Systemaattinen katsaus «Singh JA, Wells GA, Christensen R ym. Adverse effe...»1, «»1 tehtiin biologisiin lääkkeisiin liittyvien haittavaikutusten arviointia varten mitä tahansa sairautta sairastavilla. Ainoastaan HIV-infektio suljettiin pois.
Haku toteutettiin Cochrane-kirjastosta ad 1/2010, Medline 2005 – viikko 4/2010 ja Embase 2006 – viikko 5/2010. Tutkimuksessa oli 160 RCT:tä ja CCT:tä (yhteensä 48 676 tutkittavaa) ja 46 OLE-tutkimusta (11 957 tutkittavaa) ja yksilötason data analysoitiin. RCT-tutkimusten keskimääräinen kesto oli 6 kuukautta, OLE 13 kuukautta.
Biologisiin lääkkeiden käyttöön liittyy haittavaikutusten riski verrattaessa kontrolliryhmään: kaikkien haittatapahtumien (OR 1,28; 95 % luottamusväli 1,09–1,50; P = 0,00013), vakavien infektioiden riski (OR 1,37; 95 % luottamusväli 1,04–1,82; P = 0,15) ja tuberkuloosin aktivoitumisen riski (OR 4,68; 95 % luottamusväli 1,18–18,60; P = 0,028).
Vakavien haittatapahtumien (OR 1,09; 95 % luottamusväli 0,97–1,24; P = 0,20), lymfooman (OR 0,53; 95 % luottamusväli 0,17–1.66; P = 0,27) ja sydämen vajaatoiminnan ilmaantumisessa (OR 0,69; 95 % luottamusväli 0,18–2,69; P = 0,60) ei ollut tilastollisesti merkittävää eroa verrattaessa biologisia lääkkeitä saavia ja kontrolliryhmää.
Sertolitsumabilla ja anakinralla verrattaessa kontrolliin voi olla enemmän vaikeita infektiota kuin muilla biologisilla lääkkeillä (sertolitsumabi OR 4,75; 95 % luottamusväli 1,52–18,4 ja anakinra OR 4,05; 95 % luottamusväli 1,22–16,84).
Rituksimabilla on pienin riski vakavien infektioiden suhteen, joskaan se ei ollut tilastollisesti merkittävä (OR 0,26; 95 % luottamusväli 0,03–2,16).
Kaikkiin biologisiin lääkkeisiin liittyy kohonnut infektion riski, joskin anakinralla ja sertolitsumabilla se voi olla suurempi kuin muilla ja rituksimabiin liittyen se saattaa olla vähäisempi kuin muilla.
Meta-analysis «Thompson AE, Rieder SW, Pope JE. Tumor necrosis fa...»2 of 6 randomized controlled trials that involved treatment with any of the currently licensed anti-TNF biologic agents (adalimumab, etanercept, golimumab, certolizumab, and infliximab). In addition, patients with RA were required to have a disease duration of < 3 years since diagnosis, and were currently not being treated with a disease-modifying antirheumatic drug (DMARD) or biologic agent. All patients had to be allocated to receive either a biologic monotherapy versus placebo or biologic therapy plus DMARD therapy versus placebo, for at least 6 months.
The 2 primary outcomes examined were serious infection (requiring hospitalization) and malignancy. Our primary data sources were from the published data. Serious infection was defined according to the definition given within each trial protocol.
Among the 6 trials, the mean age ranged from 47 years to 52 years, ∼ 56–77 % of the patients were female, the disease duration ranged from 6 months to 12 months, and at least two-thirds of the patients in each trial were rheumatoid factor positive. The mean swollen joint count was substantial in all 6 trials, ranging from 10 to 24, and the scores for disability were high in all 6 trials, with a reported mean Health Assessment Questionnaire score ranging from 1.3–1.6. Overall, 3,419 patients with RA were randomized to receive either a TNF inhibitor or MTX treatment.
Using the NCBI database the data was extracted from the inception of the analysis until August 2009, searching for the terms early rheumatoid arthritis, biologics, anti-TNF therapy, adalimumab, infliximab, etanercept, golimumab, certolizumab, and randomized controlled trials. The data from all of the selected studies were extracted and analyzed using a predefined, peer-reviewed assessment written by the Cochrane Collaboration. The present analysis was conducted by adhering to the QUOROM statement on quality of reports on meta-analyses of randomized controlled trials.
The included studies: ASPIRE = Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; COMET = Comparison of Methotrexate Monotherapy With a Combination of Methotrexate and Etanercept in Active, Early, Moderate to Severe Rheumatoid Arthritis; ERAS = Early Rheumatoid Arthritis Study; PREMIER = Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With Adalimumab Plus Methotrexate versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis who had not had Previous Methotrexate Treatment; SWEFOT = Addition of Infliximab Compared With Addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in Patients With Early Rheumatoid Arthritis.
It showed that serious infection occurred in 73 (3.3 %) of 2,183 patients with RA who had received at least one dose of a TNF inhibitor, compared with 30 (2.4 %) of 1,236 patients in the control treatment groups. Statistical heterogeneity was low (I2 = 11 %) and not beyond variations that could be due to chance (P = 0.27). The risk of serious infection in patients treated with a TNF inhibitor was not statistically significantly different than that in MTX-treated controls, and numerically was only slightly increased in the TNF inhibitor group compared with MTX controls (OR 1.28; 95 % CI 0.82–2.00).
Review of the published data from the 6 randomized controlled trials revealed that malignancies occurred in 19 (0.87 %) of 2,183 patients with RA who had received at least one dose of a TNF inhibitor, and in 10 (0.81 %) of 1,236 control patients. Statistical heterogeneity was low (I2 = 0 %) and was not beyond variations that could be due to chance (P = 0.77). The risk of malignancy was not increased in patients treated with a TNF inhibitor compared with control patients treated with MTX (OR 1.08; 95 % CI 0.50–2.32).
Funding summer research grant from Roche Canada
A systematic literature search of the literature published up to December 2007 was performed in PUBMED, EMBASE and Cochrane library databases; without limitation of years of publication or journal, using the followings key-words: "rheumatoid arthritis", "abatacept", "rituximab", "anakinra", "clinical controlled trials", "clinical trials", "randomised controlled trials", "clinical trials phase II, III, IV". We also included congress abstracts of American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) meetings from 2004 to 2006, because we assumed that any abstract published prior to 2004 had been published in a formal full-length work. Moreover, to complete our search with unpublished data, the Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA) and the manufacturers (Roche, Amgen and Bristol-Myers Squibb) were contacted «Salliot C, Dougados M, Gossec L. Risk of serious i...»3.
The inclusion criteria were randomised placebo controlled trials in adult patients with RA according to ACR criteria. The patients had to be randomised to receive placebo or one of the three biological agents (rituximab, anakinra and abatacept), as monotherapy or with concomitant biological or non-biological DMARDs. Reviews and articles reporting trials that were not placebo controlled were excluded.
In the literature, a serious infection is usually defined as life-threatening, requiring intravenous antibiotics or hospitalisations. If another definition of serious infections was given in the trials, it was also recorded.
Twelve published trials were selected for the meta-analysis. We selected the longest follow-up (48 vs 24 weeks). All of these 12 articles were randomised double-blind placebo controlled trials with a follow-up of 12–48 weeks, for patients with RA according to the ACR criteria and with active disease despite DMARDs.
Risk of serious infections in patients with RA during rituximab, abatacept and anakinra treatments in randomised placebo controlled trials
Pooled ORs (95 % CI)
Rituximab 1.45 (0.56–3.73)
Abatacept 1.35 (0.78–2.32)
Anakinra 2.75 (0.90–8.35)
Age, concomitant intake of steroids (median 65 % of patients) and RF positivity (median positivity 78 % of patients), did not appear as confounding factors.