O uso de alfadornase em pacientes com fibrose cística

Marostica, Paulo José C.

doi:10.1590/S0103-05822013000400001

A fibrose cística (FC) é doença autossômica recessiva com incidência estimada de um para 7.500 nascidos vivos no Brasil, variando em diferentes estados⁽¹⁾. O gene em questão codifica uma proteína chamada de cystic fibrosis transmembrane conductance regulator (CFTR), envolvida no transporte transepitelial de íons e, ultimamente, de água. Acomete, assim, os órgãos epiteliais, cujas secreções são espessadas, com consequente obstrução e surgimento das alterações clínicas clássicas.

Nos brônquios, as secreções espessadas predispõem ao surgimento de infecção, que leva a um círculo vicioso de aumento da obstrução e da tendência a infecções recorrentes. Cerca de 10% do escarro, nesses pacientes, é constituído de DNA, principalmente proveniente dos leucócitos que migram para a luz brônquica para combater a infecção⁽ ²2. Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959;24:739-45. ⁾.

Dentro dessa perspectiva, o uso de mucolíticos eficazes sempre foi almejado para um melhor manejo da FC, visando à melhora na qualidade de vida e à redução da morbidade associada.

Há cerca de duas décadas, a alfadornase tem sido recomendada para uso em pacientes com FC. Sua ação, clivando o DNA, fluidifica secreções, mostrando-se eficaz para reduzir o declínio da função pulmonar e diminuir o número de exacerbações pulmonares, conforme ensaio clínico randomizado publicado em 1994⁽ ³3. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash M, Ramsey BW et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637-42. ⁾.

Posteriormente, outros ensaios demonstraram que a droga era eficaz para reduzir exacerbações pulmonares e melhorar outros desfechos funcionais, mesmo em pacientes com doença pulmonar incipiente, ainda com parâmetros funcionais normais⁽ ⁴4. Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J 2011;37:806-12.

5. Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest 2005;128:2327-35.

6. Ratjen F, Paul K, van Koningsbruggen S, Breitenstein S, Rietschel E, Nikolaizik W. DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha. Pediatr Pulmonol 2005;39:1-4.

7. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 2001;139:813-20.

8. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest 1996;110:889-95. ^- ⁹9. Jones AP, Wallis C. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2010;(3):CD001127. ⁾.

A comprovada efetividade da alfadornase em tais condições fez com que a mesma fosse incluída em consensos de manejo da doença pulmonar da FC para crianças acima de seis anos de idade⁽ ¹⁰10. Heijerman H, Westerman E, Conway S, Touw D, Döring G; Consensus working group. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus. J Cyst Fibros 2009;8:295-315. ^, ¹¹11. Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680-9. ⁾.

Nesta edição da Revista Paulista de Pediatria, Rozov et al. apresentam um elegante estudo, no qual agregam evidência para o uso de alfadornase em crianças e adolescentes com FC⁽ ¹²12. Rozov T, Abreu e Silva FA, Santana MA, Adde FV, Mendes RH; Brazilian Cystic Fibrosis Multicenter Study Group. A first-year dornase alpha treatment impact on clinical parameters of patients with cystic fibrosis: results from Brazilian cystic fibrosis multicenter study. Rev Paul Pediatr 2013;31:420-30. ⁾. O estudo multicêntrico brasileiro avaliou pacientes acima de cinco anos de idade, que ainda não recebiam o fármaco.

A FC é uma doença genética com evolução influenciada por fatores ambientais. Nesse sentido, há mérito no referido estudo, uma vez que demonstra benefício da alfadornase em pacientes brasileiros, no que diz respeito à redução de atendimentos em emergência, um desfecho associado à qualidade de vida. Anteriormente, os autores já haviam publicado resultados de qualidade de vida nesses mesmos indivíduos, demonstrando melhora em diversos domínios após a introdução da medicação⁽ ¹³13. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alpha improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ⁾.

Como limitação do estudo, tem-se o fato de o delineamento ser não controlado. Há limitações inerentes aos estudos desse tipo antes e depois. Pacientes monitorados em pesquisas tendem a ser mais aderentes e sujeitos ao efeito placebo. No entanto, restrições éticas absolvem os autores quanto à escolha do desenho, uma vez que já havia evidências do benefício da droga em maiores de seis anos, desaconselhando-se um grupo controle com uso de placebo.

References

¹
Raskin S, Pereira-Ferrari L, Reis FC, Abreu F, Marostica P, Rozov T et al. Incidence of cystic fibrosis in five different states of Brazil as determined by screening of p.F508del, mutation at the CFTR gene in newborns and patients. J Cyst Fibros 2008;7:15-22.
²
Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959;24:739-45.
³
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash M, Ramsey BW et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637-42.
⁴
Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J 2011;37:806-12.
⁵
Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest 2005;128:2327-35.
⁶
Ratjen F, Paul K, van Koningsbruggen S, Breitenstein S, Rietschel E, Nikolaizik W. DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha. Pediatr Pulmonol 2005;39:1-4.
⁷
Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 2001;139:813-20.
⁸
McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest 1996;110:889-95.
⁹
Jones AP, Wallis C. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2010;(3):CD001127.
¹⁰
Heijerman H, Westerman E, Conway S, Touw D, Döring G; Consensus working group. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus. J Cyst Fibros 2009;8:295-315.
¹¹
Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680-9.
¹²
Rozov T, Abreu e Silva FA, Santana MA, Adde FV, Mendes RH; Brazilian Cystic Fibrosis Multicenter Study Group. A first-year dornase alpha treatment impact on clinical parameters of patients with cystic fibrosis: results from Brazilian cystic fibrosis multicenter study. Rev Paul Pediatr 2013;31:420-30.
¹³
Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alpha improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82.

Instituição: Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil

Datas de Publicação

Publicação nesta coleção
Dez 2013

Histórico

Recebido
29 Jul 2013

All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License.

[1] ¹
Raskin S, Pereira-Ferrari L, Reis FC, Abreu F, Marostica P, Rozov T et al. Incidence of cystic fibrosis in five different states of Brazil as determined by screening of p.F508del, mutation at the CFTR gene in newborns and patients. J Cyst Fibros 2008;7:15-22.

[2] ²
Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959;24:739-45.

[3] ³
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash M, Ramsey BW et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637-42.

[4] ⁴
Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J 2011;37:806-12.

[5] ⁵
Robinson TE, Goris ML, Zhu HJ, Chen X, Bhise P, Sheikh F et al. Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. Chest 2005;128:2327-35.

[6] ⁶
Ratjen F, Paul K, van Koningsbruggen S, Breitenstein S, Rietschel E, Nikolaizik W. DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha. Pediatr Pulmonol 2005;39:1-4.

[7] ⁷
Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 2001;139:813-20.

[8] ⁸
McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Chest 1996;110:889-95.

[9] ⁹
Jones AP, Wallis C. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2010;(3):CD001127.

[10] ¹⁰
Heijerman H, Westerman E, Conway S, Touw D, Döring G; Consensus working group. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus. J Cyst Fibros 2009;8:295-315.

[11] ¹¹
Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680-9.

[12] ¹²
Rozov T, Abreu e Silva FA, Santana MA, Adde FV, Mendes RH; Brazilian Cystic Fibrosis Multicenter Study Group. A first-year dornase alpha treatment impact on clinical parameters of patients with cystic fibrosis: results from Brazilian cystic fibrosis multicenter study. Rev Paul Pediatr 2013;31:420-30.

[13] ¹³
Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alpha improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82.