls with delayed menarche. The BMD values and Z scores in group I were not significantly different to normal population. The BMD values and Z scores in group II were significantly decreased when compared to the normal population (p < 0.001). With a multivariate analysis only age at menarche seemed independently related to peripubertal mineralization (p = 0.025, r between -0.65 and -0.75). With a binary logistic analysis only disease activity (ESR and Hgb values) seems independently related to a menarche delay (1.24 ± 0.4 for each mm/h). Our data show a critical role for disease activity in determination of a regular pubertal onset and an optimal bone density achievement.

Chronic Recurrent Multifocal Osteomyelitis (CRMO): four cases treated with aminobisphosphonate (pamidronate)

CRMO is an autoinflammatory disease of children and young adults, characterized by the insidious onset of local pain and swelling in affected bone and fever. The bone lesions are radiologically characterized as multiple luciens surrounded by defined zones of patchy but dense sclerosis, cortical tickening from periosteal new bone formation, and increased bone size with different bones involved. Diagnosis is based upon laboratory tests (elevated levels of CRP/ESR), bone scintigraphy and MRI findings and is proved by open bone biopsy. Recently bisphosphonate therapy, and particulary i.v. pamidronate, has been proposed as treatment for patients both CRMO who do not responder to NSAIDs therapy. We report 4 cases of children affected by CRMO treated with a therapeutic cycle of aminobisphosphonate (pamidronate). In all pts. the diagnosis of CRMO was confirmed by bone scintigraphy, MRI and open bone biopsy. Pt.1. 12-years-old age (disease onset 10 yrs) presented with pain and swelling of right ankle, hip, knee and breastbone; CRP 2.4 mg/dl, ESR 100 mm/h. CRMO of right distal tibial epiphysis, right peroneal malleulus, breastbone and right hip. Pt.2. 5-years-old age presented with post-traumatic back pain in the past month and pathologic fracture of three thoracic vertebrae; normal values of CRP and ESR. CRMO of right iliac wing and thoracic spine (T8-T9-T10). Pt.3. 8-years-old age presented lumbar pain and swelling in the past month associated with antalgic scoliosis; CRP < 0.5 mg/dl, ESR 40 mm/h. CRMO of left distal tibial epiphysis, thoracic spine (T7–T8), right iliac wing. Pt.4 17-years-old age (disease onset 11 yrs) presented with post- traumatic pain and swelling of right hip and heel; CRP 1.6 mg/dl, ESR 29 mm/h. CRMO of bilateral distal tibial epiphysis, left calcaneus and neck of right femur. All 4 pts. were treated with 3 infusions of pamidronate 0.5–1.3 mg/kg/day in 250 ml of saline solution i.v. infusion at day 1,3,5 and then monthly. Severe adverse reaction was not found except for low-grade fever and lassitude on the day following administration. In all pts a remarkable improvement of painful symptoms was quikly achieved. MRI performed 1–3 months after treatment showed an important reduction of osteolytic, sclerotic and reactive bone lesions, and normalization of inflammatory values was observed. Our experience suggests that pamidronate maybe an efficacious alternative to conventional treatment in CRMO.