Vinod Chandran, MBBS, MD, DM, PhD

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.

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.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

With regard to advanced targeted therapies, there is concern about the side effects of Janus kinase (JAK) inhibitors, especially in patients with comorbidities. To address safety concerns with upadacitinib, a selective JAK1 inhibitor, Burmester and colleagues conducted an integrated safety analysis of 12 phase 3 trials that included 6991 patients (PsA n = 907; rheumatoid arthritis [RA] n = 3209; ankylosing spondylitis n = 182; and atopic dermatitis n = 2693) who received upadacitinib (15 or 30 mg once daily). Some trials included active comparators; therefore, safety among 1008 patients (RA n = 579; PsA n = 429) who received 40-mg adalimumab every other week and 314 patients with RA who received methotrexate were compared with those treated with upadacitinib. Overall, patients with PsA receiving 15-mg upadacitinib once daily had acceptable rates of treatment-emergent adverse events (TEAE; 244.8/100 patient-years [PY]), serious TEAE (11.1/100 PY), TEAE leading to discontinuation (5.4/100 PY), and death (0.8/100 PY). Patients with PsA treated with upadacitinib had higher rates of herpes zoster, nonmelanoma skin cancer, and elevations in creatine phosphokinase when compared with patients treated with adalimumab. Although these results are reassuring to clinicians treating PsA, continued surveillance regarding the risks for venous thrombosis, cardiovascular events, and cancer are required.

In a post hoc analysis of 10 clinical trials that included patients with PsA (n = 783) and psoriasis (n = 3663) who received tofacitinib, Kristensen and colleagues reported that the risk for major adverse cardiac events was higher among patients with PsA and a high 10-year atherosclerotic cardiovascular disease (ASCVD) risk vs patients with a low ASCVD risk. The incidence of cancer was highest in patients with PsA and an intermediate 10-year ASCVD risk. Although these studies are reassuring, the assessment and risk stratification of adverse events with JAK inhibitors and therapies in PsA will require longer-term comparative clinical trials as well as an evaluation of observational data from disease registries.

Comorbidities also have an impact on treatment persistence in PsA. Tillett and colleagues conducted a retrospective study including 9057 patients with plaque psoriasis alone or with concomitant PsA who received either ustekinumab or conventional systemic disease-modifying antirheumatic drugs. They demonstrated that among patients receiving ustekinumab, those with concomitant PsA had a higher comorbidity burden, including diabetes, hypertension, and obesity, and a shorter time to ustekinumab discontinuation when compared with those with psoriasis alone. Secondary failure of advanced therapies is increasingly noted in the management of psoriatic disease. Female sex, depression, previous exposure to biologics, and the presence of comorbidities are important risk factors. Comprehensive management of psoriatic disease should include appropriate management of comorbidities for better long-term treatment persistence and outcomes.

Appropriate assessment of MSK symptoms and signs by dermatologists may lead to more appropriate referral to rheumatologists. MSUS is being increasingly explored for early identification of PsA. A handheld, chip-based ultrasound device (HHUD) is a novel promising instrument that can be easily implemented in clinical practice. In a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia. Grobelski and colleagues screened for PsA using medical history, CE, and the German Psoriasis Arthritis Diagnostic PsA screening questionnaire (GEPARD) paired with MSUS examination of up to three painful joints by trained dermatologists. Nineteen patients (13.6%) were diagnosed with PsA by rheumatologists. Interestingly, in 45 of the 46 patients the preliminary diagnosis of PsA was revised to "no PsA" after MSUS. The addition of MSUS changed the sensitivity and specificity of early PsA screening strategy from 88.2% and 54.4% to 70.6% and 90.4%, respectively. The positive predictive value increased to 56.5% from 25.4% after MSUS. Thus, the use of a quick MSUS using HHUD may lead to more accurate referral to rheumatologists. The challenge is seamless integration of MSUS into busy dermatology practices.

The goal of PsA treatment is to achieve a state of remission or low disease activity. Criteria for minimal disease activity (MDA) have been established. Achieving MDA leads to better health-related quality of life (HRQOL), as well as less joint damage. In a prospective cohort study that included 240 patients with newly diagnosed disease-modifying antirheumatic drug-naive PsA, Snoeck Henkemans and colleagues demonstrate that failure to achieve MDA in the first year after the diagnosis of PsA was associated with worse HRQOL and health status, functional impairment, fatigue, pain, and higher anxiety and depression. Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain, fatigue, and functional ability and higher anxiety and depression during follow-up, which persisted despite treatment intensification. Thus, implementation of treat-to-target strategies with the aim of achieving sustained MDA within 1 year of diagnosis is likely to have better long-term benefits in this lifelong disease.

Another study emphasized the need for early treatment to improve long-term outcomes. In a post hoc analysis of two phase 3 trials including 1554 patients with PsA who received 300-mg or 150-mg secukinumab with or without a loading dose, Mease and colleagues showed that high baseline radiographic damage reduced the likelihood of achieving MDA.

Overall, these studies indicate that early diagnosis and treatment prior to developing joint damage with the aim to achieve sustained MDA within a year will lead to better long-term outcome for patients with PsA.

Appropriate assessment of MSK symptoms and signs by dermatologists may lead to more appropriate referral to rheumatologists. MSUS is being increasingly explored for early identification of PsA. A handheld, chip-based ultrasound device (HHUD) is a novel promising instrument that can be easily implemented in clinical practice. In a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia. Grobelski and colleagues screened for PsA using medical history, CE, and the German Psoriasis Arthritis Diagnostic PsA screening questionnaire (GEPARD) paired with MSUS examination of up to three painful joints by trained dermatologists. Nineteen patients (13.6%) were diagnosed with PsA by rheumatologists. Interestingly, in 45 of the 46 patients the preliminary diagnosis of PsA was revised to "no PsA" after MSUS. The addition of MSUS changed the sensitivity and specificity of early PsA screening strategy from 88.2% and 54.4% to 70.6% and 90.4%, respectively. The positive predictive value increased to 56.5% from 25.4% after MSUS. Thus, the use of a quick MSUS using HHUD may lead to more accurate referral to rheumatologists. The challenge is seamless integration of MSUS into busy dermatology practices.

The goal of PsA treatment is to achieve a state of remission or low disease activity. Criteria for minimal disease activity (MDA) have been established. Achieving MDA leads to better health-related quality of life (HRQOL), as well as less joint damage. In a prospective cohort study that included 240 patients with newly diagnosed disease-modifying antirheumatic drug-naive PsA, Snoeck Henkemans and colleagues demonstrate that failure to achieve MDA in the first year after the diagnosis of PsA was associated with worse HRQOL and health status, functional impairment, fatigue, pain, and higher anxiety and depression. Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain, fatigue, and functional ability and higher anxiety and depression during follow-up, which persisted despite treatment intensification. Thus, implementation of treat-to-target strategies with the aim of achieving sustained MDA within 1 year of diagnosis is likely to have better long-term benefits in this lifelong disease.

Another study emphasized the need for early treatment to improve long-term outcomes. In a post hoc analysis of two phase 3 trials including 1554 patients with PsA who received 300-mg or 150-mg secukinumab with or without a loading dose, Mease and colleagues showed that high baseline radiographic damage reduced the likelihood of achieving MDA.

Overall, these studies indicate that early diagnosis and treatment prior to developing joint damage with the aim to achieve sustained MDA within a year will lead to better long-term outcome for patients with PsA.

Appropriate assessment of MSK symptoms and signs by dermatologists may lead to more appropriate referral to rheumatologists. MSUS is being increasingly explored for early identification of PsA. A handheld, chip-based ultrasound device (HHUD) is a novel promising instrument that can be easily implemented in clinical practice. In a prospective study including 140 patients with psoriasis who presented to dermatologists with arthralgia. Grobelski and colleagues screened for PsA using medical history, CE, and the German Psoriasis Arthritis Diagnostic PsA screening questionnaire (GEPARD) paired with MSUS examination of up to three painful joints by trained dermatologists. Nineteen patients (13.6%) were diagnosed with PsA by rheumatologists. Interestingly, in 45 of the 46 patients the preliminary diagnosis of PsA was revised to "no PsA" after MSUS. The addition of MSUS changed the sensitivity and specificity of early PsA screening strategy from 88.2% and 54.4% to 70.6% and 90.4%, respectively. The positive predictive value increased to 56.5% from 25.4% after MSUS. Thus, the use of a quick MSUS using HHUD may lead to more accurate referral to rheumatologists. The challenge is seamless integration of MSUS into busy dermatology practices.

The goal of PsA treatment is to achieve a state of remission or low disease activity. Criteria for minimal disease activity (MDA) have been established. Achieving MDA leads to better health-related quality of life (HRQOL), as well as less joint damage. In a prospective cohort study that included 240 patients with newly diagnosed disease-modifying antirheumatic drug-naive PsA, Snoeck Henkemans and colleagues demonstrate that failure to achieve MDA in the first year after the diagnosis of PsA was associated with worse HRQOL and health status, functional impairment, fatigue, pain, and higher anxiety and depression. Compared with patients who achieved sustained MDA in the first year after diagnosis, those who did not achieve MDA had higher scores for pain, fatigue, and functional ability and higher anxiety and depression during follow-up, which persisted despite treatment intensification. Thus, implementation of treat-to-target strategies with the aim of achieving sustained MDA within 1 year of diagnosis is likely to have better long-term benefits in this lifelong disease.

Another study emphasized the need for early treatment to improve long-term outcomes. In a post hoc analysis of two phase 3 trials including 1554 patients with PsA who received 300-mg or 150-mg secukinumab with or without a loading dose, Mease and colleagues showed that high baseline radiographic damage reduced the likelihood of achieving MDA.

Overall, these studies indicate that early diagnosis and treatment prior to developing joint damage with the aim to achieve sustained MDA within a year will lead to better long-term outcome for patients with PsA.

Two new papers published recently provide evidence of the efficacy and safety of bimekizumab in psoriatic arthritis (PsA). Bimekizumab is a novel bispecific monoclonal antibody targeting interleukin (IL)-17A and IL-17F and is already approved for the treatment of chronic plaque psoriasis. McInnes and colleagues reported the results of the phase 3 BE OPTIMAL study, which included 852 patients with active PsA who were naive to biologic disease-modifying antirheumatic drugs (bDMARD) and were randomly assigned to receive bimekizumab, placebo, or adalimumab. At week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ≥ 50% improvement in American College of Rheumatology response (ACR50; 44% vs 10%; odds ratio [OR] 7.1; P < .0001). Compared with placebo, significant improvements were also noted in psoriasis, enthesitis, and dactylitis in the bimekizumab group and there was less progression of radiographic damage.

Bimekizumab was also demonstrated to be beneficial in PsA patients with inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi). In the phase 3 BE COMPLETE study, which included 400 patients with active PsA and previous inadequate response or intolerance to TNFi, patients were randomly assigned to receive 160 mg subcutaneous bimekizumab every 4 weeks or placebo. Merola and colleagues reported that at week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ACR50 response (43% vs 7%; OR 11.1; P < .0001). Thus, bimekizumab is a welcome addition to the treatment portfolio we have for PsA. In regard to side effects of special concern when inhibiting IL-17, bimekizumab was associated with higher risk for oral and genital candidiasis, occurring in 4% of the treated patients within 16 weeks in the two studies; however, no cases of systemic fungal infections occurred. The incidence of inflammatory bowel disease was also very low, but head-to-head studies against other available agents would be required to help rheumatologists decide the place of bimekizumab in PsA management.

A common clinical question is whether axial PsA is similar to ankylosing spondylitis (AS) with psoriasis. Assuming that it is, clinicians have used treatments approved for AS for managing axial PsA. Recent studies have questioned this assumption, however. Michelena and colleagues conducted a cross-sectional study that included 109 patients with axial PsA and 127 patients with AS and psoriasis from the REGISPONSER registry. Compared with patients with AS and psoriasis, patients with human leukocyte antigen (HLA)-B27–negative axial PsA had less inflammatory pain (P = .002), anterior uveitis (P = .014), and structural damage (P < .001), along with a higher prevalence of nail disease (P = .009). Patients with HLA-B27–positive axial PsA vs AS and psoriasis were similar but had less structural damage to the spine (P < .001). Thus, there seem to be significant clinical and genetic differences between these two diseases that require further investigation. Lack of an accepted definition of axial PsA, however, is a hindrance to multiple high-quality genetic, clinical, and interventional studies comparing axial PsA and AS with psoriasis.

Observational studies have recognized the clinical and familial association between psoriatic disease and Crohn's disease (CD), but such cross-sectional or retrospective studies cannot identify causal relationships. Mendelian randomization is a method used to identify causal relationships. Using this method, Sun and colleagues demonstrated that PsA was associated with a 31.9% increased risk for CD (P < .001) and genetically predicted CD was linked to a 44.8% higher risk for PsA (P = .001). No such association was found with ulcerative colitis. Thus, there is a bidirectional causal relationship between the two diseases. Patients with PsA should be evaluated for symptoms of CD, and those with CD for psoriatic disease, to facilitate early diagnosis and better long-term outcomes.

Two new papers published recently provide evidence of the efficacy and safety of bimekizumab in psoriatic arthritis (PsA). Bimekizumab is a novel bispecific monoclonal antibody targeting interleukin (IL)-17A and IL-17F and is already approved for the treatment of chronic plaque psoriasis. McInnes and colleagues reported the results of the phase 3 BE OPTIMAL study, which included 852 patients with active PsA who were naive to biologic disease-modifying antirheumatic drugs (bDMARD) and were randomly assigned to receive bimekizumab, placebo, or adalimumab. At week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ≥ 50% improvement in American College of Rheumatology response (ACR50; 44% vs 10%; odds ratio [OR] 7.1; P < .0001). Compared with placebo, significant improvements were also noted in psoriasis, enthesitis, and dactylitis in the bimekizumab group and there was less progression of radiographic damage.

Bimekizumab was also demonstrated to be beneficial in PsA patients with inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi). In the phase 3 BE COMPLETE study, which included 400 patients with active PsA and previous inadequate response or intolerance to TNFi, patients were randomly assigned to receive 160 mg subcutaneous bimekizumab every 4 weeks or placebo. Merola and colleagues reported that at week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ACR50 response (43% vs 7%; OR 11.1; P < .0001). Thus, bimekizumab is a welcome addition to the treatment portfolio we have for PsA. In regard to side effects of special concern when inhibiting IL-17, bimekizumab was associated with higher risk for oral and genital candidiasis, occurring in 4% of the treated patients within 16 weeks in the two studies; however, no cases of systemic fungal infections occurred. The incidence of inflammatory bowel disease was also very low, but head-to-head studies against other available agents would be required to help rheumatologists decide the place of bimekizumab in PsA management.

A common clinical question is whether axial PsA is similar to ankylosing spondylitis (AS) with psoriasis. Assuming that it is, clinicians have used treatments approved for AS for managing axial PsA. Recent studies have questioned this assumption, however. Michelena and colleagues conducted a cross-sectional study that included 109 patients with axial PsA and 127 patients with AS and psoriasis from the REGISPONSER registry. Compared with patients with AS and psoriasis, patients with human leukocyte antigen (HLA)-B27–negative axial PsA had less inflammatory pain (P = .002), anterior uveitis (P = .014), and structural damage (P < .001), along with a higher prevalence of nail disease (P = .009). Patients with HLA-B27–positive axial PsA vs AS and psoriasis were similar but had less structural damage to the spine (P < .001). Thus, there seem to be significant clinical and genetic differences between these two diseases that require further investigation. Lack of an accepted definition of axial PsA, however, is a hindrance to multiple high-quality genetic, clinical, and interventional studies comparing axial PsA and AS with psoriasis.

Observational studies have recognized the clinical and familial association between psoriatic disease and Crohn's disease (CD), but such cross-sectional or retrospective studies cannot identify causal relationships. Mendelian randomization is a method used to identify causal relationships. Using this method, Sun and colleagues demonstrated that PsA was associated with a 31.9% increased risk for CD (P < .001) and genetically predicted CD was linked to a 44.8% higher risk for PsA (P = .001). No such association was found with ulcerative colitis. Thus, there is a bidirectional causal relationship between the two diseases. Patients with PsA should be evaluated for symptoms of CD, and those with CD for psoriatic disease, to facilitate early diagnosis and better long-term outcomes.

Two new papers published recently provide evidence of the efficacy and safety of bimekizumab in psoriatic arthritis (PsA). Bimekizumab is a novel bispecific monoclonal antibody targeting interleukin (IL)-17A and IL-17F and is already approved for the treatment of chronic plaque psoriasis. McInnes and colleagues reported the results of the phase 3 BE OPTIMAL study, which included 852 patients with active PsA who were naive to biologic disease-modifying antirheumatic drugs (bDMARD) and were randomly assigned to receive bimekizumab, placebo, or adalimumab. At week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ≥ 50% improvement in American College of Rheumatology response (ACR50; 44% vs 10%; odds ratio [OR] 7.1; P < .0001). Compared with placebo, significant improvements were also noted in psoriasis, enthesitis, and dactylitis in the bimekizumab group and there was less progression of radiographic damage.

Bimekizumab was also demonstrated to be beneficial in PsA patients with inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi). In the phase 3 BE COMPLETE study, which included 400 patients with active PsA and previous inadequate response or intolerance to TNFi, patients were randomly assigned to receive 160 mg subcutaneous bimekizumab every 4 weeks or placebo. Merola and colleagues reported that at week 16, a significantly higher proportion of patients receiving bimekizumab vs placebo achieved ACR50 response (43% vs 7%; OR 11.1; P < .0001). Thus, bimekizumab is a welcome addition to the treatment portfolio we have for PsA. In regard to side effects of special concern when inhibiting IL-17, bimekizumab was associated with higher risk for oral and genital candidiasis, occurring in 4% of the treated patients within 16 weeks in the two studies; however, no cases of systemic fungal infections occurred. The incidence of inflammatory bowel disease was also very low, but head-to-head studies against other available agents would be required to help rheumatologists decide the place of bimekizumab in PsA management.

A common clinical question is whether axial PsA is similar to ankylosing spondylitis (AS) with psoriasis. Assuming that it is, clinicians have used treatments approved for AS for managing axial PsA. Recent studies have questioned this assumption, however. Michelena and colleagues conducted a cross-sectional study that included 109 patients with axial PsA and 127 patients with AS and psoriasis from the REGISPONSER registry. Compared with patients with AS and psoriasis, patients with human leukocyte antigen (HLA)-B27–negative axial PsA had less inflammatory pain (P = .002), anterior uveitis (P = .014), and structural damage (P < .001), along with a higher prevalence of nail disease (P = .009). Patients with HLA-B27–positive axial PsA vs AS and psoriasis were similar but had less structural damage to the spine (P < .001). Thus, there seem to be significant clinical and genetic differences between these two diseases that require further investigation. Lack of an accepted definition of axial PsA, however, is a hindrance to multiple high-quality genetic, clinical, and interventional studies comparing axial PsA and AS with psoriasis.

Observational studies have recognized the clinical and familial association between psoriatic disease and Crohn's disease (CD), but such cross-sectional or retrospective studies cannot identify causal relationships. Mendelian randomization is a method used to identify causal relationships. Using this method, Sun and colleagues demonstrated that PsA was associated with a 31.9% increased risk for CD (P < .001) and genetically predicted CD was linked to a 44.8% higher risk for PsA (P = .001). No such association was found with ulcerative colitis. Thus, there is a bidirectional causal relationship between the two diseases. Patients with PsA should be evaluated for symptoms of CD, and those with CD for psoriatic disease, to facilitate early diagnosis and better long-term outcomes.