Other Biologic Therapy for PsA

Introduction

Increasing evidence points to the important role for other cytokines in the pathogenesis of these diseases, some of which may act in parallel or even upstream to tumor necrosis factor alpha (TNF-α). Interleukins 12, 17 and 23, in particular, have emerged as attractive targets in the treatment of psoriatic disease (Figure 8-1) and a number of clinical trials have looked at agents that target these proteins. Ustekinumab, risankizumab, secukinumab, ixekizumab and abatacept have all been approved in the United States for treatment of psoriatic arthritis based on their efficacy and safety profiles (Table 8-1). The current (2021) Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations for the use of these agents are discussed and summarized in Figure 6-11.

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Ustekinumab

Ustekinumab is a human monoclonal antibody directed against the p40 subunit common to IL-12 and IL-23. It was first approved for use in treating both psoriasis and PsA in the United States, where it is administered via subcutaneous injection at a dose of 45 mg or 90 mg (based on weight) every 12 weeks after two loading doses, given 4 weeks apart.

In a phase 2, 12-week, randomized, double-blinded, multicenter trial, 146 patients were randomized to ustekinumab 90 mg or 63 mg weekly for 4 weeks or placebo. The drug was given intravenously in this trial, and a filtration procedure was introduced after the first 36 patients had been randomized, resulting in an effective dose of 63 mg. At week 12, all subjects were crossed over to the alternate therapy, with the placebo patients receiving ustekinumab at week 12 and 16, while the original ustekinumab patients received placebo infusions to maintain the blind through 16 weeks. The primary end point was the ACR20 response rate at 12 weeks.

The drug was effective, with 47% of the ustekinumab group achieving an ACR20 at 12 weeks compared with 14% of the placebo group (Figure 8-2). There were statistical differences between groups in ACR50 and ACR70 at 12 weeks as well. Function improved in the ustekinumab group, with a median decrease in HAQ of -0.25 in the ustekinumab group, compared with no change in the placebo group. Enthesitis and dactylitis both improved at week 12 as well. Finally, in the patients with > 3% body surface area (BSA) of psoriasis at baseline, a PASI75 was achieved by 52% in the treatment group compared with 5% of the placebo group.

The placebo group in the trial had a similar ACR20 response after being crossed over to ustekinumab infusions at weeks 12 and 16, although the treatment assignment was no longer masked by the time of the assessment. Only 21% of the patients in this trial were receiving concurrent methotrexate therapy, lower than the percentage seen in most of the trials with TNF inhibitors; it is not clear whether response differed depending on methotrexate usage. No major safety signals were seen in this trial. There were three serious adverse events during the placebo-controlled portion of the trial, all in the placebo arm.

Following this phase 2 study, two multicenter phase 3 registration trials were conducted, PSUMMIT 1 and PSUMMIT 2. In PSUMMIT 1, 615 patients with active PsA despite NSAIDs or DMARDs were randomized 1:1:1 to receive placebo, ustekinumab 45 mg or ustekinumab 90 mg, at baseline, week 4 and then every 12 weeks. None of the patients had previously been treated with biologic agents and 48% were receiving concomitant methotrexate. At week 16, patients with < 5% improvement in tender and swollen joints were transitioned to active therapy. The primary endpoint of the trial was the ACR20 response at week 24; for patients who had an early escape, week 16 data were carried forward to week 24. At week 24, the percentage of patients achieving an ACR20 response for placebo, ustekinumab 45 mg and ustekinumab 90 mg were 22.8%, 42.4% and 49.8% respectively (Figure 8-3). The difference from placebo was highly significant for both doses. ACR50 and ACR70 response rates were also significantly higher than placebo for both doses of ustekinumab.

Enthesitis and dactylitis scores were significantly improved with both doses of ustekinumab compared with placebo. The median decrease in the HAQ-DI was 0.3 for the combined ustekinumab dose groups compared with no change in the placebo group. In the patients with > 3% BSA psoriasis, the PASI75 response rate was 57.2% and 62.4% for ustekinumab 45 mg and 90 mg, respectively, compared with 11% for placebo. The investigators reported no differences in clinical response for either joints or skin based on concurrent methotrexate use. ACR and PASI response rates, as well as improvements in enthesitis and dactylitis, were sustained through 2 years of open-label therapy.

In the second phase 3 trial PSUMMIT 2, 312 patients with active PsA despite NSAIDs, conventional DMARDs or TNF inhibitors were randomized to receive placebo, 45 mg ustekinumab, or 90 mg ustekinumab, according to the same dosing schedule used in PSUMMIT 1. The study protocol dictated that at least half of the patients had previously been treated with TNF inhibitors; in the end, 180 of those enrolled had received TNF inhibitors, while 132 were TNF naïve. The primary endpoint was an ACR20 response, which was achieved by 20.2%, 43.7% and 43.8% of the placebo, ustekinumab 45 mg and ustekinumab 90 mg patients, respectively; both comparisons to placebo were statistically significant. The ACR50 response was also statistically different between ustekinumab and placebo, but the ACR 70 response was not. Responses were greater in the patients who were TNF inhibitor naïve. For the patients who had not received TNF inhibitors, the ACR20 response was 28.6% for the placebo group compared with 54.4% for the combined ustekinumab groups; for the TNF-experienced patients, the placebo response was 14.5% compared with 35.6% for the combined ustekinumab groups.

Enthesitis was statistically improved with both doses of ustekinumab compared with placebo, and dactylitis was also numerically improved relative to placebo but the difference was not statistically significant. Improvement in the HAQ-DI was statistically greater with both doses of ustekinumab than placebo; as with the ACR responses, the improvement in HAQ-DI was greater in those patients who were TNF inhibitor naïve. The improvement in skin in PSUMMIT 2 was significant, with PASI75 response rates at week 24 of 51.3% and 55.6% for the two ustekinumab doses compared with 5.0% for the placebo arm.

The percentage of patients with any adverse event, serious adverse events, or infections were similar between the ustekinumab groups and the placebo groups in both PSUMMIT 1 and PSUMMIT 2. No serious infections were seen during the placebo-controlled phases of either trial; a small number of serious infections were seen during open-label treatment up to 2 years. No opportunistic infections or tuberculosis were reported in either trial. There were no major cardiovascular events reported during the placebo-controlled trials; five myocardial infarctions were reported during follow-up to 2 years.

Information on the impact of ustekinumab on structural progression comes from a preplanned integrated analysis of the PSUMMIT 1 and PSUMMIT 2 trials. In this analysis, the mean change in total van der Heijde modified Sharp score was 0.4 units at 24 weeks, compared with 1.0 units for the placebo group (Figure 8-4). The inhibition of radiographic progression was maintained for the ustekinumab-treated patients from weeks 24 to 52, and the placebo patients had similar inhibition of progression when transitioned to active drug at week 24.

Overall, the improvement in joint symptoms with ustekinumab appears to be somewhat lower than that seen with TNF inhibitors, although this type of comparison should be made with caution in the absence of head-to-head trials. In addition, the response in patients who are TNF experienced is not as good as in those who are TNF naïve. Nevertheless, this drug offers an important option in patients who have had an inadequate response to TNF inhibitors, or who cannot take them, particularly when they have very active skin disease.

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Risankizumab

Risankizumab is a humanized monoclonal IgG1 antibody that binds to the p19 subunit of IL-23. This binding disrupts the interaction between IL-23 and its receptor, which inhibits the release of pro-inflammatory cyto- and chemokines. Risankizumab initially received FDA approval for the treatment of plaque psoriasis in April 2019, followed by approval for the treatment of active PsA in adults in January 2022. It is available in the form of prefilled pens (150 mg/mL) or syringes (150 mg/mL or 75 mg/mL) and is administered by subcutaneous injection. The recommended dose for PsA treatment is 150 mg at week 0, week 4 and every 12 weeks thereafter.

The safety and efficacy of risankizumab in PsA treatment was assessed in two phase 3 randomized, double-blind, placebo-controlled trials, KEEPsAKE 1 and KEEPsAKE 2. In KEEPsAKE 1, 964 patients with active PsA and an inadequate response or intolerance to at least 1 conventional synthetic DMARD were randomized 1:1 to receive either risankizumab 150 mg or placebo at weeks 0, 4 and 16. The primary endpoint was the proportion of patients who achieved ACR20 at week 24, while secondary endpoints included the ACR20 response rate at week 16 and change from baseline in HAQ-DI, among others.

At Week 24 in KEEPsAKE 1, a significantly greater percentage of patients achieved ACR20 in the risankizumab group (57.3%) compared to the placebo group (33.5%, P < .001; Figure 8-5). A significantly higher proportion of risankizumab-treated patients also achieved ACR20 by Week 16, compared to placebo (56.3% vs. 33.4%; P < .001). Patients in the risankizumab group achieved a significantly greater change in HAQ-DI from baseline (−0.31; CI: −0.36 to –0.27) compared to those randomized to placebo (−0.11; CI: −0.16 to –0.06; P < .001). While a numerically higher proportion of patients achieved ACR50 and ACR70 in the risankizumab group by week 24, because the analyses of these endpoints were not multiplicity-adjusted, a statistically valid conclusion cannot be drawn.

The overall design of KEEPsAKE 2 was similar to that of KEEPsAKE 1. A total of 444 patients were randomized 1:1 to receive either risankizumab 150 mg or placebo at weeks 0, 4 and 16.9 The eligibility criteria differed slightly, since in addition to active PsA, eligible patients must have had an inadequate response or intolerance to either at least one conventional synthetic DMARD or up to two biological therapies, or both. The primary endpoint was identical to that of KEEPsAKE 1 (the proportion of patients who achieved ACR20 at week 24). Secondary endpoints similarly included the proportion of patients achieving ACR20 at week 16 and the change from baseline in HAQ-DI.

The primary endpoint (ACR20 at week 24) was achieved by 51.3% of patients in the risankizumab group and 26.5% of those in the placebo group (P < .001; Figure 8-6). A significantly greater percentage of patients treated with risankizumab also achieved ACR20 at week 16 (48.3%) compared to patients who received placebo (25.3%; P < .001). Patients in the risankizumab group also demonstrated a significantly greater change from the baseline in the HAQ-DI score (−0.22; CI: −0.28 to –0.15) compared to those in the placebo group (−0.05; CI: −0.12 to 0.02; P < .001). Like in KEEPsAKE 1, a numerically greater proportion of risankizumab-treated patients achieved ACR50 and ACR70 at week 24; however, because the analysis was not adjusted for multiplicity, no statistically valid conclusion can be drawn from the results.

In KEEPsAKE 1 and 2, risankizumab demonstrated a generally favorable safety profile. Treatment-emergent adverse events (TEAEs) were reported at similar frequencies in the risankizumab and placebo groups within each trial (in KEEPsAKE 1: 40.4% vs 38.7%, respectively; in KEEPsAKE 2: 55.4% vs 54.8%, respectively). The most common TEAE in KEEPsAKE 1 was nasopharyngitis (3.3% in the risankizumab group and 2.9% in the placebo group). In KEEPsAKE 2, the most common TEAE was upper respiratory tract infection (7.6% with risankizumab and 5.5% with placebo). Serious TEAEs likewise had similar frequencies between treatment groups in both trials, as did AEs of special safety interest, with the exception of injection site reactions, which were more common in the risankizumab group.

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Interleukin-17 Inhibitors

Because of the importance of IL-17 in driving pathways of psoriatic skin disease, IL-17 inhibitors were first studied in skin psoriasis. However, based on the success of these agents in treating psoriasis, and evidence for a role of IL-17 in the pathophysiology of joint disease, studies in psoriatic arthritis (PsA) soon followed. Two of these agents, secukinumab and ixekizumab, are now FDA-approved for the treatment of PsA. Both are monoclonal antibodies that specifically target IL-17A. A third antibody, brodalumab, which is approved to treat psoriasis and targets the IL-17 receptor, has been studied in PsA, but development was stopped before sufficient data was obtained to apply for this indication.

Secukinumab

Secukinumab is a human monoclonal antibody directed against IL-17A that has been approved in the United States for treatment of plaque psoriasis, PsA and ankylosing spondylitis. After demonstrating signs of efficacy in a small, multicenter phase 2 trial, secukinumab was studied in two large multicenter phase 3 trials in PsA. In the FUTURE 1 trial, 606 patients with active PsA were randomized 1:1:1 to placebo or secukinumab 75 mg or 150 mg SC every 4 weeks, after a loading dose of 10 mg/kg IV at weeks 0, 2 and 4.6 The primary endpoint, ACR20 at week 24, was achieved by 50.5% and 50.0% of the patients treated with 75 mg or 150 mg of secukinumab, respectively, compared with 17.3% of those treated with placebo (P < .001; Figure 8-7).

In the 29% of patients in this trial with a previous inadequate response to a TNF inhibitor, the ACR20 response was lower but still significantly improved relative to placebo. The ACR50 response rates at 24 weeks were 30.7% and 34.7% for the two secukinumab doses compared with 7.4% for placebo (P < .001); the ACR70 response rates were 16.8% and 18.8%, compared with 2.0% for placebo (P < .001). The DAS28-CRP was also statistically improved relative to placebo in this trial. Secukinumab demonstrated inhibition of structural progression in this trial; the mean change in modified total Sharp score at 1 year was 0.02 and 0.13 for the two doses of secukinumab compared with 0.57 for placebo (P < .05).

Additional secondary endpoints in the FUTURE 1 study included the presence of dactylitis and enthesitis, both of which were significantly decreased with secukinumab therapy relative to placebo, and measures of function and health-related quality of life.6 The Health Assessment Questionnaire Disability Index (HAQ-DI) was decreased by 0.40 and 0.41 for the two doses of secukinumab at 24 weeks (both greater than the minimal clinically important difference of 0.35) but only by 0.17 for placebo. Fatigue, as measured by the FACIT-F, and the mental and physical subscales of the SF-36 were also significantly improved with both doses of secukinumab compared with placebo.

In the FUTURE 2 study, 397 patients were randomized 1:1:1:1 to receive placebo or secukinumab 75 mg, 150 mg, or 300 mg SC weekly for 4 weeks and then every 4 weeks thereafter. There was no intravenous loading dose in this study. The primary endpoint, an ACR20 response at 24 weeks, was achieved by 54%, 51%, and 29% of the secukinumab 300 mg, 150 mg, and 75 mg doses, respectively, compared with 15% of the placebo-treated patients (Figure 8-8). ACR50 and ACR70 responses were also significantly improved for the secukinumab 300-mg and 150-mg doses when compared with placebo; the 75-mg dose was less effective at achieving these higher levels of response.

A number of secondary endpoints in the FUTURE 2 trial, including DAS28-CRP, PASI75, PASI90, and HAQ-DI all showed significant benefit for the 150-mg and 300-mg doses of secukinumab compared with placebo, with no statistical benefit for the 75-mg dose. A pooled analysis of resolution of dactylitis and enthesitis in all three secukinumab arms suggested improvement relative to placebo, but the difference was not statistically significant.

TNF inhibitor inadequate responders comprised 35% of the patients enrolled in the FUTURE 2 study. As in FUTURE 1, these patients responded less well than those who were TNF inhibitor naïve, and the ACR and PASI75 responses were only significantly better than placebo for the 300-mg dose group; ACR20/50/70 responses were 45%, 27%, and 15%, respectively, compared with 14%, 9%, and 0% for placebo.

Rates of adverse events, serious adverse events, and infections were generally similar between secukinumab and placebo in both FUTURE 1 and FUTURE 2, except that the incidence of serious adverse events during the placebo-controlled portion of the study was slightly higher for the secukinumab 75-mg and 300-mg groups in FUTURE 2. Eleven candida infections were reported in the secukinumab arms in FUTURE 2, with none in the placebo arm. None of these infections were judged to be serious, and none resulted in withdrawal from the study. Candidal infections are a well-recognized complication of IL-17 inhibitor therapy, as IL-17 is an important component of the mucocutaneous defense against candida. A pooled safety analysis of five placebo-controlled psoriasis studies and the two placebo-controlled PsA studies found that rates of adverse events, serious adverse events, and infections were comparable to placebo. Candidal infections were seen in 2.1% of the secukinumab-treated patients; the rate for placebo-treated patients was not reported.

In a third large trial of secukinumab in PsA, FUTURE 5, 996 patients with active PsA were randomized to receive either placebo, secukinumab 300 mg or 150 mg on the same schedule as in FUTURE 2, or secukinumab 150 mg without a loading dose.10 The primary endpoint (ACR20 at 16 weeks) was reached in a significantly greater proportion of patients in the secukinumab groups compared to placebo (300-mg with LD, 62.6%; 150-mg with LD, 55.5%; 150-mg without LD, 59.5%; placebo, 27.4%). In anti-TNF experienced patients, the ACR20 response was lower but still significantly improved relative to placebo; anti-TNF naïve patients experienced the greatest benefit.

Radiographs were also assessed in this study and showed statistically significant inhibition of progression of Sharp scores at 24 weeks in all three secukinumab arms compared with placebo (Figure 8-9). This study represents the first radiographic data with secukinumab in PsA in a trial without an intravenous loading regimen.

For PsA, the recommended dose of secukinumab is 150 mg sc every 4 weeks, with or without a loading dose of 150 mg sc weekly for 4 weeks. For patients with concomitant psoriasis or who do not respond adequately to the 150-mg dose, a dose of 300 mg can be used. Secukinumab is designated Pregnancy Category B by the FDA; there are no well-controlled studies in humans, but no evidence of fetal harm in animal studies.

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Ixekizumab

Ixekizumab was approved for psoriatic arthritis (PsA) based two phase 3 trials, one in biologic-naïve patients (SPIRIT-P1) and one in patients with an inadequate response to a TNF inhibitor (SPIRIT-P2).

In the SPIRIT-P1 trial, 417 patients were randomized to ixekizumab 80 mg once every 2 weeks, 80 mg once every 4 weeks, adalimumab 40 mg once every 2 weeks or placebo. Both ixekizumab arms received a loading dose of ixekizumab 160 mg at the baseline visit. Adalimumab was included as an active reference arm; the study was not powered to compare the adalimumab response to that with ixekizumab. The primary endpoint of the study was the proportion of patients achieving an ACR20 response at 24 weeks. This response was achieved by 62.1% of the patients receiving once every 2 weeks dosing and 57.9% of patients receiving once every 4 weeks dosing, compared with 30.2% of the placebo arm, a difference that was statistically significant (P ≤ .001; Figure 8-10).

The ACR20 response with adalimumab at 24 weeks was 57.4%. Higher levels of response also favored ixekizumab, with ACR50 at 24 weeks of 46.6% and 40.2% and ACR70 of 34.0% and 23.4% for the once every 2 weeks and once every 4 weeks dose regimens compared with only 15.1% and 5.7% for placebo. Adalimumab had ACR50 and ACR70 responses of 38.6% and 25.7% at 24 weeks. Statistically significant differences from placebo in ACR20 and ACR50, but not ACR70, were also seen for ixekizumab at 12 weeks. Absolute improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) and the percentage of patients achieving a minimally clinically important difference in this measure at 24 weeks was also significantly greater for both ixekizumab groups compared with placebo. Improvement in dactylitis was significantly better with ixekizumab compared with placebo; improvements in enthesitis, while numerically favoring ixekizumab, did not achieve statistical significance.

Similar to secukinumab, ixekizumab demonstrated marked improvement in skin disease in the SPIRIT-P1 trial, consistent with the important role that IL-17 plays in the pathogenesis of skin psoriasis. At 24 weeks, in those patients with >3% BSA psoriasis, PASI75 and PASI90 responses were 79.7%/67.8% and 71.2%/56.2% in the once every 2 weeks and once every 4 weeks dosing groups, respectively, compared with 10.4%/6.0% with placebo (Figure 8-11). The corresponding rates for the adalimumab comparator arm were 54.4% and 36.8%. At 24 weeks, the PASI100 response rate was 52.5% with once every 2 weeks dosing in this subgroup. The nail psoriasis severity index (NAPSI) was also improved with both ixekizumab dosing regimens at 24 weeks compared with placebo. Finally, ixekizumab was shown to have structural benefit in this trial, with 24-week mean changes in modified total Sharp score that were statistically less than with placebo.

Adverse events, including infections, were comparable in the SPIRIT-P1 trial between ixekizumab and placebo. One case of esophageal candidiasis and one case of oral candidiasis were reported in ixekizumab-treated patients. After 24 weeks, all patients in the trial were re-randomized to ixekizumab 40 mg once every 2 weeks or 80 mg once every 4 weeks. Recently reported 52-week data showed sustained response in both skin and joints with both dosing regimens, with no changes in the safety profile.

SPIRIT-P2 enrolled 363 PsA patients with an inadequate response to TNF inhibitors and randomized them to ixekizumab 80 mg once every 2 weeks or once every 4 weeks, again after an initial dose of 160 mg at baseline. The primary endpoint, as in SPIRIT-P1, was the proportion of patients achieving ACR20 response at 24 weeks. At this time point, 48% of the once every 2 weeks dosing group and 53% of the once every 4 weeks dosing group achieved an ACR20 compared with 19% of the placebo group (Figure 8-12). At higher levels of response, 33% and 12% of the once every 2 weeks dosing group and 35% and 22% of the once every 4 weeks dosing group achieved an ACR50 and ACR70, respectively, compared with 5% and none of the placebo-treated patients. HAQ-DI was significantly improved with both dose regimens compared with placebo.

The improvements in dactylitis and enthesitis were numerically, but not statistically, greater than placebo at 24 weeks. Improvements in skin disease, measured by PASI75, PASI90 and PASI100, were statistically greater than placebo at 24 weeks, although the benefit was less pronounced than that seen in SPIRIT-P1 in this more refractory population. Improvements in the NAPSI were significant with both dose regimens compared with placebo. Safety was similar to SPIRIT-P1. Two cases of skin candidiasis, two cases of vulvovaginal candidiasis, and four cases of oral candidiasis were reported, all in ixekizumab-treated patients. There were three serious infections reported, all in patients receiving ixekizumab every 2 weeks.

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Brodalumab

Brodalumab is a human monoclonal antibody directed against the interleukin (IL)-17 Receptor A rather than against the cytokine itself. A phase 2 randomized trial compared placebo to two doses of brodalumab, and both were significantly more effective than placebo. Rates of adverse events and serious adverse events were similar between the two brodalumab groups and the placebo group in this trial.

In subsequent phase 3 trials, however, there were a number of reports of suicide and suicidal ideation. These trials were stopped, and development of this agent is on hold because of concerns over how these events might affect the labeling of the drug. No similar concerns for depression or suicide have been noted in the secukinumab or ixekizumab trials.

Conclusions

Overall, the interleukin (IL)-17 pathway appears to be an important element in the pathogenesis of psoriatic arthritis (PsA), and inhibition of this pathway has been shown to be a successful treatment strategy in PsA, as it has for psoriasis. Although the SPIRIT-P1 trial was not powered to compare ixekizumab to adalimumab, the overall results from the trials of both approved IL-17 inhibitors suggest that their effect on PsA is similar to that seen with TNF inhibitors. Improvement in skin disease with these agents seems to be greater than that seen with TNF inhibitors, consistent with the differences in disease pathways in skin and joints, and the relatively greater importance of IL-17 in driving skin disease.

Abatacept

Abatacept is a recombinant protein composed of the cytotoxic T lymphocyte receptor 4 (CTLA4) fused to the Fc portion of a human IgG1. This drug is believed to work by displacing the interaction between CD28 and CD80/86, thereby modulating the T cell co-stimulatory signal. Abatacept is currently approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis and adult psoriatic arthritis (PsA).

Following some preliminary data suggesting the effectiveness of abatacept in PsA, a double-blinded, randomized, placebo-controlled phase 2 trial was undertaken in 170 patients with PsA previously treated with DMARDs, including TNF inhibitors. Three dose arms with abatacept were included in this trial: 3 mg/kg, 10 mg/kg (the approved dose for RA), and 10 mg/kg after two initial doses of 30 mg/kg. Dosing was monthly, following two initial doses at day 1 and day 15. Concurrent methotrexate use was allowed; 55% to 60% of patients in the four treatment groups were also taking methotrexate. Previous use of a TNF inhibitor was reported for 29% to 51% of patients; the greatest prior use of a TNF inhibitor occurred by chance in the group assigned to receive the 30-mg loading dose.

The primary end point of the trial was the ACR20 response at day 169. The percentages of patients achieving this response were 19%, 33%, 48% and 42% of the placebo, 3 mg/kg, 10 mg/kg and 30/10 mg/kg groups, respectively. The difference from placebo was significant for the two higher dose abatacept groups but not for the 3 mg/kg group (Figure 8-13). The percentage of patients achieving an ACR50 and an ACR70 was numerically, but not statistically, greater than placebo for all three abatacept treatment arms. MRIs were obtained during this trial to assess the effect of abatacept on joint damage. There was a trend toward improvement in scores for osteitis and synovitis with abatacept, particularly for the higher dose groups, with slight worsening in the placebo arm. The Health Assessment Questionnaire (HAQ) and the 36-item Short Form Health Survey (SF36) scores also showed some improvement with abatacept in this trial. Skin response was disappointing in this trial, with only the 3 mg/kg group showing any trend towards improvement relative to placebo.

Overall, this controlled trial with abatacept appeared to demonstrate modest benefit in PsA, although there was no clear response in the patients who had received prior therapy with a TNF inhibitor, the group with the greatest unmet need (Figure 8-14). No benefit was seen when loading with 30 mg/kg of abatacept for the first two doses, although this treatment arm had a higher percentage of patients who had received prior therapy with a TNF inhibitor, which may have blunted the overall clinical response.

In a double-blinded, randomized, placebo-controlled phase 3 trial using the subcutaneous preparation of abatacept, 424 patients, approximately 60% of whom had previously been exposed to a TNF inhibitor were randomized 1:1 to treatment with abatacept 125 mg weekly or placebo. Blinded treatment was continued through week 24, although patients without a 20% improvement in joint counts were switched to open-label treatment with abatacept at week 16. The primary endpoint of the trial was the ACR20 response at 24 weeks, achieved by 39.4% of the abatacept patients and 22.3% of the placebo patients (P < .001; Figure 8-15). Abatacept did not achieve statistical significance for the first key secondary endpoint, HAQ-Disability Index (DI) response at week 24 (31.0% vs 23.7%). Because of the failure to reach this second endpoint in the statistical hierarchy for the trial, the other outcomes were reported only as nominal P values.

While there was numerical superiority for abatacept in ACR50 and ACR70 responses, neither difference was statistically significant. In the TNFi-naïve group, the ACR20 response was 44.0% vs 22.2% (nominal P value 0.003), while in the TNF inhibitor–exposed group it was 36.4% vs 22.3% (nominal P value 0.012). At week 24, complete resolution of dactylitis and enthesitis was seen in 44.3% and 32.9% of the abatacept-treated patients, respectively, compared to 34% and 21.2% with placebo, differences that were numerically, but not statistically, superior. Abatacept appeared to have an impact on radiographic damage in this study, with 42.7% of abatacept-treated patients showing no structural progression at 24 weeks vs 32.7% with placebo (nominal P value 0.034). Finally, abatacept had little impact on skin psoriasis, with a PASI 50 response of 26.7% at 24 weeks vs 19.6% with placebo (not significant).

There were no significant safety issues with abatacept in this trial. The incidences of infections and serious adverse events were comparable between abatacept and placebo. A single patient treated with abatacept, who had recently been treated with high-dose steroids for COPD, developed Pneumocystis jirovecii pneumonia that was treated and resolved.

Based upon these two trials, abatacept was approved for the treatment of PsA in July 2017. Both intravenous and subcutaneous preparations are approved for this indication, with no loading dose necessary for intravenous dosing.

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Anakinra

Anakinra, a recombinant interleukin (IL)-1 receptor, is approved for use in rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS). It has also been shown to be of benefit in systemic juvenile inflammatory arthritis and adult Still’s disease.

An open-label pilot study of anakinra enrolled 20 patients, 10 of whom were receiving concomitant methotrexate, in a planned 6-month study of anakinra 100 mg daily given subcutaneously. While the authors noted that 9 of 19 patients who had received at least 4 weeks of therapy had some improvement in signs and symptoms of psoriatic arthritis (PsA), only 6 of the 20 patients completed 24 weeks of therapy, and 13 of the 14 who discontinued did so for lack of efficacy. The low response rate in this open-label trial, along with the high incidence of injection site reactions with this agent (75% of patients in this trial), suggests a limited role for anakinra in PsA.

Alefacept

Alefacept, a fusion protein that inhibits T cell activation, showed some efficacy in a 6-month, double-blind study in 185 psoriatic arthritis (PsA) patients when used in combination with methotrexate. The likelihood of achieving an ACR20 was statistically greater than with placebo, although ACR50 and ACR70 responses were not. This agent was approved for the treatment of psoriasis; it has subsequently been withdrawn from the US market, primarily because of poor sales, although there was some concern over the drug’s impact on T cell counts.

Other Biologic Agents

Published experience with rituximab, the monoclonal anti-B cell antibody, in psoriatic arthritis (PsA) is limited to case reports a small open-label study. Publications on the efficacy tocilizumab, the anti–interleukin (IL)-6 receptor antibody, in PsA have been limited to case reports. Of interest, data from placebo-controlled trials with tocilizumab and sarilumab, an antibody directed against IL-6 itself, in ankylosing spondylitis did not demonstrate any evidence of clinical efficacy. These data raise questions about whether the IL-6 pathway is an attractive target to pursue in spondyloarthropathies, at least for axial symptoms.