Review One year in review 2018: novelties in the treatment of rheumatoid arthritis - Clinical and ...
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Review
One year in review 2018:
novelties in the treatment of rheumatoid arthritis
A. Bortoluzzi1, F. Furini1, E. Generali2, E. Silvagni1, N. Luciano3, C.A. Scirè1,4
1
Rheumatology Unit, Department ABSTRACT defined as arthralgia and autoantibody
of Medical Sciences, University of The current approach to treatment of positivity, under the hypothesis that the
Ferrara, Italy; rheumatoid arthritis (RA) includes initiation of a disease-modifying treat-
2
Division of Rheumatology and Clinical early and aggressive intervention aim- ment in these patients might prevent
Immunology, Humanitas Clinical and
Research Center, Rozzano, Milan, Italy;
ing to reach early and persistent low disease development. Glucocorticoids
3
Rheumatology Unit, Department of disease activity and remission. New (GC), rituximab (RTX), methotrexate
Clinical and Experimental Medicine, drugs have improved the therapeutic (MTX) failed to demonstrate such pre-
University of Pisa, Italy; armamentarium of rheumatologists, ventive effect, but several studies are
4
Epidemiology Unit, Italian Society providing new options for patients. Be- under way testing hydroxychloroquine
for Rheumatology, Milan, Italy. yond these innovations, new evidence (HCQ), metilprednisolone and MTX,
Alessandra Bortoluzzi, MD PhD has improved the safety of therapies abatacept (ABA), or atorvastatin. Until
Federica Furini, MD and provided tools for the optimisation positive results are obtained from any
Elena Generali, MD
of long-term management of RA. This of these studies, no evidence is avail-
Ettore Silvagni, MD
Nicoletta Luciano, MD paper reviews the most relevant studies able to support the use of DMARDs in
Carlo Alberto Scirè, MD, PhD published over the last year in the field patients without clinical arthritis.
Please address correspondence to: of treatment of RA. Though preventive strategies in asymp-
Dr Alessandra Bortoluzzi, tomatic subjects at population level are
Dipartmento di Scienze Mediche, Introduction not feasible, better stratification might
Sezione di Reumatologia, Rheumatoid arthritis (RA) is a chron- allow a timely intervention from the
Azienda Ospedaliero-Universitaria ic autoimmune disease characterised very beginning phases even in absence
Sant’Anna di Ferrara, by synovitis and joint damage, which of overt arthritis. A recent sub-analysis
Via A. Moro 8,
can produce a loss of function, impair of 22 patients with high risk of RA de-
44124 Cona (FE) Italy.
E-mail: alessandra.bortoluzzi@unife.it quality of life and enhance morbidity velopment enrolled in the PROMPT
and mortality. The current therapeu- trial, including patients with suspected
Received and accepted on April 11, 2018.
tic approach of RA includes early and RA and comparing 12-months MTX
Clin Exp Rheumatol 2018; 36: 347-361.
intensive treatment, aiming to reach vs. placebo on the 5-year risk of RA ac-
© Copyright Clinical and early and persistent low disease activ- cording to 1987 criteria, demonstrated
Experimental Rheumatology 2018.
ity and remission. Recently, new drugs that only 6 of 11 patients (55%) devel-
increased the therapeutic options for oped RA, compared to 11 of 11 patients
Key words: rheumatoid arthritis,
patients, including both novel targeted (100%) in the placebo arm (p=0.01)
biologics, treatment, management
therapies and biosimilars. New evi- (3).
dence has accumulated on real-world
safety and efficacy of various biologi- Glucocorticoids
cal disease-modifying anti-rheumatic The use of systemic GC in the manage-
drugs (bDMARDs). Starting from the ment of RA is recommended as initial
last annual review on this topic, this treatment in the early RA phase, for
paper reviews the most relevant stud- flares management and in bridge-ther-
ies published over the last year on the apy for established RA according to
management of RA (1). most of international recommendations
and consensus statements, as analysed
Prevention of rheumatoid arthritis by a recent systematic literature review
Despite fascinating, prevention of RA (SLR) including articles published
is still one of the forbidden dreams between 2011 and 2015 (4). Current
for rheumatologists. A comprehensive recommendations for use of GC are
review disentangled the potential pre- suboptimal and some aspects are par-
ventive strategies of RA and future tially or completely neglected in “of-
perspectives (2). Most of trials tar- ficial position” statements. According
Competing interests: none declared. geted the pre-arthritis phase, typically to the SLR, the recommended dosage
Clinical and Experimental Rheumatology 2018 347One year in review 2018: treatment of RA / A. Bortoluzzi et al. of steroids is defined as “low-dose” or to COBRA Classic strategy, COBRA tion. Charles-Schoeman et al. reported “the lowest possible dose”, but contro- Slim (prednisolone 30 mg/day, tapered a post hoc analysis of 6 phase III trials versies still exist about the specific GC weekly to 5 mg/day, MTX 15 mg/week) of tofacitinib, in which a stable pre- “low-dose” definition (less than 7.5/10 or COBRA Avant Garde (prednisolone trial GC dosage (less than 10 mg/day) mg/day of prednisone equivalents in 30 mg/day, tapered weekly to 5 mg/ was allowed (9). 1,767 patients already the majority of papers). Total length of day, MTX 15 mg/week, leflunomide receiving GC (out of 3,200 tofacitinib- the suggested “short-term” treatment 10 mg/day) while patients at low-risk treated) were analysed. GC did not af- period is debated as well, varying be- were randomised to COBRA Slim or fect the overall efficacy of tofacitinib tween 3 up to 24 months. Information MTX tight step-up (MTX 15 mg/week, in all studies, resulting in similar ACR of tapering schemes are scarce, as it no GC allowed). At week 34, GC were and CDAI (Clinical Disease Activity is only advocated to taper “as soon as stopped in all groups and at 52 weeks Index) responses in GC and not-GC possible” with a slow tapering strategy comparable remission rates were main- paired samples. Regarding safety, Co- (4). The balance between long-term tained between different groups, irre- hen et al. demonstrated that GC use safety and benefit and the role of GC spective of csDMARD use and GC dos- was an independent risk factor for se- use in the elderly population remain in- age. For remission induction, a high GC rious infections and Varicella-Zoster triguing points to elucidate. dose was not more advantageous than virus (VZV) infections in randomised Recently, two studies investigated the a moderate dose, regardless of the cs- clinical trials (RCTs) patients treated initial GC dosage to consider in early DMARD strategy, suggesting that CO- with tofacitinib (10). RA (5, 6). The COBRA-light exten- BRA Slim could be an effective, safe, sion study evaluated the efficacy and low-cost and feasible initial treatment Conventional synthetic safety of initial COBRA-light (predni- strategy for patients with early RA re- disease-modifying solone 30 mg/day, tapered to 7.5 mg/ gardless of their prognostic profile (6). anti-rheumatic drugs day in 8 weeks and MTX escalated to Regarding long term efficacy and safe- The prompt start of treatment with cs- 25 mg/week in 8 weeks) versus CO- ty outcomes of GC use in combination DMARDs is essential to control dis- BRA therapy (prednisolone 60 mg/day, with MTX, Safy et al. performed a fol- ease burden and prevent radiological tapered to 7.5 mg/day in 6 weeks, MTX low up analysis of the second Comput- progression and MTX remains the “an- 7.5 mg/week and sulphasalazine (SSZ) er-Assisted Management in Early RA chor drug” of the initial strategy. In a 2 g/day) after 4 years of follow-up (5). (CAMERA-II) trial (7). After 2 years recent SLR, Bergstra et al. investigated Between 6 and 12 months patients not of initial treatment with MTX plus the dose-response to MTX in early RA achieving minimal disease activity un- stable (10 mg/day) prednisone or pla- patients considering 6-month effects derwent treatment intensification of cebo, patients were treated according on DAS28, erythrocyte sedimentation MTX (in COBRA arm) and addition of to standard of care out of the protocol rate (ESR)/C-reactive protein (CRP) etanercept (ETA). 77 patients starting schedules, aiming to GC tapering (79% and HAQ-DI response in csDMARDs COBRA were compared with 72 pa- of patients discontinued prednisone at naïve subjects (11). Analysing 31 stud- tients on COBRA-light strategy. After the end of follow-up). After a median ies for a total of 5,589 patients, the au- 4 years, there were no significant dif- follow-up period of 6.7 years, a sig- thors concluded that higher MTX dos- ferences in terms of prescription of new nificantly lower proportion of patients ages did not meaningfully affect effica- bDMARDs neither in disease activity started a first bDMARD in the MTX cy outcomes when in monotherapy or score-(DAS) 28, Health Assessment plus GC arm (31%) compared to MTX in association with GC or bDMARDs. Questionnaire-Disability Index (HAQ- plus placebo (50%); safety outcomes Only one study in this SLR, however, DI), Boolean ACR/EULAR remission concerning GC-related morbidity were considered subcutaneous administra- and radiographic progression. Despite comparable between the two groups. tion of MTX, possibly resulting in a the study was not powered to explore Analysis of the ESPOIR cohort (8), as bias related to the way of administra- differences in terms of GC-related co- well, remarked long-term safety of low tion of the drug and its pharmacokinetic morbidities onset, no significant dif- dose GC use in very early RA manage- properties. These data were confirmed ference was found between groups, ment. After a median follow up period by a large international observational suggesting that moderate dosages of of 7 years, patients exposed at least database, the METEOR database, in GC can be efficacious and relatively one time to systemic GC during clini- which low (less than 10 mg/week) or safe in early RA. In the Care in Early cal history (386 patients, 64.1%, mean high (>15mg) dosages of MTX were RA (CARERA) open-label randomised 3.1±2.9 mg/day of prednisone equiva- analysed in monotherapy or in com- trial, early RA patients, stratified ac- lent) had similar safety outcomes bination with GC or csDMARDs. Dif- cording to prognostic factors, were (death, cardiovascular diseases, severe ferent dosages of MTX did not affect assigned to different conventional syn- infections, fractures) compared to 216 efficacy outcomes in all groups, even thetic DMARDS (csDMARDs) com- patients never taking GC. when adjusting for eventual confound- binations and GC remission induction Combination of GC with novel tar- ing by indication (baseline and envi- schemes during the first treatment year geted synthetic DMARD (tsDMARDs) ronmental characteristics) (12). (6). High-risk patients were randomised use in RA treatment is under investiga- In patients without poor prognosis or 348 Clinical and Experimental Rheumatology 2018
One year in review 2018: treatment of RA / A. Bortoluzzi et al. with a longer disease duration, triple Biologic disease-modifying OR 1.45 (95%CI 1.09, 1.94) for a mod- therapy seems to be a safe option to anti-rheumatic drugs erate level of evidence (18). consider before starting a biological Efficacy Observational registries indirectly therapy. Peper et al. provided results of Currently there are 10 bDMARDs ap- provided data on the efficacy of b- the open-label extension of the Rheu- proved for RA, but the optimal treat- DMARDs in terms of persistence. matoid Arthritis Comparison of Active ment strategy in patients with inad- The CORRONA registry analysed the Therapies (RACAT) trial, which ran- equate response to cDMARDs is still persistence on treatment of 1,791 bio- domised patients with active disease matter of debate. There are no indica- naive patients who started ADA. The despite MTX monotherapy to receive tions on which bDMARDs to be used percentages of patients who stayed either triple therapy (MTX, HCQ, SSZ) in patients naïve to csDMARDs. The on ADA therapy were 64.1%, 48.0%, or MTX-ETA (13). In the double-blind C-Early trial evaluated this aspect ana- 26.7%, and 13.3% at 1, 2, 5, and 10 part of the study, inadequate respond- lysing efficacy and safety of MTX as- years, respectively and a small propor- ers at 24 weeks switched from one arm sociated to Certolizumab (CZp) com- tion (10%) of patients continued to be to the other. After a mean follow-up pared to MTX + placebo in patients treated for up to 12 years (19). Also, period of 11 months, patients on triple naïve from csDMARDs, with early ac- data from RABBIT register evaluated therapy had similar efficacy outcomes tive RA (
One year in review 2018: treatment of RA / A. Bortoluzzi et al. Treatment persistence was higher in inhibition and therefore treatment with From the meta-analysis of long-term TCZ than in TNF-i (p 65 (n=12), while 18 patients started ETA bDMARD, 6,358 of non-TNF-i, and years and presence of diabetes melli- 50 mg/week (n=14) or ADA 40 mg 46,610 csDMARDs users. A general tus) (22). every 2 weeks (n=4) Endothelial func- population cohort of 107,491 subjects An SLR and meta-analysis evaluating tion was evaluated by mean increase in was identified as comparator. Evaluat- composition of body mass using dual- FMD, and was significantly improved ing the overall risk of cancer, there was energy x-ray absorptiometry in patients only in patients treated with TCZ (from no significant signal in patients start- affected by RA and spondyloarthritis 3.43% to 5.96%, p=0.03) while it was ing the first or second TNF-i (HR 0.93, revealed that TNF-i increased in the not significantly increased for TNF-i 95%CI 0.85, 1.01; HR 0.89, 95%CI short term (over 6 months) the lean (from 4.78% to 6.75%, p=0.09), and in 0.76, 1.04) and for those initiating a non mass but also the fat mass, that is as- the csDMARD group (from 2.87% to TNF-I biologics (TCZ HR 0.89, 95%CI sociated with CVD risk (23). 4.84%, p=0.21) (26). 0.67, 1.18; ABA HR 0.88, 95%CI 0.68, On the other hand, a fundamental risk 1.14 and RTX HR 0.86, 95%CI 0.73, factor for CVD is endothelial dysfunc- • Risk of malignancy 1.03), compared to biological naïve tion and clinical and preclinical evi- Due to their effect on the immune sys- patients (csDMARDs group). The risk dence has suggested a role of TNF in tem, bDMARDs are still under surveil- of developing invasive squamous cell the genesis of accelerated atherosclero- lance for the risk of malignancies and skin cancer was not significantly in- sis. Ursini et al. performed a SLR and infections. Maneiro et al. carried out creased for the first or second TNF-i a meta-analysis regarding the medium a SLR and meta-analysis of RCTs and (first 1.09, 95%CI 0.84, 1.42, second and long-term effect of TNF-i on en- long-term extension studies to verify HR 0.86, 95%CI 0.54, 1.39) whilst an dothelial function and concluded that the risk of all neoplasms and solid, hae- increased risk was found for ABA (HR the TNF-i improve endothelial dys- matological and cutaneous (non-mela- 2.15, 95%CI 1.31, 3.52). The results of function assessed by flow mediated dil- noma skin cancer (NMSC) and mela- the BSRBR-RA register confirmed a atation (FMD), laser Doppler iontopho- noma) malignancies in patients treated lack of increase of risk of melanoma in resis, peripheral arterial tonometry and with bDMARDs or tofacitinib com- RA patients exposed to TNF-i in first or venous occlusion pletismography (24). pared to the control groups (placebo second line (first HR 0.85, 95%CI 0.60, Interleukin (IL)-6 is a key cytokine in or csDMARDs). No significant differ- 1.18; second HR 0.92, 95%CI 0.52, the induction of atherosclerosis, so it ences in the risk of neoplasm emerged 1.61) (28, 29). From the same dataset, would be reasonable to think that its for patients in bDMARDs or tofacitinib. lymphoma risk was confirmed as not in- 350 Clinical and Experimental Rheumatology 2018
One year in review 2018: treatment of RA / A. Bortoluzzi et al.
creased in patients with RA treated with 95%CI 0.73, 6.12; CZp 2.38, 95%CI and safety of the individual biological
TNF-i compared to those treated with 0.42,13.42). Evaluating only patients agents used in monotherapy. 28 RCTs
cDMARDs (crude HR 0.61, 95%CI with RA, tuberculosis risk was higher were selected including 8,602 patients.
0.40, 0.92; adjusted HR 1.00, 95%CI compared to other indications (OR ACR50 (primary outcome) occurred
0.56, 1.80) (30). 2.29, 95%CI 1.09, 4.78; p=0.03). Sub- more frequently with ETA or TCZ
analysis was also performed by differ- monotherapy than with other biological
• Serious adverse effects entiating the studies conducted in high agents (36). Use of TCZ monotherapy
A network meta-analysis was per- or low tuberculosis prevalence area can be considered effective, as well as
formed to compare the risk of SAEs (OR 2.39, 95%CI 0.97, 5.90 and 1.64, on the control of disease activity, also
including death for the 10 bDMARDs 95% CI 0.70, 3.88, respectively) (32). on radiographic progression. In U-Act-
currently approved by the FDA (Food Specific AEs of TCZ (neutropenia and Early strategy trial, Sharp van der Hei-
and Drug Administration) and the EMA elevation of liver enzymes) were also jde score (SHS) changes from baseline
(European Medicines Agency) and for assessed. Moots et al. performed an were significantly lower in the TCZ
tofacitinib compared to treatment with analysis of long-term safety data from plus MTX arm compared with the MTX
cDMARDs. 117 trials were included, TCZ phases 3 and 4 trials, long-term alone arm after 52 weeks (p=0.016),
for a total of 47,615 patients with RA, extensions and pharmacology stud- but after 104 weeks, less progression
treated for approximately 30,971 per- ies involving 4,098 patients (1,454 re- in joint damage was noted in both TCZ
son-years. The analysis shows that CZp ceived placebo+csDMARDs and 2,644 arms (TCZ plus MTX, p=0.021; and
was associated with a greater risk of received TCZ ± csDMARDs). Reduced TCZ-alone, p=0.038). Joint space nar-
SAEs compared to controls (rate ratios neutrophil counts (all grades) resulted rowing did not change significantly in
(RR) 1.45, 95%CI 1.13, 1.87) and com- greater in TCZ-treated patients than in the three treatment arms, while for ero-
pared to other bDMARDs: ABA (1.58, placebo-treated patients. The occur- sion scores at 104 weeks significantly
95%CI 1.18, 2.14), ADA (RR 1.36, rence of serious infection does not ap- lower erosion progression scores were
95%CI 1.02, 1.81), ETA (RR 1.60, pear to be correlated with neutrophil found in the TCZ plus MTX (p=0.016)
95%CI 1.18, 2.17), GOL (RR 1.45, decrease (33). Genovese et al. inves- and TCZ arm (p=0.023) when com-
95%CI 1.00, 2.08), RTX (RR 1.63, tigated liver enzyme abnormalities in pared with the MTX arm. After cor-
95%CI 1.16, 2.30); but also compared data from phase 3 or 4 clinical trials, recting for DAS28 score over time, it
to tofacitinib (RR 1.44, 95%CI 1.03, long-term extensions, and a pharma- was no longer statistically significant
2.02). TCZ was associated with more cology study comparing 4,171 patients (TCZ plus MTX: mean SHS 0.55,
SAEs than ABA (1.30, 95%CI 1.03, treated with TCZ-IV and csDMARDs. 95%CI 1.22, 0.11; p=0.10 vs. MTX;
1.65), ETA (1.31, 95%CI 1.04, 1.67) and A total of 2.5% of patients withdrew TCZ: mean SHS 0.39, 95%CI 1.05,
RTX (1.34, 95%CI 1.01, 1.78). Further- from TCZ treatment following liver 0.28; p=0.26 vs. MTX) (37). A phase III
more, the sensitivity analysis revealed enzymes elevations. A total of 7 he- study (MONARCH trial) evaluated the
that with co-administered csDMARDs patic SAEs (0.04 per 100 patient-years, efficacy and safety of sarilumab (IgG1
in recommended dose, ABA associ- 95%CI 0.02, 0.09) occurred in the TCZ monoclonal antibody that binds spe-
ates with fewer SAEs than tofacitinib. studies (34). cifically to both soluble and membrane-
As monotherapy and in recommended bound IL-6RS) vs. ADA. Both drugs
dose, tofacitinib had significantly lower Monotherapy were administered as monotherapy in
rates of SAEs compared with ADA, It is known that, after MTX failure, RA patients with intolerance or inad-
TCZ, controls (i.e. no csDMARDs use) combining MTX with bDMARDs equate response to MTX. 369 patients
and tofacitinib plus csDMARDs. ADA is more efficacious than bDMARDs (185 ADA and 184 sarilumab) were
monotherapy had a higher rate of SAEs monotherapy. Data from the National included. Sarilumab achieved primary
than when used with concomitant csD- Register for Biologic Treatment in Fin- endpoints (change from baseline in
MARDs (31). land involving 2,053 patients initiating DAS28-ESR at week 24 -3.28 vs. -2.20,
Regarding the risk of tuberculosis, a TNF-i revealed that concomitant treat- mean difference −1.08, 95%CI −1.36,
meta-analysis including 29 studies (14 ment with MTX (but not with other cs- -0.79; pOne year in review 2018: treatment of RA / A. Bortoluzzi et al. therefore to the different production of remission achieved in the first and sec- Tapering anti-drug antibodies (ADAbs) that can ond year for 20% and 26% of patients The opportunity to taper bDMARDs be associated with loss of efficacy and respectively and LDA in 30 and 38% in RA patients on sustained remission risk hypersensitivity. Strand et al. per- respectively) (41). has been widely discussed in the last formed a systematic review of studies Recently a real-world analysis was years and different strategies have been evaluating the immunogenicity of 10 conducted to compare these two dif- compared in many studies, but the best approved bDMARDs for all the indi- ferent strategies, focusing on disease approach to adopt remains unknown. cation including 443 publications (394 activity and on treatment persistence; Available recommendations suggest studies) (39). As expected, ADA, inf- in this longitudinal retrospective study the order to follow for therapies reduc- liximab (IFX) and IFX biosimilar were new MOA switchers (ABA, RTX or tion: first GC, then bDMARDs and fi- associated with the increased produc- TCZ) seemed to show better clini- nally csDMARDs (45). However, there tion of ADAbs (>50%) compared to cal outcomes than TNF-i cyclers, but is limited evidence about patient or other drugs such as GOL, ustekinum- the difference was not statistically disease characteristics predicting the ab, ETA, secukinumab (
One year in review 2018: treatment of RA / A. Bortoluzzi et al. to adopt. Kikuchi et al. proved the fea- ly reduced time to flare (adjusted HR Biosimilars sibility of “spacing” drugs: they evalu- 2.81; p=0.051). In the exploratory trial, It is established that biologic treatment ated the outcomes with a six-week after one year, 45% RA patients ran- has dramatically changed the outcomes extended dosing interval of TCZ-IV domised in tapering groups achieved of RA and other inflammatory disease and demonstrated a good retention rate the complete withdrawal of bDMARD patients, however, their high cost may and an acceptable control on clinical without flaring but the mean DAS28 limit the access to these medications. outcomes and on radiographic progres- score switched from 1.51 (95%CI 1.14, In this view, biosimilars of products no sion. In fact, at week 54, 87.5% of pa- 2.65) to 2.27 (95%CI 1.71, 3.98) by 6 longer protected by patent have been tients maintained DAS28-ESR remis- months (50). developed and have lower costs than sion and CDAI and Simplified Disease Similar conclusions were obtained bio-originators. Currently, there are Activity Index were comparable to in the extension phase of the DRESS several biosimilars of IFX, ETA, RTX baseline; in addition only one of the 22 study which examined a population of and ADA, but others are under devel- patients enrolled showed a significant 172 patients reducing doses of TNF-i opment, also of other bio-originators increase in structural damage evaluated (ADA and ETA) based on disease ac- with different mechanisms of action. by the modified total SHS score (48). tivity indices. In the long-term observa- We know that biosimilars cannot be The same endpoints were evaluated in tion period of 3 years a treat-to-target considered bioequivalent, while they the MATADOR pilot trial that enrolled approach was adopted with dose adjust- are a replica of a biopharmaceutical 53 patients in sustained remission or ments to optimise the treatment, but the that has met criteria for bio-similarity, LDA using intravenous ABA; for the overall use of TNF-i remained lower in according to a defined pathway estab- maintenance therapy the dosage admin- patients randomised to dose reduction lished to demonstrate equivalent phar- istrated was reduced in all subjects with respect patients administrating the usu- macokinetics, pharmacodynamics and one year follow up. Only 5 patients al care. Clinical and radiological out- efficacy and comparable safety and im- experienced a flare and re-increased comes were similar in the two groups munogenicity, and has been reviewed the drug dose achieving a new remis- but also the AE rates were comparable; and approved by a regulatory author- sion status, while other 5 patients did so these data confirmed the non-infe- ity in a highly regulated area. Since the not complete the protocol. In all other riority of this therapeutic strategy but large areas of uncertainty, in the pre- cases high rates of remission/LDA to date the only advantage appeared the vious years a set of recommendations were observed suggesting the possibil- reduction in TNF-i use (51). for the use of biosimilars have been is- ity to continue with a reduced doses for A potential role in the tapering decision sued (53). While it is recognised that maintenance (49). Both these studies could be assigned to the therapeutic drug a biosimilar, approved by the EMA or agreed on the feasibility of a reduction monitoring with a strategy of modifying FDA, is neither better or worse than its of therapy, but they included a limited the dose or time interval on the base of bio-originator, increasing interest has number of patients and further reports concentration measurement. This ap- grown around the possibility of switch- are needed. proach has been studied for ADA in a ing between the bio-originator to the Conversely, more data are available randomised, open-label, non-inferiority biosimilar, and many RCTs and real- regarding the tapering of TNF-i. The trial: patients with serum drug concen- life studies have been published while OPTTIRA trial compared two taper- trations at baseline above 8 μg/mL were other are currently ongoing to assess the ing regimens in patients treated with assigned to a prolongation group (40 mg safety and efficacy of switching. The ETA and ADA; in this open label trial once every 3 weeks) or to a continuation extension period of the PLANETRA patients were randomised in three dif- group (standard interval of every other study, found similar efficacy and safety ferent groups: about half of patients week). With the limitations due to the results in RA patients treated with CT- continued biologic at the initial dosage, short period of observation (28 weeks), P13, an IFX biosimilar, compared to one group reduced dose by 33% and the this study confirmed the effectiveness IFX bio-originator both in combination last group tapered biologic by 66% for of this dosing down strategy: the in- with MTX, for 1 year after the switch 6 months. After this period control sub- crease of ADA dosing interval from 2 to (54). Similar results have been ob- jects were randomised to taper TNF-i 3 weeks showed no significant clinical tained with a different IFX biosimilar, by 33 or 66%, while patients of taper- consequences in most of patients, who SB2, up to 78 weeks, ETA biosimilar, ing groups further increased the time rather achieved a minimal improvement SB4, over 2 years, RTX biosimilar up between injections until they stopped of mean DAS28 (1.9±0.79 at baseline to 2 years, and ADA biosimilar, SB5 (exploratory phase). By comparing ta- vs. 2.0±0.8 at week 28). A significant in- (55–58). Of interest, similar data re- pering groups, the authors concluded crease in disease activity (DAS28 ≥0.6 garding the immunogenicity have been that a reduced TNF-i dose by one third points) was observed in similar pro- reported, with ADAbs occurring in the was not associated with a significant portion in both groups; as regard ADA same proportion of patients on the bio- number of flares (DAS28 scores ≥0.6 concentration, 73% patients remained similar or bio-originator and also after with a DAS28 >3.2 plus an increase in above 5 μg/mL, the minimum threshold switching (54–57). Real-life evidences the swollen joint count), while a fur- necessary to block TNF according to are also becoming increasingly avail- ther de-escalation showed significant- previous studies (52). able. In Denmark, a national guideline Clinical and Experimental Rheumatology 2018 353
One year in review 2018: treatment of RA / A. Bortoluzzi et al.
by May 2015 dictated a non-medical Tofacitinib out disease flare (63). Park et al. ana-
switch, that is, all patients treated with Tofacitinib is an oral JAK inhibitor lysed the topic of therapy discontinua-
IFX, of which 403 were RA, should that preferentially inhibits signalling tion rates of tofacitinib and biologics in
switch to CT-P13 for economic rea- by receptors associated with JAK1 and RA patients with inadequate response
sons. Data from the DANBIO registry, JAK3, with functional selectivity over to a previous treatment using Bayes-
which follows prospectively patients JAK2. In recent years phase 3 and long- ian network meta-analysis based on
treated with biologics, show that to CT- term extension studies have proved ef- RCTs (64). The discontinuation rates
P13 had no negative impact on disease ficacy and safety of tofacitinib adminis- between tofacitinib and biologics were
activity, however, adjusted 1-year CT- tered as monotherapy or in combination similar in the group with a previous in-
P13 retention rate was slightly lower with csDMARDs. In 2017 Fleshiman et adequate response to csDMARDs. In
than for IFX in a historic cohort (59). al. published the first phase 3b/4, dou- the group with a previous inadequate
Based on the results of a recent multi- ble-blind, head-to-head, randomised response to biologic, TNF-i and RTX
centre observational study, the discon- controlled trial (ORAL strategy trial) to showed significantly lower total dis-
tinuation of CT-P13 after open-label assess the comparative efficacy of to- continuation rate than tofacitinib (64).
switching from IFX originator could facitinib monotherapy, tofacitinib plus Various studies have explored the safe-
be mainly driven by an increase in the MTX, and ADA plus MTX for the treat- ty profile of tofacitinib. In the ORAL
subjective tender joint count and the ment of RA in patients with a previous strategy trial, safety was similar be-
Patient’s Global Assessment of Disease inadequate response to MTX (61). The tween the treatment group in terms of
Activity and/or in self-reported adverse primary outcome was non-inferiority in SAEs except for the incidence of VZV
events (AEs), rather than by an increase ACR50 at month 6 and it was attained infection that was higher in the tofaci-
in objective signs and symptoms (60). in 147 (38%) of 384 patients with to- tinib plus MTX group (2%, 8/376 pa-
The recommendations currently state facitinib monotherapy, 173 (46%) of tients vs. 4/384 (1%) in the tofacitinib
that a single switch from a bio-origina- 376 patients with tofacitinib and MTX, monotherapy and 6/386 (2%) in the
tor to one of its biosimilars is safe and and 169 (44%) of 386 patients with ADA plus MTX group (61).
effective and there is no scientific ra- ADA and MTX (61). Tofacitinib and The increase in herpes infections with
tionale to expect that switching among MTX demonstrated to be non-inferior tofacitinib motivated a further analysis
biosimilars of the same bio-originator to ADA and MTX (difference 2%, aimed to explore whether the risk of
would result in a different clinical out- 98.34% CI -6, 11), while tofacitinib VZV was greater in patients receiving
come. Conversely, multiple switching monotherapy was not shown to be non- tofacitinib and concomitant MTX and
between biosimilars and their bio- inferior to ADA and MTX or tofacitinib GC (65). Data were extracted from an
originators or other biosimilars should and MTX. This trial suggested that pa- integrated safety summary conducted
be assessed in registries. Finally, no tients generally respond better to the across the tofacitinib RA development
switch to or among biosimilars should addition of tofacitinib or ADA to MTX program including 2 phase I, 9 phase
be initiated without the prior awareness than switching from MTX directly to II, 6 phase III and two long-term ex-
of the patient and the treating health- tofacitinib monotherapy (61). tension studies in adult patients with
care provider (53). The efficacy of tofacitinib has been fur- active RA. VZV was reported in 636
ther studied in a post-hoc analysis on tofacitinib-treated patients, with an in-
Targeted synthetic disease-modifying data pooled from two open-label, long- cidence rate (IR) per 100 patient-years
anti-rheumatic drugs term extension trials that evaluated the of 4.0, 95%CI 3.7, 4.4 and classified
Several JAK (Janus kinase) inhibitors potential impact of discontinuing con- non-serious, with the involvement of
are in clinical development, each hav- comitant MTX or GC (62). By year 3, only 1 dermatome in the majority of
ing a selectivity for inhibition of one or 11.6% of patients (186/1608) discon- cases (94%). The IRs were numerically
more of the 4 identified JAKs (JAK-1, tinued MTX and 22.2% (319/1,434) lowest for monotherapy with tofaci-
JAK-2, JAK-3, Tyk-2). These small- discontinued GC (62). At year 3, pa- tinib 5 mg twice daily without GC (IR
molecule have been recently catego- tients receiving tofacitinib generally 0.56, 95%CI 0.07, 2.01) and highest
rised as tsDMARDs and intensively in- maintained the same response to treat- for tofacitinib 10 mg twice daily with
vestigated for the treatment of RA. The ment achieved at month 3, irrespective csDMARDs and GC (IR 5.44, 95%CI
current placement of tsDMARDs is as of whether they discontinued MTX or 3.72, 7.68). Enrolment in Asian coun-
monotherapy or in combination with not. Similarly, discontinuation of con- tries was an independent risk factor
MTX for the treatment of moderate to comitant GC did not negatively impact for VZV, equal to 8.0 (95%CI 6.6, 9.6)
severe active RA in adult patients with CDAI response at year 3 (62). in Japan and 8.4 (95%CI 6.4, 10.9) in
an inadequate response or intolerance to A first prospective cohort study in RA Korea (65). Integrated analysis of data
one or more bDMARDs. In the last few patients with LDA explored the con- from the global clinical tofacitinib pro-
months, various studies implemented cept of discontinuation of tsDMARDs vided additional information of long-
data on safety and efficacy introducing showing that 52 weeks after discon- term – up to 8.5 years – safety profile
some preliminary concepts on tapering tinuation of tofacitinib 37% of patients for events of special interest. Out of a
strategy summarised below. (20/54) remained tofacitinib-free with- total 19,406 patient-years’ exposure, IR
354 Clinical and Experimental Rheumatology 2018One year in review 2018: treatment of RA / A. Bortoluzzi et al. per 100 patient-years for serious AEs patients with inadequate response or baricitinib was generally consistent was 9.4 (95%CI 9.0, 9.9); IR for serious intolerance to bDMARDs (68). On with prior observations gathered dur- infections was 2.7 (95%CI 2.5, 3.0) and this background Lee et al. clarified the ing shorter durations of exposure (72). IRs did not increase with longer treat- comparative efficacy and safety of ba- In the last few months, patient reported ment exposure (10). IR for opportunis- ricitinib in various treatment regimens outcomes (PROs) data related to 3 out of tic infections (excluding tuberculosis) conducting a network meta-analysis 4 phase 3 studies mentioned above were was 0.3 (95%CI 0.2, 0.4) and was 0.2 aimed to compare the once-daily ad- published (73–75). In RA-BEACON, (95%CI 0.1, 0.3) for tuberculosis (10). ministration of baricitinib 2mg and 4mg RA-BEGIN and RA-BEAM studies, IR for malignancies (excluding NMSC) in active RA (69). Regarding efficacy, baricitinib treatment produced signifi- was 0.9 (95%CI 0.8, 1.0); IR for NMSC the network meta-analysis suggested cantly greater improvements compared was 0.6 (95%CI 0.5, 0.7) and stable up that baricitinib 4mg + csDMARD was with placebo or MTX monotherapy or to 84 months of observation (66). Of the most effective treatment for active ADA in most of the prespecified PROs the 83 patients with NMSC during the RA (OR 3.13, 95% Credible Intervals including HAQ-DI, Patient’s Global study, 19 (22.9%) had ≥1 further occur- (CrI) 2.32, 4.33), followed by baricitin- Assessment of Disease Activity, pain, rence or a second NMSC event whilst ib 4mg (OR 3.00, 95%CrI 1.50, 6.24), Functional Assessment of Chronic Ill- receiving tofacitinib (66). baricitinib 2mg + csDMARD (OR 2.83, ness Therapy-Fatigue, Short Form 36 The Maineiro et al. meta-analysis ex- 95%CrI 1.94, 4.34) with a comparable physical component score, EuroQol panded the malignancy data showing safety between the different baricitinib 5-Dimensions index scores and Work that there was no statistical significant dosages and placebo, with or without Productivity and Activity Impairment- increase in the risk of malignancies or csDMARDs. Rheumatoid Arthritis daily activity. any specific type of malignancy in RA Kremer et al. conducted a subgroup These PROs were improved at weeks 24 patients treated with either bDMARDs analysis in RA-BEAM and RA-BUILD and 52, compared to MTX monotherapy or tofacitinib in RCTs compared to pla- studies to explore the influence of base- in RA-BEGIN (74) study and at week 24 cebo or csDMARDs (27). line patient (such as age
One year in review 2018: treatment of RA / A. Bortoluzzi et al. without the early side effects seen with duction in the DAS28-CRP was seen only 1 serious event was observed in other less selective JAK inhibitors (79). in patients treated with 150 mg secuki- patients treated with ABA-122 (82). The results from these studies informed numab (p=0.049), but not in patients Targeting granulocyte-macrophage col- the design of a phase II dose-finding treated with 75 mg secukinumab. Im- ony stimulating factor (GM-CSF), a pro- study (DARWIN II) (77). In this study provements in the HAQ-DI and ACR50 inflammatory multifunctional cytokine, filgotinib induced higher ACR20 re- response rates were not significant in has demonstrated promising results. sponse rates compared to placebo after the 2 secukinumab dose groups com- In particular, Burmester et al. reported 12 weeks (≥65% vs. 29%, p
One year in review 2018: treatment of RA / A. Bortoluzzi et al. most pulmonary changes were transient elevated (OR1.46, 95% CI 0.84, 2.56). cation tools, has been explored in a 10- and only infrequently associated with Among the studies that compared the year simulation study based on Dutch adverse events. Mavrilumab treatment outcome between TNF-i users and patient data, supporting effectiveness demonstrated sustained efficacy. In to- non-users, there were no significant with a mean QALY gain of 0.09 and tal, 117 patients (65.0%) achieved low differences in the rates of live birth and mean cost saving around 1000 € (91). disease activity of DAS–CRP
One year in review 2018: treatment of RA / A. Bortoluzzi et al.
of primary cancer treated or not with been reviewed in national clinical prac- ment strategies for early rheumatoid arthritis
in a treat-to-target approach: 1-year results of
bDMARDs. 70 patients never treated tice guidelines by an inter-disciplinary
CareRA, a randomised pragmatic open-label
versus 38 patients treated with bD- panel of experts from Italy (98). Screen- superiority trial. Ann Rheum Dis 2017; 76:
MARDs developed secondary malig- ing is recommended for all RA patients 511-20.
nant neoplasms. There was no greater since the disease onset, and inactive 7. SAFY M, JACOBS J, IJFF ND, BIJLSMA J, van
LAAR JM, de HAIR M: Long-term outcome is
risk of occurrence in patients treated HBV carriers to be treated with im- better when a methotrexate-based treatment
with bDMARDs regardless of timing munosuppressive therapies should re- strategy is combined with 10 mg prednisone
of exposure (before and/or after prima- ceive prophylaxis with lamivudine that daily: follow-up after the second Computer-
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1.57). The HR of secondary malignant in the case of RTX treated patients); ac- 8. ROUBILLE C, RINCHEVAL N, DOUGADOS M,
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in early rheumatoid arthritis: data from the
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diagnosis while the HR was 0.92 (95% tions, interest has been renewed about 1797-802.
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Infection groups (geometric mean fold rise ratio ment of rheumatoid arthritis up to 8.5 years:
Novel evidence has accumulated on the tofacitinib/placebo at 14 weeks of 1.05 integrated analysis of data from the global
clinical trials. Ann Rheum Dis 2017; 76:
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