Title

 

Authors

G. Giustarini,^1,2 M. Tuccori,^1,2 L. Bazzichi,³ S. Manganelli,⁴ F. Peruzzi,⁵ O. M. Sacu,⁶ L. Picchianti,^1,2 A. Capogrosso,^1,2 M. Rossi,⁷ F. Sernissi,³ C. Giacomelli,³ R. Neri,¹ M.G. De Montis,⁷ F. Nacci,⁵ F. Lapi,⁸ A. Pergola,^1,2 C. Scollo,⁷ S. Mantarro,⁷ L. Sabadini,⁶ A. Mugelli,⁸ S. Bombardieri,³ M. Matucci-Cerinic,⁵ M. Galeazzi,⁴ C. Blandizzi,^{1  
1}Interdepartmental Centre of Clinical Pharmacology and Experimental Therapy, University of Pisa
²Tuscan Regional Centre of Pharmacovigilance
³Section of Rheumatology, University Hospital of Pisa
⁴Section of Rheumatology, University Hospital of Siena
⁵Section of Rheumatology, University Hospital of Careggi
⁶Section of Rheumatology, Hospital Garbasso, ASL 8, Arezzo
⁷Dept. of Pharmacology, University of Siena
⁸Dept. of Pharmacology, Center for Molecular Medicine (CIMMBA) - University of Florence 

 

Abstract

In the last decade, the use of drugs produced by recombinant technologies has revolutionized the treatment of several diseases, particularly in the field of rheumatology. However, the safety profile of these drugs remains matter of debate(1). ASTRAGALUS is a three-year observational study, which has been started in 2010 in Tuscany to investigate the incidence and clinical features of adverse events (AEs) in patients receiving biologic drugs for rheumatologic disorders. Patients are being enrolled in four Rheumatology Units at the Hospitals of Pisa, Firenze, Siena and  Arezzo. Medical records of eligible patients have been checked to collect retrospective information on their clinical history (adverse events, drug treatments and dose regimens, concomitant therapies, disease course, laboratory data). Patients will be then followed-up prospectively for up three years through scheduled visits. All diseases and adverse events are classified by MedDRA Term dictionary. Patients currently or formerly receiving treatments with biologic drugs (infliximab, etanercept, adalimumab, rituximab, tocilizumab, abatacept and anakinra) have been requested to read and sign informed consent to participate to the study. AEs are classified as adverse drug reactions (ADRs) when they scored at least as possible upon evaluation by Naranjo algorithm for causality assessment(2). The present analysis reports the first 6 months of observation. Patients recorded in the study database were 237 (females: 156; mean age: 54.56±13.76). Rheumatic diseases requiring biologic treatments were: rheumatoid arthritis (n=130), psoriatic arthritis (n=53), ankylosing spondylitis (n=33), undifferentiated spondyloarthritis (n=12), enteropathic arthritis (n=5), psoriasis (n=4), reactive arthritis (n=2), psoriatic spondyloarthritis (n=2) and Behçet syndrome (n=1). After 6-month observation, we recorded 344 AEs, 29 of which were classified as serious. Patients with at least one AE were 110, and 86 were classified as having experienced ADRs. Table 1 summarizes the number of patients with at least one ADR and their frequency in subgroups receiving the different biologic drugs under evaluation (Table 1). The AEs more commonly recorded in the database were: inflammatory condition (49 cases), infectious disease (39), oropharyngeal pain (36), cough (34), fever (32), diarrhea (23), reaction related to infusion (15) and increased transaminase value (13). Serious ADRs associated with biologic treatments were: angioedema, hemorrhagic cystitis, and salivary gland cancer for adalimumab; Prinzmetal angine for tocilizumab; squamous cell carcinoma, myocardial infarction and pericardial effusion for etanercept; pericarditis, pleural effusion and infusion reaction for infliximab. Overall, according to the present preliminary analysis, biologic medications are frequently associated with the development of adverse reactions, which are mild to moderate in severity. However, serious reactions may also occur. Our data confirmed also the development of infectious diseases and infusion reactions as prominent issues realated to these therapies. Accordingly, a careful monitoring of patients receiving biologic drugs is required for an early identification and management of potentially harming adverse effects.  

References
1-Singh JA et al.,Cochrane Database Syst Rev 2011 Feb 16;2:CD008794;
2-Naranjo C et al., Clin Pharmacol Ther 1981;30:239-45 

Table 1: Distribution of patients with at least one ADR (N. ADR) in the study population stratified by biologic drug treatment
 

Patient	Etanercept (n=115)	Adalimumab (n=66)	Infliximab (n=37)	Tocilizumab (n=22)	Rituximab (n=20)	Abatacept (n=15)	Anakinra (n=3)
N. ADR (%)	28 (24.34)	17 (25.75)	25 (67.56)	12 (54.54)	10 (50.00)	9 (60.00)	1 (33.34)