Characterisation of prodromal and very early psoriatic arthritis: a systematic literature review informing a EULAR taskforce.

BACKGROUND: Identifying subjects at risk of imminent psoriatic arthritis (PsA) would allow these subjects to participate in therapeutic interventions to delay or prevent PsA development. METHODS: A systematic literature review (SLR) was conducted in 2021 in Medline, Embase, PubMed, Central databases and international congress abstracts (PROSPERO CRD42022255102). All articles reporting the characteristics of patients transitioning from psoriasis (PsO) to PsA and from undifferentiated arthritis (UA) to PsA were included. Clinical and imaging characteristics were collated before PsA onset and at time of PsA diagnosis. RESULTS: Eighteen of 23 576 references evaluated for PsO/PsA transition were analysed; 14 were cohort studies, 2 case-control studies. Two SLRs were used to enrich the project but were not analysed per se. Of 7873 references focusing on UA to PsA, 3 studies were included. Meta-analysis was not possible due to excessive data heterogeneity. Patients with PsO who developed PsA often reported joint pain, joint tenderness and functional limitations. Arthralgia (PsO, n=669; incident PsA, n=99) was associated with subsequent PsA development. On imaging, subclinical enthesopathy (PsO=325; Incident PsA=39) appeared linked to later PsA development. At the time of PsA onset (incident PsA, N=214), peripheral arthritis, mainly oligo-arthritis (ie, the mean number of swollen joints ranged from 1.5 to 3.2), was the most frequent pattern of clinical presentation. CONCLUSIONS: Joint pain, arthralgia and entheseal involvement detected by imaging were frequent in individuals with PsO at risk for imminent PsA. Very early PsA was mainly oligoarticular. This review informed a EULAR taskforce on transition to PsA.

Living with foot and ankle disorders in rheumatic and musculoskeletal diseases: A systematic review of qualitative studies to inform the work of the OMERACT Foot and Ankle Working Group.

OBJECTIVES: This study aimed to determine outcome domains of importance to patients living with foot and ankle disorders in rheumatic and musculoskeletal diseases (RMDs), by exploring the symptoms and impact of these disorders reported in existing qualitative studies. METHODS: Six databases were searched from inception to March 2022. Studies were included if they used qualitative interview or focus group methods, were published in English, and involved participants living with RMDs (inflammatory arthritis, osteoarthritis, crystal arthropathies, connective tissue diseases, and musculoskeletal conditions in the absence of systemic disease) who had experienced foot and ankle problems. Quality was assessed using the Critical Appraisal Skills Programme qualitative tool and confidence in the findings was assessed using the Grading of Recommendations Assessment, Development and Evaluation Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach. All data from the results section of included studies were extracted, coded and synthesised to develop themes. RESULTS: Of 1,443 records screened, 34 studies were included, with a total of 503 participants. Studies included participants with rheumatoid arthritis (n = 18), osteoarthritis (n = 5), gout (n = 3), psoriatic arthritis (n = 1), lupus (n = 1), posterior tibial tendon dysfunction (n = 1), plantar heel pain (n = 1), Achilles tendonitis (n = 1), and a mixed population (n = 3), who live with foot and ankle disorders. Seven descriptive themes were generated from the thematic synthesis: pain, change in appearance, activity limitations, social isolation, work disruption, financial burden and emotional impact. Descriptive themes were inductively analysed further to construct analytical themes relating to potential outcome domains of importance to patients. Foot or ankle pain was the predominant symptom experienced by patients across all RMDs explored in this review. Based on grading of the evidence, we had moderate confidence that most of the review findings represented the experiences of patients with foot and ankle disorders in RMDs. CONCLUSIONS: Findings indicate that foot and ankle disorders impact on multiple areas of patients' lives, and patients' experiences are similar regardless of the RMD. This study will inform the development of a core domain set for future foot and ankle research and are also useful for clinicians, helping to focus clinical appointments and measurement of outcomes within clinical practice.

A systematic review and narrative synthesis of footwear and orthotic devices used in the management of ankle haemarthrosis and haemarthropathy in haemophilia.

INTRODUCTION: Haemarthrosis is a clinical feature of haemophilia leading to haemarthropathy. The ankle joint is most commonly affected, resulting in significant pain, disability and a reduction in health-related quality of life. Footwear and orthotic devices are effective in other diseases that affect the foot and ankle, such as rheumatoid arthritis, but little is known about their effect in haemophilia. AIMS: To review the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. METHODS: A systematic literature review was conducted. Two review authors independently screened studies for inclusion and appraised methodological quality using Joanna Briggs Institute Critical Appraisal checklists. A narrative analysis was undertaken. RESULTS: Ten studies involving 271 male participants were eligible for inclusion. All studies were quasi-experimental; three employed a within-subject design. Two studies included an independent comparison or control group. A range of footwear and orthotic devices were investigated. Limited evidence from non-randomised studies suggested that footwear and orthotic devices improve the number of ankle joint bleeding episodes, gait parameters and patient-reported pain. CONCLUSION: This review demonstrates a lack of robust evidence regarding the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methodological heterogeneities and limitations with the study designs, small sample sizes and limited follow-up of participants exist. Future studies utilising randomised designs, larger sample sizes, long-term follow-up and validated patient-reported outcome measures are needed to inform the clinical management of ankle joint haemarthrosis and haemarthropathy.

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider.

OBJECTIVE: To update the EULAR 2020 systematic literature review (SLR) on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection. METHODS: As part of a EULAR taskforce, a systematic literature search update was conducted from 11 December 2020 to 14 July 2021. Two reviewers independently identified eligible studies and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage of disease. The risk of bias (RoB) was assessed with validated tools. RESULTS: Of the 26 959 records, 520 articles were eligible for inclusion. Studies were mainly at high or unclear RoB. New randomised controlled trials (RCTs) on tocilizumab clarified its benefit in patients with severe and critical COVID-19, mainly if associated with glucocorticoids. There are emergent data on the usefulness of baricitinib and tofacitinib in severe COVID-19. Other therapeutic strategies such as the use of convalescent plasma and anti-SARS-CoV-2 monoclonal antibodies showed efficacy in subjects not mounting normal anti-SARS-CoV-2 antibody responses. CONCLUSION: This new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside the need for standardisation of inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider.

BACKGROUND: The SARS-CoV-2 pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Our objective was to summarise the available information on the pathophysiology of COVID-19. METHODS: Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration. RESULTS: Of the 55 496 records yielded, 84 articles were eligible for inclusion according to question-specific research criteria. Proinflammatory cytokine expression, including interleukin-6 (IL-6), was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. The myeloid and lymphoid compartments were differentially affected by SARS-CoV-2 infection depending on disease phenotype. Failure to maintain high interferon (IFN) levels was characteristic of severe forms of COVID-19 and could be related to loss-of-function mutations in the IFN pathway and/or the presence of anti-IFN antibodies. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalisation, disease progression or severity, and mortality. CONCLUSIONS: SARS-CoV-2 infection affects both humoral and cellular immunity depending on both disease severity and individual parameters. This systematic literature review informed the EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory therapies.

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider.

OBJECTIVE: To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection. METHODS: As part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools. RESULTS: Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results. CONCLUSION: Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.

Systematic literature review of non-topical treatments for early, untreated (systemic therapy naïve) psoriatic disease: a GRAPPA initiative.

BACKGROUND: Psoriatic disease (PsD) is a complex systemic disorder with cutaneous and musculoskeletal manifestations. Current evidence on pharmacological interventions, effective across the spectrum of clinical manifestations of early, systemic treatment-naïve PsD, is limited. This review aims to appraise such evidence. METHODS: This systematic review examined seven patient-intervention-comparator-outcome research questions to address the efficacy of the interventions on the following: across the spectrum of clinical manifestations PsD activity; peripheral arthritis; dactylitis; spondylitis; enthesitis; skin; and nails. Early PsD was defined as a disease duration of ≤2 years, except for studies investigating outcomes restricted to the skin. Eligible references were clinical trials or well-designed prospective studies/series reporting on adult humans, untreated, with cutaneous and/or musculoskeletal features of PsD. RESULTS: Nine references (out of 160 319, publication range 1946-2019) fulfilled the eligibility criteria. No study adopted comprehensive (that is, simultaneous assessment of different PsD manifestations) composite indices as primary outcome measures. Individual studies reported that apremilast and biologics successfully improved outcomes (disease activity index for PsA, minimal disease activity, PsA DAS, psoriasis area and severity index, PsA response criteria) when efficacy analyses were restricted to single manifestations of untreated PsD. Only qualitative synthesis of evidence was possible, owing to the following factors: data heterogeneity (disease classification criteria, outcome measures); unavailable data subsets (focused on early, untreated PsD) at the single study level; and insufficient data on the exposure of participants to previous treatment. CONCLUSION: Effective interventions, albeit limited in scope, were found for early, treatment-naïve PsD. No study provided evidence about the management of co-occurring cutaneous and musculoskeletal manifestations in early, treatment-naïve PsD. This review highlights an unmet need in research on early PsD.