Title: Efficacy and safety of use of rituximab in systemic sclerosis: data from a italian multicenter

Transcription

1 RELAZIONE INTERMEDIA LUGLIO 2017 Title: Efficacy and safety of use of rituximab in systemic sclerosis: data from a italian multicenter database. Prospectives for the future. BACKGROUND Systemic sclerosis (SSc) is a life-threatening connective tissue disease characterized by vasculopathy, autoimmunity and fibrosis [1-2]. It is characterized by multiple tissue involvement with severely reduced quality of life in patients. Despite advances in early diagnosis of disease and effective treatment for some complications, SSc still remains characterized by high morbidity and mortality [3-4]. Prominent visceral involvement is a risk factor for increased morbidity and mortality. Immunosuppressive strategies to treat patients with SSc are largely disappointing and the treatment of SSc with diffuse skin involvement with and without associated interstitial lung disease (ILD) is not well established, because the effects of immunosuppressive therapies in randomized, controlled trials are limited [2,5-10]. These data underscore the necessity for development of novel therapies with disease modifying properties and acceptable safety profile over a long period of time. Rituximab, an inhibitor of B-cell function, has also shown promise as a new therapeutic option in various manifestations of SSc. Rituximab is a chimeric monoclonal antibody that targets CD20, which is expressed from pre-b cell stage to the pre-plasma cell stage. It was originally approved for the treatment of non-hodgkin s lymphoma and later for the treatment of rheumatoid arthritis and ANCA-associated vasculitis. Recently, some open label trials [11-16] and case reports [17-20] and one randomized controlled study [21] suggested a possible use, as therapy, of the chimeric monoclonal antibody against human

2 CD20 (rituximab), that depletes peripheral B cells, in SSc patients with progressive skin and lung involvement. Based on the available biological and clinical data to date, the use of RTX has to been considered in a subset of SSc patients with skin involvement and interstitial lung disease. The use of RTX in systemic sclerosis varies among the different countries, either in dosage as well as in retreatment course [22], and no data on use of this drug in Italy are not available. Unfortunately, in our country some limitations derive from the availability of the prescription of the drug for this disease. The primary objective of this study is to assess the use of RTX in different Italian centers in real life scenario between 2010 and 2017 through a database building. In the past six months an excel database (in attach) has been built with all clinical characteristics to evaluate: primary organ involvement that has requested the intervention with RTX (skin, lung, arthritis) therapeutic line of use of RTX, after which immunosuppressant therapies dosages and intervals between different courses of the drug In the same database sequential data of skin score, lung parameters, inflammatory markers and clinical assessment at time 0 and after 6 months or following times are requested: to assess the efficacy of RTX on skin involvement in systemic sclerosis patients to assess the efficacy of RTX on pulmonary functional parameters in SSc patients to evaluate the efficacy of RTX on other organ manifestations (i.e. articular involvement, etc). Finally, in the last part of database information on safety of the drug have been requested. Adverse events (AEs) will be carefully recorded at every clinical evaluation for all patients during the follow-up (first treatment or retreatment). AEs will be defined as severe when hospitalisation is required and/or death and/or life-threatening manifestations occur. Infusion reactions will be considered severe when intensive care unit support is required for treatment. The database was sent to all centres involved in the project to insert all data of adult patients with SSc, meeting the

3 American College of Rheumatology (ACR) criteria for SSc [23] or the new proposed criteria treated [24] and treated with at least one course of RTX from 2010 to 2017 and have at least one follow-up six months apart. The following clinical data will be included into the analysis: patients demographics (age, gender), disease duration from the first non-raynaud s symptom, disease subtype (limited or diffuse SSc) and autoantibodies status (presence of anticentromere, anti-rna polymerase III, antitopoisomerase 1 (anti-scl-70), anti-u1 small nuclear ribonucleoprotein). Additional data with a special focus on timing of RTX exposure, different dosage regimens, intervals between different courses of the drug and immunosuppressive co-treatment, immune profile and safety issues will be provided retrospectively by the participating centres. Immunosuppressive co-treatment and steroids intake will be defined as ongoing or newly started treatment at RTX treatment including a 3-month period before the first RTX infusion. Patients will be excluded if they have autologous stem cell transplantation between baseline and follow-up. Modified Rodnan Skin Score (mrss) [25] will be used as parameter of skin fibrotic involvement and will be reported in database at different time points (baseline and every 6 months). Furthermore to assess the efficacy of RTX on other organ manifestations we will report in database the arthritis characteristics considering disease activity score and health assessment questionnaire (HAQ). At baseline and every six months after RTX, activity index [26] and severity index will be inserted in database [27]. At the same time intervals, database will be completed with data on percentage of blood CD19+ cells, levels of immunoglobulins (IgG, IgA, IgM), inflammatory parameters (ESR and C-reactive protein) and complement values. All the centres will resend us own database in October, after we will analyse all data and we will request clinical characteristics for the post hoc nested case control observational study to confirm the efficacy of RTX.

4 Patients for this analysis will be chosen from every centre from their local cohort according to the matching criteria outlined below. Patients in the matched-control group will have to fulfil the old or the new criteria for SSc [23-24], do not receive RTX treatment and have at least one 6-month followup with report of the mrss and lung functional parameters. Matching parameters will be: mrss (max±25%), follow-up duration (max±3 months), scleroderma subtype (diffuse or limited), disease duration (best match in years) and immunosuppressive co-treatment (including 10 mg/day prednisone), baseline FVC (max±10%), and immunosuppressive co-treatment. We will project to collect all clinical data before the end of the year and analyse data in the subsequent months. Data will be analysed using the SPSS 20.0 software. Categorical variables will be expressed as numbers, and quantitative variables as mean±sd if normally distributed, and as median plus range if not. T-test, Mann-Whitney s test or Wilcoxon s rank sum test, as appropriate, will be used to compare continuous variables. A value of p<0.05 will be considered statistically significant.

5 References. 1. Medsger TA Jr, MasiAT:Epidemiology of progressive systemic sclerosis. Clin Rheum Dis 1979;5: Fuschiotti P. Current perspectives on the immunopathogenesis of systemic sclerosis. Immunotargets Ther Apr 11;5: Lally EV, Jimenez SA, Kaplan SR: Progressive systemic sclerosis: mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients. Semin Arthritis Rheum 1988; 18: Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Müller-Ladner U, Distler O, Iannone F, Pellerito R, Pileckyte M, Miniati I, Ananieva L, Gurman AB, Damjanov N, Mueller A, Valentini G, Riemekasten G, Tikly M, Hummers L, Henriques MJ, Caramaschi P, Scheja A, Rozman B, Ton E, Kumánovics G, Coleiro B, Feierl E, Szucs G, Von Mühlen CA, Riccieri V, Novak S, Chizzolini C, Kotulska A, Denton C, Coelho PC, Kötter I, Simsek I, de la Pena Lefebvre PG, Hachulla E, Seibold JR, Rednic S, Stork J, Morovic-Vergles J, Walker UA. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis Oct;69(10): Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers IM, Hong P, O'Hanlon D, Kaminska E, Markland J, Sibley J, Catoggio L, Furst DE: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma.arthritisrheum 2001;44: vandenhoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB:Comparison of methotrexate with placebo in the treatment of systemicsclerosis: a 24

6 week randomized double-blind trial, followed by a 24 week observational trial. British J Rheum 1996;35: Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, dubois RM:A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenouscyclophosphamidefollowed by oralazathioprine for the treatment of pulmonaryfibrosis in scleroderma.arthritis Rheum2006; 54: Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M; SclerodermaLungStudyResearch Group: Cyclophosphamide versus placebo in sclerodermalungdisease. N Engl J Med 2006; 354: Mouthon L, Berezne A, Guillevin L, Valeyre D: Therapeutic options for systemic sclerosis related interstitial lung diseases.respir Med 2010;104:S59-S Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, Goldin J, Arriola E, Volkmann ER, Kafaja S, Silver R, Steen V, Strange C, Wise R, Wigley F, Mayes M, Riley DJ, Hussain S, Assassi S, Hsu VM, Patel B, Phillips K, Martinez F, Golden J, Connolly MK, Varga J, Dematte J, Hinchcliff ME, Fischer A, Swigris J, Meehan R, Theodore A, Simms R, Volkov S, Schraufnagel DE, Scholand MB, Frech T, Molitor JA, Highland K, Read CA, Fritzler MJ, Kim GH, Tseng CH, Elashoff RM; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related

7 interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med Sep;4(9): Smith V, Piette Y, van Praet JT, Decuman S, Deschepper E, Elewaut D, De Keyser F:Twoyear results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement.jrheumatol 2013;40: Lafyatis, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW: B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis.arthritis Rheum 2009; 60: Bosello S, De Santis M, Lama G, Spanò C, Angelucci C, Tolusso B, SicaG,Ferraccioli G: B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther. 2010;12:R Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Paliogianni F, Sirinian C, Yiannopoulos G, AndonopoulosAP:Effect of long-term treatment with rituximab on pulmonaryfunction and skinfibrosis in patients with diffuse systemicsclerosis. ClinExpRheumatol 2012;30:S Smith V, Piette Y, Van Praet JT, Decuman S, Deschepper E, Elewaut D, De Keyser F. Twoyearresults of an open pilotstudy of 2-treatment course with Rituximab in patients with earlysystemicsclerosis in diffuse skininvolvement.jrheum 2013; 40: Bosello SL, De Luca G, Rucco M, Berardi G, Falcione M, Danza FM, Pirronti T, Ferraccioli G. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum Feb;44(4): Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, KorfiatisP, Yiannopoulos G, Andonopoulos AP: Isthere a role for B-celldepletionastherapy for

8 scleroderma? A case report and review of the literature.semin Arthritis Rheum. 2010; 40: McGonagle D, Tan AL, Madden J, Rawstron AC, Rehman A, Emery P, Thomas S: Successful treatment of resistantsclerodermaassociatedinterstitiallungdiseasewithrituximab.rheumatology2008;47: Yoo W. Successful treatment of steroid and cyclophosphamide-resistant diffuse scleroderma-associated interstitial lung disease with Rituximab.RheumatolInt2012;32: Fabri M, Hunzelmann N, Krieg T, RubbertA:Discordant response to Rituximab in a systemic sclerosis patient with associated myositis. J Am AcadDermatol 2008;58:S Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, AndonopoulosAP:Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study.rheumatology (Oxford). 2010; 49: Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6): Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma).arthritis Rheum 1980;23: van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci- Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale

9 DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, FesslerBJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE classification criteria forsystemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum Nov;65(11): Valentini G, D'Angelo S, Della Rossa A, Bencivelli W, Bombardieri S. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. IV: Assessment of skin thickening by modified Rodnan skin score.ann Rheum Dis. 2003;62: Valentini G, Silman AJ, Veale D: Assessment of disease activity.clinexprheumatol.2003;21(s29):s39 S Medsger TA Jr, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W: Assessment of disease severity and prognosis.clinexprheumatol. 2003;21(S29):S42 S46. Coordinatore del progetto: Silvia Laura Bosello