Psoriatic Arthritis ICYMI

Key clinical point: No clinically meaningful treatment-related differences were observed in the efficacy, safety, and treatment persistence of ustekinumab over 3 years in younger (<60 years) and older (≥60 years) patients with psoriatic arthritis (PsA).

Major finding: At 6 months, 51.7% and 43.8% of patients aged <60 and ≥60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity, respectively, with the efficacy being maintained through 36 months. The proportions of patients reporting at least one (32.7% vs 40.9%) and serious (5.3% vs 9.6%) adverse events and treatment persistence were not significantly different among patients age < 60 vs ≥ 60 years.

Study details: This post hoc analysis of the PsABio trial included patients with PsA who received ustekinumab and were subgrouped into those age < 60 years (n = 336) and ≥ 60 years (n = 103).

Disclosures: This study was sponsored by Janssen. Six authors declared being current or former employees of Janssen or shareholders of Johnson & Johnson. Three authors reported ties with various sources, including Janssen.

Source: Gossec L et al. Response to treatment in psoriatic arthritis, the effect of age: analysis of patients receiving ustekinumab in the PsABio real-world study. Arthritis Res Ther. 2023;25:100 (Jun 9). doi: 10.1186/s13075-023-03078-8

Key clinical point: No clinically meaningful treatment-related differences were observed in the efficacy, safety, and treatment persistence of ustekinumab over 3 years in younger (<60 years) and older (≥60 years) patients with psoriatic arthritis (PsA).

Major finding: At 6 months, 51.7% and 43.8% of patients aged <60 and ≥60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity, respectively, with the efficacy being maintained through 36 months. The proportions of patients reporting at least one (32.7% vs 40.9%) and serious (5.3% vs 9.6%) adverse events and treatment persistence were not significantly different among patients age < 60 vs ≥ 60 years.

Study details: This post hoc analysis of the PsABio trial included patients with PsA who received ustekinumab and were subgrouped into those age < 60 years (n = 336) and ≥ 60 years (n = 103).

Disclosures: This study was sponsored by Janssen. Six authors declared being current or former employees of Janssen or shareholders of Johnson & Johnson. Three authors reported ties with various sources, including Janssen.

Source: Gossec L et al. Response to treatment in psoriatic arthritis, the effect of age: analysis of patients receiving ustekinumab in the PsABio real-world study. Arthritis Res Ther. 2023;25:100 (Jun 9). doi: 10.1186/s13075-023-03078-8

Key clinical point: No clinically meaningful treatment-related differences were observed in the efficacy, safety, and treatment persistence of ustekinumab over 3 years in younger (<60 years) and older (≥60 years) patients with psoriatic arthritis (PsA).

Major finding: At 6 months, 51.7% and 43.8% of patients aged <60 and ≥60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity, respectively, with the efficacy being maintained through 36 months. The proportions of patients reporting at least one (32.7% vs 40.9%) and serious (5.3% vs 9.6%) adverse events and treatment persistence were not significantly different among patients age < 60 vs ≥ 60 years.

Study details: This post hoc analysis of the PsABio trial included patients with PsA who received ustekinumab and were subgrouped into those age < 60 years (n = 336) and ≥ 60 years (n = 103).

Disclosures: This study was sponsored by Janssen. Six authors declared being current or former employees of Janssen or shareholders of Johnson & Johnson. Three authors reported ties with various sources, including Janssen.

Source: Gossec L et al. Response to treatment in psoriatic arthritis, the effect of age: analysis of patients receiving ustekinumab in the PsABio real-world study. Arthritis Res Ther. 2023;25:100 (Jun 9). doi: 10.1186/s13075-023-03078-8

Key clinical point: Apremilast led to a significant improvement in enthesitis and dactylitis activity among patients with psoriatic arthritis (PsA) presenting with enthesitis and dactylitis phenotypes, with more than one-third of patients achieving remission after 1 year of treatment.

Major finding: After 6 and 12 months of apremilast treatment, remission was achieved by 25% and 34% of patients with enthesitis and 47% and 44% of patients with dactylitis, respectively, with significant improvements in the Leeds Enthesitis and Dactylitis Indexes (P < .001).

Study details: Findings are from a retrospective study including patients with PsA who presented with either enthesitis (n = 118) or dactylitis (n = 96) phenotype and received apremilast.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Source: Lo Gullo A et al. Therapeutic effects of apremilast on enthesitis and dactylitis in real clinical setting: An Italian multicenter study. J Clin Med. 2023;12:3892 (Jun 7). doi: 10.3390/jcm12123892

Key clinical point: Apremilast led to a significant improvement in enthesitis and dactylitis activity among patients with psoriatic arthritis (PsA) presenting with enthesitis and dactylitis phenotypes, with more than one-third of patients achieving remission after 1 year of treatment.

Major finding: After 6 and 12 months of apremilast treatment, remission was achieved by 25% and 34% of patients with enthesitis and 47% and 44% of patients with dactylitis, respectively, with significant improvements in the Leeds Enthesitis and Dactylitis Indexes (P < .001).

Study details: Findings are from a retrospective study including patients with PsA who presented with either enthesitis (n = 118) or dactylitis (n = 96) phenotype and received apremilast.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Source: Lo Gullo A et al. Therapeutic effects of apremilast on enthesitis and dactylitis in real clinical setting: An Italian multicenter study. J Clin Med. 2023;12:3892 (Jun 7). doi: 10.3390/jcm12123892

Key clinical point: Apremilast led to a significant improvement in enthesitis and dactylitis activity among patients with psoriatic arthritis (PsA) presenting with enthesitis and dactylitis phenotypes, with more than one-third of patients achieving remission after 1 year of treatment.

Major finding: After 6 and 12 months of apremilast treatment, remission was achieved by 25% and 34% of patients with enthesitis and 47% and 44% of patients with dactylitis, respectively, with significant improvements in the Leeds Enthesitis and Dactylitis Indexes (P < .001).

Study details: Findings are from a retrospective study including patients with PsA who presented with either enthesitis (n = 118) or dactylitis (n = 96) phenotype and received apremilast.

Disclosures: This study received no external funding. The authors declared no conflicts of interest.

Source: Lo Gullo A et al. Therapeutic effects of apremilast on enthesitis and dactylitis in real clinical setting: An Italian multicenter study. J Clin Med. 2023;12:3892 (Jun 7). doi: 10.3390/jcm12123892

Key clinical point: Axial spondyloarthritis (axSpA) with or without concomitant psoriasis and axial psoriatic arthritis (PsA) appear distinct entities based on marked demographic, clinical, and genetic differences.

Major finding: Patients with axial PsA vs axSpA with or without psoriasis were older at symptom onset (48.6 vs 44.7 or 41.4 years, respectively; P < .001), had a higher prevalence of dactylitis (43.2% vs 18.3% or 8.4%, respectively; P < .001) and peripheral arthritis (86.7% vs 58.1% or 44.3%, respectively; P < .001), and were less frequently HLA-B27 positive (22.3% vs 55.4% or 65.5%, respectively; P < .001).

Study details: This study included 5208 patients with axSpA (with or without psoriasis) and 2771 with PsA (axial or peripheral arthritis) from the Swiss Clinical Quality Management (SCQM) registry.

Disclosures: This study was funded by Eli Lilly. Two authors declared being employees of SCQM with salary partly financed by Eli Lilly. Several authors declared receiving honoraria, speaking or consulting fees, research grants, or other financial support from various sources, including Lilly and other SCQM supporters. Two authors declared no conflicts of interest.

Source: Ciurea A et al. Characterisation of patients with axial psoriatic arthritis and patients with axial spondyloarthritis and concomitant psoriasis in the SCQM registry. RMD Open. 2023;9:e002956 (Jun 5). doi: 10.1136/rmdopen-2022-002956

Key clinical point: Axial spondyloarthritis (axSpA) with or without concomitant psoriasis and axial psoriatic arthritis (PsA) appear distinct entities based on marked demographic, clinical, and genetic differences.

Major finding: Patients with axial PsA vs axSpA with or without psoriasis were older at symptom onset (48.6 vs 44.7 or 41.4 years, respectively; P < .001), had a higher prevalence of dactylitis (43.2% vs 18.3% or 8.4%, respectively; P < .001) and peripheral arthritis (86.7% vs 58.1% or 44.3%, respectively; P < .001), and were less frequently HLA-B27 positive (22.3% vs 55.4% or 65.5%, respectively; P < .001).

Study details: This study included 5208 patients with axSpA (with or without psoriasis) and 2771 with PsA (axial or peripheral arthritis) from the Swiss Clinical Quality Management (SCQM) registry.

Disclosures: This study was funded by Eli Lilly. Two authors declared being employees of SCQM with salary partly financed by Eli Lilly. Several authors declared receiving honoraria, speaking or consulting fees, research grants, or other financial support from various sources, including Lilly and other SCQM supporters. Two authors declared no conflicts of interest.

Source: Ciurea A et al. Characterisation of patients with axial psoriatic arthritis and patients with axial spondyloarthritis and concomitant psoriasis in the SCQM registry. RMD Open. 2023;9:e002956 (Jun 5). doi: 10.1136/rmdopen-2022-002956

Key clinical point: Axial spondyloarthritis (axSpA) with or without concomitant psoriasis and axial psoriatic arthritis (PsA) appear distinct entities based on marked demographic, clinical, and genetic differences.

Major finding: Patients with axial PsA vs axSpA with or without psoriasis were older at symptom onset (48.6 vs 44.7 or 41.4 years, respectively; P < .001), had a higher prevalence of dactylitis (43.2% vs 18.3% or 8.4%, respectively; P < .001) and peripheral arthritis (86.7% vs 58.1% or 44.3%, respectively; P < .001), and were less frequently HLA-B27 positive (22.3% vs 55.4% or 65.5%, respectively; P < .001).

Study details: This study included 5208 patients with axSpA (with or without psoriasis) and 2771 with PsA (axial or peripheral arthritis) from the Swiss Clinical Quality Management (SCQM) registry.

Disclosures: This study was funded by Eli Lilly. Two authors declared being employees of SCQM with salary partly financed by Eli Lilly. Several authors declared receiving honoraria, speaking or consulting fees, research grants, or other financial support from various sources, including Lilly and other SCQM supporters. Two authors declared no conflicts of interest.

Source: Ciurea A et al. Characterisation of patients with axial psoriatic arthritis and patients with axial spondyloarthritis and concomitant psoriasis in the SCQM registry. RMD Open. 2023;9:e002956 (Jun 5). doi: 10.1136/rmdopen-2022-002956

Key clinical point: Etanercept was safe and effective with low rates of adverse events and led to better clinical outcomes in children with juvenile psoriatic arthritis (JPsA).

Major finding: The overall incidence of adverse events of special interest and serious adverse events were low and included 3 cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), 1 of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and 1 of malignancy (IR/100 person-years 0.13; 95% CI 0.02-0.90). The American College of Rheumatology provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6- and 12-month follow-ups.

Study details: This study included 226 patients with JPsA (aged ≥2 to <18 years) who received etanercept.

Disclosures: This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc. S Stryker and D Collier declared being employees of and owning stocks in Amgen. SJ Balevic and T Beukelman declared receiving grants or research support, honoraria, or consulting fees or participating in data safety monitoring boards for various sources. The other authors declared no conflicts of interest.

Source: Correll CK et al. Occurrence of adverse events and change in disease activity after initiation of etanercept in paediatric patients with juvenile psoriatic arthritis in the CARRA Registry. RMD Open. 2023;9:e002943 (May 25). doi: 10.1136/rmdopen-2022-002943

Key clinical point: Etanercept was safe and effective with low rates of adverse events and led to better clinical outcomes in children with juvenile psoriatic arthritis (JPsA).

Major finding: The overall incidence of adverse events of special interest and serious adverse events were low and included 3 cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), 1 of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and 1 of malignancy (IR/100 person-years 0.13; 95% CI 0.02-0.90). The American College of Rheumatology provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6- and 12-month follow-ups.

Study details: This study included 226 patients with JPsA (aged ≥2 to <18 years) who received etanercept.

Disclosures: This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc. S Stryker and D Collier declared being employees of and owning stocks in Amgen. SJ Balevic and T Beukelman declared receiving grants or research support, honoraria, or consulting fees or participating in data safety monitoring boards for various sources. The other authors declared no conflicts of interest.

Source: Correll CK et al. Occurrence of adverse events and change in disease activity after initiation of etanercept in paediatric patients with juvenile psoriatic arthritis in the CARRA Registry. RMD Open. 2023;9:e002943 (May 25). doi: 10.1136/rmdopen-2022-002943

Key clinical point: Etanercept was safe and effective with low rates of adverse events and led to better clinical outcomes in children with juvenile psoriatic arthritis (JPsA).

Major finding: The overall incidence of adverse events of special interest and serious adverse events were low and included 3 cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), 1 of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and 1 of malignancy (IR/100 person-years 0.13; 95% CI 0.02-0.90). The American College of Rheumatology provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6- and 12-month follow-ups.

Study details: This study included 226 patients with JPsA (aged ≥2 to <18 years) who received etanercept.

Disclosures: This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc. S Stryker and D Collier declared being employees of and owning stocks in Amgen. SJ Balevic and T Beukelman declared receiving grants or research support, honoraria, or consulting fees or participating in data safety monitoring boards for various sources. The other authors declared no conflicts of interest.

Source: Correll CK et al. Occurrence of adverse events and change in disease activity after initiation of etanercept in paediatric patients with juvenile psoriatic arthritis in the CARRA Registry. RMD Open. 2023;9:e002943 (May 25). doi: 10.1136/rmdopen-2022-002943

Key clinical point: Patients with newly diagnosed psoriatic arthritis (PsA) and rheumatoid arthritis (RA) who initiated methotrexate showed similar rates of methotrexate retention; however, the addition of any other disease-modifying antirheumatic drugs (DMARD) to the treatment regimen was more rapid in RA vs PsA.

Major finding: Overall, 71% of patients with PsA and 76% of patients with RA remained on methotrexate at 2 years after initiating methotrexate. The risk for adding any other DMARD to the treatment regimen was greater in the RA vs PsA group (adjusted hazard ratio 0.86; 95% CI 0.77-0.96), with methotrexate monotherapy improving disease activity in both the groups.

Study details: This observational study included DMARD-naive patients with newly diagnosed PsA (n = 3642) who initiated methotrexate and matched comparator patients with RA (n = 3642).

Disclosures: This study was funded by grants from the Swedish Rheumatism Association and others. Some authors declared serving as consultants or receiving lecture fees, speakers’ bureau fees, or research support from various sources.

Source: Lindström U et al. Methotrexate treatment in early psoriatic arthritis in comparison to rheumatoid arthritis: An observational nationwide study. RMD Open. 2023;9:e002883 (May 12). doi: 10.1136/rmdopen-2022-002883

Key clinical point: Patients with newly diagnosed psoriatic arthritis (PsA) and rheumatoid arthritis (RA) who initiated methotrexate showed similar rates of methotrexate retention; however, the addition of any other disease-modifying antirheumatic drugs (DMARD) to the treatment regimen was more rapid in RA vs PsA.

Major finding: Overall, 71% of patients with PsA and 76% of patients with RA remained on methotrexate at 2 years after initiating methotrexate. The risk for adding any other DMARD to the treatment regimen was greater in the RA vs PsA group (adjusted hazard ratio 0.86; 95% CI 0.77-0.96), with methotrexate monotherapy improving disease activity in both the groups.

Study details: This observational study included DMARD-naive patients with newly diagnosed PsA (n = 3642) who initiated methotrexate and matched comparator patients with RA (n = 3642).

Disclosures: This study was funded by grants from the Swedish Rheumatism Association and others. Some authors declared serving as consultants or receiving lecture fees, speakers’ bureau fees, or research support from various sources.

Source: Lindström U et al. Methotrexate treatment in early psoriatic arthritis in comparison to rheumatoid arthritis: An observational nationwide study. RMD Open. 2023;9:e002883 (May 12). doi: 10.1136/rmdopen-2022-002883

Key clinical point: Patients with newly diagnosed psoriatic arthritis (PsA) and rheumatoid arthritis (RA) who initiated methotrexate showed similar rates of methotrexate retention; however, the addition of any other disease-modifying antirheumatic drugs (DMARD) to the treatment regimen was more rapid in RA vs PsA.

Major finding: Overall, 71% of patients with PsA and 76% of patients with RA remained on methotrexate at 2 years after initiating methotrexate. The risk for adding any other DMARD to the treatment regimen was greater in the RA vs PsA group (adjusted hazard ratio 0.86; 95% CI 0.77-0.96), with methotrexate monotherapy improving disease activity in both the groups.

Study details: This observational study included DMARD-naive patients with newly diagnosed PsA (n = 3642) who initiated methotrexate and matched comparator patients with RA (n = 3642).

Disclosures: This study was funded by grants from the Swedish Rheumatism Association and others. Some authors declared serving as consultants or receiving lecture fees, speakers’ bureau fees, or research support from various sources.

Source: Lindström U et al. Methotrexate treatment in early psoriatic arthritis in comparison to rheumatoid arthritis: An observational nationwide study. RMD Open. 2023;9:e002883 (May 12). doi: 10.1136/rmdopen-2022-002883

Key clinical point: Brepocitinib, the tyrosine kinase 2/Janus kinase 1 inhibitor, was superior to placebo in reducing signs and symptoms of psoriatic arthritis (PsA) and was well-tolerated throughout the 52-week study period.

Major finding: At week 16, American College of Rheumatology 20 response was achieved by a significantly higher proportion of patients receiving brepocitinib at doses of 30 mg (66.7%; P = .0197) and 60 mg (74.6%; P = .0006) compared with placebo (43.3%), with the response being maintained through week 52. Overall, 12 serious adverse events were reported in the brepocitinib arms (30 and 60 mg) by week 52. No deaths were reported.

Study details: Findings are from a phase 2b, dose-ranging, parallel treatment group trial including 218 patients with active PsA who were randomly assigned to receive either brepocitinib (60, 30, or 10 mg once daily) or placebo.

Disclosures: This study was sponsored by Pfizer Inc. Several authors declared being current or former employees and shareholders of Pfizer. The other authors reported ties with various sources, including Pfizer.

Source: Mease P et al. Efficacy and safety of tyrosine kinase 2/Janus kinase 1 Inhibitor brepocitinib for active psoriatic arthritis: A phase IIb randomized controlled trial. Arthritis Rheumatol. 2023 (May 17). doi: 10.1002/art.42519

Key clinical point: Brepocitinib, the tyrosine kinase 2/Janus kinase 1 inhibitor, was superior to placebo in reducing signs and symptoms of psoriatic arthritis (PsA) and was well-tolerated throughout the 52-week study period.

Major finding: At week 16, American College of Rheumatology 20 response was achieved by a significantly higher proportion of patients receiving brepocitinib at doses of 30 mg (66.7%; P = .0197) and 60 mg (74.6%; P = .0006) compared with placebo (43.3%), with the response being maintained through week 52. Overall, 12 serious adverse events were reported in the brepocitinib arms (30 and 60 mg) by week 52. No deaths were reported.

Study details: Findings are from a phase 2b, dose-ranging, parallel treatment group trial including 218 patients with active PsA who were randomly assigned to receive either brepocitinib (60, 30, or 10 mg once daily) or placebo.

Disclosures: This study was sponsored by Pfizer Inc. Several authors declared being current or former employees and shareholders of Pfizer. The other authors reported ties with various sources, including Pfizer.

Source: Mease P et al. Efficacy and safety of tyrosine kinase 2/Janus kinase 1 Inhibitor brepocitinib for active psoriatic arthritis: A phase IIb randomized controlled trial. Arthritis Rheumatol. 2023 (May 17). doi: 10.1002/art.42519

Key clinical point: Brepocitinib, the tyrosine kinase 2/Janus kinase 1 inhibitor, was superior to placebo in reducing signs and symptoms of psoriatic arthritis (PsA) and was well-tolerated throughout the 52-week study period.

Major finding: At week 16, American College of Rheumatology 20 response was achieved by a significantly higher proportion of patients receiving brepocitinib at doses of 30 mg (66.7%; P = .0197) and 60 mg (74.6%; P = .0006) compared with placebo (43.3%), with the response being maintained through week 52. Overall, 12 serious adverse events were reported in the brepocitinib arms (30 and 60 mg) by week 52. No deaths were reported.

Study details: Findings are from a phase 2b, dose-ranging, parallel treatment group trial including 218 patients with active PsA who were randomly assigned to receive either brepocitinib (60, 30, or 10 mg once daily) or placebo.

Disclosures: This study was sponsored by Pfizer Inc. Several authors declared being current or former employees and shareholders of Pfizer. The other authors reported ties with various sources, including Pfizer.

Source: Mease P et al. Efficacy and safety of tyrosine kinase 2/Janus kinase 1 Inhibitor brepocitinib for active psoriatic arthritis: A phase IIb randomized controlled trial. Arthritis Rheumatol. 2023 (May 17). doi: 10.1002/art.42519

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

A version of this article originally appeared on Medscape.com.

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

A version of this article originally appeared on Medscape.com.

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

A version of this article originally appeared on Medscape.com.

The relationship between enthesitis and synovitis is of considerable interest to both clinicians and researchers. This relationship is best evaluated using imaging, particularly ultrasonography, and could provide pathophysiologic insights. Balulu and colleagues recruited 158 patients with PsA who underwent sonographic assessment of 52 joints, 40 tendons, and 14 entheses as well as clinical evaluation. Overall, total sonographic enthesitis scores were significantly associated with total sonographic synovitis and sonographic tenosynovitis scores and also with older age, male sex, swollen joint count, C-reactive protein, physical occupation, and patient-reported outcomes. The association between enthesitis and synovitis was also demonstrated at the elbows, knees, and ankles. This study demonstrates that psoriatic enthesitis and synovitis are closely related and thus may share pathophysiologic mechanisms. Longitudinal studies in very early PsA using ultrasound might provide clues to confirm the hypothesis that psoriatic synovitis is secondary to enthesitis.

Another important domain that is increasingly studied is axial PsA. Currently, the evidence for treatment of axial PsA is extrapolated from that for axial spondyloarthritis (SpA), in the belief that the two diseases are pathophysiologically similar. However, there is increasing evidence for differences between axial PsA and axial SpA that might influence the choice of treatment. In a recent study, de Hooge and colleagues demonstrated that patients with axial PsA have lower severity of damage to the spine compared with those with axial SpA. Using data from 312 patients with PsA and 213 patients with SpA who underwent radiographic imaging assessment in the Belgian Epidemiological Psoriatic Arthritis Study (BEPAS) and the Ghent and Belgian Inflammatory Arthritis and Spondylitis (Be-GIANT) study, respectively, they show that the proportion of patients with PsA vs SpA having spinal damage was comparable. Patients with SpA and spinal damage had higher modified Stoke Ankylosing Spondylitis Spine Scores, indicating more severe damage. These results are consistent with other published studies and indicate that patients with PsA have less severe spinal disease compared with other patients with axial SpA. Randomized controlled trials (RCTs) specifically investigating the treatment of axial PsA are currently underway. Nevertheless, post hoc analyses of data from PsA RCTs indicate that most drugs efficacious for PsA overall also provide benefit in axial disease.

In a recent report, Baraliakos and colleagues analyzed data from the SELECT-PsA 1 and SELECT-PsA 2 trials that evaluated the efficacy of upadacitinib in PsA. They show that, compared with placebo, 15 mg upadacitinib led to a greater improvement in axial symptoms. The improvement in overall Bath Ankylosing Spondylitis Disease Activity Index score at week 24 was significantly higher with 15 mg upadacitinib compared with placebo in both trials. However, these results are not definitive because there is yet no consensus on the definition of and outcome measures for axial PsA.

The relationship between enthesitis and synovitis is of considerable interest to both clinicians and researchers. This relationship is best evaluated using imaging, particularly ultrasonography, and could provide pathophysiologic insights. Balulu and colleagues recruited 158 patients with PsA who underwent sonographic assessment of 52 joints, 40 tendons, and 14 entheses as well as clinical evaluation. Overall, total sonographic enthesitis scores were significantly associated with total sonographic synovitis and sonographic tenosynovitis scores and also with older age, male sex, swollen joint count, C-reactive protein, physical occupation, and patient-reported outcomes. The association between enthesitis and synovitis was also demonstrated at the elbows, knees, and ankles. This study demonstrates that psoriatic enthesitis and synovitis are closely related and thus may share pathophysiologic mechanisms. Longitudinal studies in very early PsA using ultrasound might provide clues to confirm the hypothesis that psoriatic synovitis is secondary to enthesitis.

Another important domain that is increasingly studied is axial PsA. Currently, the evidence for treatment of axial PsA is extrapolated from that for axial spondyloarthritis (SpA), in the belief that the two diseases are pathophysiologically similar. However, there is increasing evidence for differences between axial PsA and axial SpA that might influence the choice of treatment. In a recent study, de Hooge and colleagues demonstrated that patients with axial PsA have lower severity of damage to the spine compared with those with axial SpA. Using data from 312 patients with PsA and 213 patients with SpA who underwent radiographic imaging assessment in the Belgian Epidemiological Psoriatic Arthritis Study (BEPAS) and the Ghent and Belgian Inflammatory Arthritis and Spondylitis (Be-GIANT) study, respectively, they show that the proportion of patients with PsA vs SpA having spinal damage was comparable. Patients with SpA and spinal damage had higher modified Stoke Ankylosing Spondylitis Spine Scores, indicating more severe damage. These results are consistent with other published studies and indicate that patients with PsA have less severe spinal disease compared with other patients with axial SpA. Randomized controlled trials (RCTs) specifically investigating the treatment of axial PsA are currently underway. Nevertheless, post hoc analyses of data from PsA RCTs indicate that most drugs efficacious for PsA overall also provide benefit in axial disease.

In a recent report, Baraliakos and colleagues analyzed data from the SELECT-PsA 1 and SELECT-PsA 2 trials that evaluated the efficacy of upadacitinib in PsA. They show that, compared with placebo, 15 mg upadacitinib led to a greater improvement in axial symptoms. The improvement in overall Bath Ankylosing Spondylitis Disease Activity Index score at week 24 was significantly higher with 15 mg upadacitinib compared with placebo in both trials. However, these results are not definitive because there is yet no consensus on the definition of and outcome measures for axial PsA.

The relationship between enthesitis and synovitis is of considerable interest to both clinicians and researchers. This relationship is best evaluated using imaging, particularly ultrasonography, and could provide pathophysiologic insights. Balulu and colleagues recruited 158 patients with PsA who underwent sonographic assessment of 52 joints, 40 tendons, and 14 entheses as well as clinical evaluation. Overall, total sonographic enthesitis scores were significantly associated with total sonographic synovitis and sonographic tenosynovitis scores and also with older age, male sex, swollen joint count, C-reactive protein, physical occupation, and patient-reported outcomes. The association between enthesitis and synovitis was also demonstrated at the elbows, knees, and ankles. This study demonstrates that psoriatic enthesitis and synovitis are closely related and thus may share pathophysiologic mechanisms. Longitudinal studies in very early PsA using ultrasound might provide clues to confirm the hypothesis that psoriatic synovitis is secondary to enthesitis.

Another important domain that is increasingly studied is axial PsA. Currently, the evidence for treatment of axial PsA is extrapolated from that for axial spondyloarthritis (SpA), in the belief that the two diseases are pathophysiologically similar. However, there is increasing evidence for differences between axial PsA and axial SpA that might influence the choice of treatment. In a recent study, de Hooge and colleagues demonstrated that patients with axial PsA have lower severity of damage to the spine compared with those with axial SpA. Using data from 312 patients with PsA and 213 patients with SpA who underwent radiographic imaging assessment in the Belgian Epidemiological Psoriatic Arthritis Study (BEPAS) and the Ghent and Belgian Inflammatory Arthritis and Spondylitis (Be-GIANT) study, respectively, they show that the proportion of patients with PsA vs SpA having spinal damage was comparable. Patients with SpA and spinal damage had higher modified Stoke Ankylosing Spondylitis Spine Scores, indicating more severe damage. These results are consistent with other published studies and indicate that patients with PsA have less severe spinal disease compared with other patients with axial SpA. Randomized controlled trials (RCTs) specifically investigating the treatment of axial PsA are currently underway. Nevertheless, post hoc analyses of data from PsA RCTs indicate that most drugs efficacious for PsA overall also provide benefit in axial disease.

In a recent report, Baraliakos and colleagues analyzed data from the SELECT-PsA 1 and SELECT-PsA 2 trials that evaluated the efficacy of upadacitinib in PsA. They show that, compared with placebo, 15 mg upadacitinib led to a greater improvement in axial symptoms. The improvement in overall Bath Ankylosing Spondylitis Disease Activity Index score at week 24 was significantly higher with 15 mg upadacitinib compared with placebo in both trials. However, these results are not definitive because there is yet no consensus on the definition of and outcome measures for axial PsA.

CLEVELAND – Patients with axial spondyloarthritis or psoriatic arthritis who used Janus kinase (JAK) inhibitors did not have higher risk of myocardial infarction, stroke, or venous thromboembolism (VTE), compared with those who used tumor necrosis factor inhibitors (TNFi), according to new research.

The information was presented in a poster at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) have increased cardiovascular risk compared with the general population. Emerging evidence has suggested that TNFi may protect the cardiovascular system and that there are cardiovascular and thrombotic concerns with JAK inhibitors.

Sali Merjanah, MD, a rheumatology fellow at Boston University, and colleagues, compared how drugs in the two treatment classes affected the likelihood of major adverse cardiovascular events (MACE) or VTE. MACE in this study were myocardial infarction and stroke.

In a search of the Marketscan Database during 2006-2021, the researchers identified 1,621 TNFi and 47 JAK inhibitor users with 273 and 8 cases of MACE, respectively. They identified 2,507 TNFi and 96 JAK users with 452 and 26 cases of VTE, respectively. Patients were aged 18-65 years and had at least one inpatient or two outpatient axSpA or PsA ICD-9 or ICD-10 diagnosis codes separated by at least 7 days.

The likelihood of MACE was 14% lower among JAK inhibitor users than TNFi users (the reference group), whereas the likelihood of VTE was 39% higher for JAK inhibitor users, but neither comparison was statistically significant. JAK/TNFi nonusers had a statistically significant 27% greater likelihood of MACE than did TNFi users. The likelihood for VTE was 12% higher for JAK/TNFi nonusers, compared with TNFi users, but this finding was not statistically significant. The researchers adjusted comparisons for age, medications, and comorbidities.
 

Small numbers complicate the research

Lianne Gensler, MD, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco, who was not part of the study, said the limitations the authors list are important to note. The researchers said that the study’s small number of JAK inhibitor users, short duration of exposure, and low event rate limit its precision, and there is potential misclassification of TNF/JAK inhibitor exposure, as well as confounding by indication.

Dr. Gensler noted that these same limitations apply to studies of patients with RA as well that try to answer the question of risk for MACE and malignancy when using these drugs,

“MACE is a rare event, malignancy is a rare event. So it’s like finding a needle in a haystack, and the haystack is really big. You either have to enrich the haystack with more needles or you have to make a smaller haystack,” Dr. Gensler said.

Nevertheless, she said, she credits the researchers for bringing the available information to light.

“I think we have to do this many different ways to try to get at the answer in a partial way,” she said.

The data were drawn from 2006 to 2021, but JAK inhibitors have only been approved for axSpA in the last one and a half years and for PsA at the end of 2017.

Additionally, the people taking JAK inhibitors would have likely already failed TNFis, she said, adding that this can make it hard to tell whether an event was linked with the JAK or the TNFi.
 

Nonusers may have other risk factors

She pointed out that in this study patients who were not using TNF or JAK inhibitors had slightly higher risk numerically for both MACE and VTE than did those using TNFis.

“There, the assumption is always that this is confounding by indication, meaning it is likely that the people who are nonusers have other risk factors for MACE, which is why we’re not giving them these drugs.”

Having heart failure, for instance, is a contraindication for using a TNF inhibitor, she noted. “So it’s not that these are protective compared to nonusers. It’s probably that the nonuser has higher risk and is not getting treated with these drugs to begin with.”

The authors properly concluded from the data that patients using JAK inhibitors did not have higher risk of MACE or VTE, compared with those who used TNFis, she said, but larger studies with more follow-up are needed.

“No evidence doesn’t mean no effect,” she said. “Part of it depends on the [statistical] power and the population you’re studying.”

Dr. Gensler is a consultant for AbbVie, Acceleron, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and has received grant support from Novartis and UCB. The authors’ financial relationships were not available.

CLEVELAND – Patients with axial spondyloarthritis or psoriatic arthritis who used Janus kinase (JAK) inhibitors did not have higher risk of myocardial infarction, stroke, or venous thromboembolism (VTE), compared with those who used tumor necrosis factor inhibitors (TNFi), according to new research.

The information was presented in a poster at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) have increased cardiovascular risk compared with the general population. Emerging evidence has suggested that TNFi may protect the cardiovascular system and that there are cardiovascular and thrombotic concerns with JAK inhibitors.

Sali Merjanah, MD, a rheumatology fellow at Boston University, and colleagues, compared how drugs in the two treatment classes affected the likelihood of major adverse cardiovascular events (MACE) or VTE. MACE in this study were myocardial infarction and stroke.

In a search of the Marketscan Database during 2006-2021, the researchers identified 1,621 TNFi and 47 JAK inhibitor users with 273 and 8 cases of MACE, respectively. They identified 2,507 TNFi and 96 JAK users with 452 and 26 cases of VTE, respectively. Patients were aged 18-65 years and had at least one inpatient or two outpatient axSpA or PsA ICD-9 or ICD-10 diagnosis codes separated by at least 7 days.

The likelihood of MACE was 14% lower among JAK inhibitor users than TNFi users (the reference group), whereas the likelihood of VTE was 39% higher for JAK inhibitor users, but neither comparison was statistically significant. JAK/TNFi nonusers had a statistically significant 27% greater likelihood of MACE than did TNFi users. The likelihood for VTE was 12% higher for JAK/TNFi nonusers, compared with TNFi users, but this finding was not statistically significant. The researchers adjusted comparisons for age, medications, and comorbidities.
 

Small numbers complicate the research

Lianne Gensler, MD, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco, who was not part of the study, said the limitations the authors list are important to note. The researchers said that the study’s small number of JAK inhibitor users, short duration of exposure, and low event rate limit its precision, and there is potential misclassification of TNF/JAK inhibitor exposure, as well as confounding by indication.

Dr. Gensler noted that these same limitations apply to studies of patients with RA as well that try to answer the question of risk for MACE and malignancy when using these drugs,

“MACE is a rare event, malignancy is a rare event. So it’s like finding a needle in a haystack, and the haystack is really big. You either have to enrich the haystack with more needles or you have to make a smaller haystack,” Dr. Gensler said.

Nevertheless, she said, she credits the researchers for bringing the available information to light.

“I think we have to do this many different ways to try to get at the answer in a partial way,” she said.

The data were drawn from 2006 to 2021, but JAK inhibitors have only been approved for axSpA in the last one and a half years and for PsA at the end of 2017.

Additionally, the people taking JAK inhibitors would have likely already failed TNFis, she said, adding that this can make it hard to tell whether an event was linked with the JAK or the TNFi.
 

Nonusers may have other risk factors

She pointed out that in this study patients who were not using TNF or JAK inhibitors had slightly higher risk numerically for both MACE and VTE than did those using TNFis.

“There, the assumption is always that this is confounding by indication, meaning it is likely that the people who are nonusers have other risk factors for MACE, which is why we’re not giving them these drugs.”

Having heart failure, for instance, is a contraindication for using a TNF inhibitor, she noted. “So it’s not that these are protective compared to nonusers. It’s probably that the nonuser has higher risk and is not getting treated with these drugs to begin with.”

The authors properly concluded from the data that patients using JAK inhibitors did not have higher risk of MACE or VTE, compared with those who used TNFis, she said, but larger studies with more follow-up are needed.

“No evidence doesn’t mean no effect,” she said. “Part of it depends on the [statistical] power and the population you’re studying.”

Dr. Gensler is a consultant for AbbVie, Acceleron, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and has received grant support from Novartis and UCB. The authors’ financial relationships were not available.

CLEVELAND – Patients with axial spondyloarthritis or psoriatic arthritis who used Janus kinase (JAK) inhibitors did not have higher risk of myocardial infarction, stroke, or venous thromboembolism (VTE), compared with those who used tumor necrosis factor inhibitors (TNFi), according to new research.

The information was presented in a poster at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) have increased cardiovascular risk compared with the general population. Emerging evidence has suggested that TNFi may protect the cardiovascular system and that there are cardiovascular and thrombotic concerns with JAK inhibitors.

Sali Merjanah, MD, a rheumatology fellow at Boston University, and colleagues, compared how drugs in the two treatment classes affected the likelihood of major adverse cardiovascular events (MACE) or VTE. MACE in this study were myocardial infarction and stroke.

In a search of the Marketscan Database during 2006-2021, the researchers identified 1,621 TNFi and 47 JAK inhibitor users with 273 and 8 cases of MACE, respectively. They identified 2,507 TNFi and 96 JAK users with 452 and 26 cases of VTE, respectively. Patients were aged 18-65 years and had at least one inpatient or two outpatient axSpA or PsA ICD-9 or ICD-10 diagnosis codes separated by at least 7 days.

The likelihood of MACE was 14% lower among JAK inhibitor users than TNFi users (the reference group), whereas the likelihood of VTE was 39% higher for JAK inhibitor users, but neither comparison was statistically significant. JAK/TNFi nonusers had a statistically significant 27% greater likelihood of MACE than did TNFi users. The likelihood for VTE was 12% higher for JAK/TNFi nonusers, compared with TNFi users, but this finding was not statistically significant. The researchers adjusted comparisons for age, medications, and comorbidities.
 

Small numbers complicate the research

Lianne Gensler, MD, director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco, who was not part of the study, said the limitations the authors list are important to note. The researchers said that the study’s small number of JAK inhibitor users, short duration of exposure, and low event rate limit its precision, and there is potential misclassification of TNF/JAK inhibitor exposure, as well as confounding by indication.

Dr. Gensler noted that these same limitations apply to studies of patients with RA as well that try to answer the question of risk for MACE and malignancy when using these drugs,

“MACE is a rare event, malignancy is a rare event. So it’s like finding a needle in a haystack, and the haystack is really big. You either have to enrich the haystack with more needles or you have to make a smaller haystack,” Dr. Gensler said.

Nevertheless, she said, she credits the researchers for bringing the available information to light.

“I think we have to do this many different ways to try to get at the answer in a partial way,” she said.

The data were drawn from 2006 to 2021, but JAK inhibitors have only been approved for axSpA in the last one and a half years and for PsA at the end of 2017.

Additionally, the people taking JAK inhibitors would have likely already failed TNFis, she said, adding that this can make it hard to tell whether an event was linked with the JAK or the TNFi.
 

Nonusers may have other risk factors

She pointed out that in this study patients who were not using TNF or JAK inhibitors had slightly higher risk numerically for both MACE and VTE than did those using TNFis.

“There, the assumption is always that this is confounding by indication, meaning it is likely that the people who are nonusers have other risk factors for MACE, which is why we’re not giving them these drugs.”

Having heart failure, for instance, is a contraindication for using a TNF inhibitor, she noted. “So it’s not that these are protective compared to nonusers. It’s probably that the nonuser has higher risk and is not getting treated with these drugs to begin with.”

The authors properly concluded from the data that patients using JAK inhibitors did not have higher risk of MACE or VTE, compared with those who used TNFis, she said, but larger studies with more follow-up are needed.

“No evidence doesn’t mean no effect,” she said. “Part of it depends on the [statistical] power and the population you’re studying.”

Dr. Gensler is a consultant for AbbVie, Acceleron, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and has received grant support from Novartis and UCB. The authors’ financial relationships were not available.

Introduction

The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.  

Background

Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.¹ PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.² This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.³ 

PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.² Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.⁴ By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA. 

There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),⁵ the European Alliance of Associations for Rheumatology (EULAR),⁶ and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).⁷ Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.

For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis. 

JAK Inhibitors and PsA

There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.⁸ Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial⁹ and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.¹⁰ A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.

The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.⁸ In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.⁸ Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.⁸

JAK Inhibitors: Clinical Experience in PsA 

Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.¹¹ Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.¹² The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.

Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,¹³ there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,¹⁴ have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences. 

Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.¹⁵ The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.  

In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.⁹ When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity. 

Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.⁸ Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies. 

While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),^16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents. 

The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice. 

Summary

Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.

Introduction

The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.  

Background

Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.¹ PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.² This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.³ 

PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.² Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.⁴ By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA. 

There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),⁵ the European Alliance of Associations for Rheumatology (EULAR),⁶ and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).⁷ Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.

For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis. 

JAK Inhibitors and PsA

There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.⁸ Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial⁹ and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.¹⁰ A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.

The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.⁸ In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.⁸ Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.⁸

JAK Inhibitors: Clinical Experience in PsA 

Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.¹¹ Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.¹² The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.

Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,¹³ there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,¹⁴ have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences. 

Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.¹⁵ The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.  

In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.⁹ When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity. 

Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.⁸ Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies. 

While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),^16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents. 

The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice. 

Summary

Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.

Introduction

The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.  

Background

Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.¹ PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.² This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.³ 

PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.² Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.⁴ By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA. 

There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),⁵ the European Alliance of Associations for Rheumatology (EULAR),⁶ and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).⁷ Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.

For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis. 

JAK Inhibitors and PsA

There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.⁸ Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial⁹ and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.¹⁰ A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.

The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.⁸ In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.⁸ Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.⁸

JAK Inhibitors: Clinical Experience in PsA 

Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.¹¹ Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.¹² The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.

Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,¹³ there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,¹⁴ have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences. 

Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.¹⁵ The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.  

In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.⁹ When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity. 

Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.⁸ Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies. 

While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),^16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents. 

The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice. 

Summary

Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.