Novel Treatment Concepts in Psoriatic Arthritis




The introduction of highly effective therapies and clearly defined targets has altered the treatment paradigm in psoriatic arthritis (PsA). Validated classification criteria and outcome measures specific to PsA have helped standardize a therapeutic approach to this heterogeneous disease that affects multiple clinical domains. This article discusses the importance of early intervention using a treat-to-target strategy; emerging evidence for tight control based on minimal disease activity criteria; disease considerations specific to PsA (prognostic markers, biomarkers, subclinical disease, comorbidities); and new treatment strategies to deal with refractory disease (eg, tumor necrosis factor inhibitor switching and use of novel disease-modifying therapies) and controlled disease (eg, tapering or discontinuing biologic therapy).


Key points








  • Early diagnosis and implementation of highly effective therapies provides the possibility of achieving better outcome in PsA.



  • Tight control with frequent adjustments to medications and a treat-to-target approach to maintain low disease activity has shown clinical benefit.



  • Refractory patients pose a challenge, but strategies to overcome treatment failure exist (eg, switching TNF inhibitors or implementing alternative therapies). Evidence for these strategies is accumulating in clinical trials.



  • Patients well controlled on treatment may be able to taper or discontinue therapy, although the long-term outcome of such an approach remains unknown.



  • New and potentially effective therapies are currently in advanced stages of clinical development.






Introduction


Psoriatic arthritis (PsA) is a chronic inflammatory condition that affects approximately 0.3% of the general population and 20% to 30% of patients with psoriasis. It is a heterogeneous condition with diverse clinical manifestations or domains, including peripheral arthritis, axial arthritis, enthesitis, dactylitis, skin and nail psoriasis, and other manifestations. The severity of involvement varies widely within domains and among individual patients, often making determination of disease activity challenging.


There have been numerous advances in the understanding of and treatment approach to PsA in the last decade. Among these, increased experience with highly effective therapies, particularly tumor necrosis factor-α inhibitors (TNFi), has altered expectations and revolutionized the approach to treatment. Several questions have been raised regarding the optimal use of these medications and other newer biologic therapies in PsA.




Introduction


Psoriatic arthritis (PsA) is a chronic inflammatory condition that affects approximately 0.3% of the general population and 20% to 30% of patients with psoriasis. It is a heterogeneous condition with diverse clinical manifestations or domains, including peripheral arthritis, axial arthritis, enthesitis, dactylitis, skin and nail psoriasis, and other manifestations. The severity of involvement varies widely within domains and among individual patients, often making determination of disease activity challenging.


There have been numerous advances in the understanding of and treatment approach to PsA in the last decade. Among these, increased experience with highly effective therapies, particularly tumor necrosis factor-α inhibitors (TNFi), has altered expectations and revolutionized the approach to treatment. Several questions have been raised regarding the optimal use of these medications and other newer biologic therapies in PsA.




Early intervention


The importance of early intervention and initiation of therapy in PsA has become increasingly recognized (discussed elsewhere in this issue). This insight resulted mainly from the growing recognition that PsA is a more severe disease than previously thought, and the introduction of medications capable of altering the disease course in PsA. This section discusses early detection and diagnosis, early treatment, and highly effective therapy.


Early Detection and Diagnosis


The onset of skin disease precedes the onset of arthritis in greater than 80% of patients, often by more than a decade. Consequently, there is a unique opportunity in PsA to identify patients with musculoskeletal manifestations early in the disease course ( Fig. 1 ). There are several challenges to the early detection and diagnosis of PsA, including who should be screened and how screening should be performed. In addition, patients may be asymptomatic or minimally symptomatic, and may fail to report symptoms. Time constraints may also hinder a comprehensive evaluation.




Fig. 1


Early intervention is recognized as the best strategy to achieve optimal outcome in PsA. Screening questionnaires help identify PsA in patients with skin psoriasis. The CASPAR classification criteria can be used to help make the diagnosis. Identifying subclinical disease remains a diagnostic challenge.


To overcome these obstacles, several screening tools have been devised to help identify musculoskeletal manifestations of PsA ( Table 1 ). These tools were developed to assist dermatologists and primary care physicians in making an appropriate referral to a rheumatologist when PsA is suspected to ultimately make the diagnosis. The target population includes patients with a history of skin psoriasis and those with a family history of psoriasis or PsA.



Table 1

Screening tools developed and validated in dermatology and rheumatology cohorts



















































Screening Tools in Psoriatic Arthritis
Screening Tool Development Cohorts Clinical Practice
Sensitivity (%) Specificity (%) Sensitivity (%) Specificity (%)
PASE 82 73 74 38
ToPAS 87 93 77 30
PEST 92 78 77 37
PASQ 97 75
EARP 85 92
ToPAS2 96 99

A comparison of the performance of three screening tools in a study of patients recruited from dermatology clinics and subsequently assessed by a rheumatologist if a positive screening test was obtained.

Abbreviations: EARP, Early ARthritis for Psoriatic patients; PASE, Psoriatic Arthritis Screening and Evaluation; PASQ, Psoriatic Arthritis Screening Questionnaire; PEST, Psoriatic Epidemiology Screening Tool; ToPAS, Toronto Psoriatic Arthritis Screen.

Data from Refs.


Although these screening questionnaires have demonstrated good and comparable sensitivity and specificity in development cohorts, a recent study suggests they do not perform as well in clinical settings. This may be partly because patients can be asymptomatic, particularly in early stages of the disease.


Some limitations of currently available screening tests include potential for poor specificity. For example, it is often difficult to differentiate PsA from other musculoskeletal conditions that can accompany psoriasis, such as osteoarthritis and fibromyalgia. Moreover, recognition of patterns of PsA other than polyarticular disease can be challenging. Refinement of available questionnaires is currently underway in hopes of improving performance in clinical practice.


Following identification of a patient at risk for PsA, the next challenge is early diagnosis. Diagnosis, particularly in the early stages, requires differentiation from other rheumatic conditions at a time when many of the clinical features may not be present. Because the diagnosis of PsA at this stage is primarily clinical, with no pathognomonic serologic or imaging tests, the disease is frequently not identifed. Also, the wide clinical spectrum, even at disease onset, poses challenges in diagnosis, particularly in patients who lack skin disease.


In 2006, the CASPAR (Classification of Psoriatic Arthritis) classification criteria were published ( Box 1 ). They include several features distinctive to PsA and have helped make study populations more uniform in clinical trials. The CASPAR criteria have been validated in early and long-standing disease and have become widely accepted and used.



Box 1


Inflammatory articular disease (peripheral or axial arthritis, or enthesitis) PLUS greater than 3 points in the following five categories (validated in early and long-standing disease):



  • 1.

    Psoriasis: current (2), personal history (1), family history (1)


  • 2.

    Psoriatic nail dystrophy (1)


  • 3.

    Dactylitis: current or previous (1)


  • 4.

    Negative test for rheumatoid factor (1)


  • 5.

    Radiograph evidence of new juxta-articular bone formation (1)



Sensitivity, 91.4%; specificity, 98.7%.


CASPAR criteria have high sensitivity and specificity for psoriatic arthritis (points scored are listed in parentheses)

Adapted from Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a larger international study. Arthritis Rheum 2006;54:2665–73; with permission.


Advantages of the CASPAR criteria include accuracy in both family medicine and rheumatology clinics, ability to diagnose PsA in patients without psoriasis, and not excluding patients who are rheumatoid factor or anticitrullinated protein antibody positive. The last point is important because, although most patients with PsA are seronegative for rheumatoid factor and anticitrullinated protein antibody, numerous studies have shown the prevalence of both rheumatoid factor and anticitrullinated protein antibody is greater among patients with PsA than in the general population. The clinical relevance of this finding is still being elucidated. Excluding patients based solely on a positive test could lead to underdiagnosis.


In recent years, the potential severity of PsA has been increasingly recognized, particularly with regard to polyarticular peripheral arthritis, supporting the importance of early diagnosis and intervention. The high sensitivity and specificity of the CASPAR criteria, in early and long-standing disease, suggest they may also be used as diagnostic criteria for PsA.


Early Treatment


PsA was previously considered a mild form of arthritis, but is now recognized as an aggressive disease with the potential to cause significant joint damage and an impaired quality of life. Approximately 40% to 60% of patients experience a severe, deforming arthritis with early radiographic changes. In a prospective study of 129 patients with PsA treated with traditional disease-modifying antirheumatic drug (DMARD) therapy, erosive disease occurred in 47% of patients at 2 years, despite clinical improvement. A delay as short as 6 months from symptom onset to first rheumatologic assessment has been associated with development of peripheral joint erosions and worse functional outcome in PsA.


In the last decade, the availability of medications that can alter the disease course in PsA has generated new ideas concerning the optimal approach to managing early disease. It seems logical that ongoing joint inflammation would lead to subsequent damage and eventual loss of function. This temporal relationship suggests that controlling inflammation may prevent downstream sequelae. Early treatment has been proven effective in rheumatoid arthritis (RA); however, the effectiveness of early aggressive therapy in the management of PsA has not been established.


Evidence from McHugh and colleagues confirmed that early treatment with disease-modifying therapy has a positive impact on long-term morbidity in PsA: disease progression was noted to be worse in patients presenting with established disease (duration >2 years), emphasizing the importance of early therapeutic intervention. Hence, similar to RA, clinicians may have a “window of opportunity” in PsA, a period during which a more robust therapeutic response is observed compared with a less impressive response when the same agent is prescribed later in the disease course.


Highly Effective Therapy


Unlike traditional DMARDs, which do not prevent disease progression or decrease structural joint damage, TNFi effectively treats all domains of disease activity in PsA ( Fig. 2 ).




Fig. 2


TNF inhibitors in psoriatic arthritis effectively treat all signs and symptoms of inflammation, improve quality of life and functional status, and have been proven to decrease radiographic progression in peripheral joints.


Currently, five TNFi are approved for use in many countries worldwide for the treatment of PsA. Although no head-to-head trials have been conducted, an indirect comparison meta-analysis demonstrated no significant difference in the effectiveness of TNFi. Despite their proven efficacy, treatment recommendations suggest that use of TNFi be reserved for patients with moderate-to-severe disease. In general, they are used only after inadequate response with anti-inflammatory drugs, corticosteroids, and traditional DMARDs, although they may be used as initial therapy in certain situations.


Aside from TNFi, the US Food and Drug Administration recently approved the use of two other highly effective medications for use in the treatment of PsA: ustekinumab (an interleukin [IL]-12/IL-23 inhibitor) and apremilast (a phosphodiesterase 4 inhibitor). Data from phase III clinical trials have shown significant improvement in PsA signs and symptoms, skin disease, enthesitis, dactylitis, and physical function for both medications. Ustekinumab has also demonstrated efficacy in decreasing progression of radiographic damage.


Finally, there are several IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) in advanced-phase clinical trials. Available data suggest significant improvement in skin psoriasis, and efficacy in treating peripheral and axial arthritis.




Disease-specific considerations


Once likened to a mild form of seronegative RA, PsA is now recognized as a distinct clinical entity with unique features. One of the most striking differences is the significant heterogeneity that occurs in PsA. In addition to affecting multiple clinical domains, several associated extra-articular manifestations and comorbidities must also be taken into account when selecting therapy ( Fig. 3 ). The term “psoriatic disease” was coined to encompass the diverse clinical spectrum, which occurs in variable degrees of severity and may influence treatment decisions. This section discusses validated outcome measures, subclinical disease, prognostic markers, and comorbidities.




Fig. 3


After PsA is diagnosed, taking into account disease-specific considerations provides more comprehensive care and may influence treatment strategy. Highly effective therapies have changed the treatment paradigm in PsA with preliminary results of a treat-to-target approach showing benefit in clinical trials.


Validated Outcome Measures


Until recently, many outcome measures used in PsA have been extrapolated or borrowed from other conditions that share similar clinical features. Although many of these measures are validated in PsA, these borrowed disease activity indices do not cover all aspects of psoriatic disease and may, therefore, overlook disease activity in other domains.


The advent of therapies capable of altering disease outcome in PsA has been proven in numerous clinical trials. These trials highlighted the need for specific PsA outcome measures to quantify disease activity optimally. Currently validated instruments to measure all clinical manifestations seen in PsA were developed over the last several years ( Table 2 ). In addition, a core set of measures to be included in all clinical trials of patients with PsA was suggested; this change will allow meaningful comparisons across studies, an important step forward.



Table 2

Outcome measures assess individual domains or a composite of several different domains
































Outcome Measures Arthritis
Individual domains
Skin psoriasis PASI
Nail psoriasis NAPSI, mNAPSI
Axial arthritis BASDAI
Peripheral arthritis TJC, SJC, ACR20/50/70, PsARC, PsAJAI
Enthesitis LEI, MEI, MASES
Dactylitis LDI
Function/quality of life PsAQoL, FACIT-F, DLQI
Composite measures DAPSA, CPDAI, GRACE index, PASDAS

Core measures (six domains recommended to be included in all clinical trials) : skin activity, peripheral joint activity, health-related quality of life, patient global assessment, physical function, and pain.

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Novel Treatment Concepts in Psoriatic Arthritis
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