New treatment alternatives in ankylosing spondylitis and psoriatic arthritis
https://doi.org/10.46856/grp.10.e111
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Ibáñez Vodnizza S, Martínez O, Valenzuela F. New treatment alternatives in ankylosing spondylitis and psoriatic arthritis [Internet]. Global Rheumatology. Vol 3 / Ene - Jun [2022]. Available from: https://doi.org/10.46856/grp.10.e111
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New treatment alternatives in ankylosing spondylitis and psoriatic arthritis
In psoriatic arthritis and spondyloarthritis, there is still room for new drugs, with different mechanisms of action, that allow better personalization of treatment. The objective of this review is to facilitate the clinician's decision to use tofacitinib, upadacitinib, or guselkumab, new treatment alternatives within the wide variety of drugs currently available.
In ankylosing spondylitis (AS) and psoriatic arthritis (PsA), there are several unmet needs despite the significant advances achieved in recent decades, including the considerable delay in diagnosis at a global level, the lack of biomarkers with true utility in daily clinical practice, the limited standardization in the use and interpretation of imaging, the absence of treatment targets with proven benefit, the lack of knowledge regarding the role of combining different disease-modifying antirheumatic drugs (DMARDs), and the place in the treatment hierarchy of Janus kinase inhibitors (JAKi) and interleukin-23 (IL-23) inhibitors(1). Although the advances in available treatments, first with biologics and more recently with JAKi, have been very significant, only a minority of patients achieve disease remission, and approximately 15% present with primary failure to biologics, with a similar percentage showing secondary failure(2). Therefore, there is still room for new drugs with different mechanisms of action that allow for even more personalized treatment.
Objectives
The objective of this narrative review is to assist clinicians in the decision to use tofacitinib (TOFA), upadacitinib (UPA), or guselkumab (GUSE), new treatment alternatives for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), considering the wide variety of DMARDs currently available.
Findings
Upadacitinib
UPA is a selective Janus kinase (JAK) 1 oral inhibitor, used in the treatment of rheumatoid arthritis (RA) since 2019, and was recently approved for use in PsA and AS(3).
Psoriatic Arthritis
In the first phase III study published for PsA, SELECT-PsA 1(4), patients with inadequate response to at least one conventional oral DMARD were randomly assigned to receive oral UPA at a dose of 15 mg or 30 mg once daily, placebo (PBO) followed by UPA at 15 mg or 30 mg from week 24, or subcutaneous (sc) adalimumab (ADA) at 40 mg every other week. The primary endpoint was at least a 20% improvement according to the American College of Rheumatology criteria (ACR20 response) with UPA compared to PBO at week 12. Both UPA doses were non-inferior to ADA for the ACR20 response at week 12; the 30 mg dose, but not the 15 mg dose, was superior to ADA. 78.5% of patients with UPA 30 mg achieved an ACR20 response, 70.6% with 15 mg, 65% with ADA, and 36.2% with placebo. ACR50 and 70 responses were significantly better with UPA than with PBO but did not differ from ADA.
UPA was also superior to PBO in inhibiting radiographic progression, treating enthesitis and dactylitis, improving skin symptoms, and improving scores on the Health Assessment Questionnaire (HAQ), Short Form 36 (SF-36) physical summary component, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, as well as the proportion of patients achieving minimal disease activity.
Patients reporting clinically meaningful improvements in key patient-reported outcomes (PROs)—fatigue, quality of life, and work productivity—were more likely to achieve stringent disease control measures(5).
Up to week 24, the incidence of adverse events was similar between UPA 15 mg and ADA, but higher with UPA 30 mg. The most common adverse event was upper respiratory tract infection. The incidence of serious infections was 1.2% with UPA 15 mg, 2.6% with UPA 30 mg, 0.9% with placebo, and 0.7% with ADA. Opportunistic infections were rare up to week 24.
Herpes zoster was diagnosed in four patients on UPA 15 mg, five on UPA 30 mg, three on placebo, and none on ADA. Cancer occurred in one patient each in the UPA 15 mg and placebo groups, and in three patients each in the UPA 30 mg and ADA groups. No major adverse cardiovascular events were reported with UPA. One pulmonary embolism occurred with UPA 30 mg; one case of deep vein thrombosis was reported with placebo and two with ADA. Hematological and liver enzyme abnormalities were generally mild. Creatine kinase (CK) was more frequently elevated with UPA, but no cases of rhabdomyolysis were reported. At one-year follow-up, efficacy responses with UPA were sustained or further improved with both doses and were numerically higher than with ADA. Radiographic progression inhibition was maintained at week 56 and was similar with UPA and ADA. Improvements were observed in patients who switched from PBO to UPA. No new safety findings emerged with longer UPA exposure(6).
In SELECT-PsA 2(7), patients who had failed or were intolerant to at least one biologic DMARD were assigned in a 2:2:1:1 ratio to UPA 15 mg, UPA 30 mg, or PBO switched to UPA 15 mg or 30 mg at week 24. At week 12, significantly more patients achieved an ACR20 response in the UPA 15 mg and 30 mg arms compared to placebo (56.9%, 63.8%, and 24.1%, respectively). Differences were already significant by week 2. The ACR20 response rate continued increasing over time in both treatment groups, plateauing at week 12 for UPA 30 mg, while UPA 15 mg responses increased through week 20, approaching the 30 mg group by the end of the placebo-controlled period. From week 2 to week 24, improvements from baseline in all ACR response components were observed with both UPA doses compared to placebo. Significant improvements in ACR50 and ACR70 were also seen with both doses by week 12.
Responses were also favorable for enthesitis, dactylitis, and various PROs. Changes in Disease Activity in PSoriatic Arthritis (DAPSA) scores and the proportion of patients achieving minimal disease activity were also significantly greater with both UPA doses versus placebo. No new safety signals were reported.
At one-year follow-up from SELECT-PsA 2(8), ACR20/50/70 response rates were 59.7/40.8/24.2% with UPA 15 mg and 59.2/38.5/26.6% with UPA 30 mg. PASI 75/90/100 response rates were 52.3/40.8/26.9% and 58.8/47.3/35.1% for UPA 15 mg and 30 mg, respectively. Responses at week 56 in both PBO and UPA groups approached or were similar to those of patients initially receiving UPA. Ten patients developed malignancies in the UPA 15 mg group (including five with non-melanoma skin cancer [NMSC]), and eight patients in the UPA 30 mg group (including four with NMSC).
The prevalence of axial involvement, per investigator assessment, was 31.3% in SELECT-PsA 1 and 34.2% in SELECT-PsA 2. Treatment with UPA 15 mg and 30 mg led to significantly greater improvements in total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI question 2 (neck/back/hip pain), question 3 (swelling/joint pain), and Ankylosing Spondylitis Disease Activity Score C-reactive protein (ASDAS-CRP) scores at weeks 12 and 24 compared to PBO, with numerically higher responses compared to ADA. Similarly, significantly higher proportions of UPA 15 mg and 30 mg patients achieved BASDAI50, inactive disease by ASDAS, low disease activity by ASDAS, major ASDAS improvement, and clinically important ASDAS improvement at weeks 12 and 24 versus PBO. One patient on UPA 30 mg developed incident uveitis. No incident inflammatory bowel disease (IBD) was reported with UPA(9,10).
Regarding enthesitis, post hoc analysis of both pivotal studies showed that UPA 15 mg achieved rapid and complete impact on enthesitis, with a high rate of maintaining an enthesitis-free state after resolution(11). At 3-year follow-up, safety profiles of UPA 15 mg and ADA were generally similar, and the rates of most adverse events were higher with UPA 30 mg compared to ADA, although adverse events leading to drug discontinuation were equal between UPA 30 mg and ADA (7.8 events/100 patient-years) and slightly lower with UPA 15 mg(12).
Thus, UPA has proven effective in PsA, including in patients previously treated with biologics, showing efficacy in joint involvement, enthesitis, dactylitis, and skin symptoms. The 15 mg daily dose (the approved dose) was at least non-inferior to ADA, with a close association between significant improvements in patient-centered outcomes and achievement of tight disease control. Although the 30 mg dose elicited a faster response, long-term responses with 15 mg daily were similar and associated with fewer adverse events. Questions remain regarding its effect on axial involvement in PsA, given the lack of imaging evaluation, but at minimum, patients reported feeling better, and the safety data are favorable.
Ankylosing Spondylitis
In ankylosing spondylitis (AS), its efficacy and safety were evaluated in a phase II/III study published in 2019 (13). Patients from 62 sites in 20 countries (excluding South America) were enrolled in the study. Eligible patients (≥18 years) met the modified New York criteria for AS and had active disease at baseline with an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs), or intolerance or contraindication to receive them. Patients with previous exposure to JAK inhibitors or biological therapy were excluded. Patients with extra-articular manifestations (i.e., psoriasis, uveitis, or IBD) that were not clinically stable for at least 30 days before study entry were also excluded. Patients with total spinal ankylosis were not eligible. Randomization to UPA 15 mg or placebo was stratified by screening CRP concentrations and geographic region. The primary endpoint was the Assessment in Ankylosing Spondylitis 40 (ASAS40) response. 93 patients were assigned to oral UPA 15 mg daily and 94 to placebo. At 14 weeks of follow-up, positive results were observed for UPA in composite disease activity indices such as ASAS, ASDAS, BASDAI, Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), as well as in quality of life assessments and inflammation on MRI of the spine and sacroiliac joints. Regarding work productivity, there was a trend toward greater improvement with UPA, although it did not reach statistical significance at week 14. Differences in ASAS and ASDAS were already significantly different from the first follow-up visit at week 2. In terms of safety, no new safety signals were observed compared to previous studies in RA. 9% of patients on UPA showed elevated CK levels, but none were clinically relevant or required treatment discontinuation. No venous thromboembolic or cardiovascular events were observed, nor any cases of cancer.
Improvement in composite scores ASAS and ASDAS was reflected in each of their individual domains at 14 weeks (14), and among baseline demographic characteristics, being male was associated with better responses measured by ASAS40, ASDAS, and BASDAI50. Notably, body mass index did not influence outcomes, unlike what occurs with TNF-alpha inhibitors (15).
At the 2-year follow-up, UPA showed sustained and consistent efficacy for ASAS40 and other clinically relevant endpoints, achieving, for example, low disease activity and inactive disease rates measured by ASDAS of approximately 80% and 50%, respectively. A low rate of radiographic progression was observed on spinal X-rays, and the response in terms of inflammation on MRIs was persistent. No new safety findings were reported (16).
Thus, UPA in AS is effective, as measured by the various commonly used scores and indices, as well as by MRI changes and low progression of damage on radiographs. Its efficacy in other possible manifestations, such as IBD or uveitis, still needs to be determined.
An important point is safety. JAK inhibitors have been under scrutiny, and evaluations by various drug regulatory agencies of tofacitinib data have led to warnings being extended to UPA due to the similarity in their mechanism of action. The United States Food and Drug Administration (FDA) has limited its authorization for use to patients with AS or PsA who have failed a TNF-alpha inhibitor (see tofacitinib safety section) (17).
Guselkumab
IL-17 plays a relevant role in the development of psoriasis and PsA (18). Th17 cells are differentiated from naïve T cells by the action of three possible cytokine combinations, one of which is IL-6, IL-23, and IL-1β. IL-23 consists of the p40 subunit (which is also a subunit of IL-12, IL-12p40) and the p19 subunit (IL-23p19) and signals through its IL-23R receptor paired with IL-12Rβ1, being necessary for the proliferation and survival of Th17 cells (19).
Some IL-17-producing cells also produce IL-22, but IL-22 expression can also be separately regulated by IL-23, and IL-23-induced IL-22 is essential for the development of enthesitis (20,21). Reports in mice with collagen-induced arthritis showed that loss of the IL-23 gene was protective, while loss of the IL-12 gene exacerbated arthritis (22).
All these findings led to efforts to neutralize only IL-23 without affecting IL-12, with GUSE being one of the products of these efforts. GUSE is a human IgG1λ monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits its downstream signaling. Its half-life is 12 to 19 days (23).
Psoriasis
In psoriasis (PsO), GUSE demonstrated high efficacy in pivotal studies when compared to ADA and PBO. At week 16, the PASI 90 response goal was achieved by 73.3% of patients receiving GUSE, versus 49.7% of patients with ADA and 2.9% with PBO. Even those who did not respond to ADA at week 28 achieved a PASI90 response in 66.1% of cases after switching to GUSE. With these findings, and thanks to the good safety profile demonstrated, GUSE was approved for use in PsO at a dose of 100 mg subcutaneously at weeks 0, 4, and then every 8 weeks (24,25). In the ECLIPSE study, GUSE was directly compared to secukinumab, showing superiority in the PASI90 response index at 48 weeks (26). This superiority was also observed in the subgroup of patients who reported having PsA (27).
In various meta-analyses published since then, GUSE is positioned among the most effective medications for combating skin and nail psoriasis involvement (28,29).
Psoriatic Arthritis
In 2018, a phase II study in PsA demonstrated the efficacy of GUSE at the same dose approved for psoriasis, comparing 100 patients treated with GUSE to 49 treated with placebo. The rates of ACR20, ACR50, and ACR70 responses were statistically significantly higher in the GUSE group. Although infections and elevated liver transaminases were the most common adverse events, their frequency was low, and only one serious adverse event (myocardial infarction) occurred in the first 24 weeks in the GUSE-treated group. Notably, 5 patients (5 %) in the GUSE group developed neutropenia, with no cases in the placebo group; only one was grade 3 and led to discontinuation of guselkumab, resolving without further intervention (30). Enthesitis and dactylitis also improved more frequently in the GUSE group (31). While all composite indices improved and significantly more patients reached low disease activity with GUSE, residual non-articular involvement was more prominent among those achieving low disease activity according to DAPSA versus other indices (32).
In the first phase III trial, DISCOVER‑1, 128 patients received GUSE 100 mg every 4 weeks, another 128 received 100 mg at weeks 0 and 4 followed by every 8 weeks, and 126 received placebo. Approximately 30 % had previous TNF‑alpha inhibitor exposure. The primary endpoint, ACR20 at week 24, was reached in 59 % of patients who received GUSE every 4 weeks, 52 % in the every‑8‑weeks group, and 22 % in the placebo group. There was a trend to lower response in the 8‑weekly group, and no significant difference versus placebo in ACR70 at week 24. Prior TNF‑alpha inhibitor exposure did not explain these differences (33).
In DISCOVER‑2 (34), which enrolled a larger number of biologic‑naïve patients, 245 received GUSE every 4 weeks, 248 on the week 0/4 then 8‑weekly regimen, and 246 received placebo. ACR20 at week 24 was significantly higher in both GUSE groups (64 %) versus placebo (33 %). No differences were observed in deeper responses between dosing regimens: ACR70 was achieved in 13 % (4‑weekly), 19 % (8‑weekly), and 4 % (placebo). Notably, only the 4‑weekly regimen showed significantly reduced radiographic progression, with smaller changes in the van der Heijde Modified Sharp (vdHS) score at week 24 compared to placebo.
In both studies, resolution of enthesitis, dactylitis, and fatigue occurred significantly more often in GUSE‑treated groups than placebo (35–37). During the first year of follow‑up, no active tuberculosis, opportunistic infections, or IBD were observed; rates of malignancy and serious cardiovascular events remained low. Injection‑site reactions occurred in 1–2 % of patients, and antibodies to GUSE were detected in 4.5 % during the first year—most non‑neutralizing. Transient mild elevations in hepatic transaminases (more common with the 4‑weekly dose) and neutrophil count decreases were generally mild and did not require discontinuation, with minimal change from week 24 to week 60 follow‑up (38).
Efficacy outcomes at week 52 and safety outcomes at week 60 confirmed that the significant improvements in joint symptoms, skin disease, physical function, and quality of life at week 24 were maintained in both patients with and without prior TNF‑alpha inhibitor exposure. The Minimal Disease Activity (MDA) achieved about 30 % of patients by week 52. For both GUSE dosing regimens, the one‑year safety profile in PsA patients was consistent with that observed at week 24 and in PsO patients treated with GUSE (37,39). A network meta‑analysis comparing GUSE with other available treatments for PsA showed favorable efficacy in arthritis, comparable to IL‑17 antagonists and TNF‑alpha inhibitors, along with better PASI responses and a higher safety profile relative to many other treatments (40).
A post‑hoc analyses of DISCOVER‑1 and DISCOVER‑2 revealed that PsA patients with active disease and imaging‑confirmed sacroiliitis treated with GUSE (every 4 or 8 weeks) experienced greater mean improvement in BASDAI and ASDAS by week 8 than placebo, with sustained improvement at week 52 (41). These results have been questioned due to lack of objective measures of inflammatory resolution and negative results for other IL‑23 inhibitors in AS (42). In a phase 3b placebo‑controlled study of PsA patients with inadequate response to 1 or 2 TNF inhibitors, GUSE 100 mg every 8 weeks (the approved PsA regimen) achieved significantly higher ACR20 at week 24 versus placebo. Safety was consistent with the favorable profile observed in PsO and biologic‑naïve PsA patients (43).
Thus, GUSE has demonstrated efficacy in PsO and PsA, with competitive responses in peripheral arthritis, enthesitis, and dactylitis, and possible benefit in axial involvement. It stands out for high skin efficacy and excellent safety profile. Further studies are needed to assess efficacy in broader manifestations, including uveitis and IBD.
Tofacitinib
Tofacitinib (TOFA) is a JAK inhibitor (JAKi) currently used in the treatment of conditions such as RA, PsA, AS, and ulcerative colitis (UC). Tofacitinib preferentially inhibits JAK3- and JAK1-dependent signaling.
Psoriatic Arthritis
The OPAL Broaden(44) and OPAL Beyond(45) studies, which evaluated the use of TOFA, 5 or 10 mg twice daily, in patients with PsA who had failed conventional DMARD therapy and TNF-alpha inhibitors, demonstrated that TOFA is superior to PBO at 3 months of treatment for peripheral arthritis, and that this response was maintained at 6 months. Regarding response times in terms of functional capacity and disease activity, these were similar in patients treated with TOFA and ADA(44).
TOFA also showed a superior response to placebo in the resolution of enthesitis and dactylitis at 3 months, which was maintained at 6 months in patients who had failed conventional and biological DMARDs(44,45). Effectiveness was assessed by changes in dactylitis severity score (DSS), the Leeds Enthesitis Index (LEI), and the SPARCC Enthesitis Index. Both 5 and 10 mg twice daily resulted in improvements in enthesitis, except for the SPARCC Enthesitis Index at the 5 mg twice daily dose, where no statistically significant difference was found compared to PBO.
A greater proportion of patients who received TOFA 5 and 10 mg twice daily achieved PASI 75 response versus PBO at 3 months. The PASI 75 response rate was numerically higher in patients who received 10 mg versus 5 mg twice daily. Furthermore, patients who received TOFA showed improvements in the Dermatology Life Quality Index (DLQI)(46,47). Subsequent analyses of the Opal Broaden and Opal Beyond studies showed that although 41.4% of PsA patients had baseline metabolic syndrome, the group receiving TOFA did not show worsening of these values(48). Additionally, an increase in both LDL and HDL cholesterol was observed at 3 months regardless of the presence of metabolic syndrome, which did not result in an increased incidence of major cardiovascular events(49).
Patients treated with TOFA showed greater effectiveness than PBO regardless of body mass index (BMI), but a decrease in effectiveness was observed in patients with a BMI >35 kg/m²(50).
Ankylosing Spondylitis
In a Phase II study published in 2017(51), which lasted 16 weeks, patients received TOFA 2, 5, or 10 mg twice daily. The primary endpoint was the ASAS20 response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes, and MRI of the sacroiliac joints and spine. TOFA 5 and 10 mg twice daily demonstrated greater clinical efficacy than placebo in reducing signs, symptoms, and objective endpoints of active AS in adult patients, with a 12-week safety profile similar to that reported for other indications. In a Phase III study published in 2021(52), it was shown that in adults with active AS, TOFA 5 mg twice daily had significantly greater efficacy than placebo, with an ASAS20 response of 56.4% vs. 29.4% at 12 weeks, and no new potential safety risks were identified. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events, or opportunistic infections.
Safety
Regarding safety, it is worth specifically mentioning studies in other diseases due to recent warnings from some regulatory agencies. A meta-analysis of 30 randomized controlled trials in RA patients treated with TOFA showed no significant differences in major cardiovascular (CV) events(53). However, the ORAL Surveillance safety study, which included patients aged 50 or older with at least one CV risk factor, recently published its results, showing a higher occurrence of CV events, thrombotic events, and infections in patients treated with TOFA compared to those treated with TNF-alpha inhibitors(54). For this reason, the FDA and the European Medicines Agency (EMA) required a warning to be published regarding the risks of TOFA, indicating that the review of final results showed a higher rate of serious cardiac events such as heart attack and stroke, cancer, blood clots, and death in patients treated with both doses of TOFA (5 or 10 mg twice daily) compared to those treated with TNF-alpha inhibitors.
For cancers, a higher rate of lymphomas and a higher rate of lung cancers were observed in current or former smokers, and this same group had an additional risk of developing cancer in general(17). Based on all this, the FDA issued warnings about the use of TOFA and only approves its use in AS and PsA when a TNF-alpha inhibitor has failed(17).
EMA recommended that TOFA be used with caution in all patients at high risk of blood clots and that the maintenance dose of 10 mg twice daily should not be used in UC patients with a high risk of blood clots unless no suitable alternative treatment exists. In addition, due to the increased risk of infections, EMA recommended that patients over 65 years of age should only be treated with TOFA when no alternative treatment exists(55).
Data on maternal or paternal prenatal exposure to TOFA are limited but appear to show no increased risks in pregnancy and newborn outcomes compared to the general population; however, there is currently no FDA or EMA approval for its use during pregnancy and lactation(56).
Guselkumab, tofacitinib, and upadacitinib are new and effective options for the treatment of PsA and AS, diseases in which there is still room to optimize current therapeutic regimens. Each of these options has strengths and weaknesses (Table 1). For example, JAK inhibitors are oral, with good efficacy data for articular involvement, and tofacitinib is approved for use in UC; however, concerns about adverse effects have led regulatory agencies to advise caution in the use of this class of drugs (although preliminary data suggest that upadacitinib may have a better safety profile than tofacitinib). In contrast, guselkumab stands out for its high efficacy in PsO, excellent safety profile, but it lacks data supporting its use in AS, a disease that has classically shown no response to IL-23 inhibitors(57).
For all these new options, further analysis is needed to determine which patient groups will benefit most from each therapy. For example, more data are needed on efficacy in IBD and uveitis, comparative effectiveness when enthesitis is predominant, objective assessment of axial involvement in PsA, and clearer information on safety during pregnancy and lactation. However, given the multiple manifestations of PsA and AS, and the significant percentage of patients who remain with active disease despite using various medications, these alternatives undoubtedly have an important role in the treatment algorithm. For instance, JAK inhibitors are a valuable option for patients with an inadequate response to one or more biologics, both in PsA and AS, for those who prefer oral medications, and TOFA may also benefit those who additionally suffer from UC. Although safety warnings regarding JAK inhibitors require close monitoring, it is important to note that most of these alerts are based on data from RA patients treated with TOFA, with a better safety profile observed in PsA and AS(58,59). GUSE is an option that can be considered as a first-line treatment in PsA with significant skin involvement and, due to its favorable safety profile, in more fragile patients, although with the current data, close monitoring is advised in those with axial involvement.
It is important for rheumatologists to remain aware of the strengths and weaknesses of the multiple treatment options currently available for PsA and AS in order to treat our patients in the most personalized, effective, and safe way possible.
Sebastián Ibáñez, speaker and Advisory Board member for Abbvie, Novartis, Fresenius Kabi; speaker for Janssen, Bristol Myers Squibb.
The authors received no financial support for the research, authorship, or publication of this article.
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