Clin Rheumatol DOI 10.1007/s10067-016-3204-2

ORIGINAL ARTICLE

Indirect comparisons of the efficacy of subsequent biological agents in patients with psoriatic arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis Patompong Ungprasert 1,2 & Charat Thongprayoon 3 & John M. Davis III 1

Received: 11 January 2016 / Revised: 26 January 2016 / Accepted: 30 January 2016 # International League of Associations for Rheumatology (ILAR) 2016

Abstract Significant portion of patients with psoriatic arthritis (PsA) could not tolerate or do not have a satisfactory response to either non-steroidal anti-inflammatory drugs (NSAIDs), non-biologic disease-modifying anti-rheumatic drugs (DMARDs), or even TNF inhibitors. Non-TNF inhibitor biologic agents have emerged as second-line therapy in such situation. However, the comparative efficacy of these agents remains unknown as head-to-head randomized controlled trials (RCTs) are not available. RCTs examining the efficacy of non-TNF inhibitor biologic agents in patients with PsA who experienced inadequate response or intolerance of TNF inhibitors were identified. If more than one RCT was available for a given biologic agent, the pooled odds ratio (OR) and 95 % confidence interval (CI) of achieving 20 % improve ment acc ording to American Colleg e of Rheumatology criteria (ACR20) response across trials were calculated. The pooled OR for each biologic agent was then compared using the indirect comparison technique. Five RCTs of four non-TNF inhibitor biologic agents, including

Electronic supplementary material The online version of this article (doi:10.1007/s10067-016-3204-2) contains supplementary material, which is available to authorized users. * Patompong Ungprasert [email protected]

1

Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, 200 First street SW, Rochester, MN 55905, USA

2

Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

3

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA

abatacept, secukinumab, ustekinumab, and apremilast, with 675 participants were identified and included in the data analyses. We found no significant difference in any comparisons, with the p values ranging from 0.14 to 0.98. Our study demonstrates that the likelihood of achieving the ACR20 response in patients with TNF inhibitor experience is not significantly different between the four non-TNF biologic agents. However, the interpretation of this analysis is limited by the small sample sizes. Head-to-head comparisons are still required to confirm the comparative efficacy. Keywords Biologic agents . Meta-analysis . Psoriatic arthritis . Systematic review . TNF inhibitors

Introduction Psoriatic arthritis (PsA) is a chronic seronegative inflammatory arthritis characterized by the presence of arthritis and psoriatic rash [1, 2]. Up to one third of patients with psoriasis develop PsA, with the arthritis typically occurring several years after the first sign of skin disease [3, 4]. Patients with PsA tend to have associated co-morbidity, particularly cardiovascular diseases, resulting in a reduced quality of life and increased mortality [5–7]. Treatment of PsA is often unsatisfactory. Non-steroidal anti-inflammatory drugs (NSAIDs) and non-biologic diseasemodifying anti-rheumatic drugs (DMARDs), particularly methotrexate, are generally used as the first-line therapy even though clinical trials have demonstrated only minimal efficacy [8–10]. Beginning in the early 2000s, tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab, golimumab and more recently, certolizumab) were approved as another treatment option for PsA. The efficacy of TNF inhibitors in patients who had active disease despite non-

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biologic DMARDs/NSAIDs or who could not tolerate DMARDs/NSAIDs has been well demonstrated in several randomized controlled trials (RCTs) [11–15]. Nonetheless, a significant proportion of patients do not have a satisfactory response to treatment with TNF inhibitors. Non-TNF inhibitor biologic agents have been developed and marketed as alternative to TNF inhibitors. The efficacy of non-TNF biologic agents as the first-line biologic agent or subsequent biologic agent after TNF inhibitor failure/ intolerance has been well-documented. The increasing availability of these non-TNF inhibitor agents suggests the need to establish the comparative efficacy of these agents. This study aims to compare the efficacy of non-TNF biologic agents in patients who previously failed or could not tolerate TNF inhibitors using the indirect comparison technique.

Material and methods Search strategy

assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and the Health Assessment Questionnaire score [17].

Data extraction A standardized data collection form was used to extract the following information: author’s name, title of the article, year of publication, countries where the study were conducted, study design, method of randomization, inclusion and exclusion criteria, length of study, primary and secondary endpoints, intention to treat analysis, drop-out rate, baseline characteristics of participants, study interventions, and concomitant treatments. To ensure the accuracy of the data extraction, this process was independently performed by two investigators. Any discrepancy was also resolved by referring back to the original studies.

Two investigators (P.U. and C.T.) independently searched published studies indexed in Medline, Cochrane Central, and EMBASE from inception to September 2015 using the combination of search terms described in the Supplementary Data. These terms consisted of names of individual drugs and mechanism of action in conjunction with terms for PsA. The bibliographies of the included articles were also manually searched. Inclusion criteria We used the following criteria to determine study eligibility: (1) Eligible studies had to be RCTs. (2) They had to compare the efficacy of non-TNF inhibitor biologic agents to placebo in patients with active PsA who either failed to respond adequately to or could not tolerate TNF inhibitors. (3) Duration of studies was greater than or equal to 12 weeks. (4) American College of Rheumatology 20 (ACR20) response was the primary or one of the major secondary outcomes. The modified Jadad scale was used to evaluate the quality of the included studies. This scale consists of three main categories including randomization, blinding, and complete accounting of all patients. Each study was considered to be of sufficient quality if they had scores of more than or equal to 3 [16]. The aforementioned investigators independently determined the study eligibility and quality appraisal. Differences in assessment were resolved by consensus among the investigators. We used ACR20 response as our primary outcome as it has been commonly used by RCTs for the evaluation of the efficacy of investigated drugs. ACR20 response is defined as at least 20 % improvement in the number of swollen and tender joints and in three of the following five parameters: physician global

Fig. 1 Outline of literature review and study identification process

1. At least 18 years old 2. Fulfilled the Classification Criteria for Psoriatic Arthritis (CASPAR) 3. Active PsA (i.e., ≥3 swollen joints and ≥3 tender joints) 4. Active psoriatic skin lesion 5. History of an inadequate response or intolerance to DMARDs or TNF inhibitors

Kavanaugh et al. (PALACE 1) [26] 2014

Placebo 83 sites in 13 countries

1. At least 18 years old 2. Fulfilled the Classification Criteria for Psoriatic Arthritis (CASPAR) 3. Active PsA (i.e., ≥3 swollen joints and ≥3 tender joints) 4. History of an inadequate response or intolerance to DMARDs or TNF inhibitors

Placebo 104 sites in Australia, Europe, and North America

1. At least 18 years old 2. Active PsA (i.e., ≥5 swollen joints and ≥5 tender joints, CRP ≥ 3 mg/L) 3. Active psoriatic skin lesion or a documented history of psoriasis 4. History of an inadequate response or intolerance to DMARDs, NSAIDs, or TNF inhibitors

RCT, double-blinded RCT, double-blinded Ustekinumab 45 or 90 mg SC at baseline, week Apremilast 20 or 30 mg oral twice daily 4, and then every 12 weeks

Richlin et al. (PSUMMIT 2) [25] 2014 RCT, double-blinded Secukinumab 10 mg per kilogram of body weight at baseline, week 2, and week 4 then 75 or 150 mg SC every 4 weeks Placebo 104 sites in Asia, Australia, Middle East, North America, South America, and Europe 1. At least 18 years old 2. Fulfilled the Classification Criteria for Psoriatic Arthritis (CASPAR) 3. Active PsA (i.e., ≥3 swollen joints and ≥3 tender joints) 4. History of an inadequate response or intolerance to DMARDs or TNF inhibitors Lack of efficacy or intolerance

Mease et al. (FUTURE 1) [27] 2015

Lack of efficacy or intolerance Lack of efficacy or intolerance Reasons for previous Lack of efficacy or intolerance TNF inhibitors discontinuation Concomitant therapy MTX was allowed if started ≥3 months prior MTX was allowed if started ≥3 months prior to MTX, leflunomide, or sulfasalazine was allowed Stable dose of MTX and to the start of study agent and if taken at a stable doses of oral if patients had been treated for at least the start of study agent and if taken at a stable stable dose. Stable regimens (≥2 weeks) of corticosteroids 16 weeks and on a stable dose (oral or dose (≤25 mg/week) for ≥4weeks. Stable NSAIDs and/or oral corticosteroids (prednisone ≤10 mg/ parenteral MTX ≤25 mg/week; leflunomide regimens (≥2weeks) of NSAIDs and/or oral (≤10 mg prednisone/day) were also day or equivalent) ≤20 mg/day; sulfasalazine ≤2 g/day) for at corticosteroids (≤10 mg prednisone/day) allowed. were permitted. least 4 weeks before the screening visit. were also allowed. Stable doses of oral corticosteroids (prednisone ≤10 mg/day or equivalent) were also permitted. ACR 20 response at week 24 (data on subgroup ACR 20 response at week 16 (data on subgroup ACR 20 response at Primary outcome ACR 20 response at week 24 (data on of anti-TNF therapy naïve patients and antiof anti-TNF therapy naïve patients was also week 24 (data on subgroup of anti-TNF therapy naïve TNF therapy experienced were provided) provided) subgroup of antipatients and anti-TNF therapy experienced TNF therapy naïve were provided) patients was also provided) ACR 50 response at Major secondary ACR 50 response at week 24 ACR 50 response at week 24 ACR 20 response at week 24 week 24 outcome ACR 70 response at week 24 ACR 70 response at week 24 ACR 50 response at week 24 ACR 70 response at PASI50 at week 24 HAQ-DI at week 24 ACR 70 response at week 24 week 24 Modified PsARC, HAQ-DI, and DAS-28 at HAQ-DI, DAS28-CRP, week 24 and SF36-PCS at week 24 PASI75 and PASI90 at week 24 Number of treatment 3 mg/kg = 16 45 mg = 60 20 mg = 36 75 mg = 60 group (TNF10 mg/kg = 13 90 mg = 58 30 mg = 39 150 mg = 59 experienced) 30/10 mg/kg = 22

Inclusion criteria

RCT, double-blinded Abatacept 3 or 10 mg per kilogram of body weight at baseline IV in days 1, 15, and 29 and every 28 days or 30 mg per kilogram of body weight at baseline IV in days 1 and 15 then 10 mg per kilogram in day 29 and every 28 days Comparison Placebo Country where study Multiple sites in North America and Europe was conducted

Study design Intervention

2011

Mease et al. [24]

Characteristics of included RCTs

Year of publication

Table 1

75 mg = 34 150 mg = 37 300 mg = 33

ACR 50 response at week 24 ACR 70 response at week 24 HAQ-DI, DAS28-CRP, and SF36-PCS at week 24 PASI75 and PASI90 at week 24

ACR 20 response at week 24 (data on subgroup of anti-TNF therapy naïve patients was also provided)

MTX was allowed to continue if the dose was stable for 4 weeks before the study starts (≤25 mg/week). Other DMARDs were discontinued. Corticosteroids were allowed if the dose was less than or equal to 10 mg/ day of prednisone.

Lack of efficacy or intolerance

1. At least 18 years old 2. Fulfilled the Classification Criteria for Psoriatic Arthritis (CASPAR) 3. Active PsA (i.e., ≥3 swollen joints and ≥3 tender joints 4. History of an inadequate response or intolerance to DMARDs, NSAIDs, or TNF inhibitors

Placebo 76 sites in Asia, Australia, North America, and Europe

RCT, double-blinded Secukinumab 75, 150, or 300 mg SC weekly for 4 weeks then every 4 weeks

McInnes et al. (FUTURE 2) [28] 2015

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12

2011

Mease et al. [24]

20 mg = 48.7 (11.0) 30 mg = 51.4 (11.7) Placebo = 51.1 (12.1) 20 mg = 5.5 (2.4) 30 mg = 5.6 (2.2) Placebo = 5.9 (2.2)

20 mg = 5.4 (2.2) 30 mg = 5.6 (2.2) Placebo = 5.5 (2.0)

20 mg = 1.2 (0.6) 30 mg = 1.2 (0.6) Placebo = 1.2 (0.6) 20 mg = 52.4 30 mg = 56.5 Placebo = 53.6 Randomization 1 Blinding 1 An account for all patient 1

45 mg = 49.0 (N.A.) 90 mg = 48.0 (N.A.) Placebo = 48.0 (N.A.) N.A.

N.A.

45 mg = 1.4 (N.A.) 90 mg = 1.3 (N.A.) Placebo = 1.3 (N.A.) 45 mg = 52.4 90 mg = 49.5 Placebo = 47.1 Randomization 2 Blinding 1 An account for all patient 1

75 mg = 47.0 150 mg = 44.0 300 mg = 44.0 Placebo = 51.0

Randomization 2 Blinding 1 An account for all patient 1

Randomization 2 Blinding 1 An account for all patient 1

75 mg = 1.2 (0.6) 150 mg = 1.2 (0.6) 300 mg = 1.3 (0.6) Placebo = 1.2 (0.7)

75 mg = 5.9 (1.8) 150 mg = 5.7 (1.6) 300 mg = 5.5 (1.5) Placebo = 5.5 (1.6)

75 mg = 5.9 (1.9) 150 mg = 6.2 (1.9) 300 mg = 6.1 (1.9) Placebo = 5.8 (2.0)

75 mg = 60.4 150 mg = 59.9 Placebo = 61.9

75 mg = 1.3 (0.7) 150 mg = 1.2 (0.7) Placebo = 1.2 (0.6)

75 mg = 5.4 (1.8) 150 mg = 5.8 (1.9) Placebo = 5.7 (1.9)

75 mg = 5.6 (2.2) 150 mg = 5.5 (2.4) Placebo = 5.6 (2.2)

75 mg = 48.6 (11.4) 150 mg = 46.5 (11.7) 300 mg = 46.9 (12.6) Placebo = 49.9 (12.5)

75 mg = 53.0 150 mg = 45.0 300 mg = 51.0 Placebo = 40.0

75 mg = 41.6 150 mg = 47.5 Placebo = 47.5

20 mg = 50.6 30 mg = 45.2 Placebo = 52.4

45 mg = 46.6 90 mg = 46.7 Placebo = 49.0 75 mg = 48.8 (12.2) 150 mg = 49.6 (11.8) Placebo = 48.5 (11.2)

35

McInnes et al. (FUTURE 2) [28] 2015

59

Mease et al. (FUTURE 1) [27] 2015

40

Kavanaugh et al. (PALACE 1) [26] 2014

62

Richlin et al. (PSUMMIT 2) [25] 2014

RCT randomized controlled trial, PsA psoriatic arthritis, ESR erythrocyte sedimentation rate, CRP C-reactive protein, TNF tumor necrosis factor, MTX methotrexate, DMARDs disease-modifying antirheumatic drugs, NSAIDs non-steroidal anti-inflammatory drugs, ACR American College of Rheumatology, HAQ-DI health assessment questionnaire disease index, DAS-28 disease activity score for 28 joints, PsARC psoriatic arthritis response criteria, N.A. not available, SF-36 36-item short-form health survey, SC subcutaneous, PASI psoriasis area and severity index score, VAS visual analogue scale

3 mg/kg = 49.0 10 mg/kg = 65.0 30/10 mg/kg = 46.0 Placebo = 55.0 3 mg/kg = 49.0 (9.9) Average age of 10 mg/kg = 65.0 (10.5) treatment and control group in 30/10 mg/kg = 46.0 (9.8) Placebo = 55.0 (12.0) years (SD) 3 mg/kg = 5.9 (2.2) Average patient’s 10 mg/kg = 6.0 (2.0) global 30/10 mg/kg = 5.6 (2.2) assessment of disease activity of Placebo = 5.9 (2.7) treatment and control group (0– 10 cm VAS) Average physician’s 3 mg/kg = 5.5 (2.2) 10 mg/kg = 5.7 (2.0) global 30/10 mg/kg = 5.7(2.1) assessment of disease activity of Placebo = 5.3 (2.7) treatment and control group (0– 10 cm VAS) 3 mg/kg = 1.1 (0.7) Average HAQ 10 mg/kg = 1.3 (0.7) disability index of treatment and 30/10 mg/kg = 1.2 (0.8) Placebo = 1.2 (0.7) control group 3 mg/kg = 82.0 Percentage of concomitant use 10 mg/kg = 85.0 30/10 mg/kg = 72.0 of MTX during study in treatment Placebo = 69.0 and control group Jadad scale Randomization 2 Blinding 1 An account for all patient 1

Number of control group (TNFexperienced) Percentage of male in treatment and control group

Year of publication

Table 1 (continued)

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Statistical analysis Data analysis was performed using Review Manager 5.3 software from the Cochrane Collaboration (London, UK). If more than one RCT was available for a given biologic agents, the pooled odds ratio (OR) of achieving ACR20 response and 95 % confidence interval (CI) across studies were calculated using a random-effect, Mantel–Haenszel analysis [18]. Cochran’s Q test was used to assess statistical heterogeneity of the ACR20 response rate. This statistic was complemented with the I2 statistic, which quantifies the percentage of total variation across studies that is due to true heterogeneity rather than chance. A value of I2 of 0 to 25 % represents insignificant heterogeneity; more than 25 % but less than or equal to 50 %, low heterogeneity; more than 50 % but less than or equal to 75 %, moderate heterogeneity; and more than 75 %, high heterogeneity [19]. We then used the indirect comparison technique described by Bucher et al. [20] and Song et al. [21] to compare the relative efficacy of these biologic agents. This indirect comparison is made through a common comparator (placebo group). The efficacy of two biologic agents was considered significantly different if the p value for their indirect comparison was less than 0.05 or if the 95 % CI did not contain one [20, 21].

Results Systematic review of the literature Our search strategy yielded 83 potentially relevant articles. After exclusion of 17 duplicate articles, 66 articles underwent title and abstract review. Twenty-five articles were excluded at this stage as they were clearly not RCTs of biologic agents in PsA, leaving 41 articles for full-length article review. Twentyfour of them were excluded because they did not report our outcome of interest while ten of them of were excluded because of duplication between databases. One study was excluded because it included only patients who were naive to DMARDs [22] while another study was excluded as it included both biologic-naive and biologic-experienced patients but did not separately report their results on each subgroup [23]. Therefore, five RCTs with 467 patients in the treatment arm and 208 patients in the placebo arm met our eligibility criteria and were included in our data analyses [24–28]. All included trials were of high quality as reflected by high Jadad scores. It should be noted that more than one dosage was often studied in one trial. Therefore, we provide the indirect comparisons for each dosage. Figure 1 outlines our literature review process. The details of study design, characteristics of participants, and Jadad scale of the included studies are illustrated in Table 1. The numbers of participants who achieved or did

not achieve the ACR 20 response according to allocation to treatment or placebo for all included studies are shown in Table 2. Efficacy of non-TNF biologic agents in active PsA despite TNF inhibitors We included two trials of secukinumab (317 patients) [27, 28], one trial of ustekinumab (180 patients) [25], one trial of apremilast (115 patients) [26], and one trial of abatacept (63 patients) [24]. Baseline characteristics of participants were similar across these trials with similar female-to-male ratio, average age, and baseline disease activity as reflected by similar patient’s global assessment of disease activity scores, physician’s global assessment of disease activity scores, and health assessment questionnaire disability indexes. The definitions of active disease were consistent across studies (i.e., more than or equal to three swollen joints and more than or equal to three tender joints). All studies allowed concomitant use of stable dose of DMARDs and steroid at the dose of not more than 10 mg daily of prednisone or equivalent. All but one of the studies reported the ACR20 response rate at week 24 as the primary outcome. First, we pooled the results of two trials of secukinumab. The first study reported efficacy of secukinumab at the dose of 75 and 150 mg monthly [27], while the second study reported the efficacy at three different doses (75, 150, and 300 mg monthly). We used random-effect Mantel–Haenszel analysis as previously described to pool the ORs of the dose of 75 and 150 mg. The pooled effects and forest plots of secukinumab at 75 and 150 mg are illustrated in Fig. 2a, b, respectively. We then indirectly compared the four agents using placebo as the common comparator. We found no significant difference in any comparisons with the p values ranging from 0.14 to 0.98. The ORs with the corresponding 95 % CIs and p values for every comparison are shown in Table 3.

Discussion PsA is a chronic systemic arthritis that could result in a permanent joint damage. In an observational cohort, up to 50 % of patients with early disease had radiographic erosive changes in the first 2 years [29]. Therefore, early aggressive treatment is indicated. Over the past three decades, biological agents were discovered and used in clinical practice. However, a significant portion of patients continue not to achieve an adequate clinical response. In fact, the percentages of patients who did not achieve ACR20 response in TNF inhibitors trials were not small, ranging from 25 to 50 % [30–33]. This study aimed to answer a common clinical question in everyday practice. What would be the non-TNF inhibitor

Clin Rheumatol Table 2 ACR 20 response rates for both arms of all included trials

Total

Study

Arms

Mease et al. [24]

Abatacept 3 mg/kg

5 (31.3)

16

Abatacept 10 mg/kg

4 (30.8)

13

Abatacept 30/10 mg/kg Placebo

8 (36.4) 2 (16.7)

22 12

Richlin et al. (PSUMMIT 2) [25]

Ustekinumab 45 mg Ustekinumab 90 mg

22 (36.7) 20 (34.5)

60 58

Placebo

9 (14.5)

62

Kavanaugh et al. (PALACE 1) [26]

Apremilast 20 mg Apremilast 30 mg

11 (30.6) 11 (28.2)

36 39

Placebo Secukinumab 75 mg

2 (5.0) 23 (38.3)

40 60

Secukinumab 150 mg

23 (39.0)

59

Placebo Secukinumab 75 mg

10 (16.9) 5 (14.7)

60 34

Secukinumab 150 mg Secukinumab 300 mg Placebo

11 (29.7) 15 (45.5) 5 (14.2)

37 33 35

Mease et al. (FUTURE 1) [27]

McInnes et al. (FUTURE 2) [28]

biological agent of choice after the patients fail or could not tolerate TNF inhibitors? As the direct head-to-head comparison between those agents in this clinical scenario is not available, we used the indirect comparison technique to answer this question. We were able to compare all four agents that were studied in such patients. We did not find a significantly different odds of achieving ACR20 response between those four agents in any studied dosages.

Fig. 2 a Forest plot of ustekinumab studies (75 mg). b Forest plot of ustekinumab studies (150 mg)

ACR 20 response, number of patients (%) Achieved

Nevertheless, we acknowledge that there are several limitations in this study. Therefore, our results should be interpreted with caution. The first limitation is the inherent limitation of the indirect comparison technique as this analysis assumes that the common comparators (i.e., placebo) are transitive, which means that the placebo arms are adequately similar across clinical trials [34, 35]. This assumption is not always true if certain

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confounders or effect modifiers are distributed unevenly across sets of comparisons. This uneven distribution can occur even if we include only RCTs since participants are randomized to different arms within a single trial but are not randomized to different trials [35]. In our study, even though the baseline characteristics and disease activity of participants were similar across trials, we cannot dismiss the possibility of uneven distribution of unknown effect modifiers. It should be noted that the ACR20 response rate in the placebo arm of Table 3 Results of all indirect comparisons

the apremilast trial [26] was relatively small at 5 % (compared with approximately 15 % in other studies). This different response rate could simply happen by chance as the study size was small (few more patients with ACR20 response in the placebo arm would raise the response rate to 15 %) or could indicate that some unknown effect modifiers are unevenly distributed. The second limitation is related to the size of the primary studies as the number of participants in each arm is relatively

Indirect comparison

ACR 20 response ORa (95 % CI)

p Value

Apremilast 20 mg/ustekinumab 45 mg

2.45 (0.40–15.10)

0.33

Apremilast 20 mg/ustekinumab 90 mg Apremilast 20 mg/secukinumab 75 mg

2.70 (0.44–16.68) 4.14 (0.62–27.55)

0.28 0.14

Apremilast 20 mg/secukinumab 150 mg Apremilast 20 mg/secukinumab 300 mg Apremilast 20 mg/abatacept 3 mg/kg

2.87 (0.51–16.30) 1.67 (0.23–12.04) 3.68 (0.32–42.14)

0.23 0.61 0.30

Apremilast 20 mg/abatacept 10 mg/kg Apremilast 20 mg/abatacept 30/10 mg/kg Apremilast 30 mg/ustekinumab 45 mg

3.76 (0.31–45.51) 2.93 (0.28–31.09) 2.19 (0.36–13.40)

0.30 0.37 0.39

Apremilast 30 mg/ustekinumab 90 mg

2.40 (0.39–16.68)

0.34

Apremilast 30 mg/secukinumab 75 mg Apremilast 30 mg/secukinumab 150 mg Apremilast 30 mg/secukinumab 300 mg

3.70 (0.56–24.46) 2.57 (0.45–14.47) 1.49 (0.21–10.69)

0.17 0.29 0.69

Apremilast 30 mg/abatacept 3 mg/kg Apremilast 30 mg/abatacept 10 mg/kg

3.28 (0.29–37.45) 3.37 (0.28–40.45)

0.39 0.34

Apremilast 30 mg/abatacept 30/10 mg/kg Ustekinumab 45 mg/secukinumab 75 mg Ustekinumab 45 mg/secukinumab 150 mg

2.61 (0.25–27.39) 1.69 (0.43–6.56) 1.17 (0.38–3.60)

0.42 0.45 0.78

Ustekinumab 45 Ustekinumab 45 Ustekinumab 45 Ustekinumab 45 Ustekinumab 90 Ustekinumab 90 Ustekinumab 90 Ustekinumab 90 Ustekinumab 90 Ustekinumab 90

0.68 (0.16–2.95) 1.50 (0.19–12.67) 1.53 (0.19–12.68) 1.19 (0.17–8.50) 1.53 (0.39–5.99) 1.07 (0.34–3.29) 0.62 (0.14–2.69) 1.36 (0.18–10.59) 1.39 (0.17–11.59) 1.08 (0.15–7.69)

0.60 0.70 0.69 0.86 0.54 0.91 0.53 0.77 0.76 0.94

0.89 (0.10–7.78) 0.90 (0.10–8.00) 0.71 (0.09–5.37) 1.28 (0.18–9.12) 1.31 (0.17–10.06) 1.02 (0.16–6.69) 2.20 (0.26–18.54) 2.25 (0.24–21.33) 1.75 (0.21–14.30)

0.92 0.93 0.75 0.81 0.80 0.98 0.47 0.48 0.60

mg/secukinumab 300 mg mg/abatacept 3 mg/kg mg/abatacept 10 mg/kg mg/abatacept 30/10 mg/kg mg/secukinumab 75 mg mg/secukinumab 150 mg mg/secukinumab 300 mg mg/abatacept 3 mg/kg mg/abatacept 10 mg/kg mg/abatacept 30/10 mg/kg

Secukinumab 75 mg/abatacept 3 mg/kg Secukinumab 75 mg/abatacept 10 mg/kg Secukinumab 75 mg/abatacept 30/10 mg/kg Secukinumab 150 mg/abatacept 3 mg/kg Secukinumab 150 mg/abatacept 10 mg/kg Secukinumab 150 mg/abatacept 30/10 mg/kg Secukinumab 300 mg/abatacept 3 mg/kg Secukinumab 300 mg/abatacept 10 mg/kg Secukinumab 300 mg/abatacept 30/10 mg/kg a

Odds ratios are the odds of achieving ACR 20 of the first agent compared with the second agent

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small ranging from 12 to 60 participants. It is possible that this analysis does not have enough power to detect statistical significance. In conclusion, our study demonstrated that the odds of achieving an ACR20 response in patients with PsA who did not have an adequate response to or could not tolerate TNF inhibitors were not significantly different between four nonTNF inhibitor biologic agents. However, this interpretation of this analysis was limited by the small sample sizes. Head-tohead comparisons are still required to confirm the comparative efficacy. Acknowledgments Author’s contribution Patompong Ungprasert did the study design, literature search, statistical analysis, and writing of the manuscript. Charat Thongprayoon did the literature search and manuscript revision. John Davis did the study design and manuscript revision.

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17. Compliance with ethical standards Funding None. Conflict of interest statement John M. Davis is a site investigator for trials sponsored by Pfizer and Roche/Genentech. Division of Rheumatology, Mayo Clinic, receives research funding from Pfizer for John M. Davis’s role on a grant.

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Indirect comparisons of the efficacy of subsequent biological agents in patients with psoriatic arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis.

Significant portion of patients with psoriatic arthritis (PsA) could not tolerate or do not have a satisfactory response to either non-steroidal anti-...
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