Elsevier

Journal of Clinical Lipidology

Volume 11, Issue 3, May–June 2017, Pages 749-756.e3
Journal of Clinical Lipidology

Original Article
Lipoprotein(a) concentrations in rheumatoid arthritis on biologic therapy: Results from the CARdiovascular in rheuMAtology study project

https://doi.org/10.1016/j.jacl.2017.02.018Get rights and content

Highlights

  • Rheumatoid arthritis on biological therapies, mainly anti-interleukin 6, displays lower lipoprotein (a) levels.

  • Patients with tocilizumab show higher total cholesterol and triglyceride levels, without differences in the atherogenic index.

  • Tocilizumab-treated patients in this study had lower disease activity but poorer scores on Health Assessment Questionnaire.

Background

Plasma concentrations of lipoprotein (a) (Lp(a)), a lipoprotein with atherogenic and thrombogenic properties, have a strong genetic basis, although high concentrations of Lp(a) have also been reported in the context of inflammation, as in rheumatoid arthritis (RA). Few studies evaluate the impact of biologic therapies (BT) on Lp(a) in RA, taking into account that with these new therapies a better control of inflammation is achieved.

Objective

The aim of the study was to evaluate the plasma concentrations of Lp(a) in Spanish RA patients on BT attending rheumatology outpatient clinics.

Methods

Baseline analysis of the CARdiovascular in rheuMAtology project, a 10-year prospective study, evaluating the risk of cardiovascular events in RA and other forms of inflammatory arthritis. RA patients were classified according to treatment: no biologic, anti-tumor necrosis factor, anti-interleukin-6 receptor tocilizumab (TCZ), and other biologic (rituximab or abatacept). A model of linear multivariate regression was built in which the dependent variable was Lp(a) concentration and the explanatory variable was BT. The model was adjusted for confounding factors.

Results

Seven hundred and seventy-five RA patients were analyzed. Plasma concentrations of total cholesterol and triglyceride were significantly higher in TCZ-treated patients. Nevertheless, no significant difference in the atherogenic index between TCZ-treated patients and patients without BT was found. After adjusting for confounding factors, patients with BT had lower concentrations of Lp(a) than those without BT; however, only TCZ-treated patients achieved statistically significant differences (β: −0.303, 95% confidence interval: −0.558 to −0.047; P = .02).

Conclusions

RA patients treated with TCZ show lower plasma concentrations of Lp(a) compared with patients without BT.

Introduction

Beyond the quantitative and qualitative alterations in lipid metabolism reported in patients with rheumatoid arthritis (RA) related to inflammation, nonconventional atherogenic risk factors may also play a role in the increased cardiovascular (CV) risk of RA patients.1 In this sense, high levels of lipoprotein(a) (Lp(a)) have been observed in RA and other types of inflammatory arthritis.2, 3

Serum concentrations of Lp(a), which has atherogenic and thrombogenic properties and is a lipoprotein regarded as an independent CV risk factor, are higher in patients with coronary artery disease.4 Lp(a) is structurally similar to the low-density lipoprotein cholesterol (LDL-C) molecule which, in addition to apolipoprotein B100 (apoB100), has another protein, the apolipoprotein (a) (apo(a)). This apolipoprotein gives Lp(a) more atherogenic properties, based mostly on its size, and is genetically determined.5 The size heterogeneity of apo(a) is related to the variable number of copies of 1 of the protein domains, the Kringle IV type II, and it has an inverse relationship with the density and the plasma concentration of Lp(a). Individuals with small apo(a) are those with the highest Lp(a) concentrations and increased CV risk.6 On the other hand, although plasma concentrations of Lp(a) have a strong genetic basis, as mentioned previously, high concentrations of Lp(a) have also been reported in the context of inflammation.

Lp(a) seems to act as an acute-phase reactant. However, unlike traditional lipid metabolism, which is effectively modulated by treatment of the disease,2, 7 the effects of therapy on metabolism of Lp(a) in patients with RA remain unclear. This may be explained in part by the fact that genetic factors have a large impact on the variation of Lp(a) levels.8

Better control of inflammation and disease activity in patients with RA has been achieved by the use of biologic therapies. However, there have been few studies that evaluate the impact of these new therapies on Lp(a) in RA.9, 10 This aspect is of particular interest because it has been observed that Lp(a) levels are higher in individuals with elevated interleukin-6 (IL-6) serum concentrations, as this proinflammatory cytokine increases the transcriptional activity of the apo(a) gene LPA.11

Taking into account all these considerations, the purpose of the present study was to evaluate the plasma concentrations of Lp(a) in Spanish patients with RA on biologic therapy attending Rheumatology outpatient clinics. These patients were enrolled in the CARdiovascular in rheuMAtology (CARMA), a 10-year prospective cohort study designed to determine the CV mortality risk in patients with chronic inflammatory rheumatic diseases, including those with RA.

Section snippets

Study design

Cross-sectional analysis from the baseline visit of a 10-year prospective follow-up study CARMA. In this study, a cohort of patients with chronic inflammatory rheumatic diseases, including those with RA, was compared with another noninflammatory cohort.12

Patient recruitment

Patients diagnosed with RA at 67 Rheumatology Units selected from Spanish National Health System hospitals participated in the study. The participant Rheumatology Units were randomly selected after a probabilistic cluster sampling from the

Results

Information on Lp(a) was available in 441 of the 775 patients (56.9%) with RA included in the CARMA study project. No baseline differences were observed between patients in whom Lp(a) was analyzed or not. The main demographic, clinical, and laboratory features of the CARMA RA cohort are summarized in Table 1. Patients undergoing biologic therapy had longer disease duration. Erosive arthritis was more commonly observed in patients treated with anti-TNF. Patients on TCZ therapy were more commonly

Discussion

The results from the present study show that TCZ-treated RA patients followed-up at rheumatology-out-patient clinics have lower plasma concentrations of Lp(a) than RA patients not treated with biologics.

The relationship between alterations in conventional lipid profiles and inflammation in patients with RA is well known.14 However, despite the fact that Lp(a) exerts atherogenic and prothrombotic effects,3 the presence of hyperlipoproteinemia(a) in RA has not received sufficient attention.2, 15

Conclusions

In conclusion, the results of the CARMA cohort confirm the claim that the use of anti–IL-6 receptor TCZ therapy is associated with low plasma concentrations of Lp(a). This association may have important clinical implications in the CV profile of patients with RA.

Acknowledgements

The authors thank Professor Xavier Pintó from Lipid and Vascular Risk Unit, Department of Internal Medicine, Hospital Universitari de Bellvitge-IDIBELL, for his help and advice in the article. This publication was aided by members of the Research Unit of the SER. Dedicated to Dr José L Fernández Sueiro who took part in the initial design of this project and passed away in 2012. The authors thank all the health professionals and patients who generously participated in this study. Furthermore,

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  • Cited by (0)

    The members of the CARdiovascular in rheuMAtology Project Collaborative Group include Eugenia Gonzalez de Rábago, Elena Alonso Blanco Morales, J. Carlos Fernández López, Natividad Oreiro Villar, Antonio Atanes Sandoval, Francisco J. Blanco García (Complejo Hospitalario A Coruña, Xubias de Arriba, A Coruña); Cayetano Alegre De Miquel, María J. González Fernández, Ramón Huguet Codina, Beatriz Yoldi, Mercedes Ramentol (Instituto Dexeus, Barcelona); Gabriela Ávila, Sara Marsal Barril (Hospital Universitari Vall d’Hebron, Barcelona); Martina Steiner, Santiago Muñoz (Hospital Infanta Sofía, Madrid); Fernando Gamero, José García Torón, María P. Moreno Gil (Hospital S. Pedro de Alcántara, Cáceres); Antonio J. Mas, Pilar Espiño, Inmaculada Ros, Mónica Ibañez, and Claudia Murillo (Hospital Son Llatzer, Palma de Mallorca); José A. Piqueras (Hospital Univ. de Guadalajara); Raimon Sanmartí, Horacio Berman, Sonia Cabrera, and Virginia Ruiz (Hospital Clinic i Provincial, Barcelona); Oscar Fontseré Patón, Benjamín Fernández Gutiérrez, and Lydia Abasolo (Hospital Clínico Univ. San Carlos, Madrid); María D. Fábregas (Hospital de Barbastro, Huesca); Joan M. Nolla (Hospital Univ. de Bellvitge, Barcelona); Miriam García Arias, Jesús A. García Vadillo, and Rosario García de Vicuña (Hospital Univ. de La Princesa, Madrid); Antonio Fernández Nebro, Maria Angeles Belmonte López, Inmaculada Ureña, María V. Irigoyen, Virginia Coret Cagigal (Hospital Regional Universitario Carlos Haya, Málaga); Ruth López González (Hospital General Virgen de la Concha); Daniel Pielfort Garrido, Juana Sampedro Alvarez, Ángel María García Aparicio, Rebeca Belmonte Gómez, Pastora Granados Bautista, Azucena Hernández Sanz (Hospital Virgen de la Salud, Toledo); Carmen O. Sánchez González (Hospital del Sureste, Madrid); Javier Bachiller, Antonio Zea (Hospital Ramón y Cajal, Madrid); Francisco J. Manero, Fernando Jimenez Zorzo, Eugenio Giménez Ubeda, Jesús Marzo Gracía, Chesús Beltrán Audera, Marta Medrano, Ángela Pecondón (Hospital Univ. Miguel Servet, Zaragoza); Celia Erausquin, Soledad Ojeda, Juan Carlos Quevedo, Félix Francisco, Carlos Rodríguez Lozano (Hospital Dr. Negrín, Las Palmas de Gran Canaria); Jesús Babío Herráez (Hospital de Cabueñes, Gijón); Francisco J. López Longo, Delia Gerona, Carlos González Fernández, Luis Carreño, Indalecio Monteagudo (Hospital Gregorio Marañón, Madrid); Javier del Pino, María Dolores Sánchez González (Hospital Univ. de Salamanca); Alfonso Corrales, María Enriqueta Peiró (Hospital Univ. Marqués de Valdecilla, Santander); José M. Senabre, José C. Rosas (Hospital de la Marina Baixa, Alicante); Isabel Rotés, Estefanía Moreno, Alba Erra, Dolors Grado (Hospital de San Rafael, Barcelona); Javier Calvo, Amalia Rueda (Hospital General. Universitario, Valencia); Ingrid Möller, Isabel Rodríguez (Instituto Poal, Barcelona); Carmen Barbadillo (Hospital Universitario Puerta de Hierro, Madrid); Enrique Raya, Pilar Morales, Ana Nieto, Inmaculada Jiménez, Cesar magro (Hospital Clínico Univ. San Cecilio, Granada); Ana Ruibal Escribano (Hospital Santiago Apóstol, Vitoria-Gasteiz); Sergio Ros Expósito (Hospital de Viladecans, Barcelona); Ginés Sánchez Nievas, Enrique Júdez Navarro, Manuela Sianes Fernández, María Ángeles García Morales, Isabel Labiano Bastero, Gloria García Consuegra, and Natalia Palmou (Hospital General de Albacete); Silvia Martínez Pardo, Manel Pujol, Elena Riera Alonso, Georgina Salvador (Hospital Mutua Terrassa, Terrassa); Beatriz González Alvarez, Alberto Cantabrana (Hospital Ntra. Sra. de Candelaria, Santa Cruz de Tenerife); Sagrario Bustabad, Esmeralda Delgado (Hospital Univ. de Canarias, La Laguna, Tenerife); Alejandro Muñoz, Sergio Rodríguez Montero, Luis María Jiménez (Hospital Univ. de Valme, Sevilla); Javier Rivera Redondo, Teresa González Hernández (Instituto Provincial de Rehabilitación, Madrid); Francisco J. González. Polo (Hospital de Cantoblanco, Madrid); Raúl Menor Almagro (Hospital de Jerez de la Frontera, Jerez de la Frontera, Cádiz); José M. Moreno, Emilio Giner Serret, Carla Lannuzzelli Barroso (Hospital Obispo Polanco, Teruel); Laura Cebrián Méndez, María Teresa Navío (Hospital Infanta Leonor, Madrid); Cristina Fernández Carballido (Hospital General de Elda, Alicante); Encarnación Pagán, Pablo Mesa del Castillo (Hospital Los Arcos, Murcia); Esperanza Naredo, Ana Cruz (Hospital Severo Ochoa, Madrid); Ana Turrión (Hospital Príncipe de Asturias, Madrid); Isabel Mateo, Julio Sánchez, María Galindo, Javier García González (Hospital Univ. 12 de Octubre, Madrid); Eduardo Collantes, Desireé Ruíz, Pilar Font (Hospital Univ. Reina Sofía, Córdoba); Gema Bonilla (Hospital Univ. La Paz, Madrid); Antonio López Meseguer (Hospital Gutiérrez Ortega, Valdepeñas, Ciudad Real); Manuel J. Moreno, Ma José Moreno Martínez; Ma Dolores Beteta Fernández, Luis F. Linares (Hospital Virgen de la Arrixaca, Murcia); Mercedes Morcillo, María L. González Gómez (Hospital del Escorial, Madrid); José M. Aramburu, Natalia A. Rivera, Olaia Fernández Berrizbeitia, María Luz García Vivar (Hospital de Basurto, Bilbao); Manel Riera, Yolanda María León (Hospital Dos de Maig, Barcelona); Joan Maymó, Miriam Amirall, Silvia Iniesta Escolano, Silvia Sánchez Serrano, María Pilar Lis Bona (Hospital del Mar, Barcelona); Jordi Fiter, Julia Fernández Melón, Luis Espadaler (Hospital Universitario Son Espases, Palma de Mallorca); Olga Maiz, Joaquín Belzunegui, Inmaculada Bañegil (Hospital de Donostia, Donostia); César Díaz (Hospital de la Santa Creu i Sant Pau, Barcelona); Ramón Valls (Hospital de Palamós, Gerona); Iván Castellví, María Bonet, Estefania Moreno Ruzafa (Hospital Comarcal de L'Alt Penedés, Vilafranca del Penedès, Barcelona); Jaime Calvo Alen (Hospital Sierrallana, Torrelavega); Trinidad Pérez Sandoval (Complejo Asistencial de León); Eva Revuelta Evrard (Hospital General de Ciudad Real); Javier R. Godo, Cruz Fernández Espartero (Hospital General de Móstoles, Madrid); Francisco J. Navarro Blasco, José Antonio González (Hospital General Universitario de Elche, Alicante); José A. Miranda-Filloy (Hospital Xeral Calde, Lugo).

    Ethics approval and consent to participate: This study was performed following the principles outlined in the Helsinki Declaration and the study protocol was approved by the Ethics Committee for Clinical Research of Galicia, Spain.

    Competing interests: The authors declare that they have no competing interests.

    1

    These authors have equally contributed to this work.

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