Rheumatoid Arthritis: Pontikaki I

Gerloni V, Pontikaki I, Gattinara M, Fantini F. · UOS di Reumatologia Infantile, Istituto Ortopedico Gaetano Pini, Milano, Italia. · Reumatismo. · Pubmed #17898886 links to  free full text

Abstract: The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some autoinflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.

De Marco G, Gerloni V, Pontikaki I, Luriati A, Teruzzi B, Salmaso A, Valcamonica E, Gattinara M, Fantini F. · Ist. Ortopedico Gaetano Pini, U.O. di Reumatologia e U.O.S. Reumatologia Infantile, Cattedra di Reumatologia, Università di Milano. · Reumatismo. · Pubmed #17435842 links to  free full text

Abstract: OBJECTIVES: To evaluate, in long-term open label prospective study, infliximab as therapeutic choice for Juvenile Idiopathic Arthritis (JIA) non responsive to conventional therapy. METHODS: We enrolled to treat with infliximab 78 JIA patients (66 females, 12 males): the mean age was 20.7+/-7.1 years (median 20.9, range 5.4-34.9); mean JIA duration was 13.6+/-7.6 years (median 13.5, range 0.4-31.4). Infliximab, at dose of 3-10 mg/kg/infusion added to weekly subcutaneous Methotrexate or other previous DMARDs, was administered by intravenous infusions at weeks 0, 2, 6 and every 8 weeks thereafter. Chest X-ray, Mantoux's test, electrocardiogram were performed at baseline; laboratory tests and clinical evaluation were performed at each infusion. Response was evaluated according to ACR improvement criteria. RESULTS: Mean treatment period was 21.6 months+/-18.8 (median 14.7, range 1.4-72.4). Just after first infusion most of patients reported significant improvement in pain, fatigue, morning stiffness. Infliximab is still successfully administered to 23 patients (29.5%); 55 (70.5%) patients suspended because of: inefficacy (7), infusion reactions (17), adverse events (9), disease flare-up after a period of effectiveness on synovitis, pain, and morning stiffness (19), remission (2), lack of compliance to treatment (1). Infusion reactions, like dyspnea, flushing, chills, headache, hypotension, anxiety, throat oedema, were observed in 29 patients (34.5%). Anti-DNA antibodies were present in 7 patients (none developed Systemic Lupus Erythematous). CONCLUSIONS: Infliximab showed impressive effectiveness treating refractory JIA, although most of patients had to discontinue treatment because of disease flare-up or adverse events. Infliximab may represent a good therapeutic choice in patients non-responders to Methotrexate.

Favalli EG, Arreghini M, Arnoldi C, Panni B, Marchesoni A, Tosi S, Pontikaki I. · No affiliation provided · Arthritis Rheum. · Pubmed #15077278 links to  free full text

This publication has no abstract.

Gerloni V, Pontikaki I, Gattinara M, Fantini F. · Department of Rheumatology, Istituto Ortopedico Gaetano Pini, Milan, Italy. · Ann Rheum Dis. · Pubmed #17981916 No free full text.

Abstract: OBJECTIVE: To report adverse events (AEs) seen in a large cohort of patients with juvenile idiopathic arthritis (JIA) treated with tumour necrosis factor (TNF)alpha 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-TNFalpha 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-TNFalpha therapy as much as possible.

Cimaz R, Cazalis MA, Reynaud C, Gerloni V, Zulian F, Biggioggero M, Martini G, Pontikaki I, Fantini F, Mougin B, Miossec P. · Unité Mixte Hospices Civils de Lyon-BioMérieux, Lyon, France. · Ann Rheum Dis. · Pubmed #17324969 No free full text.

Abstract: OBJECTIVE: To investigate the genetic contribution of cytokine gene polymorphisms (interleukin 1 (IL1) and tumour necrosis factor alpha (TNFalpha)) on disease phenotype and on response to TNF-blocking agents in a population of patients with juvenile idiopathic arthritis (JIA). METHODS: A cohort of 107 consecutive patients with JIA who were receiving treatment with anti-TNF agents was enrolled in this study. Analysis of genetic polymorphisms for IL1B +3954, IL1RA +2018, TNFalpha -238 and TNFalpha -308 was performed by enzyme-linked oligo sorbent assay, and compared with those obtained from 630 healthy Caucasians and 263 adult patients with rheumatoid arthritis. Relevant demographic, clinical and laboratory data were collected from clinical charts and entered into a customised database, and chi(2) analysis was performed to compare cytokine polymorphisms with disease type according to the International League of Associations for Rheumatology criteria, presence of uveitis, rheumatoid factor and anti-nuclear antibody positivity, erosive disease, frequency of adverse effects to anti-TNF and clinical response after 3 months. RESULTS: The T/T genotype of the IL1B +3954 polymorphism was absent in patients with JIA and present in 5% of controls (p = 0.015). No significant correlation was found between the studied polymorphisms and clinical or laboratory variables considered. Clinical response to TNF inhibitors at 3 months was not associated with the genetic polymorphisms considered. CONCLUSION: In our cohort, the absence of the rare IL1B +3954 gene polymorphism was associated with JIA, but without specificity to particular disease phenotypes. The TNF and IL1 gene polymorphism studied did not seem to be associated with response to anti-TNF treatment.

Lurati A, Pontikaki I, Teruzzi B, Desiati F, Gerloni V, Gattinara M, Cimaz R, Fantini F. · Gaetano Pini Institute, Milan, Italy. · Arthritis Rheum. · Pubmed #16646003 links to  free full text

Abstract: OBJECTIVE: There are no validated criteria to evaluate clinical response in juvenile idiopathic arthritis (JIA). The purpose of this study was to compare 4 sets of criteria (2 from the American College of Rheumatology [ACR] and 2 from the European League Against Rheumatism [EULAR]) for clinical response evaluation in JIA patients treated with methotrexate and/or anti-tumor necrosis factor alpha drugs. METHODS: Seventy-five patients with JIA were evaluated at baseline and after 6 months of therapy with second-line drugs. Mean age at study onset was 12.8 years (range 2-32.9 years). Diagnoses were systemic JIA (n = 16), rheumatoid factor-positive JIA (n = 5), rheumatoid factor-negative JIA (n = 9), persistent oligoarticular JIA (n = 10), extended oligoarticular JIA (n = 33), and psoriatic arthritis (n = 2). Clinical response was evaluated with the ACR Pediatric 30 criteria and the ACR 20% response criteria (ACR20), and with the EULAR Disease Activity Score (DAS) and 28-joint DAS (DAS28). Patients with EULAR criteria responses of "good" or "moderate" were classified as responders. Responders and nonresponders according to the different criteria were then compared. RESULTS: For patients younger than 16 years, Cohen's kappa varied between 0.51 and 0.72, with a good-to-excellent reproducibility index for all comparisons, except for the DAS28/ACR20 comparison. The best agreement was obtained by comparing the DAS and the ACR Pediatric 30. For patients older than 16 years, the reproducibility index was good or excellent in only 2 cases, i.e., comparing the DAS and the ACR Pediatric 30 and comparing the DAS and the DAS28 (as expected). CONCLUSION: Our study shows a good agreement overall for the different criteria tested. The highest concordance was observed between the DAS and the ACR Pediatric 30, the lowest between the DAS28 and the ACR20. Our data suggest that the ACR Pediatric 30 criteria can be used also in adult patients affected by JIA, and that the original DAS can be an alternative to the ACR Pediatric 30 in both children and young adults with JIA.

Pontikaki I, Gerloni V, Gattinara M, Luriati A, Salmaso A, De Marco G, Teruzzi B, Valcamonica E, Fantini F. · Unità Semplice di Reumatologia Infantile, Dipartimento e Cattedra di Reumatologia dell'Università di Milano. · Reumatismo. · Pubmed #16639486 links to  free full text

Abstract: OBJECTIVES: To report adverse events registered in our population affected by JIA and treated with anti-TNFalpha blockers. METHODS: Ninety-five patients were enrolled to be treated with Etanercept, median age 14 years (range 4-34); median duration of therapy 12 months (range 1-40). 19 patients were also treated with MTX (median dose 12.5 mg/week). Fifty-six patients were enrolled to be treated with Infliximab associated with MTX (median dose of MTX 8.8 mg/week), median age 23.2 years (range 7.8-34.9); median duration of therapy 20.1 months (range 1.4-60.4). All adverse events were divided in definitely, probably and possibly related to the biologic agent. RESULTS: Side effects definitely related to Infliximab were the reactions to infusions and the Anti-dsDNA positivity. Side effects definitely related to Etanercept were severe headache and thrombocytopenia. Side effects probably correlated to both the biological agents were behavioural modifications and pain amplification syndrome. Probably correlated to the treatment with Etanercept was the onset of Crohn's disease in 3 patients. Possibly correlated to the biological agents were the new onset or flare-up of Chronic Iridocyclitis and single cases of thyroideal cancer, hypoglossal nerve paralysis and a severe Cytomegalovirus pulmonary infection. No case of tuberculosis infection was registered during this study. CONCLUSIONS: Treatment with a TNFalpha antagonist seems to be associated with various adverse events. Some of them, like onset of Crohn's disease, behavioural modifications are unusual and others, like pain amplification syndrome were never described before. Children and young adults affected by JIA should be monitored very carefully so as to limit as much as possible the risk of serious side effects on anti-TNFalpha therapy.

Gerloni V, Pontikaki I, Gattinara M, Desiati F, Lupi E, Lurati A, Salmaso A, Fantini F. · Istituto G. Pini, Milan, Italy. <> · Arthritis Rheum. · Pubmed #15693004 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate (MTX) in juvenile idiopathic arthritis (JIA) with an active polyarticular course that is not responsive to MTX. METHODS: Twenty-four young adults with long-lasting, refractory JIA were enrolled in an open, prospective, 2-year pilot study. Patients received intravenous infliximab at 3 mg/kg of body weight at weeks 0, 2, and 6 and every 8 weeks thereafter, with weekly subcutaneous MTX. RESULTS: The median duration of therapy was 9.1 months. Significant improvements were observed in the number of joints (28-joint count) with active disease (median 6 at baseline, 2 at 2 weeks, 0 at 6 months, 0 at 1 year; P < 0.05). Pain as well as patient's and physician's global assessments of disease status were assessed on 0-100-mm (0 = best; 100 = worst) visual analog scales (VAS). There were significant improvements in VAS pain scores (45 at baseline, 25 at 2 weeks, 8.5 at 6 months, 10 at 1 year; P < 0.05), patient's global assessment of disease status (50 at baseline, 22 at 2 weeks, 11.5 at 6 months, 18 at 1 year; P < 0.05), and physician's global assessment of disease status (50.5 at baseline, 22.5 at 2 weeks, 6.5 at 6 months, 10 at 1 year; P < 0.01). In addition, there were significant improvements in the erythrocyte sedimentation rate (64 mm/hour at baseline, 36 mm/hour at 2 weeks, 23.5 mm/hour at 6 months, 35 mm/hour at 1 year; P < 0.01) and C-reactive protein level (4.9 mg/dl at baseline, 2.8 mg/dl at 2 weeks, 3.1 mg/dl at 6 months, 3.2 mg/dl at 1 year; P < 0.005). The percentage of patients meeting the American College of Rheumatology 20% improvement criteria at each assessment ranged from 54.2% to 86.7%. Of the responses on the Disease Activity Score in 28 joints, 37.5-63.6% were classified as "good," 14.3-33.3% were classified as "moderate," and 18-37.5% were classified as "no response." Twelve patients (50%) had adverse events, and 5 patients (20.8%) withdrew. CONCLUSION: Infliximab plus MTX showed high effectiveness and safety in short- and medium-term treatment of long-lasting refractory JIA. A controlled multicenter clinical trial is needed.

Gerloni V, Cimaz R, Gattinara M, Arnoldi C, Pontikaki I, Fantini F. · Rheumatology Department, University of Milan, Centre for Rheumatic Children, Gaetano Pini Institute, Milan, Italy. · Rheumatology (Oxford). · Pubmed #11511760 links to  free full text

Abstract: OBJECTIVE: This open prospective trial was performed in order to assess the efficacy and safety of cyclosporin A in the treatment of patients with juvenile chronic arthritis (JCA). METHODS: Thirty-four of the patients enrolled were affected by systemic-onset disease and seven by chronic anterior uveitis associated with JCA. The cyclosporin dose was usually 3-5 mg/kg per day. The average duration of therapy was 1.4 yr, with a maximum of 7.2 yr. RESULTS: The efficacy of treatment was mainly evident in terms of control of fever and reduction of steroid therapy. The benefits with respect to arthritis, laboratory parameters and uveitis seemed to be less clear-cut. Side-effects were frequent but usually mild or reversible. Sixty-six per cent of the study population withdrew from therapy because of inefficacy or side-effects. Eight systemic patients withdrew from therapy owing to complete remission. CONCLUSION: Cyclosporin can be used in the treatment of JCA, its main benefits being the control of fever and a steroid-sparing effect.