Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

Seminars in Arthritis and Rheumatism 47 (2017) 183–192

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Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis Fabrizio Cantini, MDa,n,1, Laura Niccoli, MDa,1, Carlotta Nannini, MDa,1, Emanuele Cassarà, MDa,1, Olga Kaloudi, MDa, Ennio Giulio Favalli, MDb,2, Andrea Becciolini, MDb, Maurizio Benucci, MDc,3, Francesca Li Gobbi, MDc, Serena Guiducci, MDd,4, Rosario Foti, MDe,5, Marta Mosca, MDf,6, Delia Goletti, MDg,7 a

Division of Rheumatology, Hospital of Prato, Piazza Ospedale, 1, 59100 Prato, Italy Department of Rheumatology, Gaetano Pini Institute, Milan, Italy c Rheumatology Unit, Hospital S.Giovanni di Dio, Florence, Italy d Department of Biomedicine, Section of Rheumatology, University of Florence, Florence, Italy e Rheumatology Unit, Vittorio-Emanuele University Hospital of Catania, Catania, Italy f UO di Reumatologia, Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy g Translational Research Unit, Department of Epidemiology and Preclinical Research, “L. Spallanzani” National Institute for Infectious Diseases (INMI), IRCCS, Rome, Italy b

a r t i c l e i n fo

Keywords: Anti-TNF Second-line biologics Switching Rheumatoid arthritis Spondyloarthritis Psoriatic arthritis

1

a b s t r a c t Objective: The Italian board for the TAilored BIOlogic therapy (ITABIO) reviewed the most consistent literature to indicate the best strategy for the second-line biologic choice in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). Methods: Systematic review of the literature to identify English-language articles on efficacy of second-line biologic choice in RA, PsA, and ankylosing spondylitis (AS). Data were extracted from available randomized, controlled trials, national biologic registries, national healthcare databases, post-marketing surveys, and openlabel observational studies. Results: Some previously stated variables, including the patients' preference, the indication for anti-tumor necrosis factor (TNF) monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. In RA, golimumab as second-line biologic has the highest level of evidence in anti-TNF failure. The switching strategy is preferable for responder patients who experience an adverse event, whereas serious or class-specific side effects should be managed by the choice of a differently targeted drug. Secondary inadequate response to etanercept (ETN) should be treated with a biologic agent other than anti-TNF. After two or more anti-TNF failures, the swapping to a different mode of action is recommended. Among non-anti-TNF targeted biologics, to date rituximab (RTX) and tocilizumab (TCZ) have the strongest evidence of efficacy in the treatment of anti-TNF failures. In PsA and AS patients failing the first anti-TNF, the switch strategy to a second is advisable, taking in account the evidence of adalimumab efficacy in patients with uveitis. The severity of psoriasis, of articular involvement, and the predominance of enthesitis and/or dactylitis may drive the choice toward ustekinumab or secukinumab in PsA, and the latter in AS. Conclusion: Taking in account the paucity of controlled trials, second-line biologic therapy may be reasonably optimized in patients with RA, SpA, and PsA. & 2017 Elsevier Inc. All rights reserved.

On behalf of the Italian board for the TAilored BIOlogic On behalf of the Italian board for the TAilored BIOlogic On behalf of the Italian board for the TAilored BIOlogic 4 On behalf of the Italian board for the TAilored BIOlogic 5 On behalf of the Italian board for the TAilored BIOlogic 6 On behalf of the Italian board for the TAilored BIOlogic 7 On behalf of the Italian board for the TAilored BIOlogic n Corresponding author. E-mail address: [email protected] (F. Cantini). 2 3

http://dx.doi.org/10.1016/j.semarthrit.2017.03.008 0049-0172/& 2017 Elsevier Inc. All rights reserved.

therapy therapy therapy therapy therapy therapy therapy

(ITABIO) (ITABIO) (ITABIO) (ITABIO) (ITABIO) (ITABIO) (ITABIO)

members: Fabrizio Cantini Laura Niccoli. members:, Ennio Giulio Favalli. members: Maurizio Benucci. members:, Serena Guiducci. members: Rosario Foti. members: Marta Mosca. members: Delia Goletti.

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F. Cantini et al. / Seminars in Arthritis and Rheumatism 47 (2017) 183–192

Introduction Recently, the ITABIO (Italian board for the TAilored BIOlogic therapy) task force focused on the first-line biologic choice driving variables in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) to ensure the best results in terms of clinical outcome and safety [1]. However, data from clinical trials and national registries show that first-line biologics, either combined with methotrexate (MTX) or in monotherapy, should be discontinued in approximate 30–40% of the patients due to inadequate response or adverse events in the majority of the cases [2–4]. Overall, biologic survival is lower in RA compared with PsA and AS [5], though in all the three disorders the discontinuation rate seems time-dependent with a progressive increase related to the length of follow-up [6]. To date, nine biologics including interleukin-6 (IL-6) inhibitor tocilizumab (TCZ), anti-CD20 rituximab (RTX), anti-interleukin-1 (IL1) anakinra (ANK), anti-CD28 abatacept (ABA), and anti-tumor necrosis factor alpha agents (anti-TNFs) adalimumab (ADA), etanercept (ETN), infliximab (IFX), golimumab (GOL), certolizumab pegol (CTP), and, limited to Europe, infliximab biosimilar (bio-IFX), are approved for RA treatment, anti-TNFs, anti-interleukin-12–23 (IL-12– 23) ustekinumab (UTK), and anti-interleukin-17 (IL17) secukinumab (SCK) for PsA, while only anti-TNFs and SCK are licensed for AS. Compared to the first-line biologic therapies, the second-line ones have been less investigated in terms of effectiveness, safety, and drug survival. Moreover, controlled trials (RCTs) and current recommendations do not provide sufficient indication concerning the best strategy between switching and swapping among biologics [1]. In absence of well-defined response predictors, several variables may drive the second biologic choice in clinical practice, including the data on the efficacy, safety, disease severity, infection risk, patient's age and gender, route of administration, and comorbidities.

Objective The aim of present paper was to provide appropriate indications for the best choice of second-line biologic therapy in patients with RA, PsA, and AS through a systematic review of the literature.

Methods As previously described [1], a multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), including specialists in rheumatology (M.B., F.C., E.F., R.F., S.G., and L.N.), infectious diseases (D.G. and F.B.), and, immunology (M.M.), was constituted to review the literature on the existing evidence on the efficacy, safety, and the different variables influencing the secondline biologic choice in patient with RA, AS, n-rx-AxSpA, and PsA. Each ITABIO member separately developed and shared by e-mail a single topic, and finally all members met to examine, discuss, assemble the single elaborates, and to draw up the final manuscript. No funding source was available. The following topics were analyzed: disease severity, second-line biologic efficacy and safety, second-line monotherapy biologic choice, comorbidities, infection, LTBI reactivation, cardiovascular and malignancy risk, interval, and route of administration, and patient's preference. Taking into account the emerging evidence on the different factors, appropriate statements and decisional trees useful to tailor the second-line biologic choice to the single patient were formulated. Literature search The literature review was made using PubMed database to identify English-language articles related to the previously

mentioned topics. Data were extracted from available recommendations, systematic reviews, and meta-analyses, RCTs, national registries of biologics, national healthcare databases, and postmarketing surveys. When these source data were not available for specific topics, the evidence was derived from open-label studies on variable sample-size clinical series. The following drugs were investigated: IFX, bio-IFX, ETN, ADA, GOL, CTP, RTX, TCZ, ANK, ABA, UTK, and SCK. The research was performed by crossing the single drug name with the following key terms: RA, SpA, PsA, efficacy, safety, monotherapy, switching, swapping, latent tuberculosis infection (LTBI), infections, tuberculosis (TB), comorbidities, cardiovascular risk, malignancy risk, and atherosclerosis. The literature review was extended to December 31, 2016. Results General indications As previously stated [1], some choice driving variables, including the patients' preference for self-administered subcutaneous route with the longest administration intervals, the indication for anti-TNF monotherapy in potential childbearing women, and its interruption at positivity of pregnancy test, are valid also for the second biologic choice after interruption of the first for inefficacy or adverse events occurrence. Choice of the second or third biologic agent in RA The first choice of biologic therapy for the treatment of synthetic DMARD (sDMARD) inadequate responders (IR) is usually an antiTNF-α (anti-TNF) agent. However, clinical response is not universal and approximately 30–40% of patients discontinue anti-TNF because of primary failure, secondary loss of response, or intolerance [7–9]. Options for the management of anti-TNF failures include switching to an alternative anti-TNF (cycling) or to another class of targeted agent with a different mode of action (swapping) [10]. The cycling strategy is a well-established approach, and the efficacy of the second anti-TNF is clearly supported only by 4 trials. An open-label, pilot study (the OPPOSITE trial) demonstrated IFX is more effective than ETN in the treatment of 28 ETN failures [11]. The GO-AFTER represents the only one controlled study designed to evaluate the effectiveness and safety of GOL in patients with RA failing ADA, ETN, or IFX administered as first- or second-line therapy [12]. Treatment with GOL produced a significantly greater 24-week ACR20, 50, and 70 responses compared with placebo [12], with a good persistence of efficacy and no new safety signals through 5 years [13] . In the REALISTIC study, treatment with CZP was associated with a greater chance of achieving low disease activity at week 12 when compared to placebo regardless of prior anti-TNF exposure [14]. More recently, the EXXELERATE study, an head-to-head trial between CZP and ADA, showed a good efficacy of cycling to the other anti-TNF after primary insufficient response to the first [15]. Beside these four RCTs, several observational studies based on national registries or multicentric cohorts have demonstrated an improvement in disease activity and a favorable drug retention rate in patients receiving a second anti-TNF [16–22]. However, at least three limitations should be considered. First, in both RCTs [12] and retrospective studies [23–25], the proportion of responders is generally lower in switchers compared with biologic naïve patients and the likelihood of clinical response declines with the increasing number of previous treatments with anti-TNF. Thus, available data support the switching to a second anti-TNF, but the rationale for the use of the third or more seems to be poor

F. Cantini et al. / Seminars in Arthritis and Rheumatism 47 (2017) 183–192

[26]. Second, effectiveness and reasons for discontinuation of a second anti-TNF seem to be related to the reasons for stopping the first [22]. In particular, switching to a second anti-TNF has been demonstrated more effective when the first was discontinued because of intolerance or secondary no response compared with primary no response [19,20]. These results suggest that a second anti-TNF can restore the response in cases of secondary loss of response and maintain it after switching due to an adverse event. Third, in 3 observational studies [19,20,27] and in a post-hoc analysis of the GO-AFTER study [28], overall better results were observed in patients who switched from antiTNF monoclonal antibodies to ETN than the other way round, or from monoclonal antibody to another. Thus, it could be reasonable to switch to ETN in ADA and IFX failures and to swap to a different mode of action in ETN failures. Clinical efficacy of swapping strategy is strongly supported by three RCTs clearly demonstrating the superiority of TCZ [29], ABA [30], and RTX [31] vs. placebo in the treatment of anti-TNF failures. Moreover, RTX is thus far the only agent that has formally demonstrated significant slowing of structural joint damage in RA patients with an inadequate response or who are intolerant to anti-TNF [32]. An head-to-head observational trial comparing the efficacy of swapping strategy when compared to cycling in anti-TNF inadequate responders showed that a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than a second anti-TNF [33]. Finally, the comparative effectiveness of cycling and swapping strategies has been analyzed by two systematic reviews of the literature and meta-analyses of RCTs, showing all biologic agents (GOL, ABA, TCZ, and RTX) have overall similar efficacy and safety profile [34,35]. Moreover, several observational studies provided comparative data, especially for RTX. A retrospective analysis from a multicentric German cohort [36], and four national registries [37–40] demonstrated that swapping to RTX may produce a significantly better 6-month clinical response compared with switching to an alternative anti-TNF. Similar conclusions were also reported by two prospective cohort studies comparing the efficacy of RTX or a different anti-TNF as second-line biologic drug at 6 and 36 months, respectively [41,42]. Nonetheless, Manders et al. [43] recently reported that in patients failing the first anti-TNF, a second anti-TNF, ABA or RTX, was similarly effective, even if RTX appeared to be the most cost-effective. On the other hand, observational data on swapping to ABA or TCZ are somewhat controversial. Favalli et al. [44] firstly reported that the 5-year probability of retaining a second anti-TNF is significantly lower compared with a differently targeted biologic agent, with no evident difference among ABA, TCZ, and RTX. Similar results were observed in the BioRx.si registry [45]. In a large German retrospective analysis, TCZ-induced remission rate was significantly higher compared with a second anti-TNF [46]. However, recent data coming from the US CORRONA registry showed that RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA [47]. Similarly, no difference was found in the Japanese TBCR registry among ETN, ABA, and TCZ used as second-line agent for the treatment of anti-TNF inadequate responders [48], even if TCZ and ETN showed a better retention rate compared with IFX and ADA [49]. Data on the management of failures of biologic agents other than anti-TNF are still lacking. A small proof-of-concept trial compared ABA and TCZ in the treatment of RTX inadequate responders, suggesting that in these cases IL-6-targeted therapy might be a more logical and effective treatment choice than T-cell co-stimulation blockade [50]. Similarly, a retrospective multicenter study among non-anti-TNF inadequate responders reported an

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overall higher decrease of DAS28 at 12 months in patients treated with TCZ when compared to ABA or RTX [51]. Data of ANK as second-line therapy are unavailable. Second-line biologic choice in RA: Summary As shown in Fig. 1, secondary insufficient responders to antiTNF monoclonal antibodies should receive ETN, whereas secondary inadequate response to ETN should be treated with a biologic agent other than anti-TNF. The cycling strategy should be preferred for responder patients who experience a common adverse event, whereas serious or class-specific side effects should be managed by the choice of a differently targeted drug. After two or more antiTNF failures, the swapping to a different mode of action should be recommended. Among the non-anti-TNF targeted biologics, to date RTX and TCZ have the strongest evidence of efficacy in the treatment of anti-TNF failures. PsA treatment strategies after the first biologic failure PsA is characterized by a wide spectrum of articular and extraarticular clinical manifestations including peripheral arthritis, spondylitis, enthesitis, dactylitis, skin and eye involvement, and systemic features such as metabolic syndrome and cardiovascular ischemic disease (CVD). The heterogeneity of areas involved by the inflammatory process may explain the number of the specific site of inflammation and complex disease activity measures used by the clinicians to assess the response to therapy [52]. As indicated by several recommendation sets [53,54], patients with peripheral PsA failing one or more traditional disease modifying anti-rheumatic drugs, and those with axial disease not responding to non-steroidal anti-inflammatory drugs should be treated with anti-TNF agents as first-line biologic therapy [55]. To date, six anti-TNFs have been licensed in Europe for the treatment of PsA, including IFX, infliximab biosimilar (bio-IFX), ETN, ADA, GOL, and CTP. In addition, due to the pathogenic role of interleukin-23/ interleukin-17 (IL-23/IL-17) immune axis both in psoriasis and in PsA inflammatory process, UTK, a fully human monoclonal antibody inhibiting IL-17 through its block of p40 protein which is shared by IL-12 and IL-23, has been licensed for the treatment of PsA. In controlled trials UTK resulted highly effective on skin features, while the percentages of ACR20, 50, and 70 responders were lower than those observed in patients receiving anti-TNFs [56]. Recently, in two RCTs, SCK, an anti-IL-17 monoclonal antibody, resulted significantly more effective than placebo and obtained the approval for PsA treatment [57,58]. Overall, systematic reviews and meta-analyses of RCTs have shown that anti-TNFs are effective in around 70% of PsA, with no significant differences among the different agents [59–62]. Hence, approximately 30% of patients require a second-line biologic therapy in the short-term. Of the 289 PsA patients receiving ADA in the 2-year long-term extension of ADEPT study [63], 44 (15.2%) dropped out for unresponsiveness or AEs. Of the initial 205 PsA patients enrolled in a controlled trial of ETN, 141 (68.7%) were evaluable after 2 years [64], and 39 (35.4%) out of 110 patients did not complete 2 years of treatment in the REPAIrE study [65]. At the end of 2-year followup, 32 (29%) of 110 IFX-treated PsA patients dropped out from the IMPACT study [66], 126/405 (31%) patients included in the GOREVEAL trial of GOL discontinued the treatment over 5 years [67], and 55 (20.1%) of 273 patients randomized to CTP at baseline did not completed to 96-week long-term extension of the RAPID-PsA trial [68]. Similar results were observed in PSUMMIT1 trial of UTK, where 125 (20.3%) out of 615 patients interrupted the treatment through 2 years of follow-up [69]. Similarly, 476 (78.5%) out of 606

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RA First biologic failure

MoAb failure

ETN failure

for primary or secondary

for primary or secondary loss of response

loss of response

GOL

RTX

ETN

ABA

ADA

TCZ

ABA

GOL

CTP

CTP

RTX TCZ

General comments An-TNF failure for intolerance or AEs

An-TNF RTX TCZ ABA

a)Paent’s preference for selfadministered biologics with the longest injecon interval. b)Regarding the infecon risk, few data indicate that RTX, ABA, and TCZ as the safest second-line biologics. c)Limited data indicate that TCZ and ABA are the best choice in RTXfailing paents. d)Cardiovascular risk has not been assessed. e) An-TNFs therapies are indicated in potenal childbearing women. f)No concerns on new malignancy generaon are envisaged.

Fig. 1. ITABIO decisional tree for second-line biological therapy choice in RA patients failing the first anti-TNF.

patients enrolled in FUTURE-1 study of SCK in PsA completed the 2-year extension phase [70]. Regarding bio-IFX, in June 2013 the drug, through a strict comparability exercise of in vitro and ex vivo pharmacological and biological characteristics, was considered biosimilar to the reference IFX, and approved for PsA treatment [71], but no controlled studies have been carried out in PsA patients. As shown in Table 1, data from real-life studies, including national registries and observational studies report a discontinuation rate of first-line anti-TNFs ranging between 17.1% and 67.5%, with increasing values related to the length of observational period. The combined therapy with methotrexate was evaluated in several studies showing a significant improvement of anti-TNF retention rate [69,70,74,77]. In view of these data, at least one-third of anti-TNF treated PsA patients fail the first-line biologic, and second biologic agent should be started. All recommendation sets indicate the switching to a second anti-TNF [53,54], but, to date, there is the possibility to swap to UTK and SCK. Several studies evaluated the efficacy of switching to a second anti-TNF. In general terms, the percentage of responders to a second course of anti-TNF was lower than those observed with the first, and the second anti-TNF survival was significantly shorter. Data from the British registry showed a significant lower retention rate of the second anti-TNF in 178 PsA patients failing the first-line biologic course [75]. In the DANBIO registry, 548 PsA patients receiving the second course of anti-TNF achieved

significantly lower response rates compared to the first anti-TNF course at 6-month evaluation, with 22%, 13%, 5%, 19%, and 34% ACR20 , ACR50, ACR70, EULAR good response, and DAS 28 remission, respectively [85]. Similar findings were reported from the NOR-DMARD registry [76], with ACR50 and DAS28 remission responses of 22.5% and 28.2% in 95 switchers at 3-month assessment, compared with 40% and 54.1% of non-switchers, respectively. In this study, the drug survival of the second anti-TNF was significantly lower than the first at 3-year evaluation (36% vs. 57%; p o 0.001). In RAPID-PsA study of CTP, 54 out of 273 patients had prior anti-TNF exposure [68]. At 96-week assessment, the response rate in this subgroup resulted not significantly different from antiTNF naïve cohort in terms of articular and skin outcome measures. Equally, in a German study [86], no significant differences in joint and skin response was observed in 66 prior anti-TNF-exposed compared to 376 non-exposed PsA patients. The same results were reported in a British cohort of 94 PsA patients switched to a second or a third anti-TNF [83]. To summarize, despite some conflicting data, in PsA patients failing the first anti-TNF, the switch strategy to a second is advisable, although the response rate and the drug survival in switchers is lower than in first-line anti-TNF receivers. The efficacy of swapping from anti-TNFs to UTK has been investigated in the phase 3 controlled PSUMMIT2 trial of UTK [87]. At week 52, an ACR20 response was observed in 35.6% of 180 PsA patients with prior 1 or more anti-TNF-exposure, with a significant difference compared to placebo group. Though the

F. Cantini et al. / Seminars in Arthritis and Rheumatism 47 (2017) 183–192

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Table 1 Anti-TNF survival in patients with PsA: data from national registries and observational studies. Overall first-line therapy discontinuation number (%)

Study

Source/country

Baseline anti-TNF treated patients number

Gomez-Reino et al. [72] Kristensen et al. [73] Heiberg et al [74]

BIOBADASER registry (Spain)

289

55 (19%)

1

SSATG (Sweden) NOR-DMARD register (Norway) BSRBR register (UK) DANBIO registry (Denmark) NOR-DMARD register (Norway) Observational Observational NOR-DMARD registry (Norway) GISEA registry (Italy) Observational Observational Observational Observational Observational

261 172

171 (34.4%) 42 (24.4%)

1 1

566 764 439

178 (31.4%) 336 (44%) 95 (21.6%)

3 2 2

194 298 440

131 (67.5%) 133 (44.6%) 216 (49%)

10 8 3

328 32 65 110 548 213

107 8 24 39 94 72

Saad et al [75] Glintborg et al. [3] Fagerli et al. [76] Biggioggero et al. [6] Favalli et al. [77] Fagerli et al. [78] Iannone et al. [79] Voulgari et al. [80]a Saougou et al. [81] Gladman et al. [82]b Jani et al. [83] Fabbroni et al. [84] a b

(32.6%) (25%) (36.9%) (35.4%) (17.1%) (33.8%)

Follow-up years

2 3 5 2 1 2

Only IFX was evaluated in this study. Only ETN was evaluate in this study.

response rate was lower than in anti-TNF non-exposed (ACR20 54.4%), the results of this study indicate that swapping to UTK may represent a good option in anti-TNF resistant or intolerant PsA patients. Similarly, at week 24, 23 (39%) out of 59 patients nonresponders to a previous ant-TNF achieved an ACR20 in the FUTURE2 study of SCK [57].

Second-line biologic therapy in PsA: Practical indication First-line anti-TNF therapy should be interrupted for two main reasons including inefficacy or adverse events. Adverse events, with predominance of infection, lead to drug discontinuation in around 7–11% of the cases [63,75,84]. In addition, patient's preference causes the interruption in 7–11% of the cases [6,72]. Hence, these aspects should be considered when starting a second biologic. Considering the overall evidence of efficacy on both articular and skin manifestations of anti-TNFs and the paucity of data on swapping to UTK or SCK, switching to a second anti-TNF represents the more appropriate strategy in PsA patients failing the first-line biologic. However, as we recently pointed out [1], the treatment requires to be optimized in function of the principal clinical manifestation and of choice driving variables, including infection, cardiovascular risk, history of anterior uveitis, and patient's preference. Monoclonal anti-TNFs are indicated in the presence of history of uveitis or current uveitis, and, in view of a recent study [88], ADA should be preferred. The evidence of a good efficacy of UTK and SCK on skin disease, dactylitis, and enthesitis may drive the choice toward UTK or SCK when these manifestations are predominant [57,89,90], while ETN may constitute the better option in patients failing monoclonal anti-TNF, and who are at high infection or cardiovascular risk, or have comorbidities such as metabolic syndrome, and chronic obstructive lung disease. As a few data are available on cardiovascular risk, on potential childbearing women, and on efficacy on uveitis, UTK or SCK as second-line choice seem unadvisable in patients with these characteristics. Figure 2 illustrates the ITABIO proposed decisional tree in PsA patients failing the first-line biologic.

Ankylosing spondylitis and axial-SpA treatment after the first line biologic failure Anti-TNF therapy has revolutionized the management of SpA, but 20–30% of SpA patients discontinue biologic treatment because of primary inadequate response, loss of efficacy (LOE), or adverse events (AEs) [91,92]. Concerning the LOE of anti-TNFs in SpA, immunogenicity with production of anti-drug antibodies seems to play a more pronounced role than in RA and PsA [93,94], possibly due to the use of anti-TNFs in monotherapy. In a recent paper [93], in patients with SpA anti-drug antibodies could be detected in 25.9% of patients, most frequently in infliximab-treated patients (81.8%) compared to those treated with adalimumab (18.2%), and etanercept (0%). However, despite the different development of anti-drug antibodies, in two Spanish studies no differences resulted in drug survival rates of different anti-TNF agents used in SpA patients [95,96]. Recently, FDA and EMA approved SCK for the treatment of ankylosing spondylitis (AS), thus raising the possibility of a swapping strategy in patients failing anti-TNFs. The efficacy of switching strategy in axial-SpA has been evaluated in several observational studies from real-life clinical practice and from national registries. Delaunay et al. [97] firstly reported that switching to another anti-TNF drug may be useful for SpA patients unresponsive or intolerant to the first. Subsequent observational prospective studies confirmed the safety and efficacy of switching anti-TNF drugs in these patients [91,98–101]. In a large, 12-week, open-label trial [86], a significant lower BASDAI 50 and ASAS40 response rates were observed in 326 patients receving ADA as second-line therapy compared to 924 patients treated with ADA as first-line therapy (ASAS40 37.7% vs. 59.3%, p o 0.001; BASDAI50 40.8% vs. 63%, p o 0.001). Comparable results were observed in a real-life, multicenter, Italian study of 283 AS patients [101]. In the DANBIO registry [4], the clinical response and the drug survival was lower in 432 AS patients switching to a second antiTNF and in 137 patients switching to a third compared to 1004 non-switchers. Similar results were reported in the NOR-DMARD register [102]. In these two databases, the percentage of AS

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General comments

Peripheral PsA Axial PsA

An-TNF

a) Paent’s preference for self-administered biologics with the longest injecon interval. b) Only an-TNFs therapies are indicated in axial PsA c) Switching to a second an-TNF therapy or swapping to UTK strategy is driven by the predominance of skin or arcular manifestaons. d) An-TNF therapies are indicated in potenal childbearing women. e) ETN is indicated in paents with high cardiovascular risk. f) MoAb an-TNFs, especially ADA, are indicated in paents with a history of uveis.

If MoAb an-TNF

SCK

as 1st

ETN SCK

Any Pso

Mild-moderate Pso

Severe Pso

Oligoarthris

Oligoarthris

Predominant enthesis/dactylis

UTK

An-TNF

UTK

Severe Pso

Any Pso

Any Pso

Polyarthris

Any arthris

Infecon risk

Uveis

TB risk

An-TNF

SCK

SCK

SCK

CTP

An-TNF

UTK

MoAb an-TNF

SCK UTK

IFX

Fig. 2. ITABIO decisional tree for second-line biological therapy choice in PsA patients failing the first anti-TNF. Abbreviations: MoAb anti-TNF, monoclonal antibody anti-TNF; Pso, psoriasis; CV risk, cardiovascular risk; ADA, adalimumab; IFX, infliximab; ETN, etanercept; UTK, ustekinumab; SCK, secukinumab.

patients switching to a second anti-TNF were 15% and 30% over a 8- and 9-year follow-up, respectively. Similar switching frequencies have been reported in observational studies which included around 100 AS patients [103–105]. Two RCTs of SCK demonstrated the efficacy and safety of IL-17 inhibition in patients with AS. In a phase II, proof-of-concept study of 37 AS patients receiving intravenous SCK, 59% of the treatment arm subjects achieved ASAS20 response with a significant difference vs. the placebo arm [106]. These results were confirmed by a phase III, 16-week trial showing an ASAS20 response in 60% of AS patients treated with SCK 150 mg/sc/ monthly [107]. In both studies around 30% of enrolled subjects have failed a previous anti-TNF, but results concerning this subgroup are not available. Second-line biologic therapy in AS: Summary To summarize, around 30% of SpA patients fail the first anti-TNF course and, to date, switching to a second anti-TNF represents the preferable strategy. Data on swapping to SCK are not available, even if SCK, due its different cytokine inhibition, may be a reasonable option in selected patients (i.e., patients failing the second or the third anti-TNF). Is infection risk increased after biologic switching or swapping? A few studies, limited to patients with RA, have evaluated whether the switching or swapping to another biologic may increase the risk of infections. It is well known that patients with RA present an increased risk to develop infectious diseases with an almost double estimated incidence as compared to matched controls [108]. This higher risk is probably due to the underlying autoimmune disease itself (altered immunological function, disability, immobility, and joint surgery), the extra-articular manifestations, comorbidities

(chronic obstructive pulmonary disease, diabetes, and obesity), use of immunosuppressive drugs and corticosteroids [1]. Based on the literature, there is a limited evidence of a substantial increased overall risk of serious infections in patients exposed to anti-TNF agents, particularly in patients receiving concomitant treatment with corticosteroids, or with comorbidity [109,110]. Probably, also older age, disease duration, disease activity, and type of biological treatment may have an impact on the augmented risk [1]. In RA, non-responders to the first-line anti-TNF, or those developing adverse events require the switching to a second-line anti-TNF or to a differently targeted biologic. This strategy may potentially induce an additional increased risk of infection. Nguyen-Khoa et al. [111] described the rates of first severe infection of 16,045 RA patients who switched or not between anti-TNF-α inhibitors in an insurance claims database from 2001 to 2007. Non-switchers remained on one anti-TNF throughout the study period while switchers received at least a second anti-TNF. The risk of significant infections was not different between the two groups, and regardless of switching status, the rate of infection was greater in the first year. This study was limited by the lack of clinical data to determine the reason for switching and the analyses by individual drugs. Part of these information are available in a retrospective analysis using a large USA claims database, in which Johnstons et al. [112] evaluated the hazard of infections and severe infections across 4332 RA patients failing a first-line anti-TNF and who required a second-line biologic, including ABA, ADA, ETN, IFX, or RTX between 2004 and 2010. Patients switching to a second anti-TNF had a 30–44% higher hazard of all infection compared to treatment with RTX; moreover a 62% higher hazard of severe infections was observed in patients treated with IFX compared to those under RTX. The finding that the risk of severe infection was not significantly different between RTX and ABA, ADA, and ETN but was

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significantly higher in IFX exposed was also reported in a nonrandomized, observational study by Curtis et al. [113]. Similarly, Favalli et al. [44] reported a significant lower proportion of adverse events, including infections, in 41% of 201 RA patients followed between 1999 and 2013 who swapped to ABA, RTX, or TCZ compared with 59% of patients switching to a second anti-TNF. Infection risk in second-line biologic-exposed: Summary Based on the few available studies, the risk of infections resulted not different between non-switchers and switchers, with the lowest hazard observed in patients receiving RTX, ABA, or TCZ, and the highest in those treated with IFX as second-line biologic therapy. The more common infectious diseases in switchers were pneumonia, cellulitis and abscess, urinary tract infections, septicemia, and chronic bronchitis. Further studies are needed to better elucidate whether the presence of risk factors for infections (i.e., age, diabetes, chronic bronchitis) may influence the rate of infections in the patients exposed to multiple biological agents. Cardiovascular and malignancy risk in second-line biologic-exposed With respect to previous analyses on first-line biologic receivers [1,114,115], no new alerts are available on cardiovascular and malignancy risk assessment after switching or swapping in patients with RA, PsA, and AS.

Conclusion Though the lack of head-to-head trials reduces the strength of our recommendations for the proper second-line biologic choice in RA, PsA, and AS, the available data from the literature provide useful indications for the optimization of therapy in patients failing the first biologic agent, and offer the opportunity to make some final considerations. First, as previously underlined, the rather relevant percentage of at least 20% of patients with RA PsA, and AS failing the first biologic is related to adverse events, mainly infections, and to patient's preference [2,6,72]. In keeping with the previous statements of ITABIO group [1], in our opinion this percentage of biologic failures may be reduced through a careful evaluation of the patient's characteristics before the beginning of biologic therapy, including the presence of comorbidities and other factors that favor infections, and the psychological profile of the patient that may greatly influence the acceptation of the proposed therapy and the adherence to treatment. The latter issue is crucial, especially if we consider that non-adherence is responsible for biologic primary nonresponse in a consistent proportion of patients [116]. Second, despite the elevated percentage of patients failing the first biologic, it is rather surprising that the low number of both controlled studies and reports from real-life practice on the efficacy of different biologics as second-line therapy, and on the effectiveness of cycling strategy compared to swapping to a differently targeted biologic in RA, PsA, and AS. However, as we tried to emphasize in this paper, the current data on the cause of first-line biologic failure and the different mechanism of action of available targeted therapies may properly drive the second-line biologic choice, thus increasing the possibility of a good response. Third, though the limited number of available studies, an appropriate choice of the second or third biologic may ensure a better safety in terms of infections. In this sense, the swapping strategy seems to ensure the better outcome [44,112]. To conclude, a proper evaluation of the single biologic mechanism of action, of its efficacy and safety as second-line therapy,

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and of the reason of discontinuation together with an appropriate awareness of the patient's characteristics may allow to achieve a good result in patients with RA, PsA, and AS failing the first biologic.

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