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Štetni učinci lijekova biologika: mrežna meta‐analiza i prikaz svih Cochrane sustavnih pregleda

Background

Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since important risks such as lymphomas, serious infections and tuberculosis (TB) reactivation may be more common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain  much needed risk estimates.

Objectives

To compare the potential adverse effects of tumor necrosis factor inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin (IL)‐1 antagonist (anakinra), IL‐6 antagonist (tocilizumab), anti‐CD28 (abatacept), and anti‐B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS).

Methods

Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open‐label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre‐specified adverse outcomes (serious adverse events (SAEs), withdrawals due to adverse events (AEs), total AEs, serious infections; specific AEs, namely, tuberculosis (TB) reactivation, lymphoma and congestive heart failure) were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta‐analysis, we performed both Bayesian mixed‐treatment comparison models and arm‐based generalized linear mixed models.

Main results

We included 160 RCTs with 48,676 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for TB reactivation, lymphoma, and congestive heart failure. Using standard dose, compared with control, biologics as a group were associated with a statistically significant higher rate of total AEs (odds ratio (OR) 1.28, 95% credible interval (CI) 1.09 to 1.50; number needed to treat to harm (NNTH) = 22, 95% confidence interval (CI) 14 to 60), withdrawals due to AEs (OR 1.47, 95% CI 1.20 to 1.86; NNTH = 26, 95% CI 15 to 58), serious infections (OR, 1.37, 95% CI 1.04 to 1.82, NNTH = 108 95% CI, 50 to 989) and TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706).

The rate of SAEs, lymphoma and congestive heart failure were not statistically significantly different between biologics and control treatment. 

Certolizumab pegol (OR 4.75, 95% CI 1.52 to 18.65; NNTH = 12, 95% CI 4 to 79) and anakinra (OR 4.05, 95% CI 1.22 to 16.84; NNTH = 14, 95% CI 4 to 181) were associated with a statistically significantly higher risk of serious infections compared with control treatment. Compared with control, certolizumab was associated with a statistically significantly higher risk of SAEs (as defined in included studies: OR 1.57, 95% CI 1.06 to 2.32; NNTH = 18, 95% CI 9 to 162). Infliximab was associated with a statistically significantly higher risk of total AEs OR 1.55, 95% CI 1.01 to 2.35; NNTH = 13, 95% CI 8 to 505) and withdrawals due to AEs compared with control (OR 2.34, 95% CI 1.40 to 4.14; NNTH = 10, 95% CI 5 to 30). 

The overall numbers were relatively small for indirect comparisons. Indirect comparisons revealed that certolizumab pegol was associated with a statistically significantly higher odds of serious infections compared with abatacept, adalimumab, etanercept, golimumab and rituximab; and anakinra was statistically significantly more likely than rituximab to be associated with serious infections. Certolizumab pegol was associated with a statistically significant higher odds of SAEs compared with adalimumab and abatacept. No statistically significant differences were noted between biologics in total AEs or withdrawals due to AEs in indirect comparisons.

Authors' conclusions

Overall, in the short term biologics were associated with statistically significantly higher rates of serious infections, TB reactivation, total AEs and withdrawals due to AEs. Serious infections included opportunistic infections as well as bacterial infections in most studies. Some biologics had a statistically higher association with certain adverse outcomes compared with control, but there was no consistency across the outcomes so caution is needed in interpreting these results.

There is a need for more research regarding the long‐term safety of biologics and an urgent need for comparative safety reports of different biologics; preferably without industry involvement. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short‐ and longer‐term safety of biologics. 

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Štetni učinci devet vrsta lijekova biologika koji se često koriste: prikaz svih Cochrane sustavnih pregleda

Sažetak ovog Cochrane sustavnog pregleda prestavlja cjelokupno trenutno znanje o štetnim učincima lijekova biologika, koji se primjenjuju u liječenju brojnih stanja kao što su upalni artritis i druge upalne bolesti, karcinom i neurološki poremećaji. Nisu uključene studije u kojima su sudjelovali pacijenti oboljeli od HIV/AIDS‐a. Uključeno je devet biologika: abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliksimab (Remicade®), rituksimab (Rituxan ili Mabthera®) i tocilizumab (Actmera®).

Sustavni pregled pokazuje da osobe koje uzimaju te biologike kroz kratko vrijeme:

‐ vjerojatno imaju nešto veći rizik od ozbiljnih infekcija ili tuberkuloze u odnosu na osobe koje uzimaju placebo (lažni lijek);

‐ vjerojatno imaju nešto veći rizik od razvoja nuspojava ili ranijeg odustajanja od sudjelovanja u istraživanju zbog nuspojava nego osobe koje uzimaju placebo;

‐ vjerojatno neće razviti više ozbiljnih nuspojava* (ako se isključe ozbiljne infekcije), karcinoma ili kongestivnih zatajenja srca nego osobe koje uzimaju placebo.

(*Ozbiljna nuspojava je štetni učinak lijeka opasan po život koji može uzrokovati smrt ili hospitalizaciju te onesposobljenost i trajnu štetu).

Nemamo precizne informacije o drugim mogućim nuspojavama i komplikacijama, uključujući rijetke i dugoročne štetne učinke.

Što su biologici?

Biologici su skupina lijekova koji potiskuju imunološki sustav i smanjuju upalu, iako potiskivanje imunološkog sustava otežava tijelu borbu protiv infekcija.

Najbolja procjena što se događa osobama koje uzimaju biologike kroz kratko vrijeme (1‐63 mjeseca)

Ozbiljne nuspojave

Među ljudima koji su uzeli bilo koji biologik,127 od 1000 imat će ozbiljne nuspojave u usporedbi sa 118 od 1000 koji su uzeli placebo (1% apsolutne štete).

Sve prijavljene nuspojave

Među ljudima koji su uzeli bilo koji biologik,770 od 1000 imat će nuspojave u usporedbi sa 724 od 1000 koji su uzeli placebo (5% apsolutne štete).

Odustajanje od sudjelovanja u istraživanju zbog nuspojava

Među ljudima koji su uzeli bilo koji biologik,137 od 1000 odustat će od sudjelovanja u istraživanju u usporedbi s 98 od 1000 koji su uzeli placebo (4% apsolutne štete).

Ozbiljne infekcije

Među ljudima koji su uzeli bilo koji biologik, 35 osoba od 1000 razvit će ozbiljne infekcije u usporedbi sa 26 od 1000 koji su uzeli placebo (1% apsolutne štete).

Tuberkuloza

Među ljudima koji su uzeli bilo koji biologik, 20 od 1000 razvit će tuberkulozu u usporedbi sa 4 od 1000 koji su uzeli placebo (0,16% apsolutne štete). Međutim, zabilježeno je vrlo malo slučajeva tuberkuloze pa ne možemo vjerovati tim rezultatima.

Limfom

Tijekom kratkog roka može biti mala ili nikakva razlika u broju osoba koje su razvile karcinom tijekom uzimanja biologika u usporedbi s onima koje su uzimale placebo. Međutim, broj karcinoma bio je malen pa ne možemo vjerovati tim rezultatima.

Kongestivno zatajenje srca

Razlika između broja osoba koje su doživjele zatajenje srca uzimajući bilo koji biologik i osoba koje su uzimale placebo može biti mala ili nikakva. Međutim, broj zabilježenih kongestivnih zatajenja srca bio je malen pa ne možemo vjerovati tim rezultatima.