A clinical and health economical observational study of anti-tumor necrosis factor therapy in the treatment of rheumatoid arthritis in Finland

Biological antirheumatic drugs are biotechnologically produced antibodies or fusion proteins that are used if rheumatic inflammation is not sufficiently ameliorated with conventional antirheumatic drugs. Approximately 10% of Finnish rheumatoid arthritis (RA) patients use biological drugs. Biological antirheumatic drugs target inflammatory mediators and cells. Tumor necrosis factor inhibitors (TNFi) have been used since the beginning of the 2000s, and they are still the primarily used type of biological antirheumatic drug. The efficacy and safety has been assessed in clinical drug trials usually of 6 to 12 months duration with strict inclusion and exclusion criteria. In practice these drugs are used for much longer and in very diverse patient populations. In this work, the effectiveness and adverse events (AEs) of TNFi treatment in a routine care setting were assessed using the national register of biological drugs. Biological drugs are expensive, and therefore also their cost-effectiveness and the outcomes of switching a TNFi to another one were assessed. The effectiveness of the TNFi infliximab (IFX) was similar to its efficacy in clinical trials. In about 2/3 of the patients clinically significant symptom relief was achieved within 3 months, and 42% achieved remission within the first year. The need of glucocorticoid and pain medication was reduced. In addition to methotrexate assessed in clinical trials, also other conventional antirheumatic drugs were suitable concomitant drugs. The most frequent AEs of TNFi treatment were infections, eczemas, and infusion reactions. AEs were reported in 17% of patients using biologicals, serious ones in 3.1%. No unexpected AEs were reported. 76% of RA patients benefited from IFX in terms of quality-adjusted life years (QALY); their functional capacity and subjective health improved. The median price of a QALY was 51884 . The best cost-effectiveness was achieved in patients with particularly high disease activity and significant response to the treatment. The IFX dose and methotrexate use also affected the cost-effectiveness. Switching a TNFi to another one was useful in cases where initial effectiveness was lost, and in cases of AEs such as infusion reactions, eczemas, or local injection site reactions, which did not require discontinuation of TNFi treatment altogether; in these cases the switch led to a similar or even better effect. The register research indicates that TNFi treatment is effective and relatively safe in RA refractory to other treatments. It was cost-effective in a significant portion of the patients; new drug alternatives (including biosimilars) and the contemporary treatment aim of remission may further improve the cost-effectiveness.Nivelreumaa hoidetaan reumalääkkein, joista uusimpia ovat nk. biologiset lääkkeet eli bioteknologisesti valmistetut vasta-aineet tai fuusioproteiinit. Niitä käytetään, jollei tauti muuten rauhoitu riittävästi; n. 10% suomalaisista nivelreumapotilaista käyttää niitä. Biologiset reumalääkkeet vaikuttavat tulehdustekijöihin ja -soluihin. 2000-luvun alusta on käytetty tuumorinekroositekijän (TNF) salpaajia, jotka ovat edelleen ensisijaisia biologisia reumalääkkeitä. Tehoa ja turvallisuutta on tutkittu yleensä 6-12 kk kliinisissä lääketutkimuksissa, joissa on tiukat sisäänotto- ja poissulkukriteerit. Käytännössä lääkkeitä käytetään huomattavasti kauemmin ja hyvin erilaisille potilaille. Työssä selvitettiin kansallisen biologisten lääkkeiden rekisterin avulla arkielämän olosuhteissa TNF-salpaajien tehoa ja haittoja. Biologiset lääkkeet ovat kalliita, joten myös kustannusvaikuttavuutta ja TNF-salpaajan vaihtamista toiseen tutkittiin. TNF-salpaaja infliksimabin teho oli samanlainen kuin kliinisissä lääketutkimuksissa. Noin 2/3:lla oireet lievenivät merkittävästi 3 kk:ssa ja 42% saavutti lähes täyden oireettomuuden ensimmäisen vuoden aikana. Kortisonin ja kipulääkkeiden tarve väheni. Oheislääkkeiksi sopivat aiemmin tutkitun metotreksaatin lisäksi muutkin perinteiset reumalääkkeet. Tavallisimmat TNF-salpaajien haitat olivat infektiot, ihottumat ja infuusioreaktiot. Haittoja raportoitiin 17%:lla biologisia reumalääkkeitä käyttävistä, vakavia 3,1%:lla. Odottamattomia haittoja ei ilmennyt. Laatupainotteisina elinvuosina 76% nivelreumapotilaista hyötyi infliksimabista; toimintakyky ja vointi paranivat. Laatupainotteisen elinvuoden mediaanihinta oli 51884 . Kustannustehokkuus oli paras, jos tauti oli erityisen aktiivinen ja hoitovaste merkittävä. Infliksimabiannos ja metotreksaatti vaikuttivat kustannustehokkuuteen. TNF-salpaajan vaihtamisesta toiseen oli hyötyä, jos teho hiipui tai ilmeni infuusioreaktioita, ihottumaa tai paikallisia injektioreaktioita, jotka eivät vaatineet TNF-salpaajahoidon lopettamista; näissä tapauksissa vaihdolla saavutettiin vähintään sama oireiden lievitys. Rekisteritutkimuksessa TNF-salpaajahoito on tehokas ja suhteellisen turvallinen muuhun hoitoon reagoimattomassa nivelreumassa. Se oli kustannustehokasta huomattavalla osalla potilaista; uudet lääkevaihtoehdot (ml. biosimilaarit) ja entistä tiukemmat hoitotavoitteet saattavat edistää kustannustehokkuutta

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Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis

Background and Objectives: Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT). Methods: A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias. Results: Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo. Conclusions No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.Peer reviewe