Psoriatic arthritis (PsA) is a chronic, clinically heterogeneous disease that affects approximately 1% of the general population and 30% of individuals with psoriasis.^1,2 PsA can affect peripheral joints (arthritis) and their surrounding structures, such as tendons, ligaments, and soft tissues, as well as the axial skeleton (spondylitis). Extra-articular features, such as nail pitting, ridging, and onycholysis, are also common.^3,4

PsA is associated with five phenotypes, including polyarthritis, asymmetrical oligoarthritis, mutilans, spondyloarthritis, and distal interphalangeal arthritis; however, the degree of involvement of different PsA domains and subtypes can vary for individual patients over the trajectory of the disease.¹ The combination of peripheral joint, axial, and skin involvement affects patient function, well-being, and health-related quality of life.⁵ Therefore, effective management of this chronic, inflammatory disease involves addressing peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail disease. Clinical, functional, and radiographic outcomes have been found to be better with early control of disease activity; notably, joints can be progressively damaged if not treated.^2,6

As with the treatment of rheumatoid arthritis (RA), the paradigm of treat-to-target is gaining traction within PsA. This relatively new approach is based on precise, clinically relevant physiologic targets and rapid therapeutic adjustment as necessary. There is broad agreement across the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, and the European League Against Rheumatism (EULAR) that the goal of therapy in PsA is to achieve remission or the lowest possible level of disease activity. Building on this consensus, 2018 updates by an international task force advise a treat-to-target approach for managing peripheral and axial arthritis, with a target of remission/inactive disease or, alternatively, low/minimal disease activity, which is considered more appropriate in some patients with long-standing disease or multiple comorbidities.^7-10 Patients should also be involved in decision making about the choice of the target.

Given the emerging emphasis on treating to target in patients with PsA, it is increasingly important to use effective tools to define therapeutic targets and measure the degree of disease activity, damage, and impact on the patient for each clinical domain. Although there are currently no simple assessment measures of disease severity in PsA—especially for joint activity—several indices and composite measures have been developed for assessing remission and disease activity that show high sensitivity and specificity.¹¹

Determining Disease Activity Goals For Patients With PsA

Guideline Recommendations on Setting Disease Activity Goals

Historically, treatment options for PsA were limited to therapies that were originally developed for patients with RA, including non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying therapies (DMARDs) such as methotrexate (MTX), sulfasalazine, and leflunomide. In the last decade or so, pharmacologic options have expanded to include several drug classes that target distinct autoimmune and inflammatory pathways, including tumor necrosis factor (TNF), interleukins (ILs), Janus kinase (JAK), T cells, and phosphodiesterase 4 (PDE 4).^12-15 These therapies have demonstrated efficacy in treatment-naïve and treatment-experienced PsA patients. Several additional novel agents are also under late-stage investigation. Biologic therapies not only offer options for patients who experience toxicity with, or do not respond to, NSAIDs or conventional DMARDs but also are being increasingly used as first- and second-line options to treat patients with more severe disease.^5,9

Although in practice, the intensity of therapy is often driven by the disease domain that is deemed most severe by patients and clinicians,11 guideline-recommended treatment goals for PsA emphasize controlling overall disease activity, improving physical function and quality of life, and preventing structural damage to joints.^8,10 Concomitantly, the development of new biologic therapies that address multiple PsA domains has led to updated guideline recommendations that recognize remission as the principal treatment target for patients with PsA.^7,8,10 While several definitions of remission have been proposed, broadly speaking, remission in PsA is viewed as the control of inflammation across all disease domains, including skin, in order to avoid disease sequelae and maintain quality of life.¹⁶ Depending on the outcome measures used to define remission, it is estimated that up to 36% of PsA patients can achieve remission.¹⁷ However, due to the heterogeneity of PsA pathogenesis, the effects, timing, and degree of completeness of treatment at which remission is achieved can vary across disease domains.¹¹ Low or minimal disease activity (MDA) has been proposed as an alternative to remission by some groups as a more achievable target in patients with PsA.

Minimal Disease Activity

In 2002, Outcome Measures in Rheumatology Clinical Trials (OMERACT) defined minimal disease activity (MDA) in RA as “that state of disease activity deemed a useful target of treatment by both the patient and physician, given current treatment possibilities and limitations.”¹⁸ This definition has also been validated in PsA,19 and the multi-center Tight Control of Inflammation in Early Psoriatic Arthritis (TIPOCA) trial is regarded as the first treatment strategy trial that used MDA as the treatment target. MDA corresponds to a low state of disease in PsA and is defined by clinically significant improvement in five of seven response domains (Figure 1).¹⁷

MDA is considered a more attainable therapeutic target than remission. The target of MDA has been validated as a target for therapy in PsA in several clinical studies involving TNF inhibitors and secukinumab, an IL-7A inhibitor.^20,21 In an observational cohort of patients with PsA, 34% of patients sustained MDA for at least 1 year; these patients also demonstrated less progression of damage than patients who did not achieve MDA.²² Similarly, a recent randomized controlled trial (RCT) investigating golimumab in patients with PsA reported that patients who achieved persistent MDA (for at least three or more follow-up visits) had less radiographic progression and more long-term functional improvement than those who did not attain this level of improvement.²³

Clinical data from both interventional and observational studies provide clues to predictors of achieving MDA (Table 1).

Sustained achievement of MDA is also associated with better prognosis in terms of limiting the progression of joint damage, long-term functional improvement, and improving patient global assessment of disease activity.²⁴ However, studies have not yet shown correlation between skin improvement and achievement of MDA.²⁵

Based on the results from the TIPOCA trial, an international task force published treat-to-target recommendations in 2010, which were updated in 2017. This task force recommended that remission for all clinical domains should be the treatment target for patients with PsA. Remission was defined as “the absence of clinical and laboratory evidence of significant inflammatory disease activity.”⁷ However, as alluded to earlier in this issue, there is little consensus on how such a narrow definition might be applied in practice, and other consensus groups have acknowledged that remission is not appropriate for all patients with PsA, especially those with comorbidities, established disease, and significant joint damage.^7,26 Therefore, if clinical remission is unlikely to be achieved, MDA or the lowest possible level of disease activity in all disease domains represents an alternative therapeutic target.⁷ Whether clinicians select remission or low/minimal disease activity to support a treat-to-target approach, it is critical at baseline to identify and evaluate PsA disease activity across multiple clinical domains.¹¹

Assessing and Scoring Disease Activity

Single-Instrument Disease Activity Assessment Tools

In 2002, OMERACT identified a core set of PsA domains to use in clinical trial settings. These domains have recently been updated to include peripheral joint and skin assessment, patient global assessment, pain, physical function, and quality of life as measures of disease activity in research settings.²⁸ Other domains that OMERACT identified as important but not mandatory to measure when assessing disease activity include dactylitis, enthesitis, nail assessment, spinal involvement, radiology, physician global assessment, and acute phase reactants. Several single-instrument PsA-specific disease scoring tools have been developed to assess the core OMERACT-defined PsA domains.

Patients with PsA frequently have significant peripheral arthritis; therefore, clinical trials for PsA therapies have, historically, incorporated disease severity measures initially developed and validated for RA. These measures of disease activity include the American College of Rheumatology Responder Index (ACR-20) and the Disease Activity Score for 28 joints (DAS28).⁶ The DAS28 assesses pain and swelling in 28 joints; however, DAS28 disease activity criteria are limited in their capacity to evaluate all domains of PsA.³ In addition, the DAS28 excludes the assessment of feet, ankles, and distal interphalangeal joints (DIP), which are all commonly affected in patients with PsA. Moreover, use of the DAS28 alone has the potential to misclassify approximately 20% of patients with PsA and may fail to identify active disease.²⁹ One potential alternative to the DAS28 is an ACR joint count of 68 tender and 66 swollen joints, which can be used to assess peripheral arthritis and includes DIP as well as several other PsA-relevant joints.³⁰

Other tools have been developed to assess particular PsA domains such as the Leeds Enthesitis Index (LEI), the Leeds Dactylitis Index (LDI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Body Surface Area (BSA) score, the Psoriasis Area and Severity Index (PASI), and the Nail Psoriasis Severity Index (NPSI).³¹

The LEI quantifies tenderness at enthesitis sites and can distinguish between patients with and without active disease, while the LDI quantifies and differentiates between the size and tenderness of swollen digits. The NPSI evaluates the severity of nail matrix and nail bed psoriasis. In addition, global patient and physician assessments (PGA) using a 100 mm visual analogue scale (VAS) provide subjective perspectives on joint involvement and pain. A GRAPPA study showed that a single question, “In all the ways in which your psoriasis and arthritis, as a whole, affect you, how would you rate the way you felt over the last week?” can address both joint and skin disease in a reliable measure. The Health Assessment Questionnaire (HAQ) can be used to assess quality of life, while fatigue can be assessed using the Fatigue Severity Scale or other measures.³⁰

Composite Disease Activity Measures and Scoring Tools

Disease activity measures derived from single-instrument tools (e.g., PSAI, TJC/SJC) provide uni-dimensional information on individual, discrete variables (e.g., digital tenderness as measured by the LDI). Because PsA involves many domains, PsA-specific disease scoring tools have been developed and validated to assess PsA core domains in an integrated fashion. In contrast to capturing a single measure with a single instrument at a single moment in time, these composite measures are calculated using information that is captured via several single instrument assessment tools. Composite measures pull together the information that these tools provide and depict the diverse manifestations of PsA in a single score to provide a glimpse of overall disease activity (Figure 2).

As discussed earlier in this issue, MDA is a treatment target for patients with PsA. In some clinical trials, MDA has also been used as a scoring tool to assess the need for increasing or decreasing therapy. MDA is scored by assessing seven PsA domains that are each measured using single instrument tools (Figure 1).⁶ Other composite scoring tools include the Psoriatic Arthritis Disease Activity Score (PASDAS) and the Composite Psoriatic Disease Activity Index (CPDAI). PASDAS is designed to provide an absolute measure of disease activity as well as response to therapy. This weighted instrument is based on seven domains that include articular disease characteristics (i.e., joint counts, enthesitis, and dactylitis) as well as a quality of life measure, and both patient and physician global scores that include skin and axial involvement.³³ The overall score (range 0-10) is calculated using a formula.

CPDAI is a composite score based on calculation of peripheral joints, skin, enthesitis, dactylitis, and spine, and uses several instruments to produce one score (e.g., BSA, Leeds Enthesitis Index [LEI], NPSI). Each single instrument assesses the extent of disease activity and the effect on patient function and quality of life in a particular domain, awarding each domain a score of 0-3.4 Individual scores for each domain are summed to provide a composite score from 0-15. PASDAS and CPDAI are also considered effective indices to measure MDA domains.

The Psoriatic Arthritis Impact of Disease Questionnaire (PsAID) is a 12-item domain of health questionnaire designed for clinical practice that collects patient reported outcomes (PRO) such as weighted psychological and physical domains scored between 0-10 (Figure 3).³⁴ Pain, fatigue, and skin issues are weighted more heavily than other domains. PsAID captures both physical function and health-related quality of life information without requiring clinicians to use specific measurements for these domains. Information can be collected quickly from patients in approximately 2 minutes using electronic forms and touch screen/tablet-based tools that have the potential to reduce the time burden for data collection in busy clinics.³⁵ Patients have found this touch screen PRO tool easy to understand and use, and clinicians have immediate access to disease activity data. GRAPPA has also launched a mobile device application that includes the PsAID questionnaire.³⁶

Disease Activity in Psoriatic Arthritis (DAPSA) is a continuous index of patient global and pain assessments, 68 tender joint count (TJC) and 66 swollen joint count (SJC), and C-reactive protein (CRP) levels (Figure 4). Although this tool assesses musculoskeletal activity and provides thresholds for low, moderate, and high disease activity, as well as remission, it does not assess skin, enthesitis, dactylitis, or axial disease.^6,37 In contrast, newer tools use several items to achieve a composite assessment of disease activity. For instance, the Psoriatic Arthritis Response Criteria (PsARC) is based on patient global assessment, physician global assessment, TJC (68 joints), and SJC (66 joints).

Using Disease Activity Measures in Clinical Practice

Composite measures are increasingly considered more efficient in setting treatment goals and measuring disease activity and remission than unidimensional instruments.³² Indeed, many of the composite indices discussed earlier in this issue are currently used in both research and clinical practice settings, and real-world analysis of their performance has shown good validity and discriminant capacity.⁶ In particular, PASDAS and CPDAI have both been shown to be highly sensitive and specific for PsA domains. There are overlaps among many composite indices in terms of the domains they measure, with CPDAI, PASDAS, and MDA all measuring arthritis, enthesitis, and patient global function.³¹ In practice, composite measures should be capable of assessing each individual disease domain and its potential for differential treatment response. However, real-world studies highlight different estimates of remission rates across existing disease activity measures, which, in practice, could also limit their ability to discriminate between responses across individual domains.⁶ At the same time, while many disease activity measures have been used in clinical trials to assess remission, they can be complex to administer and therefore less feasible for busy rheumatology clinics. With these complexities in mind, GRAPPA is currently involved in developing and comparing different composite measures in its GRAppa Composite Exercise (GRACE) project.³²

Practice Pearls on Setting Therapeutic Targets and Selecting Disease Activity Measures

When using a treat-to-target approach, clinicians should consider individual patient characteristics to determine whether remission or low/minimal disease activity should be established as the treatment goal. For instance, patients with multiple comorbidities, a history of recurrent treatment-related adverse effects, or longer disease duration might not be good candidates for remission as a therapeutic goal. Additionally, patient preferences or insurance coverage might preclude the use of biologic therapies and reduce the feasibility of remission as a therapeutic goal. Experts suggest that therapeutic goals can also be modified by disease stage. For instance, low disease activity as measured by meeting all seven MDA criteria could be considered a valid goal for patients with early disease and limited joint involvement.¹¹ Meeting five of seven MDA criteria could constitute a suitable therapeutic goal for patients with established disease and significant joint damage.¹¹

It is also important to use reliable tools that are validated for PsA and offer capacity to assess individual disease domains. Notably, current treatment algorithms that are recommended in GRAPPA and EULAR guidelines focus on individual disease domains.^8,10 When biologic and conventional therapies are prescribed for PsA, patients require regular monitoring for response to therapy and treatment-related adverse events. GRAPPA and EULAR guidelines recommend monitoring patients frequently when new therapy is being initiated (e.g., every 6-8 weeks) and at 3-month intervals for patients with active disease. Six-month intervals are considered adequate for monitoring patients with stable disease.^8,10

Future Strategies for Measuring Disease Activity

Several studies indicate that magnetic resonance imaging (MRI) and/or ultrasound (US) imaging could also have potential as tools to monitor PsA disease activity and assess therapeutic response. The use of US imaging in RA suggests that, despite the achievement of low disease activity, subclinical synovitis can be present in some patients.¹⁷ In PsA, studies using MRI and US have also shown that subclinical inflammation may persist in patients with PsA even after successful therapy.³² Of currently available composite disease activity measures, DAPSA has been shown to correlate most closely with US-verified remission.³⁸

Conclusion

Treatment in PsA is shifting toward a treat-to-target paradigm based on well-defined, quantifiable targets. Research is ongoing to validate definitions of remission. In the meantime, many rheumatology experts consider low or minimal disease activity to be a realistic therapeutic target for patients with PsA. In order to assess disease activity within a treat-to-target approach, however the target is defined, clinicians may find validated scores that combine data from single instrument assessment tools (e.g., DAS28, PASI) and measure both articular involvement and other core clinical PsA domains to be helpful.

Currently, validated uni-dimensional scores exist to determine disease activity in each PsA disease domain and help guide therapeutic decisions as per GRAPPA treatment recommendations. Although cutoffs for acceptable disease activity remain widely debated due to the heterogeneity of PsA, efforts are underway to validate biomarker and imaging measures of disease activity that will enable the appropriate use of novel therapies to control symptoms and disease activity, maintain functional ability, and optimize quality of life.

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