Psoriatic arthritis treatment to the target: a consensus, evidence-based clinical practice recommendations for the management of psoriatic arthritis and its concomitant clinical manifestations

We aimed to provide up-to-date, evidence-based and consensus-based recommendations for Treat-to-Target management of psoriatic arthritis (PsA) and associated clinical manifestations. In this recommendations, 14 key clinical questions were identified by scientific committee according to the Patient/Population, Intervention, Comparison, Outcomes and Timing (PICOT) approach. Literature Review team performed a systematic review to summarize evidence advocating the benefits and harms of available pharmacologic and non-pharmacologic therapies for psoriatic arthritis. Subsequently, recommendations were formulated. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A 3-round Delphi process was conducted with 19 experts whom were drawn from different governorates and health centers across Egypt with diverse in their experiences, including private, governmental workplace, tertiary university hospitals, and insurance hospitals. All rounds were conducted online. A consensus was achieved on the direction and the strength of the recommendations. An online questionnaire was sent to an expert panel who participated in the three rounds (response rate 100%). At the end of round 3, a total of 51 recommendation items, categorized into 6 sections to address the main 6 psoriatic arthritis categories, were obtained. Agreement with the recommendations (rank 7–9) ranged from 89.5 to 100%. Consensus was reached (i.e., ≥ 75%of respondents strongly agreed or agreed) on the wording of all the 51 clinical standards identified by the scientific committee. Algorithms for the management of psoriatic arthritis have been suggested. These recommendations provide an updated consensus on the pharmacological treatment of psoriatic arthritis and strategies to reach optimal treat-to-target outcomes in in common clinical scenarios, based on a combination of evidence and expert opinion. Best treatment decisions should be tailored to each individual patient situation.

Background Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that can affect up to 30% of subjects living with psoriasis over their lifetime course [1]. Psoriatic arthritis (PsA) is distinct from other inflammatory arthritic conditions in several aspects including pathogenesis, clinical manifestations as well as response to therapy [2]. Peripheral arthritis, spondylitis, dactylitis, and enthesitis are all musculoskeletal manifestations of PsA. Psoriatic skin patches and nail disease are two cutaneous symptoms of PsA. Patients with PsA have difficulties doing daily activities, which has a negative impact on their quality of life, and social involvement [3]. There are also other extra-articular symptoms of psoriasis, such as uveitis and inflammatory bowel disease (IBD). Obesity and metabolic syndrome, as well as depression and anxiety, are all linked to PsA [4]. All these factors play an important role in identifying the priorities to manage in psoriatic patients as well as their therapy selection [5][6][7]. The benefits of a treat-to-target approach for psoriatic arthritis were first revealed in the TICOPA trial (TIght COntrol of inflammation in early Psoriatic Arthritis) [8], but its translation into clinical practise necessitates a refinement of the conventional therapeutic routine. Given the disease's heterogeneity, it is possible that, under the Treat-to-Target (T2T) method, personalising therapy options to the individual's disease severity and accompanying comorbidities could improve this form of management.
Treatment guidelines are developed aiming at several goals: to educate clinicians, particularly in a landscape of changing therapeutics; to define 'best care' through processing of the best available scientific evidence and broad consensus; also, to simultaneously point out where there is little information to guide treatment decisions; to reduce inappropriate variation in care and set standards for quality control; to promote efficient use of resources; and to highlight the research that needs to be done to inform future care [6]. The overall objective of this guideline is to provide up-to-date, evidence-based recommendations for Treat-to-Target management of psoriatic arthritis and its associated clinical manifestations.

Design
The study design was developed using a qualitative synthesis of scientific evidence and consensus based on existing scientific evidence as well as clinical experience.
This was a multi-step procedure that followed the protocol of the "Clinical, Evidence-based, Guidelines" (CEG) program, which aimed to establish an actionable clinical gold standard for Treat-to-Target management of rheumatic and bone disorders. The manuscript's evidencebased section followed the preferred reporting items for systematic reviews and meta-analyses criteria for publishing systematic reviews [9]. The Egyptian Academy of Rheumatology led the project.

Core team
It is formed of 4 experts with recognized experience in rheumatology, particularly psoriatic arthritis. The core team supervised and coordinated the teamwork, assisted with developing the scope of the project and initial Patient/ Population, Intervention, Comparison, Outcomes and Timing (PICOT) [10] clinical questions, reached a consensus on the key questions to include in the guidelines, nominated the expert panel, and drafted the manuscript.

Literature review team
The literature evaluation was undertaken with the proper help in methodology and was led by two experienced literature review consultants and based on particular research questions established to focus on the diagnosis and treatment of psoriatic arthritis [11]. The search for items lasted from January 2000 to July 2021.

Data sources and search strategies
The PICOT questions (Table 1) were used to conduct the literature search in PubMed, Embase, and Cochrane Library databases. Literature search strategies were carried out to locate randomized clinical trials evaluating the efficacy of psoriatic arthritis and associated clinical manifestations quality improvement strategies published from 1990 to June 2021. The language was limited to English for practical reasons. The search strategies were made to be broad in order to find relevant material with high sensitivity. We used the following medical terms: (1) population: psoriasis, psoriatic arthritis, polyarthritis, peripheral arthritis, spondylitis, spondyloarthritis, spondyloarthropathy, sacroiliitis, axial joint disease, enthesitis, nail, psoriatic nail, uveitis, prognosis, prognostic factors.

Study selection
The relevant studies were selected by applying inclusion and exclusion criteria to the literature retrieved with the search strategies

Inclusion criteria
Studies published in English reporting on the ability to adopt treat to target management approach to induce remission in adult patients with psoriasis/psoriatic arthritis and its associated clinical manifestations. Systematic reviews, randomised controlled trials (RCTs), uncontrolled trials, observational studies such as cohort, case-control, and cross-sectional studies, and economic evaluations were among the articles considered. When numerous publications reported data from the same study, the most comprehensive data was used, while duplicate data was discarded. Studies were screened for inclusion or exclusion in two stages: first, titles and abstracts were evaluated, and then full-text reviews were conducted on those indicated as potentially relevant by the title/abstract screen.

Exclusion criteria
Editorials, commentaries, conference abstracts, and non-evidence-based narrative/personal reviews were excluded.

Study selection and data extraction
Two reviewers independently evaluated all reports for inclusion. A third investigator was consulted in the event of a disagreement. Year of publication, study design, number of patients, type, severity, and duration Table 1 Key questions for PSA guidelines 1-Early diagnosis of psoriatic arthritis 2-Role of radiological studies in PSA assessment 3-Disease activity assessment 4-Cut off points of remission and low disease activity, high disease activity 5-Monitoring: clinical/radiographic/functional 6-Treat to target strategy (1ry and alternative target) 7-Communication, shared decision making, self-management and patient education 8-Management of PSA patient presented with peripheral arthropathy 9-Management of PSA patient presented with dactylitis or enthesitis 10-Management of PSA patient presented with axial affection 11-Management of PSA patient with predominant skin or nail affection 12-Management of PSA comorbidities 13-Best approach to management in standard practice 14-Personalized management of psoriasis, dosage and/or dosing scheme, therapy duration, definition of treatment success, result, side-effects, and the number and reasons for drop-outs were all documented from each report.

Expert panel
The core leadership team nominated 19 participants. The criteria for their selection included having professional knowledge and experience (at least 8 years of experience) in the field of rheumatology, management of inflammatory arthritis as well as active participation in scientific research on inflammatory arthritic conditions. The Delphi method and the project's aim were included in the invitation extended to the experts. Those who accepted the invitation were told that they had to answer to the first round in order to participate in the subsequent rounds of voting. The expert panel aided in the development of the project's scope, the refinement of the PICOT questions, and the voting on the recommendations.

Key questions used to develop the guideline
This guideline was based on a series of structured key questions that define the target population, classification criteria, the intervention, diagnostic test, or exposure under investigation, the comparison(s) used, the outcomes used to assess efficacy, effectiveness, or risk, as well as when the proper management should be implemented. Formulation of clinical questions, structure of questions, search for evidence, critical evaluation and selection of evidence, presentation of results, and recommendations were all used to gather evidence to answer the clinical questions. The systematic literature search and, as an outcome, clinical care guidelines are based on these questions, as indicated in Table 1.

Developing the clinical care standards framework
Based on the answers to the structured key questions and the literature review, a structured template was developed to facilitate standardized identification of the guideline components. For each component, the format in which the recommendations/information will be provided and extracted, have been identified.

Delphi process
The Delphi method's focus is to create consensus forecasts from a group of experts in a structured iterative manner. Its methodology is based on a sequence of "rounds" of questionnaires sent to experts. The stages of the Delphi technique are usually as follows: (1) a panel of experts is assembled. (2) Forecasting tasks/challenges are set and distributed to the experts. (3) Experts provide preliminary predictions and justifications. In order to provide input, these are collated and summarized. (4) The experts receive comments, which they consider when revising their forecasts. This process can be repeated until there is a reasonable degree of agreement. (5) The final forecasts are created by combining the forecasts of the experts. The anonymity of this method is one of its most important qualities.

Consensus process
Three Delphi rounds were carried out to establish consensus regarding the T2T strategy in psoriatic arthritis. After the main aspects of the strategy were identified, a discussion group worked with the scientific committee to define the aspects that would be included in the questionnaire. The structured Delphi approach ensures that all participants' opinions are taken into account equally, and it is especially useful for geographically diverse centres like Egypt. Online surveys were used to conduct the Delphi procedure. Three survey rounds were used since this allows for enough contemplation on group responses and is thought to be the most effective method for reaching consensus [13]. In addition, free-text responses from Round 1 were included as new assertions in Round 2 and re-evaluated in Round 3 in light of the group consensus. The 14 domains involved in the T2T strategy were included in the first round of the electronic questionnaire.

Voting process
Three rounds of live online voting were held, each with a strict time limit. All members of the task force were invited to participate, and the start and end times of each round of voting were announced ahead of time. Anonymous votes were gathered and evaluated, and unique access links were sent out. At the same time as the voting procedure, comments on rephrasing, potential ambiguity, and unidentified overlaps were received for each statement. The task force members were the only ones who could vote on the statements.

Rating
Each statement was scored on a scale of 1 to 9, with 1 representing "total disagreement" and 9 representing "complete agreement. " Disagreement, uncertainty, and agreement are represented by the numbers 1-3, 4-6, and 7-9. It is not necessary for members to vote on all statements, and they are invited to abstain if they believe a statement is outside their area of competence. As a result, a vote of "uncertainty" indicates "inconvenience about the veracity of the recommendation. " All statements allow for comments, which are reviewed by the scientific committee after each round of voting. In all of the voting rounds, members were also asked to make comments wherever they voted a disagreement. This will allow the panel to notice a misinterpretation of a statement and invalidate the vote on that statement.

Definition of consensus
Definition of consensus was established before data analyses. It was determined that consensus would be achieved if at least 75% of participants reached agreement (score 7-9) or disagreement (score 1-3) [11,12,14,15]. If a statement received a mean vote of less than 3 or a 'low' level of agreement, it was retired. In view of the comments, statements with an uncertainty score of (4-6) were changed. The levels of agreement on each statement of recommendation were regarded as 'high' if all votes on a statement fell into the agreement bracket (7-9) following the second round of votes [16][17][18]. If the differences between round group responses were less than 10%, consensus was termed stable [19].

Chronogram of Delphi rounds
The first round took place between 10th and 13th July 2021 (4 days). The aspects about which respondents did not reach consensus in this first round were revised in view of the comments and included in the second round. The second round took place (1 week after the first round) and remained for 4 days, between 18nd and 21st July 2021 (4 days). The third round took place (2 weeks after the second round) and remained for 4 days between 28th and 30th July 2021 (4 days).

Ethical aspects
This study was performed in accordance with the Helsinki Declaration. This was a multistep process which followed the CEG initiative protocol (ethical approval code: 34842/8/21, ethical board Tanta University) aiming at setting up an actionable clinical gold standard for Treat-to-Target management of rheumatic and bone diseases. As per the Egyptian national Ethical Committee regulations, verbal informed consent was required from all the participants included in the study. All the participants included in the study gave their verbal informed consent. All the participants were kept anonymous, in compliance with data protection regulations.

Literature research and evidence selection
In the study selection process, 7498 potentially relevant studies were found by search strategy. 7287 were excluded for duplicate or after screening the titles and abstracts. So, relevant 211 studies were included as full article review plus additional 3 studies identified in an updated literature search. 127 studies were excluded as studies did not examine population or intervention of interest, did not match study design of interest, or did not report outcome measures of interest. Therefore, we included 87 studies in this work (Fig. 1). Definitions and cut-off points of remission were identified (Table 3).

Delphi round 1
Round 1 was done on key clinical questions to be included in this work. The response rate for round 1 was 100% (19/19). Consensus was reached on the inclusion of clinical standards on 95% of the items (i.e., ≥ 75% of respondents strongly agreed or agreed). Comments (excluding minor editing suggestions) were more frequent for management of PSA comorbidities. Table 1 showed Key questions for PSA guidelines.

Delphi round 2
The response rate for round 2 was 100% (19/19). Consensus was reached on the inclusion of clinical standards on 88.5% of the items (i.e., ≥ 75% of respondents strongly agreed or agreed). There were comments raised regarding the wording of some of the recommendations.
Comments (excluding minor editing suggestions) were more frequent on the statements regarding patients with peripheral arthritis. Diversity of opinion was greatest for the item "using combination therapy in patients presented with peripheral arthritis. " Two statements were retired, one statement for similarity to other statements and the other one was about Madrid sonography enthesitis index score. Three statements which were added, after round two, one of them were in overarching principles, another one in peripheral arthritis, and the third statement in patients with comorbidities. Several statements were revised after round two; most edited statements were in patients with peripheral arthritis: section (4 statements). The section of patients with dactylitis or enthesitis was divided further into two separate sections: one for patients with dactylitis and another one for patients with enthesitis sections).

Delphi round 3
The response rate for round 3 was 100% (19/19). Frequency of high rank recommendation (rank 7-9) ranged from 89.5 to 100. Consensus was reached (i.e., ≥ 75% of respondents strongly agreed or agreed) on all the clinical standards. Table 2 also shows the level of evidence assigned to each statement, in accordance with the Oxford Centre for Evidence-Based Medicine (CEBM) criteria as well as mean ± standard deviation and level of agreement. Agreement was unanimous  (>80% agreement) for the wording of the statements. Table 3 shows disease remission and low disease activity as clinical, ultrasonographic remission and functional response as we rely on these parameters on reaching the target of treatment.

Recommendations for management PSA
At the end of round 3, a total of 51 recommendation items, categorized into 6 sections (peripheral arthritis, dactylitis, enthesitis, axial affection, predominant skin or nail affection, and patients with comorbidities), were obtained. Tables 4 and 5 show the overarching principals and breakdown of statements of recommendations, its individual rank by Experts Opinion and level of agreement.

Application of the primary recommendations to standard clinical practice and personalized management
Clinical practice guidelines include recommendations meant to optimize patient care that are informed by the benefits and harms of alternative care options. Table 6 shows how personalized management can be applied on PSA and shows a scheme to treat psoriatic arthritis manifestations and its associated clinical manifestations, adopting a treat-to-target approach and identifying the cut-off points of remission. Clinical practice recommendations provide an assessment of the quality of the relevant scientific literature, as well as an assessment of the likely benefits and harms of a particular treatment, rather than prescribing a onesize-fits-all approach to patient care. This information allows health care clinicians to choose the best treatment for a specific patient based on their own preferences and in consultation with the patient. Therapy should be more customized based on the most presenting domain, prognostic variables, genetics, responsiveness to therapy, and comorbidity for each individual. Figure 2 shows an algorithm for personalized management approach presenting with PSA patients and/or one of its clinical manifestations.

Discussion
This work was carried out aiming at helping healthcare professional in managing their patients living with active PsA, including optimizing therapy to achieve treatment targets. PsA is distinct from other inflammatory arthritis in terms of pathogenesis, clinical manifestations and response to treatment [2]. The diversity of PsA manifestations, as well as its known associated comorbidities, make the patients respond variably to different lines of management. Despite the breakthroughs in treatment alternatives that have changed PsA management over the last two decades, there is still a scarcity of comparative efficacy/effectiveness data to guide treatment decisions [23]. As a result, it was critical to use an evidence-based, consensus decision-making approach, which is the best way to ensure that daily practice follows the clinical recommendations. The connection that closes the circle between evidence in the literature, clinical research, writing of guidelines, distributing them, and putting them into clinical practice will be the expert consensus [24]. Furthermore, despite evidence of efficacy of several therapy modalities from randomized controlled trials, the place of new medications in the treatment algorithm is now defined only by expert opinion [25]. All international treatment recommendations have supported the treat-to-target concept but have concluded that there is a lack of evidence to support what should be the primary target of PsA. Furthermore, since, for many PsA patients, complete remission may be difficult to attain, MDA, low or very low disease activity (VLDA) have been proposed as alternative goals. The ACR suggested that the clinically meaningful endpoint to assess the impact of interventions on PsA disease activity (treatment target) would be minimal disease activity (MDA) [26,27]. Despite an increase in drugrelated side effects, the Tight Control of PsA (TICOPA) research [8] found that treatment to target using the minimal disease activity (MDA) criteria improved clinical and patient-reported outcomes in PsA. The MDA criteria, on the other hand, include both remission and low disease activity and are not comparable to clinical remission/inactive illness. Disease Activity in Psoriatic Arthritis (DAPSA; focuses solely on arthritis), Composite Psoriatic Disease Activity Index (CPDAI), Psoriatic Arthritis Disease Activity Score (PASDAS), Psoriatic Arthritis Response Criteria (focuses solely on arthritis), and GRAPPA Composite Exercise Index are some of the composite disease measures that have been proposed. Additional instruments, such as the Psoriasis Area Severity Index (PASI) and assessments for the existence of dactylitis and enthesopathy, are added in RCTs to assess these manifestations [28][29][30]. These measures are all continuous and remission is generally defined as a score below a cut-off value; for example, very low disease activity (VLDA) is defined as meeting all 7 MDA cut-off points [20], Disease Activity in PsA (DAPSA) remission (≤ 4) [27], or PsA Disease Activity Score (PASDAS) near remission (≤ 1.9) [20]. VLDA and PASDAS are designed as composite measures of psoriatic disease, while DAPSA is a measure of peripheral arthritis disease activity only. This work considered 3 parameters as a target for therapy. These are clinical, ultrasonographic, and functional remission. Bearing in

The targeted subjects are patients who have psoriatic skin lesions and/or any psoriatic inflammatory musculoskeletal disorders
3. Treatment strategies are treat-to-target, and the targets should be sustained clinical remission or low disease activity.

The goals of treating patients with PsA are to control signs and symptoms; to prevent structural damage; to avoid comorbid conditions and drug toxicities;
and to optimize function, growth and development, quality of life, and social participation.

5.
It's advisable to use the cost effective therapy whenever possible. 6. Treatment to target by regularly assessing disease activity and adapting therapy accordingly is important to achieve these goals.   • Physiotherapy: adults with PsA should have access to specialist physiatrist, with periodic review to: improve general fitness and encourage regular exercise, learn about the short-term pain relief provided by methods such as transcutaneous electrical nerve stimulators (TENS).
• Psychological interventions: offer psychological interventions (for example, relaxation, stress management, and cognitive coping skills) to help adults with PSA adjust to living with their condition. • Diet therapy: Patients could be encouraged to follow the principles of a Mediterranean diet (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils, and it may be of value in management metabolic comorbidities.    arthritis, also updated GRAPPA added uvitis and IBD as new domains. In our recommendations; we agreed to GRAPPA recommendations in many subjects, but in our work we add other target to treat upon them as we consider clinical and ultrasonographic remission and functional response to reach the target of treatment. Also, we consider an important issue to non-pharmacological treatment modalities, and also in communication, shared decision-making, self-management, and patient education. Also, in this recommendation, we develop an algorithm which contain methods of assessment and disease activity measures which is not present in the updated GRAPPA recommendations. Also, we tried to be more personalized medicine manner by giving more focus on other comorbidities. Regarding the European League against Rheumatic Diseases (EULAR) which had published recommendations for the PsA management with pharmacological therapies [25,32]. On the other hand, traditionally, EULAR adopted an algorithmic approach that focused mainly on peripheral arthritis [25], and in the recent updated recommendation, more considerations have been given to the other manifestations, namely polyarthritis, oligoarthritis, enthesitis, dactylitis, and axial diseases [32]. Bearing in mind the high degree of heterogeneity in the presentation and course of PsA coupled with the involvement of multiple domains in a single patient, this guideline relied on a different strategy to choose the right treatment for every patient. This was achieved by individualising the choice of therapy by matching the most severely affected domains of the patients with the best available evidence of efficacies of therapies for those domains. In cases who do not respond to a medical therapy, cycling or shifting through other alternatives would be the rational steps. The treatment decision also considered the associated comorbidities, and the positive/negative impact of the chosen therapy.
The terminology used to describe the outcome of this work was "recommendations". The terms 'guidelines' and 'recommendations' are used differently by variable research groups. The American College of Rheumatology adopted the term 'guidelines' to describe to the full set of recommendations within the research work [23]. The term 'recommendations' which has been used by the EULAR [25]. The term recommendation is more malleable as leaves the final decision up to the physician and patient the rather than enforcing a 'guideline' , which is felt to be a term that is more stringent.
The main strengths of the study are related to the diversity as well as the expertise of the participants, the high levels of consensus achieved, and the agreement with the most recently published recommendations. Also, the adoption of the PICOT methodology approach as well as the Treat-to-Target outcome as the main pillars of this work.
Limitations of the guideline: Though the guideline reflects the best data available at the time the report was prepared, one of its limitations is the limited comparative evidence to inform selection of therapies. This incorporates the primary comparative benefit/efficacy and harms evidence. In view of the absence of head-to-head comparative studies identified in the literature review, indirect comparisons among trials/therapies were used for the purpose of this work. Another limitation is that we searched only English-language literature. Interpreting the data should be done with caution; the findings of future studies may need changes to the conclusions or recommendations in this report. In the interests of unique patients and special circumstances, it may be necessary or even advantageous to deviate from the standards.
In conclusion, this evidence/consensus-based recommendations did take into account the full complexity of PsA and the full range of possible therapies. It endorsed an individualized treatment approach tailored to the patient's predominant clinical manifestation and associated morbidity. The main objective is to help health care professionals as well as patients in making challenging disease management decisions and achieve remission of their disease activity status.