Costs, effectiveness and cost-effectiveness of biological drugs in the treatment of rheumatoid arthritis and inflammatory bowel diseases

Background: Rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD), including Crohn´s disease (CD), ulcerative colitis (UC) and IBD unclassified, are chronic inflammatory disorders. In Finland, the prevalence of RA is estimated to be around 0.8% based on the data collected in the late 1980s, whereas the prevalence of IBD is around 0.9% in 2019. In the case of an insufficient response or intolerance to conventional drugs in the treatment of RA and IBD, biological drugs are a treatment option. Until May 2019, the European Medicines Agency (EMA) has approved ten biological drugs for the treatment of RA, four for CD, and four for UC. Biological drugs have proven to be an effective treatment for RA and IBD, and they have comparable efficacy and not significantly differing safety profiles. However, they are significantly more expensive than conventional drugs. Because of the high costs of original biological drugs, interest has grown in biosimilars and EMA has approved four biosimilars for the treatment of RA and two for IBD. RA and IBD, as chronic diseases, have a negative impact on patients’ lives, and, therefore, they decrease health-related quality of life (HRQoL). Furthermore, poorly treated RA and IBD may cause disability and uncontrollable costs for social and health care. Objectives: The aim of this study was to evaluate the costs, effectiveness, and cost-effectiveness of biological drugs in the treatment of RA and IBD. Methods: Systematic literature reviews (SLRs) were performed to identify published data on the cost-effectiveness of biological drugs for RA and IBD (study I and II). The SLRs were performed following current recommendations for SLR of economic evaluations to improve the quality and reliability of the study. A patient-level simulation model (study III) was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and Tumour Necrosis Factor Alpha (TNF) inhibitors) in the treatment of RA patients who have previously been treated with TNF inhibitors. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. The patients’ baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments for RA patients in Finland. Several subgroup and deterministic sensitivity analyses were conducted. In the single-centre prospective observational study (IV), all IBD patients receiving maintenance infliximab therapy at Helsinki University Hospital (HUS) were switched to biosimilar infliximab (CT-P13). HRQoL was measured using the generic 15D utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn´s Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and faecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and at 3 and 12 months after switching. Patients´ characteristics and clinical background information were collected from patient records and costs were obtained from the clinical patient administration database of the hospital. Results: The SRL (I) of the cost-effectiveness of biological drugs for the treatment of RA showed that biological drugs did not seem to be cost-effective among conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) naïve or csDMARD resistant RA patients with the cost-effectiveness threshold of 35000 €/QALY (Quality-Adjusted Life Year), but they might be cost-effective among csDMARD resistant patients with the threshold of 50,000-100,000 €/QALY. Rituximab was the only biological drug that seemed to be cost-effective among RA patients with a previous exposure to TNF inhibitors. According to the patient-level simulation model (III), drug costs were the lowest for rituximab in RA patients who had been previously been treated with TNF inhibitors, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest outpatient and inpatient care costs. In total, TNF inhibitors had the lowest and rituximab the highest direct costs (including drug costs, administration costs, costs of switching, outpatient and inpatient care costs). The amount of QALY gained ranged from 9.41 for rituximab to 9.66 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and were therefore dominant in comparison to rituximab. According to the SLR (II), biological drugs seemed to be cost-effective for the treatment of active severe IBD with the cost-effectiveness threshold of 35,000 €/QALY, but the cost-effectiveness remained unclear in the maintenance treatment. Based on the prospective observational study (IV), no statistically significant difference was observed over one year following switching to the IFX biosimilar when the generic 15D instrument for the measurement of HRQoL in IBD patients was used. HRQoL measured with the IBDQ was, in CD patients, statistically significantly better (p=0.018) 3 months after switching to the infliximab biosimilar than at time of switching. Statistically significant finding was not observed in UC patients. Disease activity, in light of CDAI, pMayo and FC, was similar over one year following switching in IBD patients. The costs of biosimilar infliximab were around one third of the costs of originator one, whereas costs related to secondary healthcare (excluding the costs of infliximab) were similar before and after switching to biosimilar. Conclusions: The patient-level simulation model based on Finnish real-world data showed that TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to rituximab in RA patients, who had been previously been treated with TNF inhibitors. Significant differences were not observed in effectiveness between biological drugs. As TNF inhibitors had the lowest costs and highest QALYs, so they were the most cost-effective treatment option. In contrast to the results of patient-level simulation model, rituximab was the most cost-effective biological drug among RA patients with an adequate response to TNF inhibitors based on SLR. The systematic search of the literature revealed that biological drugs seemed to be cost-effective for the treatment of active and severe IBD. Based on the Finnish observational data, it suggested that HRQoL and disease activity of the infliximab-biosimilar were comparable to the originator one in the maintenance treatment of IBD. The costs of the infliximab-biosimilar were significantly lower than the costs of the originator one, and switching from originator infliximab to a biosimilar one had no effect on costs related to secondary healthcare (excluding the costs of infliximab).Tausta: Nivelreuma (RA) ja tulehdukselliset suolistosairaudet (IBD), joihin kuuluvat Crohnin tauti (CD), haavainen paksusuolitulehdus (UC) sekä määrittämätön IBD, ovat kroonisia tulehdussairauksia. Suomessa RA:n esiintyvyyden on arvioitu olevan 1980-luvun lopulla kerättyihin aineistoihin perustuen noin 0,8 % aikuisväestöstä, kun taas IBD:n esiintyvyys on noin 0,9 % vuonna 2019. Biologiset lääkkeet ovat hoitovaihtoehto RA:n ja IBD:n hoidossa, mikäli tavanomaisista lääkkeistä ei ole saatu vastetta tai tavanomainen lääke on sopimaton. Toukokuuhun 2019 mennessä Euroopan lääkevirasto (EMA) on hyväksynyt kymmenen biologista lääkettä nivelreuman hoitoon, neljä CD:n hoitoon sekä neljä UC:n hoitoon. Biologisten lääkkeiden on osoitettu olevan vaikuttavia hoitoja RA:n ja IBD:n hoidossa, ja niillä on verrattavissa oleva tehokkuus, eivätkä niiden turvallisuusprofiilit eroa merkitsevästi toisistaan. Biologiset lääkkeet ovat kuitenkin merkitsevästi kalliimpia kuin tavanomaiset lääkkeet. Biologisten lääkkeiden korkeiden kustannusten vuoksi kiinnostus on kasvanut biosimilaarivalmisteita kohtaan. EMA on hyväksynyt neljä biosimilaaria nivelreuman hoitoon ja kaksi IBD:n hoitoon. RA ja IBD ovat kroonisia sairauksia, jotka heikentävät potilaan terveyteen liittyvää elämänlaatua (HRQoL). Huonosti hoidettu RA ja IBD saattavat aiheuttaa myös työkyvyttömyyttä ja hallitsemattomia kustannuksia sosiaali- ja terveydenhuollolle. Tavoitteet: Tämän tutkimuksen tavoite oli arvioida biologisten lääkkeiden kustannuksia, vaikuttavuutta ja kustannusvaikuttavuutta RA:n ja IBD:n hoidossa. Menetelmät: RA:n ja IBD:n kustannusvaikuttavuudesta julkaistu tutkimustieto kartoitettiin tekemällä kaksi järjestelmällistä kirjallisuuskatsausta (tutkimukset I ja II). Järjestelmälliset kirjallisuuskatsaukset tehtiin noudattaen voimassa olevia suosituksia taloudellisia arviointeja käsitteleville katsauksille. Potilastason simulaatiomalli (tutkimus III) kehitettiin ennustamaan neljään biologiseen lääkkeeseen (abatasepti, tosilitsumabi, rituksimabi ja tuumorinekroositekijä alfan (TNF) estäjät) liittyviä kustannuksia ja lopputulosmuuttujia RA-potilailla, joita oli aiemmin hoidettu TNF-estäjillä. Biologinen lääke vaihdettiin toiseen biologiseen lääkkeeseen tehon puutteen tai haittavaikutusten vuoksi kunnes kaikki neljä vaihtoehtoa oli käytetty. RA-potilaiden lähtötiedot ja simulaatiossa käytetyt regressiomallit perustuivat ROB-FIN –rekisteriaineistoon. Tutkimuksessa tehtiin useita alaryhmäanalyyseja sekä deterministisiä herkkyysanalyyseja. Prospektiivisessa, havainnoivassa yksikeskustutkimuksessa (tutkimus IV), kaikilla IBD-potilailla, jotka saivat infliksimabi-hoitoa ylläpitohoitona Helsingin yliopistollisessa sairaalassa (HUS), vaihdettiin infliksimabi alkuperäisestä valmisteesta biosimilaariin (CT-P13). HRQoL mitattiin geneerisellä 15D utiliteettimittarilla ja sairausspesifisellä Inflammatory Bowel Disease Questionnaire (IBDQ) -mittarilla. Tautiaktiivisuuden mittaamiseen käytettiin Crohn´s Disease Activity Index (CDAI) ja Partial Mayo Score (pMayo) –mittareita sekä ulosteen kalprotektiinimääritystä (FC). Tiedot kerättiin 3 ja 12 kuukautta sen jälkeen, kun alkuperäinen valmiste oli vaihdettu biosimilaariin. Potilaiden tausta-ja kliiniset tiedot kerättiin potilasrekistereistä ja kustannukset sairaalan potilastietojärjestelmästä. Tulokset: Järjestelmällinen kirjallisuuskatsaus biologisten lääkkeiden kustannusvaikuttavuudesta RA:n hoidossa (I) osoitti, että biologiset lääkkeet eivät näyttäisi olevan kustannusvaikuttavia RA-potilailla, jotka eivät ole aiemmin saaneet tavanomaista lääkehoitoa tai ovat resistenttejä tavanomaisille lääkkeille kustannusvaikuttavuuden kynnysarvolla 35000 €/QALY (laatupainotettu elinvuosi). RA-potilailla, jotka ovat resistenttejä tavanomaisille lääkkeille, biologiset lääkkeet saattavat kuitenkin olla kustannusvaikuttavia kynnysarvolla 50000–100000 €/QALY. RA-potilailla, jotka olivat saaneet aiemmin TNF-estäjähoitoa, rituksimabi oli ainut biologinen lääke, joka näytti olevan kustannusvaikuttava kustannusvaikuttavuuden kynnysarvolla 35000 €/QALY. Potilastason simulaatiomallin (III) perusteella rituksimabilla oli matalimmat lääkekustannukset RA:n hoidossa potilailla, joita oli aiemmin hoidettu TNF-estäjillä. Kun annostelu- ja lääkevaihdon kustannukset otettiin huomioon, TNF-estäjillä oli matalimmat lääkekustannukset. Abataseptilla oli korkeimmat lääkekustannukset, kun taas rituksimabilla oli korkeimmat avo- ja sairaalahoidon kustannukset. Kaiken kaikkiaan TNF-estäjillä oli matalimmat ja rituksimabilla korkeimmat suorat kustannukset (sisältäen lääkekustannukset, annostelukustannukset, lääkevaihdon kustannukset sekä avo- ja sairaalahoidon kustannukset). QALY-arvo vaihteli 9,41:stä (rituksimabi) 9,66:een (TNF-estäjät). TNF-estäjillä, abataseptilla ja tosilitsumabilla oli matalemmat kustannukset ja korkeammat QALYt kuin rituksimabilla. Näin ollen ne dominoivat rituksimabia. Kustannusvaikuttavuuden kynnysarvolla 35000 €/QALY biologiset lääkkeet näyttivät olevan kustannusvaikuttavia aktiivisen ja vaikean IBD:n hoidossa, mutta ylläpitohoidossa biologisten lääkkeiden kustannusvaikuttavuus oli epäselvä (II). Prospektiivisen havainnoivan tutkimuksen (IV) perusteella ylläpitohoidossa olevien IBD-potilaiden HRQoL ei eronnut tilastollisesti merkitsevästi yhden vuoden seurannassa, kun verrattiin alkuperäistä infliksimabi-hoitoa infliksimabi-biosimilaariin. Sairausspesifisellä IBDQ-mittarilla mitattuna HRQoL oli CD-potilailla tilastollisesti merkitsevästi parempi (p=0,018) kolme kuukautta biolosimilaarivaihdon jälkeen kuin vaihdettaessa infliksimabi-biosimilaariin. Tilastollisesti merkitsevää eroa ei havaittu UC-potilailla. IBD-potilaiden tautiaktiivisuus CDAI:n, pMayo:n ja FC:n perusteella oli samankaltainen IBD-potilailla ensimmäisen vuoden aikana, kun verrattiin alkuperäistä infliksimabi-hoitoa infliksimabi-biosimilaariin. Infliksimabi-biosimilaarin kustannukset olivat noin yksi kolmasosa alkuperäisen lääkkeen hinnasta, kun taas erikoissairaanhoidon kustannukset (poissulkien infliksimabin lääkekustannukset) olivat samansuuruiset ennen ja jälkeen biosimilaarivaihdon. Johtopäätökset: Suomalaiseen rekisteritietoon perustuva potilastason simulaatiomalli osoitti, että TNF-estäjät, abatasepti ja tosilitsumabi dominoivat rituksimabia RA-potilailla, jotka olivat aiemmin käyttäneet TNF-estäjiä. Biologisten lääkkeiden välillä ei havaittu merkitseviä eroja vaikuttavuudessa. TNF-estäjät olivat kustannusvaikuttavin hoitovaihtoehto, koska niillä oli matalimmat kustannukset ja korkeimmat QALYt. Toisin kuin potilastason simulaatiomallissa, järjestelmällisen kirjallisuuskatsauksen perusteella rituksimabi oli kustannusvaikuttavin biologinen lääke RA-potilailla, jotka olivat saaneet riittämättömän vasteen aiemmasta TNF-estäjähoidosta. Järjestelmällisen kirjallisuuskatsauksen perusteella biologiset lääkkeet näyttivät olevan kustannusvaikuttavia aktiivisen ja vaikean IBD:n hoidossa. Suomalaiseen tietoon perustuvan prospektiivisen havainnoivan tutkimuksen perusteella infliksimabi-biosimilaari oli HRQoL:n ja tautiaktiivisuuden perusteella verrattavissa alkuperäiseen infliksimabi-hoitoon ensimmäisen vuoden aikana IBD:n ylläpitohoidossa. Infliksimabi-biosimilaarin kustannukset olivat merkitsevästi alhaisemmat kuin alkuperäisen infliksimabi-valmisteen, eikä infliksimabi-biosimilaarivaihdolla ollut vaikutusta erikoissairaanhoidon kustannuksiin (poissulkien infliksimabin lääkekustannukset). Tämän väitöskirjan tuloksia arvioitaessa nykypäivään on otettava huomioon, että lääkehoito, erityisesti biologisten lääkkeiden osalta, on muuttunut huomattavasti järjestelmällisten kirjallisuuskatsausten kirjallisuushakujen suorittamisen jälkeen

A Systematic Review of the Cost-Effectiveness of Biologics for the Treatment of Inflammatory Bowel Diseases

Background Biologics are used for the treatment of inflammatory bowel diseases, Crohn's disease and ulcerative colitis refractory to conventional treatment. In order to allocate healthcare spending efficiently, costly biologics for inflammatory bowel diseases are an important target for cost-effectiveness analyses. The aim of this study was to systemically review all published literature on the cost-effectiveness of biologics for inflammatory bowel diseases and to evaluate the methodological quality of cost-effectiveness analyses. Methods A literature search was performed using Medline (Ovid), Cochrane Library, and SCOPUS. All cost-utility analyses comparing biologics with conventional medical treatment, another biologic treatment, placebo, or surgery for the treatment of inflammatory bowel diseases in adults were included in this review. All costs were converted to the 2014 euro. The methodological quality of the included studies was assessed by Drummond's, Philips', and the Consolidated Health Economic Evaluation Reporting Standards checklist. Results Altogether, 25 studies were included in the review. Among the patients refractory to conventional medical treatment, the incremental cost-effectiveness ratio ranged from dominance to 549,335 (sic)/Quality-Adjusted Life Year compared to the incremental cost-effectiveness ratio associated with conventional medical treatment. When comparing biologics with another biologic treatment, the incremental cost-effectiveness ratio ranged from dominance to 24,012,483 (sic)/Quality-Adjusted Life Year. A study including both direct and indirect costs produced more favorable incremental cost-effectiveness ratios than those produced by studies including only direct costs. Conclusions With a threshold of 35,000 (sic)/Quality-Adjusted Life Year, biologics seem to be cost-effective for the induction treatment of active and severe inflammatory bowel disease. Between biologics, the cost-effectiveness remains unclear.Peer reviewe

Health-related quality of life and costs of switching originator infliximab to biosimilar one in treatment of inflammatory bowel disease

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment. In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database. Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX. HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.Peer reviewe

Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients

Background: Clinical use of biosimilar infliximab (CT-P13) in inflammatory bowel diseases (IBDs) is based on extrapolation of indication from clinical studies performed in rheumatological diseases. Only few data exist of behaviour of infliximab trough levels (TLs) and anti-drug antibodies (ADAs) during switching.Aim: The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one.Methods: All our IBD patients receiving maintenance infliximab therapy were switched to biosimilar infliximab. TLs and ADAs were measured before the last originator infusion and before the third biosimilar infusion. Laboratory values, disease activity indices (partial Mayo score and Harvey-Bradshaw index) and demographic data were collected from patient records.Results: A total of 62 patients were included in the final analysis (32 Crohn's disease, 30 ulcerative colitis (UC) or IBD-unclassified). No significant changes in median TLs before (5.5mg/l) and after switching (5.5mg/l, p=.05) occurred in the entire study group or in the Crohn's disease (CD) subgroup (5.75 and 6.5mg/l, p=.68). However, in the subgroup of ulcerative colitis, the change in median TL was significantly different (from 5.2 to 4.25mg/l, p=.019). Two patients developed ADAs after switching. No changes in disease activity were detected during switching and no safety concerns occurred.Conclusions: Switching from originator to biosimilar infliximab resulted in statistically significant differences in infliximab TLs in patients with UC but not in patients with Crohn's disease. The clinical significance for this difference is doubtful and in neither group changes in disease activity occurred.Peer reviewe

Effects of pre-emptive pregabalin and multimodal anesthesia on postoperative opioid requirements in patients undergoing robot-assisted laparoscopic prostatectomy

Background: Previous findings indicate that pre-emptive pregabalin as part of multimodal anesthesia reduces opioid requirements compared to conventional anesthesia in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). However, recent studies show contradictory evidence suggesting that pregabalin does not reduce postoperative pain or opioid consumption after surgeries. We conducted a register-based analysis on RALP patients treated over a 5-year period to evaluate postoperative opioid consumption between two multimodal anesthesia protocols. Methods: We retrospectively evaluated patients undergoing RALP between years 2015 and 2019. Patients with American Society of Anesthesiologists status 1-3, age between 30 and 80 years and treated with standard multimodal anesthesia were included in the study. Pregabalin (PG) group received 150 mg of oral pregabalin as premedication before anesthesia induction, while the control (CTRL) group was treated conventionally. Postoperative opioid requirements were calculated as intravenous morphine equivalent doses for both groups. The impact of pregabalin on postoperative nausea and vomiting (PONV), and length of stay (LOS) was evaluated. Results: We included 245 patients in the PG group and 103 in the CTRL group. Median (IQR) opioid consumption over 24 postoperative hours was 15 (8-24) and 17 (8-25) mg in PG and CTRL groups (p = 0.44). We found no difference in postoperative opioid requirement between the two groups in post anesthesia care unit, or within 12 h postoperatively (p = 0.16; p = 0.09). The length of post anesthesia care unit stay was same in each group and there was no difference in PONV Similarly, median postoperative LOS was 31 h in both groups. Conclusion: Patients undergoing RALP and receiving multimodal analgesia do not need significant amount of opioids postoperatively and can be discharged soon after the procedure. Pre-emptive administration of oral pregabalin does not reduce postoperative opioid consumption, PONV or LOS in these patients.</div

The Cost-Effectiveness of Biologics for the Treatment of Rheumatoid Arthritis : A Systematic Review

Background and Objectives Economic evaluations provide information to aid the optimal utilization of limited healthcare resources. Costs of biologics for Rheumatoid arthritis (RA) are remarkably high, which makes these agents an important target for economic evaluations. This systematic review aims to identify existing studies examining the cost-effectiveness of biologics for RA, assess their quality and report their results systematically. Methods A literature search covering Medline, Scopus, Cochrane library, ACP Journal club and Web of Science was performed in March 2013. The cost-utility analyses (CUAs) of one or more available biological drugs for the treatment of RA in adults were included. Two independent investigators systematically collected information and assessed the quality of the studies. To enable the comparison of the results, all costs were converted to 2013 euro. Results Of the 4890 references found in the literature search, 41 CUAs were included in the current systematic review. While considering only direct costs, the incremental cost-effectiveness ratio (ICER) of the tumor necrosis factor inhibitors (TNFi) ranged from 39,000 to 1 273,000 (sic)/quality adjusted life year (QALY) gained in comparison to conventional disease-modifying antirheumatic drugs (cDMARDs) in cDMARD naive patients. Among patients with an insufficient response to cDMARDs, biologics were associated with ICERs ranging from 12,000 to 708,000 (sic)/QALY. Rituximab was found to be the most cost-effective alternative compared to other biologics among the patients with an insufficient response to TNFi. Conclusions When 35,000 (sic)/QALY is considered as a threshold for the ICER, TNFis do not seem to be cost-effective among cDMARD naive patients and patients with an insufficient response to cDMARDs. With thresholds of 50,000 to 100,000 (sic)/QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs. Standardization of multiattribute utility instruments and a validated standard conversion method for missing utility measures would enable better comparison between CUAs.Peer reviewe

Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis

Objectives The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. Methods A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. Results Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. Conclusions TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.Peer reviewe

Quality assessment of the included studies.

<p>Quality assessment of the included studies.</p

Flow chart of study selection.

<p>Flow chart of study selection.</p

A Rare Mitochondrial DNA Haplotype Observed in Koreans

The haplogroup affiliations of Korean mitochondrial DNAs (mtDNAs) were determined by restriction analysis. Out of the 101 mtDNAs analyzed, 91 (90%) belonged to Asian-specific haplogroups M, C, D, G, A, B, and F. Haplogroup E was not detected among the Korean mtDNAs. Three mtDNAs represented an unusual mtDNA haplotype characterized by simultaneous presence of E and G haplogroup-specific polymorphisms. To characterize this haplotype in more detail, we sequenced the hypervariable segment I (HVSI) from these mtDNAs as well as from those from selected individuals representing each haplogroup. Sequence data were further used to compare Korean mtDNAs with mtDNAs from other Asian populations. The observed rare haplotype was also found among Japanese, which suggests that it is one of the ancestral lineages originally peopling Japan