Abstract
As in other inflammatory rheumatic diseases, the objective of psoriatic arthritis (PsA) treatment is the achievement of a defined target. Recent recommendations propose aiming for remission or low disease activity; however, a consensual definition of remission is lacking. A state of minimal disease activity (MDA) has been established and is defined by low activity assessed by tender/swollen joint counts, tender entheseal points, Psoriasis Area and Severity Index or body surface area, patient pain and global activity visual analog scale, and functional evaluation by Health Assessment Questionnaire. Since its development, MDA has been used increasingly in studies and clinical trials. In this article, the potential use of MDA as a treatment target in PsA is reviewed. The frequencies of MDA achievement with biologic disease-modifying antirheumatic drugs are summarized based on data from registries, observational studies, and clinical trials. Predictors and the prognostic effect of attaining MDA are also evaluated.
- REMISSION
- DISEASE ACTIVITY
- BIOLOGIC THERAPY
- PSORIATIC ARTHRITIS
Historically, treatment options for psoriatic arthritis (PsA) were limited to nonsteroidal antiinflammatory drugs (NSAID) and conventional synthetic disease-modifying antirheumatic drugs (csDMARD) such as methotrexate (MTX), sulfasalazine, and leflunomide. These drugs, originally developed to treat rheumatoid arthritis (RA), have shown some benefit in treating inflammation and the heterogeneous symptoms of PsA1. However, over the past decade, the availability of targeted synthetic and biologic DMARD, including tumor necrosis factor (TNF) inhibitors, phosphodiesterase 4 inhibitors, interleukin (IL)-12/23 inhibitors, and IL-17A inhibitors, has revolutionized treatment, offering effective disease control for patients with NSAID and csDMARD toxicity and/or lack of efficacy2,3. Further, the availability of a greater range of treatment options has led to significant advances in treatment strategies for PsA. Specifically, a “treat-to-target” (T2T) approach to PsA management has been proposed, following its successful application in other rheumatic diseases, such as RA2,4,5.
Treating to target necessitates defining a quantifiable target; in PsA, this target is recognized as remission both by the international T2T task force and by the recently updated European League Against Rheumatism treatment recommendations2,6. Although the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations do not specifically recommend a treatment target, they do agree that the ultimate goal of therapy is to achieve the lowest possible level of disease activity in all domains of disease3.
Clinical remission or inactive disease, defined as “the absence of clinical and laboratory evidence of significant inflammatory disease activity,” is proposed as the major treatment target according to the T2T recommendations6. As remission by its most stringent definition may be difficult to attain in many patients, minimal or low disease activity has also been proposed as an alternative target for treatment6.
Despite the evolution of treatment recommendations, universally accepted and validated definitions of low disease activity and remission are currently lacking. Further, there is no consensus on the best measure of disease activity in PsA. Studies often refer to the RA-derived American College of Rheumatology (ACR) response criteria and sometimes to the 28-joint Disease Activity Score7. Because PsA is a multi-faceted disease that displays variability in both presentation and disease course, including not only synovitis but also extraarticular musculoskeletal inflammation (e.g., in the digits, entheses, and spine) and inflammation of the skin and nails, several PsA-specific composite measures of disease activity have been developed8,9. These include measures covering multiple domains of PsA (e.g., Composite Psoriatic Disease Activity Index7, Psoriatic Arthritis Disease Activity Score8, Psoriatic Arthritis Response Criteria10, and the GRAPPA Composite Exercise Index11), and the Disease Activity index for PSoriatic Arthritis (DAPSA), a composite measure of articular disease12. These measures are continuous, with remission subsequently defined as a level below a set cutoff value.
Minimal disease activity (MDA) is a “state” of disease activity in PsA rather than a continuous measure. It is a simple, easy-to-use index that is widely used in clinical and observational studies13, and has also been investigated as a treatment target in a randomized strategy trial5,13. The objective of our review was to summarize evidence gathered from clinical trials, observational studies, and registries regarding the achievement, and predictors thereof, of MDA in patients with PsA. The validity of MDA as a treatment target and the relevance of these data to the T2T strategy and to clinical practice are also discussed.
Our article was drafted following a Novartis-funded roundtable discussion attended by the authors and a patient representative in February 2016 to review the status of remission in PsA. The meeting included short presentations followed by moderated discussions. MDA featured prominently in these discussions, during which the authors identified a gap in the literature for a review article on this topic. Outcomes were analyzed thematically, with no formal method of gathering consensus.
The Concept of MDA
To our knowledge, MDA was first discussed for RA at the Outcome Measures in Rheumatology Clinical Trials (OMERACT) 6 conference in 2002, in response to challenges posed by targeting remission in its most stringent form. MDA was defined as “that state of disease activity deemed a useful target of treatment by both the patient and physician, given current treatment possibilities and limitations14.”
In PsA, MDA was developed based on the PsA core set of outcomes13. The operational definition of MDA in PsA was developed by a group of 60 experts, including both rheumatologists and dermatologists, who evaluated 40 patient profiles from an observational PsA database13. Statistical analysis allowed for cutoff points to be determined for several of the key core clinical components of PsA that were combined to form a single composite measure. In the resulting definition, a patient achieves MDA when 5 of the following 7 criteria are met: tender joint count ≤ 1; swollen joint count ≤ 1; Psoriasis Area and Severity Index ≤ 1 or body surface area ≤ 3%; patient pain visual analog score (VAS) ≤ 15; patient global disease activity VAS ≤ 20; Health Assessment Questionnaire (HAQ) Disability Index ≤ 0.5; tender entheseal points ≤ 1. Of note, MDA does not include acute-phase reactants and spondylitis activity.
Frequency of MDA in Randomized Controlled Trials
MDA has been assessed in several trials with biologic DMARD in PsA, including trials with TNF inhibitors, and more recently, the IL-17A inhibitor, secukinumab15,16,17,18,19,20.
TNF inhibitor therapy
Across the randomized controlled trials with TNF inhibitors, the proportion of patients achieving MDA is variable (24–52%, Table 1)15,16,17,18. It is noteworthy that about 45–56% of patients in the randomized controlled studies with TNF inhibitors, including those receiving placebo, were receiving MTX and the vast majority of patients were naive to previous biologic therapy. Longterm data from these trials indicate that MDA response rates were sustained in patients who continued the therapy (Table 2)15,18,21,22,23.
Short-term achievement of MDA in patients with PsA treated with anti–TNF-α therapies.
Longterm achievement of MDA in patients with PsA treated with anti–TNF-α therapies.
Secukinumab
To date, the fully human anti–IL-17A monoclonal antibody, secukinumab, is the only other approved biologic therapy with available data on MDA response rates19. In the FUTURE 2 study, treatment with secukinumab 150 mg and 300 mg resulted in 32% and 34% of anti–TNF-naive patients, respectively, achieving MDA at Week 16 versus 14% of patients with placebo (Table 3)19. In the roughly 35% of patients with a previous inadequate response or intolerance to anti-TNF therapy, 8% and 16% achieved MDA with 150 mg and 300 mg, respectively, versus 3% with placebo19. In the overall group, treatment with secukinumab 150 mg and 300 mg resulted in 23% and 28% of patients, respectively, achieving MDA at Week 16 versus 10% of patients with placebo. These response rates were all sustained through Week 5219.
Short-term and longterm achievement of MDA in patients with PsA treated with secukinumab in the randomized controlled trial, FUTURE 2.*
Higher MDA response rates were also observed in patients ≤ 2 years since diagnosis versus those > 2 years since diagnosis19. MDA response rates were in fact highest among anti–TNF-naive patients with disease duration ≤ 2 years who were treated with secukinumab 300 mg (50% at Week 16). Because skin involvement is one of the aspects that often prevents patients achieving MDA24, the high proportion of patients achieving MDA with secukinumab treatment may be a result of its superior efficacy in psoriasis25.
Frequency of MDA in Observational Studies
A number of real-world clinical studies have assessed MDA in patients with PsA (Table 2)26,27,28,29,30. In these observational and open-label cohorts, the proportion of patients treated with TNF inhibitors meeting MDA criteria at least once in 12 months ranged from 44% to 64%. With standard care, 60% of patients were found to achieve MDA on at least 1 visit, and 34% achieved MDA on consecutive visits for at least 12 months30. In an early PsA observational cohort, the Swedish Early PsA Register, 40% of patients achieved MDA at the 5-year followup, following treatment with predominantly DMARD or biologic therapies (etanercept, adalimumab, infliximab, or tocilizumab)29.
Predictors of Achieving MDA
If MDA is to be adopted in a real-world setting, it is imperative to understand which patient populations will be most likely to achieve MDA. To this end, predictors have been evaluated from both interventional and observational data from patients treated with biologic therapies.
In registries and observational studies, demographic characteristics such as younger age and male sex, lower functional impairment at baseline (assessed by the Bath Ankylosing Spondylitis Functional Index and HAQ), low disease activity at baseline, and other factors such as shorter symptom duration and greater general well-being (assessed by global VAS) have been reported as predictors of achieving MDA upon treatment with TNF inhibitors24,26,31,32.
Predictors of achieving sustained MDA include lower functional impairment, lower disease severity, lower enthesitis count, and absence of dactylitis at baseline28,30,33. The relationship between a low HAQ score at baseline and an increased likelihood of achieving MDA has been substantiated in a clinical trial setting with both golimumab (GOL)17 and adalimumab34, with evidence from the Adalimumab Effectiveness in Psoriatic Arthritis trial (ADEPT) also supporting the correlation between low baseline enthesitis and achievement of MDA. It remains unclear whether inflammatory burden, as measured by erythrocyte sedimentation rate and C-reactive protein (CRP), is a predictor of achieving MDA27,30,32.
A range of common comorbidities in PsA have also been identified as negative predictive factors for achieving MDA, including metabolic syndrome, increased weight, hepatic steatosis, carotid plaques, and coexistence of fibromyalgia35,36,37,38. There is also some evidence that successful weight loss may improve the attainment of MDA with anti-TNF therapies39.
Prognostic Relevance and Patient-relevant Effect of MDA
Emerging evidence suggests that achieving MDA may be of prognostic relevance. Sustained achievement of MDA has been shown to be associated with improved prognosis in terms of joint damage progression in both observational studies and registries15,31. Further, in a randomized controlled study with GOL, the 36% of patients who had MDA for ≥ 3 consecutive visits had significantly less radiographic progression compared with patients who did not reach MDA at 5 years18. Patients also experienced greater longterm functional improvements and improved patient global assessment of disease activity when they attained persistent MDA5. While low skin symptoms have been observed in patients with MDA in some trials5, achievement of MDA does not necessarily correlate with more improvements in skin symptoms15 because MDA is a multidomain outcome score.
The triad of persistent joint swelling, raised CRP, and baseline radiographic damage are all key for determining the longterm prognosis of patients with PsA31,40. Further research is required to assess the effect of MDA attainment, or lack thereof, on longterm prognosis of PsA.
MDA as a Treatment Target: The Tight Control in Psoriatic Arthritis Trial
To our knowledge, the first treatment strategy trial in spondyloarthritis was Tight Control in Psoriatic Arthritis (TICOPA), which had MDA as the treatment target5. In this trial, 206 patients with PsA were enrolled and randomly assigned to receive tight control or standard care. For the tight control strategy, patients were assessed at monthly intervals and had their treatment adjusted according to a strict treatment protocol based on whether they achieved MDA. Patients in the standard care arm were followed at 3-month intervals and managed according to the treating rheumatologist5.
At 12 weeks, 24% of patients in the tight control arm of the study had achieved MDA. Following escalation of treatment in 71% of the patients in this arm, the proportion of patients reaching MDA at least once through Week 48 increased to 72%5. In patients who were treated with MTX only, 22% achieved MDA at 12 weeks and continued with MTX monotherapy throughout the study41.
Serious adverse events were more frequent in the tight control group than the standard care group, and no differences were observed between the 2 treatment arms in radiographic progression, perhaps as a result of the overall low rate of progression in the relatively short duration of the study (48 weeks)5. Overall, the TICOPA trial provides evidence of the benefits of a T2T approach using MDA as a target in patients with early PsA. The T2T strategy significantly improved not only the primary clinical outcome, which is the ACR20 response criteria, but also more stringent clinical outcomes5. However, although the TICOPA study indicates that steering therapy toward MDA improves patient outcomes, this may also be achieved with other T2T measures that have not yet been tested, including objective measures of inflammation and/or other composite indices, some of which are mentioned below.
Incorporating MDA into Clinical Practice and Its Limitations
Several concerns remain regarding the validity of MDA as well as its incorporation into clinical practice. Further, although outside the scope of our review, the debate surrounding the most appropriate measure of disease activity in PsA is ongoing. Further studies to establish the relative merits of MDA versus other disease measures, particularly DAPSA-defined remission, are required (Table 4).
MDA research agenda.
Content validity
There are 3 potential issues with content validity for MDA. First, overlap between MDA and patient-reported outcomes needs to be addressed42. Second, the lack of acute-phase reactants as objective measures of inflammation could be considered a hindrance to the face validity of MDA. Finally, MDA includes a low level of HAQ, which may be difficult to achieve in an established disease irrespective of disease activity levels.
Relationship with imaging remission
Conflicting evidence has been shown regarding the relationship between ultrasound (US) remission and MDA43,44. Although a recent study suggested that MDA was predictive of US remission44, another study has shown the presence of US-verified active inflammation at PsA-specific sites in patients with MDA42. There is evidence that alternative measures of disease activity such as DAPSA may correlate better with US remission than MDA43. Magnetic resonance imaging (MRI) offers an alternative imaging tool for measuring disease activity in PsA, and unlike US, it can measure all disease manifestations, including osteitis45; however, the relationship between MRI and MDA has yet to be investigated.
Feasibility in clinical practice
Although our review has indicated reasonable percentages of patients achieving MDA in published studies, there is still the question of how low the target should be regarding inflammation. A variant of MDA (very low disease activity) has recently been proposed but remains to be validated9. Remission, and indeed MDA, may be an unattainable treatment goal in patients with particularly aggressive or established PsA, and the question of how to treat such patients also remains to be answered. Low disease activity may be a more attainable goal under these circumstances.
On top of these theoretical limitations, it also remains to be seen how practical MDA will be for everyday treating rheumatologists in clinical practice. Consultation times are often limited, so the relative simplicity or complexity of the MDA criteria versus other scores needs to be considered. MDA is certainly simpler than some other measures in PsA; however, it does necessitate a formalized assessment of enthesitis and skin involvement, as well as the HAQ Disability Index score in all patients. This full clinical assessment and the inclusion of HAQ may be limited in some clinics where such assessments are not routinely performed.
MDA and the patient’s perspective
The importance of shared decision making between the patient and the rheumatologist is well established2; although MDA may be deemed an appropriate target by the treating physician, this may not necessarily be the preference of a particular patient5. Recent data do indicate a link between MDA and patient-reported outcomes46,47, but further research is warranted. Patients may also have difficulty understanding MDA; initiatives to educate patients on the T2T strategy and simple definitions of measures and targets may therefore be beneficial to ensure its use in clinical practice.
Treatments strategies and MDA
The optimal treatment strategy for obtaining and maintaining MDA, in terms of treatment sequencing, combination, and tapering, is currently unclear. Additional strategy trials are required to investigate this topic. As alluded to previously, further longterm data assessing the relevance of MDA are also required. The prognostic relevance of MDA through 5 years has been assessed with GOL in a clinical trial setting18, but more data are required with greater numbers of patients treated with additional agents and in a real-world setting. Exactly what MDA and other composite outcomes are measuring, and to what degree reversible inflammatory disease is being evaluated, remains to be determined.
Limitations
The outcomes presented in our discussion are subject to some limitations. The key themes are based on the opinions of individuals with an interest in MDA, and gaps in the evidence may exist. A detailed review of other composite measures of disease is outside the scope of this article. Of the composite indices mentioned, DAPSA is covered in slightly more detail because of its inclusion as a target in the 2017 T2T recommendations6.
Status of MDA
Evidence from clinical trials and registries suggests that MDA may be an attainable treatment outcome in PsA. Data from the TICOPA trial provide proof of the concept that tight control of disease activity in PsA results in better outcomes than standard care5. Nevertheless, several open issues remain, including the longterm significance of achieving and maintaining MDA and whether MDA is the optimal treatment target in PsA. The treatment paradigm for PsA is likely to evolve further over the coming years and the key goal will be to identify the optimal treatment strategy to ensure the best outcomes for patients.
Acknowledgment
This article was drafted based on a gap in the literature identified by the authors during a roundtable discussion funded by Novartis to review the status of remission in PsA. We thank David Trigos, a patient representative, for providing his input during the initial discussion. Medical writing support was provided by Antonia Bowman, Ben Drever, and Saira Zaman, medical writers from Seren Communications, an Ashfield Company, part of UDG Healthcare PLC. Novartis provided funding for the writing.
Footnotes
This article was drafted following a roundtable discussion funded by Novartis and attended by the authors, for which they received honoraria from Novartis.
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- Accepted for publication August 16, 2017.
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