systematic literature review on psoriatic arthritis

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Research Article

Psoriatic arthritis screening: A systematic literature review and experts’ recommendations

Roles Conceptualization, Funding acquisition, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Affiliation Rheumatology Department, Hospital Can Misses, Ibiza, Spain

Roles Data curation, Formal analysis, Investigation, Writing – review & editing

Affiliation Rheumatology Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain

Roles Investigation, Validation, Writing – review & editing

Affiliation Primary Care, San Juan de la Cruz Health Center, Pozuelo de Alarcón, Madrid, Spain

Affiliation Rheumatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain

Roles Investigation, Validation, Visualization, Writing – review & editing

Affiliation Department of Dermatology, Hospital General Universitario de Alicante-ISABIAL-UMH, Alicante, Spain

Affiliation Dermatology Department, Hospital Universitario Infanta Leonor, Madrid, Spain

Affiliation Rheumatology Department, Hospital Universitario de Elda, Alicante, Spain

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Software, Supervision, Validation, Writing – original draft, Writing – review & editing

Affiliation Instituto de Salud Musculoesquelética, InMusc, Madrid, Spain

Roles Conceptualization, Funding acquisition, Methodology, Supervision, Validation, Visualization, Writing – review & editing

* E-mail: [email protected]

Affiliation Rheumatology Department, Hospital Universitari Parc Taulí, Sabadell, Spain

¶ Membership of the Cribado Working Group is listed in the Acknowledgments.

• Ana Urruticoechea-Arana, 
• Diego Benavent, 
• Fernando León, 
• Raquel Almodovar, 
• Isabel Belinchón, 
• Pablo de la Cueva, 
• Cristina Fernández-Carballido, 
• Estíbaliz Loza, 
• Jordi Gratacós, 
• Cribado Working Group

• Published: March 15, 2021
• https://doi.org/10.1371/journal.pone.0248571
• Peer Review
• Reader Comments

To analyze the performance of psoriatic arthritis (PsA) screening tools, examine their implementation in daily practice, and reach a consensus about the best screening tool for implementation in daily practice in different medical settings.

A systematic literature review (SLR), structured telephone interviews to hospitals, and a multidisciplinary nominal group meeting were all conducted. The SLR employed sensitive search strategies using Medline, Embase, and the Cochrane Library up to January 2020. Two reviewers independently selected articles that reported data on PsA screening tools and that included sufficient data to at least calculate the sensitivity and specificity of those tools ( e . g ., questionnaires, algorithms, specific questions, and biomarkers). The hospital interviews collected data regarding the process of suspected PsA diagnosis and referral to rheumatology, the implementation of PsA screening tools, and barriers and facilitators to implementation of those tools. In the nominal group meeting, a multidisciplinary team of experts discussed all these data and subsequently recommended a screening tool for implementation.

The SLR included 41 moderate-quality studies that analyzed 14 PsA screening tools, most of which were questionnaire-based tools. All of these studies reported a moderate-good performance but presented different characteristics regarding the time to completion or the number and type of items or questions. The implementation of screening tools was low (30.5%). The experts ultimately recommended regular use of a PsA screening tool, preferably the PURE-4 questionnaire.

Conclusions

The implementation of PsA screening tools like the PURE-4 questionnaire in daily practice likely improves the prognosis of PsA patients.

Citation: Urruticoechea-Arana A, Benavent D, León F, Almodovar R, Belinchón I, de la Cueva P, et al. (2021) Psoriatic arthritis screening: A systematic literature review and experts’ recommendations. PLoS ONE 16(3): e0248571. https://doi.org/10.1371/journal.pone.0248571

Editor: Emiliano Giardina, Universita degli Studi di Roma Tor Vergata, ITALY

Received: August 24, 2020; Accepted: March 1, 2021; Published: March 15, 2021

Copyright: © 2021 Urruticoechea-Arana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its supporting Information files.

Funding: This study was funded by an independent and unrestricted grant from Pfizer (Grant Number 53038823) awarded to JG and AUA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have read the journal’s policy and have the following competing interests: IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Amgen, Leo-Pharma, Pfizer-Wyeth, UCB, and MSD; EL has received research grants from Roche, AbbVie, Novartis, Amgen, Leo-Pharma, Pfizer-Wyeth, UCB, Astellas, BMS, Sanofi and MSD but these research grants received by EL are not associated with this study; DB received grants/speaker/research supports from Roche, Novartis and Abbvie but these grants and support received by DB are not associated with this study; PDC acted as consultant, advisory board member, honorary for speaking and participation in clinical trials with the following pharmaceutical companies: Abbvie, Almirall, Astellas, Biogen, Boehringer, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, and did not receive any funding, including in the form of salary, for this study from mentioned entities. FL has received honoraria from Novartis. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Introduction

Psoriatic arthritis (PsA) is a prevalent chronic inflammatory disease that is associated with joint destruction and disability [ 1 , 2 ]. According to previous studies, up to 30% of patients with psoriasis will develop PsA during the disease course, mostly after the onset of psoriasis and usually within 10 years of their skin disease’s first manifestations [ 3 ]. PsA is a heterogeneous and complex disease that has several patterns of joint involvement, including axial and peripheral disease, and other extra-articular manifestations like enthesitis, dactylitis, and uveitis [ 2 ].

Currently, undiagnosed PsA is common in patients with psoriasis. Several studies and meta-analyses reveal that between 5% and 15.5% of patients with psoriasis may have undiagnosed PsA [ 4 , 5 ]. Interestingly, it has also been shown that even a six-month delay in the diagnosis of PsA from symptom onset is associated with structural damage and worse long-term physical function [ 6 ]. Accordingly, several national and international consensus documents, as well as other projects, recommend a multidisciplinary approach that includes primary care physicians, dermatologists and rheumatologists, in order to establish effective strategies for early and accurate PsA detection [ 7 , 8 ].

Given this context, different variables have been identified to predict whether a person with psoriasis may develop PsA, including clinical characteristics of psoriasis such as the severity of psoriasis or the presence of certain features of psoriasis ( e . g ., scalp lesions, nail disease, and intergluteal/perianal psoriasis), the presence of soluble biomarkers, like highly sensitive C-reactive protein or certain susceptibility genes [ 9 – 11 ]. However, their prediction role is or remains unclear [ 10 , 12 ].

On the other hand, different questionnaires and strategies can be used to detect PsA in patients with psoriasis. Several simple and validated screening tests have been proposed, including the Psoriatic Arthritis Screening and Evaluation (PASE) tool [ 13 ], the Psoriasis Epidemiology Screening Tool (PEST) [ 14 ], the Toronto Psoriatic Arthritis Screen (ToPAS) [ 15 ], and the Early Arthritis for Psoriatic Patients (EARP) questionnaire [ 16 ]. More recently, the Psoriatic arthritis UnclutteRed screening Evaluation (PURE-4) questionnaire [ 17 , 18 ]. However, the heterogeneity, paucity of data regarding feasibility and applicability in clinical settings, and lack of consensus regarding which tool is best all hinder the widespread use of such screening tests [ 19 ].

Based on the details outlined above, we decided to perform a systematic literature review (SLR) to assess the performance of available PsA screening tools. We also conducted telephone interviews with rheumatology and dermatology departments to analyze the level of implementation of these tools and to identify barriers and facilitators to their implementation. Finally, we assembled a multidisciplinary nominal group to discuss which screening tool is most appropriate for implementation and to identify further actions.

This project was conducted using a pragmatic approach. First, we conducted an SLR of existing evidence in order to assess the performance of screening tools. Second, through structured telephone interviews with rheumatology and dermatology departments, we analyzed the implementation level of screening tools, as well as their related barriers and facilitators. Finally, a multidisciplinary nominal group meeting was held to discuss the results of the previous steps. This project was reviewed and approved by the ethical oversight committee of the Parc Taulí Hospital Universitari. This study was also conducted in accordance with Good Clinical Practice guidelines and the current version of the revised World Medical Association’s Declaration of Helsinki.

Participants consent was informed and obtained verbally. Before starting the telephone interview, participants were informed verbally by the interviewer about the objectives of the project, and that the results of the project were going be published in a scientific journal. It was also explained to the participants that the project would not collect any personal data. Then, all participants were asked to authorize and voluntary consent their participation in the project. If they accepted the conditions, the telephone interview continued, and if they did not, the telephone interview did not take place. To document the verbal consent, the interviews were recorded.

Systematic review of the literature

The coordinators of the study generated a review protocol that followed the structure of the Cochrane Collaboration. This protocol included the patient-intervention-comparison (PICO) question and selection criteria, as well as procedures and key terms for the design of the search strategies.

Studies were identified using sensitive search strategies in the main medical databases. For this purpose, an expert librarian designed and checked the search strategies. The strategy combined disease- and screening tool-related terms with a controlled vocabulary for specific MeSH headings and additional keywords. This included keywords like “psoriatic arthritis” and “screening” (see S1–S3 Tables in the S1 File ). The following databases were screened: Medline (PubMed) and Embase ( Embase.com ) from 1961 to January 2020, and the Cochrane Library until January 2020. All the retrieved references were managed using Endnote X5 (Thomson Reuters). Due to the number of retrieved articles from the main databases, we decided not to further investigate scientific meeting abstracts or other non-peer reviewed sources. Finally, a hand search was performed to review the references of the included studies.

Studies were included if they met the following pre-established inclusion criteria. Articles had to report on a PsA screening tool and had to include sufficient data to enable us to at least calculate the tool’s sensitivity and specificity. This included questionnaires, algorithms, the application of specific questions, and biomarkers, among others. There were no restrictions regarding the type of screening tool or setting (primary or secondary care). SLRs, randomized controlled trials (RCTs), and observational studies in English, French, or Spanish were all considered.

Screening of the studies, data collection, and analysis were performed by two reviewers (EL and DB). Both reviewers independently screened the titles and abstracts of the retrieved articles, considering the selection criteria. In the event of discrepancy, the reviewers discussed the articles in an attempt to reach an agreement. When consensus was not reached, a third reviewer (LC) was asked to resolve the issue. Articles from the previous selection process were then read in detail, which ultimately resulted in establishing a list of included studies. Data collection was also doubled by article and was independent. Similarly, when discrepancies were not resolved, the third reviewer (LC) took the final decision. The QUADAS-2 score was used to grade the quality of the RCTs [ 20 ].

Finally, evidence tables were produced that described the main characteristics of the included studies. Descriptive Results were expressed as either a number and percentage (%) for categorical tests and mean and standard deviation (SD), or median and interquartile range (p25–p75) for normal and no normal continuous variables, respectively. Information regarding diagnostic efficacy was collected through the validation dimensions provided in the articles included in the SLR: internal consistency (Cronbach’s alpha), intra- and interobserver reliability (intraclass correlation coefficient in quantitative tests and kappa in categorical tests), criterion validity (sensitivity, specificity, predictive values and likelihood ratios), and overall value of quantitative tests (ROC curve and AUC, along with their confidence interval). Meta-analysis was only planned for cases of homogeneity.

Hospital telephone interviews

We decided to invite a minimum of 60 hospitals, using the following selection criteria. Hospitals had to be part of the National Health System, with the availability of rheumatology and dermatology departments, geographical representativeness (centers all over the country), and representativeness regarding the type of hospitals (e . g ., general hospitals, county hospitals). The National Hospital Database was used to select the centers. The people responsible for the rheumatology and dermatology departments were contacted for interviews.

Subsequently, a structured telephone interview was conducted in those hospitals that agreed to participate. A trained researcher asked several questions regarding the following main topics: the process of suspected PsA diagnosis (in dermatology and primary care) and referral to rheumatology; the use of PsA screening tools, strategies, and pre-established criteria; and barriers and facilitators to implementation of PsA screening tools.

The structured telephone survey also collected data regarding the hospital’s features and its rheumatology and dermatology departments (e . g ., attended population, number of health professionals in the department, presence of a multidisciplinary care model).

Multidisciplinary nominal group meeting

Finally, a multidisciplinary nominal group meeting was held via video conference. This group comprised five rheumatologists, two dermatologists, and one primary care physician, who were selected according to the following criteria: 1) Rheumatologist, dermatologist or primary care physician; 2) Specialized in psoriatic disease with demonstrated clinical experience; 3) Clinical experience ≥8 years and/or ≥5 publications; 4) Participation in multidisciplinary projects in psoriasis and PsA; 5) Members of national and international medical societies. In the selection process a balanced territorial representation of Spain was considered. The number of rheumatologists was a bit higher compared with other health professionals because they have been specifically working in this field for a long time.

The group discussed the results of the SLR and telephonic interviews, and they then agreed on the best screening tool, which they recommend for implementation.

The search strategies retrieved 3,084 citations (including 429 duplicates). A flowchart summarizing the search results is presented in Fig 1 . After the first selection process, 2,594 citations were rejected and 61 were selected for detailed review. Subsequently, 27 citations were excluded [ 19 , 21 – 46 ], mainly because they did not provide data on screening tools’ performance (see S4 Table in the S1 File ). Finally, 41 studies were included (including seven from the secondary search) [ 10 , 13 – 17 , 41 , 47 – 81 ].

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https://doi.org/10.1371/journal.pone.0248571.g001

The main characteristics of the included studies are outlined in Table 1 and the results are presented in Table 2 . Most of the included studies were validation studies [ 13 – 17 , 47 , 50 , 54 , 58 , 64 , 68 , 77 , 78 ], cross-cultural validation studies [ 49 , 51 , 52 , 54 , 59 , 61 – 63 , 71 – 73 ], or diagnostic performance studies [ 10 , 53 , 55 – 57 , 60 , 65 , 67 , 69 , 70 , 74 , 75 , 80 , 81 ]. We also found other designs, including case-control studies [ 48 ], clinical trials [ 66 ], and prospective observational designs [ 79 ]. The oldest article was published in 2007 [ 13 ], while the most recent one was published in 2019 [ 47 , 49 , 72 , 73 ]. The quality, according to the QUADAS-2 scale, was variable but was moderate in most cases (see S5 Table in the S1 File for more information). However, when the QUADAS-2 scale was evaluated, the quality of the articles tended to decrease as the risk of bias was high or unclear in many articles, especially in terms of patient selection. Similarly, it must be noted that cross-cultural validations do not describe all the necessary requirements to be considered adequate, so we must be very careful with their results.

Main characteristics of the included studies.

https://doi.org/10.1371/journal.pone.0248571.t001

https://doi.org/10.1371/journal.pone.0248571.t002

We found great variability in the features of the patient samples. Some patients were recruited in primary care, while others were recruited in outpatient dermatology or rheumatology consultations (e.g., centers of excellence, specific consultations, multidisciplinary units, and regular consultations). The number of included patients varied from 54 [ 68 ] to 1,225 [ 74 ]. The percentage of men was slightly higher than women, and most patients were aged between 40 and 55 years. The duration of psoriasis also varied, with most patients presenting long-standing disease ranging between five [ 68 ] and 31 years [ 62 ]. Although baseline treatments were generally poorly described, some patients with psoriasis were on synthetic conventional and biological disease-modifying antirheumatic drugs (DMARDs). However, many of the included studies lacked a clear description of the underlying disease (see Tables 1 and 2 ). It was not always possible to ascertain the percentage of patients with mild, moderate, or severe disease. In addition, very few articles included healthy subjects or patients with other diseases, who were usually included in a differential diagnosis or cases of difficult diagnosis.

Although most of the analyzed studies included questionnaire-based tools (see below), other tools were also employed, such as the PsA-Disk (a novel 16-item visual instrument) [ 47 ] and a combination of serum biomarkers [ 48 ].

The following questionnaire-based tools were included in the present SLR: PEST [ 10 , 14 , 49 , 54 – 57 , 67 , 69 , 73 – 75 , 81 ], PASE [ 10 , 13 , 16 , 49 , 51 , 52 , 55 , 56 , 59 , 60 , 63 , 66 , 67 , 70 , 75 , 79 – 81 ], EARP [ 16 , 49 , 54 , 67 , 71 , 75 , 80 ], ToPAS [ 10 , 15 , 49 , 53 , 55 , 56 , 62 , 74 , 75 , 79 ], ToPAS 2 [ 61 , 78 ], SiPAT (45) [ 54 ], PURE-4 [ 17 ], CONTEST [ 49 , 56 – 58 ], GEPARD [ 65 , 72 ], PASQ [ 50 , 74 ], ePASQ [ 68 ], and SiPAS [ 77 ]. The number of items included in these questionnaires varied from 4 [ 17 ] to 15 [ 13 ], and the time to completion varied from less than five minutes to ten minutes ( Table 3 ).

https://doi.org/10.1371/journal.pone.0248571.t003

Most studies focused on assessing joint and soft-tissue involvement in PsA ( Table 4 ), all included questions related to joint inflammation, and many included questions about joint pain, dactylitis, and spinal involvement. Four of the questionnaires asked about a prior diagnosis of PsA. The only tools that included psoriatic skin involvement were ToPAS and ToPAS 2. Although most tools shared the same domains, the formulation of questions was generally very different. For example, in questions about dactylitis, PASE and EARP enquired whether the patient has swollen "sausage" fingers, which can facilitate understanding. PEST asked, "Have you ever had heel pain?" but EARP asked, "Has your Achilles tendon become swollen?” Some questionnaires, such as ToPAS and PEST, included images (e.g., of skin, nails) and/or homunculi to aid completion of the questionnaires. Some of the included studies also compared the diagnostic performance of various questionnaires in the same population [ 10 , 16 , 49 , 54 – 58 , 67 , 74 , 75 , 80 ].

https://doi.org/10.1371/journal.pone.0248571.t004

The gold standard for PsA diagnosis also varied. The CASPAR criteria were widely used [ 10 , 15 – 17 , 47 – 50 , 52 , 54 , 55 , 58 , 59 , 61 – 63 , 65 , 67 – 73 , 75 , 77 – 79 ], but the Moll and Wright criteria [ 13 , 51 , 60 ], rheumatologist’s criteria [ 14 , 50 , 53 , 56 , 57 , 64 , 74 ], and others were all also employed [ 80 ].

Diagnostic performance was analyzed using different outcomes, the most frequent of which were sensitivity, specificity, and AUC. Although different test cut-off points were sometimes analyzed, especially with PASE [ 51 , 52 , 70 , 76 ], a single cut-off was evaluated most of the time. Diagnostic performance was generally good/high but very variable. This was expected, and it is probably related to the type of population included and their recruitment.

The AUC of screening tools was higher than 80% in the majority of studies. This was not the case for the following individual studies, which are grouped by PsA screening tool: PASE [ 55 , 58 , 67 , 80 ], PEST [ 55 , 58 , 59 , 67 ], CONTEST [ 59 ], ToPAS [ 55 , 58 ], PASQ [ 14 ], and EARP [ 67 , 80 ].

Although sensitivities and specificities were generally high, we found a great variability in the results among studies. The data of sensibility were as follows: PEST ranged from 27.5% [ 10 ] to 92% [ 14 ], PASE ranged from 24% [ 10 ] to 100% [ 80 ], EARP ranged from 78% [ 49 ] to 100% [ 80 ], ToPAS ranged from 41% [ 10 ] to 95.8% [ 61 ], ToPAS 2 ranged from 87.2% [ 78 ] to 95.8% [ 61 ], SiPAT was 91% [ 54 ], PURE-4 was 85.7% [ 17 ], CONTEST ranged from 53% [ 57 ] to 86% [ 58 ], PASQ ranged from 67% [ 74 ] to 86.2% [ 50 ], ePASQ was 97.6% [ 68 ], and SiPAS was 79% [ 77 ]. Specificities were also variable but tended to be even higher than sensitivities: PEST ranged from 37.2% [ 55 ] to 98% [ 10 ], PASE ranged from 19.5% [ 80 ] to 94% [ 10 ], EARP ranged from 34% [ 67 ] to 97.2% [ 71 ], ToPAS ranged from 29.7% [ 55 ] to 97% [ 75 ], ToPAS 2 ranged from 87.2% [ 78 ] to 98% [ 61 ], SiPAT was 69% [ 54 ], PURE-4 was 83% [ 17 ], CONTEST ranged from 71% [ 57 ] to 91% [ 49 ], PASQ ranged from 64% [ 74 ] to 88.8% [ 50 ], ePASQ was 75% [ 68 ], and SiPAS was 87% [ 77 ].

Some of the included studies compared the diagnostic performance of several questionnaire-based tools in the same population [ 10 , 16 , 49 , 54 – 58 , 67 , 74 , 75 , 80 ]. Here, we list the screening tools from best to worst, according to the reported AUC: EARP > SiPAT > PEST [ 54 ], PEST > PASE > ToPAS [ 55 ], COTEST > PEST > PASE > ToPAS [ 58 ], PEST > CONTEST [ 57 ], PEST > EARP > ToPAS > CONTEST > PASE [ 49 ], PEST > EARP > PASE [ 67 ], EARP > PASE = ToPAS > PEST [ 75 ].

Telephone interviews

Overall, 68 hospitals in the National Health System were invited to participate, 36 of which accepted the invitation (response rate 53%). These hospitals were distributed throughout the country. Most were teaching hospitals (about half of them are considered referred centers) of different sizes (14% were county hospitals). These hospitals’ attended populations varied from <100,000 to >500,000 inhabitants. Thirty hospitals displayed implemented digitalization, such as electronic medical history and citations, while implementation was in progress in a further six hospitals. We found that 20 hospitals (55%) had a multidisciplinary care model for patients with psoriasis and PsA. Patients with suspected PsA were referred to rheumatology from primary care and especially from dermatology departments.

Eleven hospitals had implemented a PsA screening tool or system (30.5%). Some of these (n = 8) used questionnaire-based screening tools in dermatology departments ( e . g ., PURE-4, PEST, PASE, and modified CASPAR), while others used a system of four predefined questions (n = 2). We also identified one hospital in which primary care doctors that refer patients to that hospital followed specific training in psoriasis and PsA, which included a tele-medical consultation with a dermatologist so as to facilitate early referral of those with suspected PsA. None of the hospitals had analyzed the effectiveness of the screening tools.

Table 5 outlines the barriers and facilitators to implementation of PsA screening tools in clinical practice. In brief, the most reported barriers were lack of time, complexity of the disease, and number and heterogeneity of screening tools. On the other hand, increased collaboration and coordination among physicians, along with the use of new technologies, were identified as the main facilitators to implementing PsA screening tools.

https://doi.org/10.1371/journal.pone.0248571.t005

Nominal group meeting

Finally, a multidisciplinary nominal group meeting was held, in which the results of the SLR and hospital interviews were discussed. First, the experts considered implementing PsA screening tool in primary care and dermatology departments as very useful in order to achieve early diagnosis of PsA. The selection of a screening tool was mainly based on its characteristics and on the features of the Spanish National Health System. Considering most clinics are very busy, the experts agreed that a screening tool with high specificity should be selected, in order to avoid over-referral. However, they agreed that it must also be very simple (i.e., short and clear), homogeneous in primary and secondary care, and with good sensitivity. Finally, the experts proposed PURE-4 as the preferential screening tool to be implemented [ 17 ]. However, they found no reason to reject other tools, where they are considered appropriate in a given setting, and no reason to replace an existing tool that has already been implemented efficiently. The experts also suggested using the PURE-4 questionnaire at least once per year (but ideally less time), as well as when a patient with psoriasis presents with any suggestive clinical signs or symptoms.

This three-step project was designed to explore PsA screening tools, examine their implementation in clinical practice, and generate related recommendations. There are different PsA screening tools, but their performance is variable depending on the study. Despite its reported effectiveness, their implementation in clinical practice is low. The experts agree that the use of a PsA screening tool can be very useful in clinical practice. The same way they consider that the tool should have a good performance and be simple and clear.

Early referral to rheumatology is central in PsA. It has been observed that up to two thirds of PsA patients present at least one joint erosion at the first visit to a rheumatologist [ 83 ]. A significant association between late consulters with peripheral joint erosions and worse Health Assessment Questionnaire scores has also been observed [ 6 ]. Moreover, tight control of newly diagnosed PsA patients, including review every four weeks and escalation of treatment if minimal disease activity criteria are not met, showed significant improvement in joint outcomes [ 84 ].

We first performed an SLR to assess the characteristics and quality of existing PsA screening tools, regardless of their characteristics. The SLR identified different questionnaire-based screening tools [ 13 – 17 , 54 , 58 , 64 , 78 ], a visual instrument named PsA-Disk [ 47 ], and a combination of serum biomarkers [ 48 ]. Overall, diagnostic performance across these tools was good. However, the results were very variable. This may be partly explained by the heterogeneity of the studies’ designs and their included populations (characteristics and recruitment). Therefore, we must be very careful when interpreting the findings of these PsA screening studies. Moreover, when QUADAS-2 was applied, many articles reported a high or unclear risk of bias, especially with regards to patient selection, which cannot exclude an overestimation of the effect. For example, the study sample was not consecutive or random in many studies, while others lacked a clear description of age ranges, disease severity, type of cutaneous disease or treatments. In addition, only a few of the studies included healthy subjects or patients with other diseases, who should be included for differential diagnosis or in cases where making a diagnosis is difficult. Aligning with our observations, an SLR and meta-analysis that analyzed the diagnostic performance of questionnaire-based PsA screening tools found substantial heterogeneity across studies. Meta-regressions were subsequently conducted, in which age, risk of bias for patient selection, and the screening tool accounted for some of the observed heterogeneity [ 19 ].

We also included some articles that compared the diagnostic performance of different questionnaires in the same population [ 10 , 16 , 49 , 54 – 58 , 67 , 74 , 75 , 80 ]. Although the results were variable, PEST and EARP presented slightly better performance.

We would also like to highlight that there was great variability in the number of items and domains included in the questionnaires, as well as variability in the way questions were presented. This might have also influenced the results and probably influenced implementation of these tools in daily practice.

Considering all the limitations and considerations that are described above, determining which tool is the most useful for clinical practice is very complicated.

However, it is essential to note the lack of published data from secondary care regarding the level of implementation, feasibility, sensitivity, and specificity of such tools. This prompted us to conduct structured telephone interviews with rheumatology and dermatology physicians, as this enabled us to analyze PsA patients’ diagnostic journeys and explore the implementation of PsA screening tools, including their effectiveness (where possible) and barriers and facilitators to their implementation. Only one-third of hospitals reported the use of a PsA screening tool, which included questionnaires, predefined questions, or teleconsultations. All but one of these tools were implemented in secondary care; only one tool was implemented in primary care. Unfortunately, none of the hospitals evaluated the effectiveness of their screening tools in daily practice. However, several barriers to the implementation of PsA screening tools arose, most of which related to a lack of resources (including time or health professionals) and organizational issues. In this sense, more collaboration and coordination between levels of health care and among specialists was found to be essential to ensuring patients are referred in an appropriate and timely fashion, as well as to facilitate the implementation of PsA screening tools. The use of new technologies was also emphasized as a valuable facilitator.

Finally, the experts discussed the results of the SLR and interviews. We would like to comment that this project was performed by a multidisciplinary group of experts, representing all the health professionals involved in the screening of PsA, that have been working closely in different projects in psoriasis and PsA [ 85 – 87 ]. They first addressed the need for implementation of PsA screening tools, in order to facilitate early referral to rheumatology. Although no evidence indicated that a given tool is best, the experts proposed the PURE-4 questionnaire [ 17 , 18 ] as a promising tool for implementation, considering the features of the National Health System and its clinics. PURE-4 is a recently devised screening tool that only contains four easy-to-collect items. Little or no training is required for its effective implementation and performance. It is therefore suitable for busy clinic, especially in primary care. The experts underlined the simplicity of the questionnaire, its inclusion of some of the most characteristic signs and symptoms of PsA, and the exclusion of others that might lead to over-referral (e.g., spinal pain). Nevertheless, according to the experts, other screening tools are also viable options for implementation in settings that are considered appropriate. Besides, more research is needed with the use of PURE-4.

We would like to comment some of the strengths and limitations of the present study. We have addresses the problem from different perspectives. For this purpose we performed a SLR to assess the performance of PsA screening tools, telephone interviews to analyze the implementation of such tools, barriers and facilitators along with an expert consensus. On the other hand, PsA screening tools available evidence is heterogeneous, and there is a lack of data regarding to their implementation and effectiveness in daily practice. All of this complicates the decision-making. Finally, the selected group of experts tried to be representative including health professionals from rheumatology, dermatology and primary care. However we are aware that the first group was overrepresented and might have influenced some of the discussions.

In summary, early diagnosis and prompt treatment are crucial in PsA [ 4 – 6 ]. This is highlighted in the 2019 update to the EULAR recommendations for the management of PsA with pharmacological therapies [ 88 ]. The implementation of PsA screening tools could positively contribute to addressing this situation. In the context of busy clinics, the PURE-4 questionnaire could be a good means of implementing PsA screening.

Supporting information

S1 checklist. prisma 2009 checklist..

https://doi.org/10.1371/journal.pone.0248571.s001

https://doi.org/10.1371/journal.pone.0248571.s002

Acknowledgments

We would like to thank the Cribado working group for their contribution in the project : José Luis Pinto Tasende, Manel Pujol Busquets, Beatriz Joven, Fernando José Rodríguez Martínez, Eva Galindez, Rubén Queiro, Juanjo Lerma, Teresa Font, Jaime Calvo, Delia Reina, Manuel Moreno, Luis Espadaler, Alex Gómez-Gómez, Mª Dolores López Montilla, Irene Martin, Jose Luis Alvarez Vega, Julio Ramirez, Paulina Cuevas, Javier Manero, Lourdes Mateo, Elena Martínez Castro, Carmen Castro, Natalia Palmou, Carlos Rodríguez Lozano, Agustí Sellas i Fernàndez, Azucena Hernández, Andrea García Valle, Rosa Roselló, Javier Rueda Gotor, Susana Romero, Teresa Clavaguera, Trinidad Pérez Sandoval. The lead author for this group is Ana Urruticoechea-Arana ( [email protected] )

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• Published: 12 August 2021
• Psoriatic arthritis
• Oliver FitzGerald   ORCID: orcid.org/0000-0002-6607-6070 1 ,
• Alexis Ogdie 2 ,
• Vinod Chandran   ORCID: orcid.org/0000-0002-8297-0275 3 , 4 ,
• Laura C. Coates 5 ,
• Arthur Kavanaugh   ORCID: orcid.org/0000-0001-6942-5830 6 ,
• William Tillett 7 ,
• Ying Ying Leung 8 ,
• Maarten deWit   ORCID: orcid.org/0000-0002-8428-6354 9 ,
• Jose U. Scher   ORCID: orcid.org/0000-0002-1072-6994 10 &
• Philip J. Mease   ORCID: orcid.org/0000-0002-6620-0457 11  

Nature Reviews Disease Primers volume  7 , Article number:  59 ( 2021 ) Cite this article

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• Chronic inflammation
• Immunopathogenesis
• Rheumatic diseases

Psoriatic arthritis (PsA) is a complex inflammatory disease with heterogeneous clinical features, which complicates psoriasis in 30% of patients. There are no diagnostic criteria or tests available. Diagnosis is most commonly made by identifying inflammatory musculoskeletal features in joints, entheses or the spine in the presence of skin and/or nail psoriasis and in the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The evolution of psoriasis to PsA may occur in stages, although the mechanisms are unclear. In many patients, there may be little or no relationship between severity of musculoskeletal inflammation and severity of skin or nail psoriasis. The reason for this disease heterogeneity may be explained by differences in genotype, especially in the HLA region. New targeted therapies for PsA have been approved with additional therapies in development. These developments have substantially improved both short-term and long-term outcomes including a reduction in musculoskeletal and skin manifestations and in radiographic damage. With efforts underway aimed at improving our understanding of the molecular basis for the heterogeneity of PsA, a personalized approach to treating PsA may become possible.

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Acknowledgements

V.C. acknowledges support of the Pfizer Chair Rheumatology Research Award from the Department of Medicine, University of Toronto. L.C.C. is an NIHR Clinician Scientist funded by a National Institute for Health Research Clinician Scientist award. The research was supported by the National Institute for Health Research (NIHR) and the Oxford Biomedical Research Centre (BRC). Y.Y.L. is supported by National Medical Research Council, Singapore.

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Oliver FitzGerald

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Alexis Ogdie

Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

Vinod Chandran

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Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

Laura C. Coates

Center for Innovative Therapy, Division of Rheumatology, Allergy & Immunology, University of California, San Diego Medical School, San Diego, CA, USA

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Royal National Hospital for Rheumatic Diseases, Pharmacy and Pharmacology, University of Bath, Bath, UK

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Maarten deWit

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Introduction (O.F. and P.J.M.); Epidemiology (A.O.); Mechanisms/pathophysiology (O.F. and V.C.); Diagnosis, screening and prevention (L.C.C.); Management (P.J.M. and A.K.); Quality of life (W.T., Y.Y.L. and M.deW.); Outlook (J.U.S.); Overview of Primer (O.F.).

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Correspondence to Oliver FitzGerald .

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O.F. has received research grants and/or consulting fees from AbbVie, Amgen, Bristol Myers Squibb (BMS), Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc. and UCB. A.O. has consulted for AbbVie, Amgen, BMS, Celgene, Corrona, Gilead, Janssen, Lilly, Novartis, Pfizer and UCB, and has received grants from Novartis and Pfizer. Her husband has received royalties from Novartis. V.C. reports grants and personal fees from Amgen, grants and personal fees from AbbVie, grants and personal fees from (and other potential interest (spouse employment) in) Eli Lilly and personal fees from BMS, Janssen, Novartis, Pfizer and UCB, outside the submitted work. L.C.C. is a recipient of research funds from AbbVie, Amgen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer and UCB. She has received consultancy fees from AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Domain, Gilead, Janssen, Lilly, Novartis, Pfizer, Serac and UCB. She reports reimbursement for attending a symposium from Janssen and AbbVie, and fees for organizing education from UCB. She has received fees for speaking and hospitality from AbbVie, Amgen, BMS, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and UCB. A.K. conducted clinical trials sponsored by and/or consulted for Amgen, AbbVie, BMS, Eli Lilly, Janssen, Novartis, Pfizer and UCB. W.T. has received research grants, and consulting or speaker fees from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB. Y.Y.L. is supported by the National Medical Research Council, Singapore. She has received honoraria from Janssen, AbbVie, Novartis and DKSH. M.deW. has received fees for lectures or consultancy through Stichting Tools from Celgene, Eli Lilly, Pfizer and UCB. J.U.S. has received funding for investigator-initiated studies from Novartis and Janssen and has served as a consultant for Janssen, Novartis, Pfizer, Lilly, AbbVie, Sanofi and UCB. P. J. M. has received research grants from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun and UCB. He acts as a consultant with AbbVie, Amgen, Boehringer Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Sun and UCB. He has been a speaker for AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB.

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Psoriasis is a skin disease that causes itchy, scaly patches commonly on the extensor aspects of the knees and elbows and in the scalp.

The enthesis is the site of attachment of ligament to bone.

Rheumatoid factor is an anti-immunoglobulin antibody found commonly in patients with rheumatoid arthritis.

This peptide is an antibody found commonly in patients with rheumatoid arthritis.

Uveitis is inflammation of the uveal tract of the eye.

Inflammation of the sacroiliac joints

Synovitis is inflammation of the synovial tissue, which is normally a thin layer of tissue lining the inside of joints.

Joint erythema is one of the features of an inflamed joint or arthritis when the joint is red in appearance.

Dactylitis is sausage-like swelling of a finger or toe.

A questionnaire designed to screen for psoriatic arthritis in patients with psoriasis.

Treatment to target of remission is where treatment is escalated according to patient response until a target of remission has been achieved.

A questionnaire commonly used to assess disease activity in patients with ankylosing spondylitis.

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• Volume 13, Issue 11
• Systematic literature review and network meta-analysis of therapies for psoriatic arthritis on patient-reported outcomes
• Article Text
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• http://orcid.org/0000-0002-2571-788X Peter Nash 1 ,
• Jan P Dutz 2 ,
• Steve Peterson 3 ,
• Barkha P Patel 4 ,
• Kiefer Eaton 4 ,
• May Shawi 5 ,
• Federico Zazzetti 6 ,
• http://orcid.org/0000-0002-1235-0679 James Cheng-Chung Wei 7 , 8 , 9
• 1 School of Medicine , Griffith University , Brisbane , Queensland , Australia
• 2 Department of Dermatology and Skin Sciences , The University of British Columbia , Vancouver , British Columbia , Canada
• 3 Immunology Global Commercial Strategy Organization , Janssen Global Services LLC , Horsham , Pennsylvania , USA
• 4 EVERSANA , Burlington , Ontario , Canada
• 5 Immunology Medical Affairs , Janssen Global Services LLC , Horsham , Pennsylvania , USA
• 6 Immunology Medical Affairs , Janssen Latin America, LLC , Buenos Aires , Argentina
• 7 Department of Allergy Immunology & Rheumatology , Chung Shan Medical University Hospital , Taichung , Taiwan
• 8 Institute of Medicine , Chung Shan Medical University , Taichung , Taiwan
• 9 Graduate Institute of Integrated Medicine , China Medical University , Taichung , Taiwan
• Correspondence to Dr James Cheng-Chung Wei; jccwei{at}gmail.com

Objectives Head-to-head clinical trials are common in psoriasis, but scarce in psoriatic arthritis (PsA), making treatment comparisons between therapeutic classes difficult. This study describes the relative effectiveness of targeted synthetic (ts) and biologic (b) disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes (PROs) through network meta-analysis (NMA).

Design A systematic literature review (SLR) was conducted in January 2020. Bayesian NMAs were conducted to compare treatments on Health Assessment Questionnaire Disability Index (HAQ-DI) and 36-item Short Form (SF-36) Health Survey including Mental Component Summary (MCS) and Physical Component Summary (PCS) scores.

Data sources Ovid MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily),Embase and Cochrane Central Register of Controlled Trials.

Eligibility criteria Phase III randomised controlled trials (RCTs) evaluating patients with PsA receiving tsDMARDS, bDMARDs or placebo were included in the SLR; there was no restriction on outcomes.

Data extraction and synthesis Two independent researchers reviewed all citations. Data for studies meeting all inclusion criteria were extracted into a standardised Excel-based form by one reviewer and validated by a second reviewer. A third reviewer was consulted to resolve any discrepancies, as necessary. Risk of bias was assessed using the The National Institute for Health and Care Excellence clinical effectiveness quality assessment checklist.

Results In total, 26 RCTs were included. For HAQ-DI, SF-36 PCS and SF-36 MCS scores, intravenous tumour necrosis factor (TNF) alpha inhibitors generally ranked higher than most other classes of therapies available to treat patients with PsA. For almost all outcomes, several interleukin (IL)-23, IL-17A, subcutaneous TNF and IL-12/23 agents offered comparable improvement, while cytotoxic T-lymphocyte-associated antigen 4, phosphodiesterase-4 and Janus kinase inhibitors often had the lowest efficacy.

Conclusions While intravenous TNFs may provide some improvements in PROs relative to several other tsDMARDs and bDMARDs for the treatment of patients with PsA, differences between classes of therapies across outcomes were small.

• Adult dermatology
• RHEUMATOLOGY

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. The data underlying this article are sourced from the public domain and are available in the articles cited throughout.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2022-062306

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STRENGTHS AND LIMITATIONS OF THIS STUDY

The findings from this network meta-analysis highlight the importance of including health-related quality of life/patient-reported outcomes (PROs) as additional outcomes when assessing the totality of evidence for the most effective treatment options for patients with psoriatic arthritis (PsA).

To account for potential heterogeneity between trials, the analyses accounted for variation in placebo response through network meta-regression when model fit statistics suggested these adjusted models offered a better fit for the data.

This study relies on randomized controlled trial (RCT) data. As PsA is a chronic condition, alternate data should be explored to assess the long-term impact of treatments on PROs for PsA patients.

Introduction

Psoriatic arthritis (PsA) is a chronic, inflammatory disease with diverse clinical manifestations, including peripheral arthritis, axial disease, enthesitis, dactylitis and skin and nail psoriasis. 1 As a result of these various clinical symptoms, patients experience substantial physical and mental impairments that affect health-related quality of life (HRQoL) measured through patient-reported outcomes (PROs). 2

Several targeted synthetic (ts) and biologic (b) disease-modifying antirheumatic drugs (DMARDs) are currently approved for PsA. While clinical trials have assessed the safety, efficacy and influence on PROs of these agents relative to placebo, few have directly compared these therapies in head-to-head trials, making relative treatment comparisons difficult for clinicians and decision-makers. 3 4 When lacking direct evidence, network meta-analysis (NMA) is a well-established methodological approach that retains randomisation and can be used to assess treatment effectiveness indirectly through a common anchor, such as placebo. 5

We previously published a systematic literature review (SLR) and NMA comparing tsDMARD and bDMARD therapies for PsA on American College of Rheumatology responses, Psoriasis Area and Severity Index responses, van der Heijde-Sharp Score, adverse events and serious adverse events. 6 In these analyses, interleukin (IL)-23p19 subunit inhibitors (eg, guselkumab) demonstrated favourable skin efficacy and comparable joint efficacy relative to IL-17A (eg, secukinumab, ixekizumab), IL-12/23 (eg, ustekinumab 90 mg) and most tumour necrosis factor (TNF) alpha inhibitors (eg, adalimumab, etanercept). Notably, intravenous TNFs (eg, golimumab, infliximab) also demonstrated significantly better joint efficacy compared with subcutaneous agents of multiple classes. 6 However, relative treatment effectiveness in terms of PROs was not evaluated.

Compared with the general population, patients with PsA have significantly lower HRQoL across all dimensions of the 36-item Short Form (SF-36) Health Survey, including the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. 7 8 Along with SF-36, the Health Assessment Questionnaire Disability Index (HAQ-DI) allows assessment of physical functioning in PsA. 9 Both HAQ-DI and SF-36 PCS comprise the physical function part of the PsA Core Domain Set and were examined in this NMA due to their importance in clinical trials. 10 Although SF-36 MCS is excluded from the Core Domain Set, it was selected as an HRQoL measure that is useful for understanding the patient’s emotional well-being. 2 Taken together, the evaluation of PROs allows for a comprehensive assessment of treatment effectiveness on a variety of clinical domains that influence HRQoL. Therefore, the objective of this study was to compare the relative efficacy of the latest tsDMARD and bDMARD therapies available to treat PsA on HAQ-DI and SF-36 MCS and PCS through NMA.

Systematic literature review

Study methods are described in detail in our previous publication. 6 The SLR and NMA protocols were drafted a priori, registered with PROSPERO ( CRD42020152614 ) in April 2020, and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement 11 and the corresponding extension statement for NMA. 12

Briefly, the literature search was conducted by an experienced information specialist ( online supplemental data S1 ). Search strategies used a combination of controlled vocabulary and keywords (eg, psoriatic arthritis, biologic). Using the Ovid search interface, the following electronic databases were searched: Ovid MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily), Embase and Cochrane Central Register of Controlled Trials. The original search was conducted in October 2018 and updated in January 2020 to expand the comparator scope. A search of ClinicalTrials.gov was also performed in January 2020. There were no date restrictions on the search strategy or results.

Supplemental material

Prespecified inclusion and exclusion criteria were used to identify relevant studies ( online supplemental table S1 ). In brief, the PICOS included the following: Population—adult patients with active PsA; Intervention/Comparators—tsDMARDS, bDMARDs and placebo; Outcomes—no restriction on outcomes; and Study design—published phases II/III and III randomised controlled trials (RCTs).

Two independent researchers reviewed all citations at the title/abstract and full-text screening. Data for studies meeting all inclusion criteria were extracted into a standardised Excel-based form by one reviewer and validated by a second reviewer. A third reviewer was consulted to resolve any discrepancies, as necessary. On completion of data extraction from studies identified in the SLR, additional sources (ie, The National Institute for Health and Care Excellence (NICE), ClinicalTrials.gov) were searched to collect any additional data for the outcomes of interest. Data from the primary publications were used in the quantitative synthesis where available; data from supplementary full-text articles and sources were used where needed. NICE clinical effectiveness quality assessment checklist 13 was used to assess the risk of bias (quality) of RCTs at the study level; publication bias was not included as part of the assessment.

Network meta-analysis

NMAs were conducted using a Bayesian framework. 14–16 Network diagrams were used to visualise the evidence base for each outcome of interest (change from baseline in HAQ-DI, SF-36 MCS and PCS), where each treatment is shown as a node and trials as lines connecting these nodes. Data used in the NMAs were from the primary timepoint of assessment for each study, which varied from 12 to 24 weeks ( table 1 ).

• View inline

Summary of outcome data available for studies included in network meta-analyses

A continuous model was used to assess change from baseline in HAQ-DI, MCS and PCS scores. Treatment effects for continuous outcomes were modelled and reported on the mean difference (MD) scale. League tables from best-fitting models were used to present pairwise comparisons between available interventions in each network in terms of MD and associated 95% credible intervals (CrI). Within each table, the column header treatment is compared with the reference row treatment, with the highest-ranked treatments found at the top-left of the table. Pairwise results are interpreted according to overlap of 95% CrI with zero. When pairwise 95% CrI do not overlap with zero, there is a >95% probability that treatments are different, summarised as describing one treatment as ‘better’ or ‘worse’ than the other, according to the direction of effect. For pairwise 95% CrI that do overlap with zero, treatments are described as ‘comparable’, although point estimates may trend in favour of one treatment over another.

The approach to model selection was conservative, with random effects models conducted by default, as clinical heterogeneity has been described in previous PsA NMA publications. 17–19 Fixed-effect models were considered when evidence networks were limited (ie, comprised entirely of single or double-study connections) rendering random effects models underpowered. To account for heterogeneity, meta-regressions on baseline risk were considered for all analyses to adjust for variations in placebo response across trials, an important effect modifier in PsA that represents a proxy for variation in measured and unmeasured effect-modifying variables. 15 Criteria outlined in NICE Decision Support Unit Technical Support Document (TSD) series 14–16 were used to assess model fit.

Analyses were conducted using R (R Core Team, Vienna, Austria) and JAGS, based on code reported in NICE Evidence Synthesis TSD Series. 14–16 Convergence was confirmed using the latest implementation Gelman-Rubin diagnostic ( Rhat ) based on four chains ( online supplemental data S2 ). Models were fit using four chains and used vague priors. An unrelated mean effects model was used to test for the presence of inconsistency.

Patient and public involvement

Slr results.

In total, 3804 citations were identified; 113 citations reporting on 66 trials were included in the qualitative assessment. 6 Studies were excluded from the NMAs because they included a treatment or dose regimen that is not approved by the European Medicines Agency or Food and Drug Administration, they did not include a biologic or were a phase II study. In total, 26 phase III trials (62 citations) that evaluated tsDMARDs and bDMARDs that were approved by the US Food and Drug Administration or the European Medicines Agency for treatment of active PsA were included in the NMAs. Studies evaluated inhibitors of the following treatment classes: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; abatacept), IL-12/23 (ustekinumab), IL-17A (ixekizumab, secukinumab), IL-23 (guselkumab), Janus kinase (JAK; tofacitinib), subcutaneous TNF (adalimumab, certolizumab, etanercept, golimumab), intravenous TNF (golimumab, infliximab) and phosphodiesterase-4 (PDE4; apremilast). The IL-17 receptor A inhibitor brodalumab and JAK inhibitor upadacitinib were not approved for PsA at the time of the search (October 2018 to January 2020). Studies identified in the SLR are detailed in our original review. 6 The PRISMA diagram for the selection of these studies is presented as online supplemental figure S1 .

Table 1 summarises the data available for use in the NMAs according to each outcome assessed. Of the 26 trials included, SF-36 MCS was reported by 16, and HAQ-DI and SF-36 PCS were reported by 24. Of note, the SPIRIT-H2H trial did not report any of these outcomes at the time of the search. The primary timepoint of assessment varied from 12 to 24 weeks across studies, but was consistent within each treatment, except for the IL-17A inhibitor secukinumab, which varied from 16 to 24 weeks across the FUTURE trials. 20–23 Most trials were either bDMARD naïve or had a mix of bDMARD-naïve and bDMARD-experienced patients; only two trials were conducted in an entirely bDMARD-experienced population. 24 25 Risk-of-bias assessments are presented in online supplemental table S2 . The random sequence generation, incomplete outcomes, blinding of participants and selective reporting generally had a low risk of bias across the trials. The allocation concealment, blinding of personnel and outcome assessment had more unclear risk. A high risk of bias was rarely detected in any of the categories, for any of the included RCTs.

NMA results

No inconsistency was observed across networks ( online supplemental tables S3–S5 and figures S2–S4 ). A conservative approach to the interpretation of results was used (see Methods for a detailed description). A baseline risk-adjusted, random effects model provided better model fits for analyses of SF-36 PCS, while unadjusted, random effects models were preferable for HAQ-DI and SF-36 MCS ( online supplemental table S6 ). The league table of results from the non-preferred, unadjusted model of SF-36 PCS is presented in the online supplemental material R2 .

Health Assessment Questionnaire Disability Index

Change from baseline in HAQ-DI Score was reported in 24 studies. All treatments were anchored to placebo through single study or multistudy connections ( figure 1 ). Most classes had comparable improvement in scores, including most subcutaneous TNF, IL-23, IL-17A, IL-12/23, JAK and CTLA-4 inhibitors ( figure 2 ). Intravenous golimumab was better than agents in all other classes except for subcutaneous etanercept. The PDE4 inhibitor apremilast had worse scores versus most TNF inhibitors, as well as IL-23 inhibitor guselkumab 100 mg every 4 weeks (Q4W) and both doses (80 mg every 2 weeks and 80 mg Q4W) of IL-17A inhibitor ixekizumab. Similar scores were observed between CTLA-4 and JAK and PDE4 inhibitors. All classes had better change from baseline scores versus placebo, except for IL-17A inhibitor secukinumab 150 mg without a loading dose and CTLA-4 modulator abatacept 125 mg.

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Evidence network for HAQ-DI. BIW, twice weekly; HAQ-DI, Health Assessment Questionnaire Disability Index; LD, loading dose; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks.

League table of mean differences for change from baseline in HAQ-DI. Interventions are ordered from top-left to bottom-right in order of decreasing mean rank. For each pairwise comparison, the row treatment serves as the reference group. Pairwise comparisons from the unadjusted, random effects NMA model are shown in terms of MDs and 95% CrIs. An MD<0 favours the treatment in a given column. MDs with CrIs that do not span zero are shown with a grey background. ABA, Abatacept; ADA, adalimumab; APL, apremilast; BIW, twice weekly; CERT, certolizumab; Crl, credible interval; CTLA-4i, cytotoxic T-lymphocyte associated antigen 4 inhibitor; ETA, etanercept; GOL, golimumab; GUS, guselkumab; HAQ-DI, Health Assessment Questionnaire Disability Index; IL-17Ai, interleukin-17A inhibitor; IL-12/23i, interleukin-12/23 inhibitor; IL-23i, interleukin-23 inhibitor; INF, infliximab; IXE, ixekizumab; JAKi, Janus kinase inhibitor; LD, loading dose; MD, mean difference; NMA, network meta-analysis; PBO, placebo; PDE4i, phosphodiesterase-4 inhibitors; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; SEC, secukinumab; TNFi, tumour necrosis factor inhibitor; TOF, tofacitinib; UST, ustekinumab; WT, weight-based (ie, intravenous).

SF-36 MCS and PCS

In total, 16 trials reported change from baseline in SF-36 MCS. All treatments were anchored to placebo through single study or multistudy connections ( online supplemental figure S5 ). Intravenous TNF inhibitors had better scores versus subcutaneous TNF inhibitors certolizumab 400 mg and adalimumab, as well as CTLA-4 inhibitors, but were comparable to JAK, IL-12/23 and IL-17A inhibitors ( figure 3 ). Out of the eight classes available, five had better scores versus placebo, including intravenous TNF, IL-23, IL-12/23 and JAK inhibitors, as well as subcutaneous TNF inhibitor certolizumab 200 mg.

League table of mean differences for change from baseline in SF-36 MCS. Interventions are ordered from top-left to bottom-right in order of decreasing mean rank. For each pairwise comparison, the row treatment serves as the reference group. Pairwise comparisons from the unadjusted, random effects NMA model are shown in terms of MDs and 95% CrIs. An MD>0 favours the treatment in a given column. MDs with CrIs that do not span zero are shown with a grey background. ABA, Abatacept; ADA, adalimumab; BIW, twice weekly; CERT, certolizumab; Crl, credible interval; CTLA-4i, cytotoxic T-lymphocyte associated antigen 4 inhibitor; ETA, etanercept; GOL, golimumab; GUS, guselkumab; IL-17Ai, interleukin-17A inhibitor; IL-12/23i, interleukin-12/23 inhibitor; IL-23i, interleukin-23 inhibitor; INF, infliximab; IXE, ixekizumab; JAKi, Janus kinase inhibitor; MCS, Mental Component Summary; MD, mean difference; NMA, network meta-analysis; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; SF-36, 36-Item Short Form Survey; TNFi, tumour necrosis factor inhibitor; TOF, tofacitinib; UST, ustekinumab; WT, weight-based (ie, intravenous).

In total, 24 trials reported change from baseline in SF-36 PCS. All treatments were anchored to placebo through single study or multistudy connections ( online supplemental figure S6 ). Comparable scores were observed for IL-23 and all TNF inhibitors ( figure 4 ). Specifically, intravenous TNF inhibitors had better scores than IL-12/23, JAK, PDE4, CTLA-4 inhibitors and both 150 mg doses of IL-17A inhibitor secukinumab, which were all comparable to one another. Both IL-23 inhibitors had better scores than both 150 doses of secukinumab and PDE4 inhibitors. All classes had better scores versus placebo. Conclusions were broadly similar in non-preferred models that did not adjust for placebo response, although ranks for both doses of IL-23 inhibitors were lower and scores were worse than TNF inhibitors infliximab and etanercept ( online supplemental figure S7 ).

League table of mean differences for change from baseline in SF-36 PCS. Interventions are ordered from top-left to bottom-right in order of decreasing mean rank. For each pairwise comparison, the row treatment serves as the reference group. Pairwise comparisons from the baseline risk-adjusted, random effects NMA model are shown in terms of MDs and 95% CrIs. An MD>0 favours the treatment in a given column. MDs with CrIs that do not span unity are shown with a grey background. ABA, Abatacept; ADA, adalimumab; APL, apremilast; BIW, twice weekly; CERT, certolizumab; Crl, credible interval; CTLA-4i, cytotoxic T-lymphocyte associated antigen 4 inhibitor; ETA, etanercept; GOL, golimumab; GUS, guselkumab; IL-17Ai, interleukin-17A inhibitor; IL-12/23i, interleukin-12/23 inhibitor; IL-23i, interleukin-23 inhibitor; INF, infliximab; IXE, ixekizumab; JAKi, Janus kinase inhibitor; LD, loading dose; MD, mean difference; NMA, network meta-analysis; PBO, placebo; PCS, Physical Component Summary; PDE4i, phosphodiesterase-4 inhibitors; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; SEC, secukinumab; SF-36, 36-Item Short Form Survey; TNFi, tumour necrosis factor inhibitor; TOF, tofacitinib; UST, ustekinumab; WT, weight-based (ie, intravenous).

Currently available treatment options for PsA include several classes of tsDMARDs and bDMARDs, but few studies have directly compared these treatments through head-to-head RCTs. NMAs can estimate the relative effectiveness of these treatments in the absence of direct comparisons to help inform evidence-based decision-making for clinicians. 14–16 Our original NMA compared multiple classes of PsA treatments on skin and joint efficacy 6 and found that the IL-23 inhibitor guselkumab was comparable to IL-17A and subcutaneous TNF inhibitors on joint efficacy and had among the highest efficacy on skin outcomes relative to other treatments. Intravenous TNFs (ie, golimumab, infliximab) offered the highest joint responses. Findings from the current NMA offer additional insight into the effectiveness of tsDMARDS and bDMARDS on PROs, measures which are critical to the HRQoL of patients living with PsA. 2

Overall, these latest results suggested that some intravenous TNF therapies provide greater efficacy relative to most other classes of therapies for HAQ-DI. For SF-36 MCS and PCS scores, most agents offered comparable improvement. For almost all outcomes, several IL-23, IL-17A, subcutaneous TNF and IL-12/23 agents offered comparable improvement, while CTLA-4, PDE4 and JAK inhibitors had the lowest efficacy. Although the use of intravenous TNFs for PsA may vary by region or country, these findings suggest that this class of therapy may offer some benefits in PROs relative to other tsDMARDs and bDMARDs; however, differences between classes of therapies across outcomes were small.

The findings for HAQ-DI are in line with a 2020 NMA evaluating the efficacy of tsDMARDs and bDMARDs in patients with PsA who were either naïve to TNF inhibitor therapy or who had an inadequate response. 26 The authors found that etanercept 25 mg two times per week was the highest median ranked therapy in change from baseline HAQ-DI scores and significantly better versus all comparators assessed in the TNF-naïve population. However, no data were reported for any intravenous TNF therapies. In the population with an inadequate response to TNF inhibitors, IL-17A inhibitor, ixekizumab 80 mg Q4W and Q2W were the highest median ranked therapy in change from baseline HAQ-DI scores; however, data were not reported for any intravenous or subcutaneous TNF inhibitor. In addition, the superiority of TNF inhibitors on HAQ-DI is consistent with a systematic review, NMA and economic evaluation of these biologic agents for the management of active PsA. 27 Our NMA adds further support for the efficacy of TNF inhibitors for PsA treatment.

This study has several strengths. First, the relative efficacy of all targeted therapies for PsA was compared, including the latest IL-23p19 inhibitor, guselkumab, which is largely absent from previous NMAs in PsA. Second, the checklist used to assess the methodology of the RCTs included in the NMA indicated trials were of sufficient quality, as the risk of bias was generally low. Third, this study included SF-36 MCS and PCS, PROs which are critical to understanding the patient experience, treatment effectiveness and disease management. 2 In the current analysis, HAQ-DI was selected as it is a meaningful clinical outcome that captures the extent of disability a patient experiences due to PsA. 9 It should be noted that other composite measures exist (eg, Disease Activity Index for PsA, Minimal Disease Activity, Very Low Disease Activity, PsA Disease Activity Score), but are not as commonly reported. Further research may include these measures to the extent that they are sufficiently reported across studies. Although the EuroQoL 5-Dimension Health Questionnaire health utility scores are also important HRQoL measures, they were not sufficiently reported in many studies to warrant exploration in our NMAs. Lastly, two strengths consistent with our previous NMAs include: (1) adopting a conservative approach to interpretation of results, relying on overlap of pairwise 95% CrI, with no difference to determine comparability of treatments and (2) accounting for variation in placebo response through network meta-regression when model fit statistics suggested these adjusted models offered a better fit for the data. The latter point is an approach that aligns with NICE TSDs. 14–16 These baseline risk-adjusted models can account for both measured and unmeasured effect modifiers, including timepoint of assessment, prior biologic therapy status and other variables that may influence treatment effects, which can reduce heterogeneity, as previously observed in psoriasis. 17 Although not all networks were best fit by a baseline risk-adjusted model, such as HAQ-DI and SF-36 MCS, these models did not reveal a mild-to-moderate relationship between placebo response and treatment effect ( online supplemental table s6 ).

There are some limitations associated with the SLR. First, few studies provided direct evidence from head-to-head trials, which is common in NMAs. 28 While we intended to include head-to-head data from the SPIRIT-H2H trial identified in the SLR, no data were available for the outcomes of interest at the time of the search, limiting the ability to measure inconsistency through any closed loops in the networks. Third, limiting the SLR to English-only trials, while common, may result in biased estimates of effect and reduce generalisability. 29 Relatedly, publication bias was not assessed, which may have also influenced the NMA findings. Lastly, the SLR was conducted in 2020 and should be updated to include more recent trial data. For instance, inclusion of the COSMOS trial evaluating IL-23 inhibitors in patients who have had an inadequate response to prior TNF therapy will further broaden the evidence base available for analysis.

There are also additional limitations regarding inherent differences among the trials included in the NMA. First, the timepoint of assessment from each study varied from 12 to 24 weeks, which may introduce some heterogeneity in findings. Second, analyses included both bDMARD-naïve and bDMARD-experienced populations, including patients with no prior exposure to anti-TNF therapy, as well as inadequate response or intolerance to prior anti-TNF therapy. Although inclusion of both populations allowed a broader evidence base to explore outcomes, this may have been at the cost of potentially introducing heterogeneity associated with prior bDMARD use. Third, comparisons between historical and more recent trials may have increased heterogeneity due to potential differences in patient characteristics. To mitigate some of this heterogeneity, baseline risk adjustment was used in networks where it offered improved model fit. Fourth, assessment of long-term outcomes was deemed unfeasible due to lack of a placebo anchor beyond the induction period. Future studies should consider alternative analytical methods to capture the long-term value of treatments for patients with PsA. Lastly, two limitations related to the treatments in the NMA include: (1) comparisons between intravenous and oral medications, which may have biased the results in favour of intravenous drugs which work more quickly over the first few weeks and (2) comparisons of DMARDs administered using a loading dose to those without a loading dose, which may have introduced variability; however, evidence on the superiority of regimens with loading doses in autoimmune rheumatic diseases is inconclusive. 30

While intravenous TNFs may provide some improvements in PROs relative to several other tsDMARDs and bDMARDs for the treatment of patients with PsA, differences between classes of therapies across outcomes were small. Relative to other treatment classes, CTLA-4, PDE4 and JAK inhibitors often showed lower efficacy. These findings highlight the importance of including HRQoL/PROs as additional outcomes when assessing the totality of evidence for the most effective treatment options for patients with PsA.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

Ethics approval was not obtained because this study did not involve human or animal subjects.

Acknowledgments

This work acknowledges the intellectual contributions made by the broader team at EVERSANA and Janssen Pharmaceuticals, including Alicia Pepper, Fareen Hassan, Cheryl Druchok, Raji Rajalingam, Meaghan Bartlett and Sheryl Fogarty. Janssen manufactures the following products discussed in this manuscript: guselkumab (TREMFYA), golimumab (SIMPONI ARIA), ustekinumab (STELARA) and infliximab (REMICADE).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Contributors SP and KE contributed to the concept and design of this review. SP, BPP and KE contributed to data acquisition and data analysis. PN, JPD, SP, BPP, KE, MS, FZ and JC-CW contributed to interpretation of data, critically revised the manuscript and gave final approval of the submitted manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JC-CW is the author acting as a guarantor.

Funding This study was supported by Janssen Research and Development.

Competing interests PN has received research grants and funding for clinical trials and honoraria for advice and lectures on behalf of Abbvie, BMS, Boehringer Ingelheim, Celgene, Eli-Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. JPD has performed clinical trials for Corbus, Eli Lilly and Company and Janssen; has received honoraria from AbbVie, Amgen, Bausch, Celgene, Leo, Janssen, Novartis and Sanofi; and has worked on the speaker bureau for Celgene and Eli Lilly and Company. SP and MS are employees of Janssen Global Services LLC. BPP is an employee of CRG-EVERSANA Canada, which received funding from Janssen Global Services LLC to conduct this analysis. KE is an employee of Janssen Canada. FZ is an employee of Janssen Latin America LLC. JC-CW has received consultation fees from Abbvie, BMS, Celgene, Chugai, Eisai, Eli Lilly, GSK, Janssen, Novartis, Pfizer, Sanofi-Aventis, TSH Taiwan and UCB pharma; research grants from BMS, Janssen, Pfizer, Sanofi-Aventis, Novartis, GSK, Abbvie, Eli Lilly, Celgene, Amgen, TSH Taiwan, JHL Taiwan; speakers bureaus for Abbvie, BMS, Chugai, Eisai, Janssen and Pfizer

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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• Open access
• Published: 11 April 2024

Ultrasonographic and power doppler parameters of nails fail to differentiate between onychodystrophy in patients with psoriasis vulgaris or psoriatic arthritis

• Anber Ancel Tanaka   ORCID: orcid.org/0000-0003-0963-0837 1 ,
• Betina Werner   ORCID: orcid.org/0000-0002-9671-5603 2 , 3 ,
• Annelise Correa Bueno Bragatto   ORCID: orcid.org/0009-0003-4630-689X 1 ,
• Thelma Larocca Skare   ORCID: orcid.org/0000-0002-7699-3542 4 &
• Bárbara Stadler   ORCID: orcid.org/0000-0001-5292-2777 4  

Advances in Rheumatology volume  64 , Article number:  25 ( 2024 ) Cite this article

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Metrics details

Nail involvement is frequent in patients with psoriasis (Pso) and psoriatic arthritis (PsA) and there is a relationship between nail involvement and inflammation of the enthesis. The main objective of the present study is to describe the ultrasound findings and clinical characteristics of nails from patients with psoriasis and psoriatic arthritis with and without nail dystrophy.

A cross-sectional study including consecutive patients with PsO and PsA was carried out. The study patients were divided into 4 groups, totaling 120 participants. Group 1: patients with psoriasis vulgaris and clinically normal nails; Group 2: patients with psoriasis vulgaris and onychodystrophy; Group 3: patients with psoriatic arthritis and clinically normal nails; Group 4: patients with psoriatic arthritis and onychodystrophy; All patients were submitted to dermatological and rheumatological clinical analysis. Ultrasound examinations was performed by a single examiner, blinded to all clinical data, with ultrasound high resolution, in B-mode or gray-scale (GS), Power Doppler (PD) and Spectral Doppler.

A significant difference was found between the groups regarding the variable Psoriasis Area and Severity Index (PASI) ( p  = 0.008) and body surface area (BSA) ( p  = 0.005), with patients with psoriatic arthritis having lower PASI and BSA compared to patients with only cutaneous psoriasis. A positive relationship was found with the average ultrasound thickness of the nail bed and the Nail Psoriasis Severity Index (NAPSI) in correlation analysis ( rho  = 0.344). When we grouped patients with psoriasis and psoriatic arthritis, there was no significant difference between the cutaneous psoriasis groups and the psoriatic arthritis groups in terms of nail plate GS ( p  = 0.442), nail bed PD ( p  = 0.124).

Greater nail bed thickness indicates early psoriatic nail disease, as confirmed in our study correlating NAPSI with nail bed thickness. Ultrasonography is a low-cost exam, promising in the evaluation, showing that the ultrasound grayscale is consistent with those who have dystrophic nails, but it can’t distinguish psoriasis from psoriatic arthritis, even in those with nail dystrophy.

Introduction

Psoriasis is a common, chronic papulosquamous skin disease that occurs worldwide, presenting at any age and imposing a substantial burden on individuals and society. It is associated with several significant medical conditions, including depression, psoriatic arthritis, and cardiometabolic syndrome [ 1 ]. Nail involvement is a common occurrence among patients with psoriasis, present in approximately 56% of cases of psoriasis vulgaris and around 80–90% of individuals with psoriatic arthritis. In 6% of cases, nail involvement may be the only manifestation. Nail psoriasis is correlated with more severe disease, characterized by earlier onset and a higher risk of psoriatic arthritis, and it may be employed as an early diagnostic parameter among patients with psoriasis [ 2 ].

Psoriatic arthritis, a heterogeneous, inflammatory, musculoskeletal disease that can cause permanent damage to both peripheral and axial joints, is the most common comorbidity of psoriasis [ 3 ]. A notable association has been established between nail involvement and inflammation of the enthesis at distal joints, potentially acting as a triggering factor in the development of joint symptoms within the spectrum of psoriatic disease [ 4 ]. Because skin symptoms associated with psoriasis often precede psoriatic arthritis, proactive screening of patients with all severities of psoriasis for the signs and symptoms of psoriatic arthritis is key to early diagnosis and intervention [ 3 , 4 ].

Ultrasound (US) has proven its efficacy as a sensitive imaging technique and a valuable tool for assessing inflammatory enthesis involvement in patients with psoriatic arthritis. Ultrasound in nail psoriasis is a diagnostic technique that has been used to assess structural changes in nails associated with psoriasis. Ultrasound is a non-invasive tool that uses high-frequency sound waves to create detailed images of internal body structures. In the context of nail psoriasis, ultrasound can provide valuable information about changes in the nail bed, nail matrix, and surrounding structures [ 5 ]. Subclinical inflammations detectable by US has been noted even in psoriasis patients lacking a prior history of arthropathy or psoriatic arthritis, underscoring its potential significance [ 6 ]. However, uncertainties persist regarding whether ultrasonographic findings obtained solely through US examination can effectively differentiate between patients with psoriasis devoid of arthritis yet exhibiting nail lesions and those with psoriatic arthritis coupled with nail involvement. The primary objective of this study is to compare the sonographic findings and clinical characteristics of nails in patients affected by psoriasis and psoriatic arthritis, both with and without nail dystrophy. Additionally, we aim to discern potential associations among sonographic findings that might contribute to distinguishing between these distinct populations.

A cross-sectional study is being conducted from November 2020 to January 2022, enrolling consecutive patients with psoriasis and psoriatic arthritis based on the CASPAR classification criteria [ 7 ]. Participants were recruited from the outpatient Dermatology Service Unit at Hospital Evangélico Mackenzie. Patients who were seen at the outpatient clinic were evaluated consecutively. Only those who met the inclusion criteria and agreed to participate in the research were included.

Inclusion criteria: The selected individuals will consist of adult patients aged 18 and above, with no age cutoff, of both genders. Participants must be volunteers who are well-informed and have agreed to the collection of clinical information and materials after reading and completing the informed consent form. Exclusion criteria were patients who did not provide informed consent, those with positive results in direct mycological exams or nail lesion cultures for fungi and/or bacteria, individuals with a history of trauma in fingernails in the last 6 weeks, local glucocorticoid injections in the distal interphalangeal (DIP) joints, or a diagnosis of osteoarthritis in the hands.

The study adhered to the principles outlined in the Declaration of Helsinki and complied with local regulations. Ethical approval for the study was granted by the Hospital’s Local Ethics Committee and received a favorable opinion for the study to proceed under protocol 4.279.067 on September 15, 2020, and written informed consent was obtained from all participating patients.

Patients diagnosed with psoriasis and psoriatic arthritis were sequentially assessed for age, sex, clinical presentation of psoriasis and psoriatic arthritis, disease duration, presence of nail abnormalities, Psoriasis Area and Severity Index (PASI) scores, Nail psoriasis Severity Index (NAPSI) scores for cases with onychodystrophy, and epidemiological profiles were obtained on the same day, while ultrasound examinations were conducted on a separately scheduled day. The study cohort comprised participants equally divided into four groups, as follows.“: Group 1 - patients with psoriasis vulgaris and no evident nail abnormalities; Group 2 - patients with psoriasis vulgaris and onychodystrophy; Group 3 - patients with psoriatic arthritis and clinically normal nails; Group 4 - patients with psoriatic arthritis and onychodystrophy. All participants from Groups 1 to 4 underwent thorough dermatological and rheumatological clinical assessments.

Ultrasound examinations were conducted on the following nails: Groups 1 and 3 (patients with clinically normal nails): Third finger of both the right and left hands. Groups 2 and 4 (patients with nails with dystrophy): The most dystrophic nails on each hand, both left and right, as determined by NAPSI measurements (thus, two nails per individual).

This approach aimed to comprehensively evaluate the clinical and ultrasound characteristics of patients in various groups, shedding light on the potential differentiating factors between psoriasis and psoriatic arthritis with or without nail involvement.

Ultrasound examinations were conducted by a single examiner, an experienced rheumatologist trained in this imaging technique (B.S). The examiner was blinded to all clinical data during the assessments. Ultrasound imaging was performed using an Mylabel40 model from the Esaote brand (Italy) device, a high-resolution system equipped with B-mode or gray-scale (GS), Power Doppler (PD), and Spectral Doppler capabilities, utilizing a linear transducer with a frequency range of up to 18 MHz. The examinations took place in a climate-controlled room at an approximate temperature of 24 degrees Celsius. The room was semi-lit, and patients were positioned in front of the examiner, separated by a stretcher, with their hands resting on it in a relaxed manner. Patients were instructed not to discuss their medical condition with the operator.

For B-mode nail analysis, the linear transducer operating at an 18 MHz frequency was employed to assess various parameters, including nail bed thickening, undulations, and loss of the trilaminar pattern of the nail layer. To achieve optimal image definition and sharpness, gain adjustments were made. A significant amount of gel was applied to the nail plate to minimize artifacts and enhance image clarity. The examination involved analyzing nail structures in both longitudinal and transverse planes.

Nail bed thickness was measured in the longitudinal plane at the level of the eponychium. A straight line was drawn, referencing the first point on the ventral lamina to the second point on the periosteum. A normal reference value for nail bed thickness was considered to be less than or equal to 2 mm, following established guidelines [ 8 , 9 ].

For the analysis of the nail plate, a semi-quantitative scale was utilized as follows: GS0: Trilaminar pattern preserved; GS1: Slight alteration in the trilaminar pattern, or presence of 1 tortuosity or flaw in the nail. GS2: Intense alteration in the laminar pattern, but some segment of the nail is still preserved; more than one tortuosity or flaw in the nail. GS3: Total loss of the trilaminar pattern, thickening, deformity, or loss of the entire nail shape; severe abnormalities with destruction of the entire nail segment.

Examinations falling within the GS1, GS2, and GS3 criteria of the semi-quantitative scale was deemed as abnormal nail plate.

The analysis of the nail bed was conducted in Power Doppler (PD) mode to quantify blood flow and was achieved using the linear transducer operating at a frequency of 15 MHz, with a Pulse Repetition Frequency (PRF) of 0.7 and a low wall filter. To ensure accurate results, a substantial amount of gel was applied to prevent artifacts and vessel collapse. Like the nail plate analysis, evaluations were performed in both longitudinal and transverse planes.

A semi-quantitative scale for PD was adopted as follows: PD0: Absence of PD signal in any part of the nail bed. PD1: Presence of 1 point or 25% of PD signal in any part of the nail bed, primarily at the nail insertion. PD2: Presence of 2 or 3 isolated points or between 25% and 50% of PD signal in any part of the nail bed, mainly at the nail insertion. PD3: Presence of more than 50% of PD signal across the entire nail bed, particularly at the nail insertion [ 5 , 7 , 8 ].

The PD2 and PD3 criteria of the above semi-quantitative scale were considered as indicative of nail bed abnormal blood flow. It is important to note that the nail bed may exhibit physiological vascularization, and therefore PD1 will be considered as normal.

Spectral Doppler measurements were taken at the location with the highest PD signal, and the resistance index was calculated using the equation: minimum peak systolic flow - end diastolic flow divided by systolic flow. This calculation was automatically calculated by the ultrasound device after recording the spectral wave and manually marking the peaks of the systolic and diastolic waves on the displayed curve. A resistance index less than 1 was considered as suggestive of inflammation [ 8 , 9 ].

The data were tested for their distribution using the Shapiro-Wilk test. Descriptive statistics median (minimum-maximum) was employed to summarize the results involving quantitative variables, while categorical variables were expressed in terms of absolute and relative frequencies. For group comparisons, the Kruskal-Walli’s test was employed for quantitative variables and Pearson Chi-square test for categoric variables. Correlation analysis was performed using the Spearman coefficient. The analyzes were carried out using the software Statstica Statsoft 7.0., considering a p-value < 0.05 to indicate statistical significance.

A total of 120 patients were enrolled in the study, with a balanced distribution of sex and age among individuals with psoriasis and psoriatic arthritis. Within the arthritis groups, 75% exhibited peripheral arthritis, while 25% presented axial arthritis. Significant differences were observed between the groups regarding the PASI variable ( p  = 0.008) and BSA ( p  = 0.005), as indicated in Table  1 .

Patients with psoriatic arthritis (groups 3 and 4) demonstrated lower PASI and BSA values compared to those with psoriasis alone (groups 1 and 2). On the other hand, no significant differences were found in terms of NAPSI ( p  = 0.119) between patients with and without arthritis as indicate in Table  2 .

A positive correlation was identified between the average ultrasound thickness of the nail bed and the Nail Psoriasis Severity Index (NAPSI) through correlation analysis (rho = 0.344). Ultrasound findings revealed that the GS ratio of the nail plate in groups 1 and 3 were similar, while groups 2 and 4, comprising patients with nail dystrophy, displayed clinical similarities. This suggests that there is no discernible distinction in dystrophic nails between individuals with psoriasis alone and those with psoriasis accompanied by arthritis. In terms of Power Doppler results, groups 3 and 4 exhibited resemblances, as did groups 1 and 2. Specifically, when analyzing only patients with nail dystrophy, no significant divergence was noted between cutaneous psoriasis and psoriatic arthritis groups concerning Power Doppler ( p  = 0.16).

Upon grouping patients with psoriasis and psoriatic arthritis, there were no significant differences between the cutaneous psoriasis groups (groups 1 and 2) and the psoriatic arthritis groups (groups 3 and 4) regarding GS nail plate ( p  = 0.442), PD nail bed ( p  = 0.124), and IR E ( p  = 0.758). The gray scale and power doppler results are summarized in the Table  3 .

The nail apparatus is commonly affected in psoriasis, with varying prevalence rates reported in the literature [ 2 ], which can reach up to 90% over a person’s lifetime. However, nail manifestations are often overlooked in clinical practice, leading to aesthetic deformities, functional limitations, pain, decreased quality of life and overall well-being [ 10 ]. This burden of nail involvement emphasizes the importance of early diagnosis, given that nail psoriasis is believed to be a significant risk factor for developing psoriatic arthritis and serves as an important parameter for early diagnosis in these patients [ 11 , 12 ].

In this study, the psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) were used as clinical metrics for evaluating patients. Patients in the psoriatic arthritis groups (groups 3 and 4) exhibited significantly lower PASI and BSA values compared to patients in the psoriasis groups without joint disease (groups 1 and 2). One possible explanation for this disparity is that patients with psoriatic arthritis often receive systemic treatment, resulting in better clinical control of cutaneous manifestations. The Nail psoriasis Severity Index (NAPSI) was used to assess the nail plate in groups with affected nails. However, no significant difference was observed between the groups without psoriatic arthritis (group 2) and those with psoriatic arthritis (group 4). Similar results were obtained in the evaluation of nails clippings in which it was not possible to determine whether the patient had arthritis or not based on the severity of microscopical findings [ 13 ].

In the present study ultrasound was employed as a method for characterizing the inflammatory process in patients with psoriasis and psoriatic arthritis.

Considering that the nail apparatus is linked to the musculoskeletal system and serves as a connection between the integument and the joint, ultrasound evaluation of nails emerged as a promising tool for early identification of nail psoriasis. It could potentially differentiate between patients with psoriasis and psoriatic arthritis patients. This study used parameters such as gray scale (GS) to visualize the nail plate’s trilaminar pattern and measure the nail bed, as well as Power Doppler (PD) to assess circulation and resistance index in the nail bed.

Patients with visible nail disease (groups 2 and 4) displayed a more pronounced loss of the trilaminar pattern compared to groups without nail disease (groups 1 and 3). Increased nail bed thickness is considered an early indicator of psoriatic nail disease, [ 14 – 15 ] a correlation supported by our study when correlating NAPSI with mean nail bed thickness ( p  = 0.0072) from the Spearman test (Table  1 ). However, when comparing groups with nail disease, including the patients with psoriasis and arthritis, no significant differences were noted concerning gray scale measurements. The degree of loss in the trilaminar pattern directly correlated with clinical nail involvement (NAPSI), though, being consistent with previous studies [ 10 , 11 , 12 ]. These findings align with De Rossi et al.‘s study [ 12 ], which also did not find a significant difference between patients with psoriasis, psoriatic arthritis, and the control group. A systematic review by Mendonça et al. [ 11 ] similarly found no statistically significant difference in nail bed thickening values between patients with psoriasis and psoriatic arthritis. The wide variation in measurements across the literature may be partly attributed to ethnic differences [ 12 ]. Our findings support that GS trilaminar disturbances seen in US is as good as clinical examination in the ability of discerning the presence or absence of dystrophy, but not in the diagnosing of inflammation in the enthesis.

Power Doppler assessment of the nail apparatus visualizes vascularization in the nail bed, revealing elongated, dilated, and tortuous vessels resulting from local inflammation. Increased blood flow in the nail bed directly correlates with disease activity. [ 16 – 17 ] While patients with psoriatic arthritis (groups 3 and 4) displayed similar vascular alterations in the nail bed, there were no significant differences observed in Power Doppler for patients with nail dystrophy (in the presence or absence of arthritis). The literature contains conflicting data on the utility of Doppler techniques in evaluating nail involvement in psoriasis and psoriatic arthritis [ 11 ]. This study’s results further emphasize these discrepancies. Mendonça et al.‘s [ 11 ] systematic review showed variable Power Doppler signals in both psoriasis and psoriatic arthritis patients, along with an observed increase in vascularity in healthy controls. Naredo et al. [ 18 ]., also unable to use the Power Doppler parameter to discriminate between control and psoriatic groups, or between clinically affected and non-clinically affected nails [ 18 , 19 ].

Regarding the Power Doppler Resistance Index, no significant difference was noted between evaluated groups, consistent with De Rossi et al.‘s findings [ 12 ]. Some studies [ 20 ] indicate higher Resistance Index in psoriasis patients compared to controls, potentially due to endothelial dysfunction and capillaroscopy findings. In contrast, other studies show lower Resistance Index in psoriatic arthritis patients, possibly linked to inflammation extending to the nail apparatus [ 11 ]. These variations in Resistance Index findings reinforce the need for further evaluation in future studies to better determine how to apply the measure in clinical practice, including possible differences between specific subgroups.

The study’s limitations include single-examiner ultrasound assessments and patients undergoing clinical treatment, which may impact sonographic findings.

The choice to have a single examiner conduct the ultrasound assessments may introduce bias into the results. Different examiners may have slightly different approaches and interpretations, which could influence the study’s conclusions. The fact that patients were undergoing clinical treatment may affect sonographic findings. Depending on the type of treatment, whether medicinal or physiotherapeutic, ultrasound characteristics may be altered, and the results may not be generalizable to a broader population that includes those not undergoing treatment.

Further research is necessary to elucidate these nuances and refine the diagnostic utility of ultrasound in distinguishing between these conditions.

In conclusion, ultrasound, a cost-effective method, holds consistency between grayscale and power doppler abnormalities and nail dystrophy severity but fails to be useful in the differentiation between patients with or without arthritis.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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AAT: contributed to the project coordination; conception and design of the study; data collection; statistical analysis; article writing and critical review of the content; obtaining, analyzing, and interpreting data; critical review of the literature; final approval of the final version of the manuscript. BW: contributed to the project coordination; conception and design of the study; data collection; statistical analysis; article writing and critical review of the content; obtaining, analyzing, and interpreting data; critical review of the literature; final approval of the final version of the manuscript. ACBB: contributed to the data collection; statistical analysis; article writing and critical review of the content; obtaining, analyzing, and interpreting data; critical review of the literature; final approval of the final version of the manuscript. TLS: contributed to the statistical analysis; article writing and critical review of the content; obtaining, analyzing, and interpreting data; critical review of the literature; final approval of the final version of the manuscript. BS: contributed to the statistical analysis; article writing and critical review of the content; obtaining, analyzing, and interpreting data; critical review of the literature; final approval of the final version of the manuscript.

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Tanaka, A.A., Werner, B., Bragatto, A.C.B. et al. Ultrasonographic and power doppler parameters of nails fail to differentiate between onychodystrophy in patients with psoriasis vulgaris or psoriatic arthritis. Adv Rheumatol 64 , 25 (2024). https://doi.org/10.1186/s42358-024-00367-x

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Original article

Systematic literature review of domains assessed in psoriatic arthritis to inform the update of the psoriatic arthritis core domain set, umut kalyoncu.

1 Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA

2 Division of Rheumatology, Hacettepe University, Ankara, Turkey

Alexis Ogdie

3 University of Pennsylvania, Philadelphia, Pennsylvania, USA

Willemina Campbell

4 Patient Research Partner, Toronto, Ontario, Canada

Clifton O Bingham, III

Maarten de wit.

5 Department of Medical Humanities, Patient Research Partner, VU University Medical Centre, Amsterdam, The Netherlands

Dafna D Gladman

6 Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Philip Mease

7 Swedish Medical Center and University of Washington, Seattle, Washington, USA

Ingrid Steinkoenig

8 Patient Research Partner, Cleveland, Ohio, USA

Vibeke Strand

9 Division of Immunology, Stanford University, Palo Alto, California, USA

Victoria G Riese

10 National Institutes of Health Library, Education Services Branch, Bethesda, Maryland, USA

Ana-Maria Orbai

Associated data.

rmdopen-2015-000217supp_references.pdf

rmdopen-2015-000217supp_table.pdf

The objectives of this systematic literature review (SLR) were to identify domains and outcome measures used in psoriatic arthritis (PsA) studies in the past 5 years, and to compare the measurement of the Outcome Measures in Rheumatology (OMERACT) 2006 PsA Core Domain Set in studies published in 2010–2015 vs those published in 2006–2010. We performed a systematic literature search in two databases, PubMed and Embase, to identify randomised controlled trials (RCTs) in PsA. We also identified PsA longitudinal observational studies (LOS). Three patient research partners provided input into study conception, and data collection and interpretation. We identified 41 studies representing 22 unique RCTs, 27 LOS and 12 registries. Across all studies, we identified 24 domains and 169 outcome measures. In addition to the PsA Core Domain Set (6 domains), the following domains were also assessed in more than 30% of RCTs: acute phase reactants, dactylitis, enthesitis, fatigue and work productivity. We identified a range of 1–15 outcome measures per domain with a mean (SD) of 7 (4.7) per domain. The complete PsA Core Domain Set was assessed in 59% of RCTs in 2010–2015 compared to 23.5% RCTs in 2006–2010. There has been increased measurement of the PsA Core Domain Set in RCTs and LOS in the past 5 years. Numerous additional outcomes were also measured. The PsA Core Domain Set needs an update to standardise PsA outcome assessments. This SLR will inform the development of an updated PsA Core Domain Set with patient research partner input.

Key messages

• There is great heterogeneity in PsA manifestations and assessment.
• There is an ever increasing number of PsA outcomes and outcome measures as quantified in this review.
• It is difficult to draw conclusions on comparative effectiveness with such heterogeneity across PsA clinical trial outcomes. This has direct implications for clinical practice by increasing the complexity of evidence based treatment decisions.

Introduction

Psoriatic arthritis (PsA) is a chronic form of immune-mediated inflammatory arthritis that can lead to permanent joint damage. 1 The prevalence of PsA is 0.01–0.47% in the general population 2 and, depending on classification methods, 11–34% 2–5 among people with psoriasis. The heterogeneity of clinical manifestations (eg, oligoarthritis and polyarthritis, and spinal, ligamentous and tendon involvement) complicates assessment of PsA outcomes and broadens its impact on daily life. 6 PsA has been shown to negatively impact health-related quality of life (HRQL) independently of psoriasis skin manifestations. 7 Given the heterogeneity of the clinical manifestations, measuring disease activity and disease impact can be difficult. A Core Domain Set for the assessment of PsA was endorsed at the Outcome Measures in Rheumatology (OMERACT) meeting in 2006 and includes: pain, joints, physical function, skin, patient global and HRQL. 8 To date, a PsA core outcome measurement set has not been endorsed by OMERACT due to lack of patient involvement in core set development. 9 10

Recently, new therapeutic agents with novel mechanisms of action have been approved for PsA. The outcome measurement instruments used in PsA randomised controlled trials (RCTs) are based on instruments adopted from rheumatoid arthritis (RA), with the example of American College of Rheumatology (ACR) 20/50/70 responses as primary efficacy endpoints. PsA-specific manifestations (dactylitis, enthesitis, spondyloarthritis, skin and nail disease) were reported only as secondary outcomes in recent years. Furthermore, fatigue, skin symptoms, and aspects of psychological and social well-being, all prioritised by patient research partners (PRPs) as important for disease impact, 11 have not been consistently measured in PsA RCTs.

The purpose of this review is twofold: (1) to review and summarise domains assessed in the past 5 years in PsA RCTs, as well as longitudinal observational studies (LOS) and studies of patient-generated domains, and (2) to compare domains assessed in recent clinical trials (published 2010–2015) to those published in 2006–2010. 12 This systematic literature review will inform the development of an updated PsA core set of domains and outcome measures that will include patient input, 9 13 and will integrate disease-specific aspects of clinical relevance to PsA for longitudinal care and interventional trials.

We searched two databases, PubMed and Embase, with the search terms ‘Psoriatic Arthritis’ combined with the Cochrane RCT sensitivity filter, 14 15 using the Boolean operator ‘AND’, on 19 May 2015. We excluded paediatric studies (children age 0–18 years), and used the following limits: human studies, English language and time 1/2010 forward ( box 1 ). We extended the search to the past 5 years to allow overlap with the most recent review of the topic which covered clinical trials from 2006 to 2010. 12 We included, for full-text review, all RCTs that reported PsA patient outcomes.

Search parameters and strategies of psoriatic arthritis literature review

PubMed : ("Arthritis, Psoriatic"[Mesh] OR "Psoriatic arthritis" OR "psoriatic arthropathy" OR "arthritis psoriatica" OR "arthropathic psoriasis" OR "psoriasis arthropathica" OR "psoriatic arthropathy" OR "psoriatic polyarthritis" OR "psoriatic rheumatism") AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR "clinical trials as topic"[Mesh] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT ("Animals"[MeSH] NOT ("Animals"[MeSH] AND "Humans"[MeSH])) NOT ("Child"[Mesh] OR "Infant"[Mesh] OR "Infant, Newborn"[MH] OR "Adolescent"[Mesh] OR "Child, Preschool"[MH] OR "child"[all] OR "infant"[all] OR "adolescent"[all] OR "children"[all] OR "infants"[all] OR "adolescents"[all] OR "pediatric patient"[all] OR "pediatric patients"[all] OR "adolescence"[all] OR "youth"[all] OR "youths"[all] OR "juvenile"[all] OR "childhood"[all] OR "teenager"[all] OR "teenagers"[all] OR "teen"[all] OR "teens"[all] OR "preschool child"[all] OR "neonate"[all] OR "newborn"[all] OR "baby"[all]) AND English[lang] AND ("2010/01/01"[PDAT] : "3000/12/31"[PDAT])

Embase : (‘psoriatic arthritis'/exp OR "Psoriatic arthritis" OR "psoriatic arthropathy" OR "arthritis psoriatica" OR "arthropathic psoriasis" OR "psoriasis arthropathica" OR "psoriasis pustulosa arthropathica" OR "psoriatic arthropathy" OR "psoriatic polyarthritis" OR "psoriatic rheumatism") AND (random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR doubl* NEXT/1 blind* OR singl* NEXT/1 blind* OR assign* OR allocate* OR volunteer* OR 'crossover procedure'/exp OR 'double-blind procedure'/exp OR 'randomized controlled trials'/exp OR 'single-blind procedure'/exp) NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('Child'/de OR ‘Infant'/de OR ‘Adolescent'/de OR 'preschool child'/exp OR 'child’:ti,ab OR ‘infant’:ti,ab OR ‘adolescent’ OR ‘children’ OR ‘infants’ OR ‘adolescents’ OR ‘pediatric patient’ OR ‘pediatric patients’ OR ‘adolescence’ OR ‘youth’ OR ‘youths’ OR ‘juvenile'/exp OR 'juvenile’ OR ‘childhood’ OR ‘teenager’ OR ‘teenagers’ OR ‘teen’ OR ‘teens’ OR ‘preschool child’ OR ‘neonate’ OR ‘newborn'/de OR 'newborn’:ti,ab OR ‘baby’ OR ‘babies’ OR ‘pediatric’:ti,ab OR ‘pediatrics’:ti,ab OR ‘paediatric’:ti,ab OR ‘paediatrics’:ti,ab OR ‘toddler'/exp OR 'toddler’ OR ‘toddlers’) AND [english]/lim AND [2010-2015]/py

We searched LOS, registries and patient-generated domain studies (eg, Psoriatis Arthritis Impact of Disease (PsAID)) by hand, after consultation with experts in the field and reference lists from review articles. Search terms were ‘psoriatic arthritis’ and ‘cohort’, ‘registry’, ‘observational study’, with a time limit from 1 January 2010 forward.

We used a standardised data collection form for all included studies and extracted the following data: population (adults with PsA), type of intervention and control, number of participants, age, sex, psoriasis/PsA duration, primary and secondary outcomes, and outcome measures (including composite indices). We illustrated the process as recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 16 Domains and corresponding outcome measures are organised in the order of the PsA core domain set, and also grouped domains according to the broad OMERACT Filter 2.0 core areas: pathophysiologic manifestations, life impact and resource use. 17 18 We are also reviewing the European League Against Rheumatism–PsAID (EULAR–PsAID) outcome measure 11 domains since it was recently developed (2014) with international PRP involvement. Beginning at the conception phase of this systematic literature review, we involved three PRPs, who provided input into the search strategy, data extraction form and interpretation of results.

PsA RCTs reported 2010–2015

PubMed and EMBASE literature searches retrieved 1738 entries and, after exclusion of abstracts and off-topic items ( figure 1 ), we included 41 full-text articles representing 22 distinct RCTs (see online supplementary references ). The total number of PsA patients included within the studies reviewed was 5970, female 46.7%, mean (SD) age 47.8 (5.9) years, psoriasis duration 15 (2.6) years and PsA duration 6.5 (2.7) years. Eighteen (81.8%) trials used placebo as control group, two used standard therapy and two used active control arm. Interventions were: biological drugs (16), DMARDs (2), other drug (zolendronic acid) (1), tight control protocol (1), educational intervention (1) and mud-bath therapy (1).

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram, record identification, screening, eligibility and inclusion. PsA, psoriatic arthritis; RCT, randomised controlled trials.

Supplementary references

Composite indices were primary or secondary outcomes in a majority of PsA RCTs as follows: ACR responses (82%), DAS28 (73%), Psoriatic Arthritic Response Criteria (Psoriatic Arthritis Response Criteria; PsARC)/modified PsARC (no grading of joint tenderness) (36%), EULAR response (27%) and minimal disease activity (MDA) (18%). Other composite indices were calculated as secondary analyses of RCT data (see table 1 for complete list).

Table 1

Composite indices assessed in PsA randomised controlled trials 2010–2015

Patient Reported Domains: Joint and Skin is 100 mm visual analogue scale, Physical Function is Short Form-36 Physical Component Score, Disability is Health Assessment Questionnaire, Spine is Bath Ankylosing Spondylitis Disease Activity Index, Quality of Life is Psoriatic Arthritis Quality of Life Index in GRACE/AMDF; and Dermatology Life Quality Index and Ankylosing Spondylitis Quality of Life Index (both included) in CPDAI. Ref 15 is secondary data analysis of RCT ref 31 and ref 11 is secondary data analysis of RCT ref 25.

ACR, American College of Rheumatology; AMDF, Arithmetic Mean of the Desirability Function; CDAI, Clinical Disease Activity Index; CPDAI, Composite Psoriatic Disease Activity Index; CRP, C reactive protein; DAPSA, Disease Activity Index for Psoriatic Arthritis; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; GRACE, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis Composite Exercise; MDA, Minimal Disease Activity; PASDAS, Psoriatic Arthritis Disease Activity Score; PsARC, Psoriatic Arthritis Response Criteria; RCTs, randomised controlled trials.

We collected outcome domains reported in PsA RCTs (22 domains in total) with corresponding outcome measures for each domain, and summarised these data in table 2 . The 2006 PsA core domain set was reported in its entirety in 13 (59%) of 22 RCTs, which reported individual core domains as follows: pain 100%, peripheral joints 95%, physical function 91%, skin 86%, patient global assessment 82% and HRQL 77%. The majority of RCTs also reported domains not included in the current PsA core set: acute phase reactants 100%, physician global assessment 82%, enthesitis 59% and dactylitis 59%. Fatigue was reported in 35% of RCTs, productivity in 32%, radiographic outcomes in 27%, nail pathology in 23%, MRI/ultrasound outcomes in 20%, stiffness in 18%, depression/anxiety in 9%, and participation and coping in 5%. The number of outcome measures reported in PsA RCTs ranged from 1 to 9 with an average (SD) of 4.1 (2.4) outcome measures per domain. We observed the greatest heterogeneity in reporting for skin, with nine outcome measures, followed by enthesitis, fatigue, nail and productivity with seven measures each, and physician global and radiological outcomes with six measures each. Of note, tissue analysis, self-efficacy and sleep outcomes included in the ‘outer circle’ of the 2006 PsA Core Domain Set were not assessed in any RCT.

Table 2

Domains and number of corresponding outcome measurement instruments in PsA randomised controlled trials, longitudinal observational studies and registries in 2010–2015

Domains are listed in decreasing order of frequency of their assessment in PsA randomised controlled trials. The original unabbreviated version of this table is listed as online supplementary table S2a and contains the complete list of all outcome measurement instruments used to assess each domain.

HRQL, health-related quality of life; PsA, psoriatic arthritis; PsAID, Psoriatis Arthritis Impact of Disease; US, ultrasound.

Supplementary table

Psa los and registries reported from 2010 to 2015.

Searches and review of reference lists identified 27 LOS and 12 registries (see online supplementary references ). PsA LOS reported a total of 23 domains ( table 2 ). Nine of 27 (33.3%) LOS reported the complete 2006 PsA core domain set and individual domains as follows: pain 66.7%, peripheral joints 88.9%, physical function 77.8%, skin 70.4%, patient global assessment 74.1% and HRQL 51.8%. Acute phase reactants were reported in most LOS (74.1%). Physician global was reported in 48.1% and fatigue, enthesitis and dactylitis were each reported in 44.4%. One of the 12 (8.3%) registries reported the complete 2006 PsA core domain set. Fatigue (33.3%), skin (33.3%), enthesitis (25%) and dactylitis (8%) were reported at a lower frequency in registries than in LOS.

PsAID outcome measure domains

The EULAR-PsAID outcome measure 11 developed in 2014 is unique among PsA outcome measures since its domains are entirely patient-generated. It contains domains prioritised by PRPs from 13 European countries after they were presented with results of a literature review of outcomes and measures assessed in PsA studies. 12 At the end of the meeting, patients decided on 16 domains, which were further reduced through ranking by a larger number of patients (n=139 from 13 European countries) to 12 domains for longitudinal clinical care and 9 domains for use in RCTs. Selection of domains for the final PsAID questionnaire was in median order of importance to patients, from 1, most important, to 16, least important. The PsAID uses a weighted score; weights for each domain were based on patient preferences. There are three overlapping PsAID and 2006 PsA Core Set domains: pain, physical function and skin.

Domains and corresponding outcome measures assessed in PsA studies from 2010 to 2015

We identified 24 domains assessed across all PsA studies ( table 2 ). These are listed in order of decreasing frequency of assessment in RCTs, and organised as follows: (1) 2006 PsA core domain set: pain, joints, physical function, skin, patient global assessment and HRQL, (2) 2006 PsA outer circle domains: acute phase reactants, physician global, enthesitis, dactylitis, fatigue, nail, spine and radiology, (3) 2006 PsA research agenda: MRI/CT/ultrasound, participation and tissue analysis; and (4) other domains assessed but outside of the 2006 domains: productivity, stiffness, anxiety, depression, coping, well-being, self-efficacy and sleep. At the extremes of the spectrum, pain and acute phase reactants were assessed in all RCTs, and tissue analysis was assessed in none.

At least 1 outcome measure was found for each domain with a mean (SD) number of outcome measures per domain of 7 (4.7) and range 1–15. Across all studies, there was great heterogeneity for outcome measure selection and reporting as follows (domain and corresponding number of outcome measures identified in order of listing in table 2 ): pain 8, joints 14, physical function 8, skin 15 (include 8 physician and 7 patient reported measures), patient global assessment 9, HRQL 10, acute phase reactants 2, physician global 10, enthesitis 10, dactylitis 5, fatigue 10, nail 8, spine 11 (symptoms and mobility), radiology 10 (peripheral joints, spine and hip), MRI 2 (1 MRI score, imaging of peripheral joints, large joints, pelvis and spine)/CT none/ultrasound 7 (2 synovitis scores, 3 enthesitis scores, ultrasound examination for enthesitis, dactylitis and joints), participation 3, tissue analysis (not assessed), work productivity 15, stiffness 4, anxiety 1, depression 2, coping 2, well-being 1, self-efficacy 1 and sleep 1. For most domains, there was a preferred outcome measure that was assessed/reported in a majority (>50%) of studies except for: joint count, physician global, fatigue, nail and productivity. Specifically for productivity, each of the seven RCTs assessing this domain used a different productivity outcome measure.

We then sorted all domains measured in RCTs into OMERACT-recommended core areas 17 18 ( table 3 ), including pathophysiologic manifestations, life impact and resource use. Pathophysiology was well measured in all RCTs with pain and acute phase reactants universally measured, however, disease-specific manifestations were measured in only 55% or less. Most common domains within life impact were physical function (91%), patient global (82%) and quality of life (77%), whereas fatigue and productivity were 32–35%, with participation, mood, coping and well-being not frequently measured (5–10%). Productivity was the only domain within the area of resource use, but this was only measured in 32% of the RCTs.

Table 3

Domains assessed in PsA RCTs by OMERACT Recommended Core Areas

2006 PsA Core Domain Set: white background; Outer circle: light grey; Research agenda: dark grey; Domains assessed in RCTs not in the PsA core set: darkest grey; Domains in bold belong to more than one core area. HRQL health-related quality of life; PsA, psoriatic arthritis; OMERACT, Outcome Measures in Rheumatology; RCT, randomised controlled trials; US, ultrasound.

From 2010 to 2015, a majority of PsA RCTs (59%) included measures that addressed the complete 2006 PsA core domain set. This is an increase compared to 23.5% of RCTs assessing the PsA core set in the prior assessment period from 2006 to 2010. 12 The increased inclusion of the PsA core domain set in RCTs can be explained at least in part by its availability in published form since 2007, and supports the idea that such a core set is needed, and that it is widely accepted and used.

Of importance, many other domains (enthesitis, dactylitis, spine and nails) specific to PsA are now being assessed to supplement the 2006 PsA core set in a considerable proportion of PsA RCTs, but the selection of additional domains is heterogeneous across trials. Furthermore, the strategy of domain supplementation of the core domain set in PsA RCTs led to demonstrated PsA-specific effects of new therapeutic agents and US FDA approval of new medications for PsA as primary indication in the past 2 years, while prior medications in PsA were initially approved for RA. Enthesitis, dactylitis, spine and nail involvement, in addition to skin, are PsA-specific pathophysiological manifestations that distinguish it from other forms of inflammatory arthritis and should be included in regular PsA assessments to facilitate better understanding of disease risk factors, and prognosis and development of targeted treatments. 19 However, disease specificity of the PsA core set would have to be reconciled with feasibility/simplicity. LOS and registries lag behind RCTs in terms of reporting the complete PsA core set (33.3% and 8.3% vs 59%). This may be due to lack of reporting of all data collected, the primary focus on peripheral arthritis rather than the other disease manifestations, collecting of PsA data as add-on in RA cohorts, or the difficulty of collecting large amounts of data in clinical practice. Another difference is the adoption of simpler outcome measures in longitudinal studies compared to RCTs. For example, composite indices, although developed and tested in PsA, include proprietary outcome measures (eg, SF-36, PsAQoL) and are not feasible to assess in regular clinical care.

An aspect that could be improved in the updated PsA Core Domain Set is clarity. Some items currently listed as core set domains actually represent methods of measurement (examples are Radiology, CT/MRI/US, acute phase reactants and tissue analysis). Domains are measurable disease concepts. Methods of measurement are techniques that may be applied to developing outcome measurement instruments for each domain. Corresponding domains for the above techniques may be PsA radiographic damage (vs Radiology), synovial/entheseal/digital/spinal tissue inflammation/activity (vs MRI/CT/US techniques), or PsA-specific biomarkers (vs acute phase reactants and tissue analysis). Precise definition of PsA Core Domains is necessary so that outcome measurement instrument selection and development can proceed.

We identified domains corresponding to all core areas recommended by Filter 2.0. 17 18 The area of life impact is currently least represented in all studies. Physical function is the most highly assessed domain in the area of life impact (91% of RCTs), however, physical function represents only a fraction of how patients conceptualise the impact of PsA on their lives. 11 20 21 In the PsAID study, 11 patients from 13 European countries decided on and ranked PsA domains in order of decreasing importance as follows: pain; skin; fatigue; ability to work/leisure; functional capacity; feeling of discomfort; sleep disturbance; anxiety, fear and uncertainty; coping; embarrassment and/or shame due to appearance; social participation; and depression. This is important information regarding PsA patient priorities and three of the PsAID domains (pain, skin and physical function) are present in the 2006 PsA core set. In the case of skin assessments, measures used in PsA RCTs are almost exclusively physician measures (>88%) while PRPs prioritised the symptom aspect of the skin domain. Skin symptoms can only be captured with patient reported measures. Fatigue and ability to work, although ranked as third and fourth priority by PRPs, are missing from the current core set. The finding that patient treatment goals go beyond pathophysiological improvement and encompass being able to participate in specific life activities was replicated in qualitative studies in other chronic diseases. 22–24

Heterogeneity of outcome measures per domain emphasises the need for uniform standards that can be adopted for outcome measure selection. For productivity, none of the seven RCTs assessed the same measure, which is problematic for comparison of results. Similarly for enthesitis, 13 RCTs used 7 enthesitis outcome measures, which is again problematic for comparative effectiveness analyses. Another consideration is heterogeneity in collecting and reporting the same measure: visual analogue scales for global assessment (patient and provider) or pain, fatigue, stiffness where it is uncertain if the question stem, anchors and recollection period are all the same across studies. Yet another consideration is representativeness or content validity of the outcome measure for the domain to be measured. For example, skin assessment in the PsAID is patient reported, whereas RCTs predominantly use physician assessments of psoriasis. Depending on how HRQL is assessed, fatigue, depression, anxiety and social functioning may be included in some outcome measures, and it should be noted that HRQL subdomain recommendations are not specified in the PsA core set. These findings reflect the need to precisely define each outcome to be measured in PsA so that a decision can be made on whether it is best measured using a patient or a physician reported measure, or if there is added value to use both. The evidence for each outcome measure in adequately capturing the construct is also needed before implementation, and this is the object of a continuation of this work.

Limitations of our review consist of a limited review period of 5 years, however, this is an update of a previous review. 12 Searches for LOS are not exhaustive since there is no validated filter, and we were as inclusive as possible when screening for these publications. Additionally, we did not specifically contact the authors of the LOS and registries to inquire about the data collected as more data may have been collected than reported in the representative papers identified. Synthesising information on outcome measurement instrument properties and validation evidence in PsA is beyond the scope of this review and will be addressed in future work.

In conclusion, an updated PsA core set is much needed to increase its validity for PsA, to clarify domain definitions, to include patient priorities and to add disease-specific manifestations. Precise definition of constructs to be measured as PsA domains is a critical first step. This will facilitate the development of a core outcome measurement set that can be standardised for use in PsA research and clinical care. The consistent use of a standardised outcome measurement instrument set for PsA will then allow comparisons of the effects of various interventions, and improve the quality of the information available to patients and their doctors for making informed treatment decisions.

Acknowledgements: The authors acknowledge Dr Laure Gossec for kindly reviewing the manuscript and providing feedback.

Contributors: A-MO, UK, AO, WC, COB and IS were involved in the study design. UK, A-MO and VGR were involved in the data collection and analysis. A-MO, UK, AO, WC, COB, MdW, DDG, PM, IS, VS and VGR were involved in the data interpretation. UK and A-MO were involved in the writing the first version of the manuscript. UK, AO, WC, COB, MdW, DDG, PM, IS, VS, VGR and A-MO were involved in the revision for critical intellectual content and final approval of manuscript.

Funding: UK was supported by an exchange research fellowship grant to Hacettepe University from the Rheumatology Society of Turkey and the Association for Monitoring Rheumatic Diseases. A-MO was supported in part by a Scientist Development Award from the Rheumatology Research Foundation. AO was supported by research grant K23 AR063764 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. This work was supported in part by the Johns Hopkins Arthritis Center Discovery Fund.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

Data sharing statement: Data used in this publication are articles available in the public domain in the following two databases: Medline via PubMed and EMBASE. We provided a complete list of our references in the manuscript and online supplementary appendix . For additional data from our data extraction sheets, address questions to the corresponding author.

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Difficult to treat psoriatic arthritis — how should we manage?

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• Published: 25 April 2023
• Volume 42 , pages 2251–2265, ( 2023 )

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• Anand Kumthekar   ORCID: orcid.org/0000-0001-7374-5837 1 ,
• Maedeh Ashrafi 2 &
• Atul Deodhar 3  

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A Correction to this article was published on 11 May 2023

This article has been updated

Psoriatic arthritis (PsA) is a chronic, multi-domain immune–mediated inflammatory arthritis with a high disease burden. PsA patients have significant co-morbidities like obesity, depression, fibromyalgia which can impact disease activity assessment. The management of PsA has undergone a paradigm shift over the last decade due to the availability of multiple biologic and targeted synthetic disease modifying anti-rheumatic drugs. Despite the availability of multiple therapeutic agents, it is not uncommon to find patients not responding adequately and continuing to have active disease and/or high disease burden. In our review, we propose what is “difficult to treat PsA”, discuss differential diagnosis, commonly overlooked factors, co-morbidities that affect treatment responses, and suggest a stepwise algorithm to manage these patients.

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11 may 2023.

A Correction to this paper has been published: https://doi.org/10.1007/s10067-023-06627-3

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Kumthekar, A., Ashrafi, M. & Deodhar, A. Difficult to treat psoriatic arthritis — how should we manage?. Clin Rheumatol 42 , 2251–2265 (2023). https://doi.org/10.1007/s10067-023-06605-9

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Does arthroscopic or open washout in native knee septic arthritis result in superior post-operative function? A systematic review and meta-analysis of randomised controlled trials and observational studies

• Grace E. M. Kennedy   ORCID: orcid.org/0000-0002-1693-6052 1 ,
• Abisha Tharmaseelan 2 ,
• Jonathan R. A. Phillips 1 ,
• Jon T. Evans 1 , 3 &
• Setor K. Kunutsor 4  

Systematic Reviews volume  13 , Article number:  106 ( 2024 ) Cite this article

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Septic arthritis (SA) of the native knee joint is associated with significant morbidity. This review compared post-operative functional outcomes (patient-reported outcome measures (PROMs) and range of movement (ROM)) following arthroscopic washout (AW) and open washout (OW) amongst adult patients with SA of the native knee. The need for further operative intervention was also considered.

Electronic databases of PubMed, MEDLINE, Embase, Cochrane, Web of Science and Scopus were searched between 16 February 2023 and 18 March 2023. Randomised controlled trials (RCTs) and comparative observational analytic studies comparing function (reflected in PROMs or ROM) at latest follow-up following AW and OW were included. A narrative summary was provided concerning post-operative PROMs. Pooled estimates for mean ROM and re-operation rates were conducted using the random-effects model. The risk of bias was assessed using the Cochrane risk-of-bias assessment tool-2 for RCTs and the Risk of Bias in Non-Randomized Studies of Interventions tool for observational analytic studies.

Of 2580 retrieved citations, 7 articles (1 RCT and 6 cohort studies) met the inclusion criteria. Of these, five had some concerns/moderate risk of bias, and two had serious risk. There was a slight tendency for superior mean PROMs following AW compared with OW, but due to small effect sizes, this was unlikely clinically relevant. Additionally, the use of four different PROMs scales made direct comparisons impossible. AW was associated with superior ROM (mean difference 20.18° (95% CI 14.35, 26.02; p  < 0.00001)), whilst there was a tendency for lower re-operation requirements following AW ( OR 0.64, 95% CI 0.26, 1.57, p  = 0.44).

Conclusions

AW was associated with equivalent to superior post-operative function and lower requirement for further intervention compared with OW. Results need to be interpreted cautiously, taking into consideration the methodological and clinical heterogeneity of the included studies.

Systematic review registration

PROSPERO 2022, CRD42022364062.

Peer Review reports

Introduction

Septic arthritis (SA) of the native knee joint is an orthopaedic emergency, with treatment delays potentially resulting in significant cartilage disruption, or even life-threatening sepsis [ 1 , 2 , 3 ]. The incidence is approximately 2–10 per 100,000 persons in the UK [ 3 , 4 ]. Risk factors include rheumatoid arthritis, skin infections, increasing age, bacteraemia, diabetes mellitus, liver disease, immunosuppression, and joint penetration [ 5 , 6 ]. In adults, typical micro-organisms include Staphylococcus aureus ( S. aureus ) and streptococci [ 3 , 4 , 7 ].

Diagnosis of SA requires consideration of clinical and laboratory features. Patients typically report knee pain, swelling, erythema, restricted range of movement, and decreased weight bearing [ 6 ]. White blood cell counts and C-reactive protein levels may be elevated, whilst joint fluid aspirate reveals a causative micro-organism in approximately 50–75% cases [ 3 , 6 ]. Culture-negative SA may arise due to sampling after antimicrobial therapy, rare micro-organisms not grown on regular culture media, and other technical factors [ 8 , 9 , 10 ]. Such absence of micro-organisms may be falsely reassuring, delaying treatment, and hindering ability to target antimicrobial therapy [ 10 ].

Management of native knee SA typically involves irrigation and debridement of the joint, commonly known as a ‘washout’. This can be performed arthroscopically (‘keyhole’) or via arthrotomy (‘open’) [ 6 ]. Removal of the synovial lining of the joint, synovectomy, may be undertaken as part of an arthroscopic or open washout and is thought to maximise the reduction of the bacterial burden, although the evidence for this is limited [ 11 ]. Antimicrobial therapy typically is recommended for up to 6-week post-washout [ 12 ] but may vary according to clinical and microbiological findings.

To our knowledge, no systematic review has compared post-operative function (reflected in patient-reported outcome measures (PROMs) and range of movement (ROM)) as a primary outcome following arthroscopic washout (AW) or open arthrotomy washout (OW) of native knee SA. Additionally, the literature varies regarding requirement for subsequent intervention, a potential complication of both AW and OW. Two recent meta-analyses explored this as their primary outcome [ 13 , 14 ]. Liang found that AW and OW were associated with comparable rates of reinfection (odds ratio (OR) = 0.85) [ 13 ], whilst Panjwani et al. reported a lower pooled relative risk (RR) of reoperation following AW ( RR  = 0.69) [ 14 ].

We hypothesised that AW would be associated with favourable post-operative PROMs and ROM, owing to smaller incisions and reduced scarring. We also hypothesised that AW would be associated with as good, or superior, rates of infection eradication, in keeping with previous meta-analyses [ 13 , 14 ]. Therefore, the primary aim of this review was to compare post-operative function following AW and OW. Secondary aims were to compare rates of reoperation in the early post-operative phase (30 days) and following typical cessation of antimicrobial therapy (90 days).

Materials and methods

Data sources and study selection.

This systematic review was registered with PROSPERO (CRD42022364062) and was conducted based on a predefined protocol and in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 15 ].

We searched for studies that compared functional outcomes following AW and OW as the index procedure for native knee SA in adult patients (> 18 years).

The online databases PubMed, MEDLINE, Embase, Cochrane, Web of Science, and Scopus through OvidSP were searched independently by two authors (G. K., A. T.) between 16 February 2023–18 March 2023, according to the agreed search strategies, using combined text and MeSH headings (Table  1 ). Databases were searched from database inception with no date range imposed on the retrieval of studies.

Article titles and abstracts, and then full manuscripts of potentially relevant studies, were independently reviewed by two authors (G. K., A. T.) who discussed and resolved any disagreements regarding inclusion, without needing to consult the senior authors (S. K., J. E.). The reference lists of relevant publications were also hand-searched for additional relevant studies.

Studies were included if they were interventional or comparative observational analytic studies (randomised controlled trials (RCTs), cohort studies, case–control studies) involving human subjects. We excluded narrative reviews, case reports, letters to the editor, and studies describing prosthetic joint infections or noninfectious arthritis.

Data extraction

One author (G. K.) used a standardised form to extract data. A second reviewer (A. T.) independently checked these data against those in original articles.

Data were extracted on the following: geographical location, publication year, study design, level of evidence [ 16 ], participants (age, sex), sample size, duration of follow-up, risk factors, microbiological findings, post-operative PROMs and ROM, re-operation requirements, and synovectomy at index procedure.

In publications where data were inadequate, we contacted the authors to request the information needed. Where no response was obtained, the study was excluded from analysis.

The primary outcomes were post-operative PROMs and ROM (at latest follow-up) following AW and OW. The secondary outcomes were rates of reoperation for persistent or recurrent infection within 30 and 90 days of index procedure. We also aimed to present an overview of microbiological findings, risk factors, and whether synovectomy was undertaken during the index procedure.

Assessment of risk of bias and evidence quality

The risk of bias was independently assessed by two authors (G. K., A. T.) who discussed and resolved any disagreements. The Cochrane risk-of-bias assessment tool-2 (RoB2) [ 17 ] was used for RCTs and the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool [ 18 ] for observational studies.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria were used to assess the quality of the evidence for each outcome [ 19 ].

Data synthesis and analysis

A narrative summary was provided concerning PROMs, microbiological features, risk factors, and undertaking of synovectomy. Regarding ROM and reoperation, summary measures were presented as mean differences and odds ratios (OR) with 95% confidence intervals (95% CI ). The random-effects model was used to obtain pooled estimates for each outcome, to account for interstudy heterogeneity and provide a more conservative evaluation of the significance of the association [ 20 ]. The extent of interstudy heterogeneity was assessed with the I 2 statistic [ 21 ], with values of 30–60% representing moderate heterogeneity [ 22 ].

Statistical analysis was conducted using Review Manager (RevMan Web), version 5.4, the Cochrane Collaboration 2020, available at revman.cochrane.org.

Article selection

In total, 2580 potentially relevant citations were identified, 2573 of which were subsequently excluded (Fig.  1 ). Seven eligible studies were included.

PRISMA flow chart outlining the study selection process

Study characteristics

Table 2 outlines characteristics of the seven studies (one RCT, six cohort studies) reporting functional outcomes after AW and OW. In total, 394 patients (243 arthroscopic, 151 open) were included.

Key microbiological findings are outlined in Table  3 . Staphylococcus aureus was the most common micro-organism (96, 24.4%), whilst over 15% were culture negative (66, 16.5%). Where described, antimicrobial regimes were typically administered for a total of 4–6 weeks [ 23 , 24 , 25 , 26 , 27 , 29 ]. No risk factors were present in at least 24.4% of patients (Table  3 ).

Regarding disease severity, of the three studies [ 24 , 26 , 29 ] reporting Gächter stage [ 30 ], there was a tendency for patients with earlier changes (stages I/II) to be managed arthroscopically and more advanced changes (III/IV) to be managed with OW.

Assessment of risk of bias

Moderate risk of bias was present in five studies and serious risk in two studies (Table  4 ). Bias in participant selection was mostly considered moderate because there may have been an association between the interventions and outcomes (patients with more severe symptoms were more likely to undergo OW). Bias relating to measurement of interventions, outcomes, and departures from intended interventions was judged low because the intervention and outcomes were objective and insusceptible.

Patient-reported outcome measures

Four studies reported on post-operative PROMs using four different scales (Table  5 ). Due to heterogeneity of constructs measured, study design, and one study describing categorical results, PROMs were not pooled and synthesised quantitatively using standardised mean difference [ 31 ]. Overall, there was weak evidence of a slightly favourable effect of AW on PROMs. However, the small mean differences were likely not clinically significant, and overlapping confidence intervals would suggest no real difference in effect estimates.

Range of movement

Four cohort studies described ROM at latest follow-up (Table  6 ). The mean difference in ROM was 20.18° (95% CI 14.35, 26.02; p  < 0.00001), favouring AW (Fig.  2 ). No significant heterogeneity was observed ( I 2  = 14%). Findings by Kalem et al. [ 27 ] were excluded from this meta-analysis, as necessary information regarding the interquartile range was neither reported nor provided when requested from the corresponding author.

Forest plot of the comparison of AW and OW for post-operative ROM

On age-adjusted subgroup analysis, Böhler et al. [ 25 ] found the difference in mean ROM between AW and OW groups persisted ( p  = 0.008).

Secondary outcomes

Table 7 details the requirements for re-operation and whether synovectomy was performed during the index procedure. Re-operation was necessary in 31.7% (77/243) of patients following AW and 33.8% (51/151) of patients following OW. Practice regarding synovectomy varied. Owing to inconsistency in reporting, we were unable to look for association between synovectomy and re-operation requirements.

As the timeframe from index to second procedure was often not specified, we were unable to report 30- and 90-day re-operation rates. The second procedure typically paralleled the index; 53 AW patients (68.5%) underwent further AW, and 33 OW patients (64.7%) underwent further OW. The nature of subsequent procedure(s) was not specified for 21 patients.

Additionally, it was often not reported whether single or multiple repeat procedures were necessary. Johns et al. [ 26 ] reported that fewer irrigation procedures were required following AW (1.79 ± 0.96) than following OW (2.42 ± 1.5) ( p  = 0.010).

Meta-analysis of the six cohort studies suggested a tendency for lower re-operation requirement following AW ( OR 0.64, 95% CI 0.26–1.57, p  = 0.44) (Fig.  3 ). Moderate interstudy heterogeneity was observed ( I 2  = 52%). Data from Peres et al. [ 23 ] were not included in this model owing to the difference in study design; however, the authors reported no difference in effectiveness of treatment.

Forest plot of the comparison of arthroscopic washout and open washout regarding need for further washout

After age adjustment, Böhler [ 25 ] found the difference in re-operation requirements between groups persisted ( p  = 0.008). Similarly, Johns [ 26 ] found that the superiority of AW persisted after adjustment for age, sex, comorbidity, and positive joint culture ( OR 2.56, 95% CI 1.1, 5.9; p  = 0.027).

Quality of evidence

The summary of the GRADE assessment [ 19 ] for each outcome is outlined in Table  8 . The evidence certainty ranged from moderate to very low for all outcomes assessed in this systematic review. This was mostly because of starting with a low rating because the data were mostly from observational studies, and the certainty of the evidence was further downgraded for risk of bias or inconsistency.

Publication bias

We were unable to undertake Egger’s test for publication bias, as Egger’s test has insufficient power to distinguish chance from real funnel plot asymmetry with fewer than 10 studies [ 36 ].

Septic arthritis of the native knee can be joint- and life-threatening; thus, prompt, effective management is paramount. Our findings suggest that AW has a tendency for favourable functional outcomes and re-operation rates compared with OW. However, the evidence is uncertain due to moderate-serious risk of bias and inter-study heterogeneity.

Comparison with other studies

The present study represents the first systematic review focusing primarily on function following AW and OW. Our findings agree with PROMs and ROM described in reviews by Panjwani [ 14 ] and Liang [ 13 ], respectively. This was predictable, as we retrieved just one additional study reporting PROMs [ 28 ], and none further reporting ROM. Findings by Kalem [ 27 ], which did not show a difference regarding ROM, were not included in the meta-analysis because information required for pooling of the data was not provided.

Our findings suggested that AW may be associated with lower re-operation rates, given the direction and magnitude of the risk estimate ( OR 0.64). However, the confidence intervals were imprecise suggesting heterogeneity, so the results should be interpreted cautiously. In keeping with our findings, Liang [ 13 ] showed a possible trend for lower rates of reinfection following AW ( OR  = 0.85; p  = 0.44), whilst Panjwani [ 14 ] reported substantially reduced risk of reoperation ( RR  = 0.69; p  = 0.0006). Both these reviews included additional studies in their pooled analyses which were excluded from the present study due to omission of PROMs [ 37 , 38 , 39 , 40 , 41 ]. Additionally, Panjwani [ 14 ] combined effect estimates from randomised and non-randomised studies, which is generally inappropriate [ 42 ].

Explanation of findings

It could be suggested that the less-invasive AW is associated with superior post-operative function, owing to smaller surgical incisions and shorter post-operative recovery. The reported difference in mean ROM (20.18°) is likely highly clinically significant; whilst not previously studied in the septic arthritis setting, in the setting of stroke, the minimum clinically important difference (MCID) was under 10° [ 43 ]. However, given the observational nature of six of the included studies, there is the risk of confounding. We noted that patients with higher Gächter-stage disease [ 24 , 25 , 29 ], mean preoperative temperature [ 23 ], and more risk factors for SA development [ 26 ] were selected for OW. Such preference for OW in higher Gächter-stage disease has been described elsewhere [ 44 ]. Thus, poorer functional outcomes might be expected.

Requirement for reoperation may be confounded by patient factors, including Gächter stage, pyrexia at presentation, body mass index > 45 kg/m 2 , elevated inflammatory markers, and immunosuppression [ 5 , 44 , 45 , 46 ]. Of the included studies, only Böhler [ 25 ] and Johns [ 26 ] adjusted for confounders. Similarly, re-operation requirement may be influenced by intervention factors, including time from presentation to index and subsequent procedures, total number of procedures, and individual surgeons’ thresholds for synovectomy and reoperation. Due to inconsistent reporting, we were unable to stratify or adjust for these factors which may have affected outcomes in the pooled analysis; thus, one should interpret these results with caution.

It is also possible that the observed associations may have arisen due to underpowering, as no prior sample size calculation was undertaken. Post hoc analysis suggested adequate power in the RCT [ 23 ] and two cohort studies [ 25 , 26 ]; however, this may not be the case for the remaining studies.

Implications of findings

We suggest that AW is acceptable to patients and efficacious in the treatment of native knee SA and thus should be routinely used in the management of this condition. We have presented strong evidence in favour of AW regarding ROM and weak evidence regarding PROMs.

As AW was associated with a tendency for reduced re-operation requirement, this may decrease healthcare costs, and we suggest further investigation is warranted. We note, however, that none of the studies utilised a generic health-related quality-of-life assessment tool, which has been recommended to be used in combination with condition-specific scales to facilitate economic assessment [ 47 ].

Additionally, the use of four different PROMs scales has rendered direct comparison between studies impossible, and with the data provided, it was not possible to calculate standardised mean difference. Of the scales used, only the BBFS has been described in SA of the native knee [ 33 ], and the MCID has been established in the SA context for none of the scales. Such use of unvalidated tools may render results less reliable, and differences observed may not be clinically relevant. Furthermore, it is possible that the scales used do not actually reflect what is pertinent to the patient population; to our knowledge, this has not been explored qualitatively. Additionally, we have considered PROMs and ROM at latest follow-up. As average follow-up duration varied, and it was often unclear when measurements were obtained, these functional results may not be directly comparable.

Strengths and limitations

A robust search of multiple databases and rigorous approach to study selection was employed. This ensured that all available relevant citations were identified and outcomes extracted. However, owing to the lack of high-quality studies, the findings should be interpreted with caution. Limitations of the six cohort studies include their retrospective nature, typically small sample sizes, and no blinding of outcome assessors, whilst the small, single-centre nature of the RCT may limit the external validity of their findings. Furthermore, owing to the small number of studies included, we were unable to test for publication bias.

As SA represents an increasing clinical concern, a definitive RCT is warranted. In contrast to the RCT by Peres [ 23 ], this should be multicentre and with prior sample size calculation, in order to improve external validity and ensure sufficient power to capture the outcomes of interest. Subgroup analysis may also wish to consider the appropriateness for AW or OW by disease severity, association between disease severity and functional outcomes, and the role of synovectomy at initial washout. Despite RCTs being the gold standard for clinical research, their use in assessing the effectiveness of orthopaedic interventions has limitations. They are labour intensive, expensive, and need large sample sizes. Real-world evidence, such as nesting analysis within arthroplasty registries, may represent better investigative avenues.

Based on the available evidence, we conclude that AW results in favourable post-operative ROM, similar PROMs, and a tendency for lower re-operation rates compared with OW. Thus, AW is acceptable for use in the treatment of native knee SA. However, as OW tended to be used in those with more severe disease, there may be confounding by indication. Therefore, there is no evidence to suggest that OW should not be used, for example, should arthroscopic treatment be unavailable.

Despite SA being a growing area of clinical concern, higher-quality evidence is lacking. Clinical and methodological heterogeneity of the included studies limits one’s ability to make meaningful comparisons. This systematic review highlights the need for more definitive large clinical trials, with a particular focus on patient-reported and functional outcomes.

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Grace E. M. Kennedy, Jonathan R. A. Phillips & Jon T. Evans

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GK undertook the PROSPERO registration, literature search, data extraction, quality grading, results collation, manuscript preparation. AT served as second reviewer in manuscript retrieval, data extraction and quality grading, and assisted in results collation and manuscript preparation. JRAP assisted in proof-reading and manuscript preparation. JTE oversaw the project and assisted in data presentation and manuscript preparation. SKK oversaw the project and assisted in PROSPERO registration, meta-analysis, data presentation and manuscript preparation.

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Kennedy, G.E.M., Tharmaseelan, A., Phillips, J.R.A. et al. Does arthroscopic or open washout in native knee septic arthritis result in superior post-operative function? A systematic review and meta-analysis of randomised controlled trials and observational studies. Syst Rev 13 , 106 (2024). https://doi.org/10.1186/s13643-024-02508-1

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DOI : https://doi.org/10.1186/s13643-024-02508-1

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The Efficacy and Safety of Apremilast in the Management of Psoriatic Arthritis: A Systematic Review and Meta-Analysis

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• 1 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU.
• 2 College of Medicine, King Abdullah International Medical Research Center, Jeddah, SAU.
• 3 College of Medicine, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia, Jeddah, SAU.
• 4 Internal Medicine/Rheumatology, King Abdulaziz Medical City, Jeddah, SAU.
• 5 Internal Medicine/Rheumatology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU.
• PMID: 38590459
• PMCID: PMC11000044
• DOI: 10.7759/cureus.55773

Psoriasis is a chronic autoimmune inflammatory skin disease that is associated with other conditions, one of them being psoriatic arthritis (PsA). Apremilast, a phosphodiesterase-4 inhibitor, displayed promising results in multiple trials for patients with PsA. This systematic review and meta-analysis aims to showcase its efficacy and safety when compared to placebo. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was adopted after registration on the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023476245). Four databases were systematically searched from their inception until October 25, 2023. As a result, five randomized controlled trials were included with 1,849 participants, after thorough screening. The primary efficacy endpoint evaluated in this meta-analysis was the American College of Rheumatology Response Criteria 20 (ACR20). The results significantly favored apremilast (risk ratio [RR] = 1.92, 95% confidence interval [CI] 1.66-2.21; P < 0.00001; I 2 = 0%) as opposed to placebo. Similarly, secondary efficacy endpoints, ACR50 (RR = 2.34, 95% CI 1.79-3.06; P < 0.00001; I 2 = 0%), ACR70 (RR = 2.89, 95% CI 1.62-5.18; P = 0.0003; I 2 = 0%), and the Health Assessment Questionnaire and Disability Index (HAQ-DI; standardized mean difference [SMD] = -0.26, 95% CI -0.34 to -0.17; P < 0.00001; I 2 = 0%) were also in significant favor of apremilast. However, apremilast had a higher occurrence of gastrointestinal adverse events than placebo (RR = 1.21, 95% CI 1.12-1.30; P < 0.00001; I 2 = 19%). To conclude, apremilast shows promising efficaciousness with some nonserious side effects when compared to placebo, but further trials are needed for comparison with other management lines.

Keywords: apremilast; medicine; meta-analysis; pde-4 inhibitors; psoriatic arthritis.

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