Psoriatic dactylitis: from immunopathogenesis to anti-cytokine and targeted synthetic therapies.

OBJECTIVES: Psoriatic arthritis (PsA) is an immune-inflammatory disease occurring in a subgroup of patients suffering from psoriasis. Dactylitis is recognised as a hallmark of PsA, being present in about 50% of patients. This article gives an overview of the complexity of psoriatic dactylitis, looking at clinical aspects as well as pathogenetic aspects and subsequent insights into treatment strategies. METHODS: The review focuses on the main evidence on pathogenesis, clinical features, and management of psoriatic dactylitis. RESULTS: In recent years, more studies have focused their attention on dactylitis in PsA patients, leading to a greater understanding of its pathogenesis and clinical presentation and to a growing expansion of the therapeutic armamentarium. Dactylitis is frequently associated with more severe PsA phenotype, often representing the initial feature of the disease. Its prompt recognition can be key for addressing early diagnosis and therapy of PsA, thus leading to better clinical and radiographic outcomes. CONCLUSIONS: There has been considerable progress in understanding psoriatic dactylitis, but major challenges remain. Although there has been a recent expansion in the therapeutic armamentarium for psoriatic dactylitis, there is still a paucity of evidence on a precision approach to this manifestation.

The transition from enthesis physiological responses in health to aberrant responses that underpin spondyloarthritis mechanisms.

PURPOSE OF REVIEW: Despite immunology and translational therapeutics advances in inflammatory arthritis over the past two decades, the enthesis, which is the epicentric of the spondyloarthritis family pathological process, retains many mysteries because of tissue inaccessibility that hampers direct immune study. As entheses are subject to almost continuous mechanical stress and spondyloarthritis is linked to microdamage or injury and joint stress, it is cardinal to understand the physiological changes occurring within the entheses not only to be able to differentiate disease from health but also to understand the transition normal physiology break down and its merges into spondyloarthritis-related disease. RECENT FINDINGS: Imaging has played a major role in understanding the enthesis in human. Remarkable insights from enthesis functioning and microdamage in normal and with ageing including those linked to body mass index is emerging. The impact of mechanical stress and degenerative conditions on the development of the secondary entheseal vascular changes is not understood. Of note, ultrasound studies in psoriasis have shown higher power Doppler changes compared to controls pointing towards a role for vascular changes in the development of enthesitis in psoriatic arthritis. SUMMARY: The literature pertaining to normal entheses changes with age, microdamage and vascular changes in health is providing a roadmap for understanding of the enthesis and its potential role in evolution of spondyloarthritis including psoriatic arthritis.

Sensitivity to change and clinical correlations of the novel DACtylitis glObal Sonographic (DACTOS) score in psoriatic arthritis.

OBJECTIVE: The aim of the study is to assess the performance of the DACTOS (DACtylitis glObal Sonographic) score in a PsA dactylitis clinical setting. In particular, we evaluated the ability of DACTOS to identify the affected fingers, its sensitivity to change after treatment, the correlations between DACTOS and clinical parameters, and the capacity of the score to identify the treatment responders. METHODS: Forty-six consecutive patients with symptomatic PsA hand dactylitis were enrolled. A total of seventy-three dactylitic digits were evaluated clinically and sonographically before and after treatment in this observational and prospective study. Clinical assessment included the Leeds Dactylitis Index-basic (LDI-b) score and visual analogue scales for pain (VAS-p) and functional impairment (VAS-FI). Sonographic lesions were investigated using high-frequency ultrasound with grey scale and power Doppler features according to the DACTOS score. Correlations between the DACTOS score and the clinical parameters were assessed at baseline, 1 month (T1) and 3 months (T3). RESULTS: We observed significant improvements in all of the assessed clinical parameters and the DACTOS scores after dactylitis treatment. There was a statistically significant correlation between the variation of all clinical parameters (VAS-p, VAS-FI and LDI-b) and the DACTOS score at T1 and T3 evaluations. We found statistically significant differences in the DACTOS score between clinical responder and non-responder groups (P < 0.001) and between clinical remission and non-remission groups (P < 0.001). CONCLUSION: The DACTOS score performs well in real-life clinical settings in terms of sensitivity to change and correlations with clinical features in PsA dactylitis.

Novel and reliable DACTylitis glObal Sonographic (DACTOS) score in psoriatic arthritis.

OBJECTIVES: Dactylitis is one of the most typical features of psoriatic arthritis (PsA), with a high lifetime prevalence and inclusion in PsA clinical indices. Musculoskeletal ultrasonography (Msk-US) can readily detect inflammatory involvement of finger anatomical structures particular to dactylitis and monitor therapeutic effects. In this study, we aim to identify the characteristic lesions in PsA dactylitis of the hands, assess the reliability of Msk-US in scoring those lesions and develop a DACTylitis glObal Sonographic (DACTOS) score. METHODS: After a systematic literature review on the use of Msk-US in PsA dactylitis, 12 rheumatologists participated in a three-round Delphi procedure and consensus meeting to agree on the sonographic elementary lesions characterising dactylitis and on the composition of a global sonographic score. Then, a web-based and a patient-based intra-rater and inter-rater reliability exercise was performed to assess those lesions included in the score. RESULTS: DACTOS score was obtained by summing the scores of each lesion selected in the Delphi survey: subcutaneous soft tissue oedema, flexor tenosynovitis, peritendon extensor inflammation and synovitis. The DACTOS score ranges from 0 to 25. In the reliability exercises, we obtained moderate-to-excellent agreement for the sonographic lesions included in the score. CONCLUSIONS: The novel DACTOS score is a reliable measure to interpret the multiple characteristic sonographic features of dactylitis. The DACTOS score provides a useful global analysis of dactylitis of the hand and can represent a support to clinical diagnosis as well as a useful tool for the management and research in patients with PsA with dactylitis.

Association between Leeds Dactylitis Index and ultrasonographic features: a multicentre study on psoriatic hand dactylitis.

OBJECTIVES: The aim of this study was to explore the link between specific sonographic findings and Leeds Dactylitis Index basic (LDI-b) score in psoriatic arthritis (PsA) patients with hand dactylitis. METHODS: Ninety-one hand dactylitis were evaluated in a multicentre study for the presence of pain, functional limitation and tenderness (2-point scale) and LDI-b score. Dactylitic fingers were investigated using high-frequency US in grey scale (GS) and power Doppler (PD). According to median LDI-b score value of 12, fingers were then divided into two groups and categorised into quartiles on the basis of the value of ratio of circumference. RESULTS: Dactylitic fingers with a LDI-b score >12 showed a significantly higher prevalence of GS flexor tenosynovitis (p=0.015), PD flexor tenosynovitis (p=0.001) and soft tissue oedema (p=0.004), when compared with those with those with LDI-b score <12. GS synovitis at proximal interphalangeal (PIP) level (p=0.003) showed more frequent in dactylitic fingers with a LDI-b score <12, than those with a higher LDI-b value. Fingers in the fourth quartile showed a significantly higher prevalence of GS flexor tenosynovitis of grade ≥2 (p=0.046) and joint synovitis of grade ≥2 at PIP level (p=0.028). CONCLUSIONS: We found that high values of LDI are associated with US flexor tenosynovitis and soft tissue oedema in PsA dactylitis. Results suggest a potential role of PIP joint synovitis in the genesis of hand digital swelling and of extra-articular structures alterations in determining the LDI score.

Emerging drugs for psoriatic arthritis.

INTRODUCTION: The majority of Psoriatic Arthritis patients experience a good clinical response to anti-Tumor Necrosis Factor (TNF)-α therapies. However, treatment failure with anti-TNF-α can represent a relevant clinical problem. AREAS COVERED: We review the efficacy and safety profile of biological therapies that have been reported from randomized, controlled trials in phase II and phase III available in Pubmed Database for agents targeting IL-12/23p40 antibody (ustekinumab) and IL-17 (secukinumab), inhibitor of phosphodiesterase 4, (apremilast), and of JAK/STAT pathways (tofacitinib) and CTLA4 co-stimulation (abatacept) in Psoriatic Arthritis. EXPERT OPINION: In Psoriatic Arthritis, main emerging drugs are represented by the fully human monoclonal IL-12/23p40 antibody, ustekinumab, the agent targeting IL-17, secukinumab, and the inhibitor of phosphodiesterase 4, apremilast. Results on T cell co-stimulation inhibition by abatacept are insufficient both in psoriasis and in PsA. In vitro investigations on JAK/STAT pathways in PsA suggest that tofacitinib could represent a further valuable therapeutic option. Emerging biological treatments other than anti-TNF agents, ustekinumab, secukinumab and apremilast appear promising for Psoriatic Arthritis and recent studies have showed a good efficacy and an acceptable safety profile; however, further and long-term studies are advocated.

Upadacitinib for the treatment of adult patients with active psoriatic arthritis.

INTRODUCTION: Psoriatic arthritis (PsA) is a rheumatic disorder that may be responsible for relevant articular impairment. The recently licensed Janus Kinase (JaK) inhibitors represent a new opportunity to improve PsA treatment. This review deals with the clinical usefulness of the selective JaK-1 inhibitor upadacitinib (UPA) in patients with PsA. COVERED AREAS: Two phase-III studies are available: SELECT-PsA 1, performed in patients with an inadequate response to non-biological therapies, and SELECT-PsA 2, conducted in biologic-experienced patients. Long-term extension results and post-hoc analysis data of these two trials are also available. EXPERT OPINION: The results provided by the trials indicate that UPA may be used to treat all of the clinical manifestations of PsA. Venous thromboembolism, cardiovascular events, and malignancy, the most feared adverse events associated with JaK inhibitor use, were not increased in the trial populations, yet long-term observational studies are needed to make sure that UPA is safe in this respect.

Ultrasound Examination of Common Carotid Adventitial Thickness Can Differentiate Takayasu Arteritis and Large Vessel Giant Cell Arteritis.

Pathological studies have demonstrated that the adventitial layer is markedly thickened in Takayasu (TAK) as compared to large vessel giant cell arteritis (LV-GCA). An ultrasound (US) examination of the arterial vessels allows the determination of intima media thickness (IMT) and of adventitial layer thickness (extra media thickness (EMT)). No previous study has evaluated if there are differences in EMT thickness between TAK and LV-GCA. In this cross-sectional retrospective study of stored ultrasound (US) imaging, we have compared common carotid artery (CCA) EMT and IMT in a series of consecutive TAK and LV-GCA patients. US examination CCA IMT and EMT were significantly higher in TAK as compared to LV-GCA. With ROC curve analysis, we have found that an EMT > 0.76 mm has high sensitivity and specificity for TAK CCA examination. The percentage of CCA at EMT > 0.76 mm and the total arterial wall thickening were significantly higher in TAK group examinations. EMT thickness correlated with disease duration and IMT in the TAK group, as well as with the IMT and ESR values in the LV-GCA group. Upon multivariate logistic regression analysis, factors independently associated with TAK CCA were EMT > 0.76 mm and age. No significant variation in IMT and EMT could be demonstrated in subsequent US CCA examinations.

Ultrasound Effectiveness of Steroid Injection for hand Psoriatic Dactylitis: Results from a Longitudinal Observational Study.

INTRODUCTION: To assess clinical and ultrasound effectiveness of steroid injection (local treatment, LT) into the digital flexor tendon sheath for the treatment of psoriatic dactylitis compared to systemic treatment (ST) alone. METHODS: In this observational, multicentre, prospective study, 88 cases of symptomatic hand dactylitis were evaluated clinically and sonographically by high-frequency ultrasound (US) probe in both greyscale (GS) and power Doppler (PD). The presence of flexor tenosynovitis (FT), soft tissue oedema (STO), peritendon extensor inflammation and synovitis was assessed (including DACtylitis glObal Sonographic-DACTOS-score) before treatment, at 1-month (T1) and 3-months (T3) follow-up. LT was proposed to all patients. Patients refusing LT were treated with oral NSAIDs. Patients continued the same baseline csDMARDs and/or corticosteroid therapy during the whole follow-up period. US response was defined for DACTOS score < 3 and US remission for DACTOS score = 0. RESULTS: At T3 evaluation the ST group showed a significantly higher persistence (grade > 1) of FT and STO (p < 0.001 for all) and MCP synovitis (p = 0.001). US remission was achieved only in the LT group (at T3 31% vs. 0, p < 0.001). The percentage of patients with DACTOS < 3 was significantly greater in the LT group compared with ST group, at both T1 (49% vs. 5%, p < 0.001) and T3 evaluation (76% vs. 7%, p < 0.001). In multiple conditional logistic regression analysis, the only factor associated with US remission was LT (T3 odds ratio = 41.21, p < 0.001). CONCLUSIONS: US confirmed the effectiveness of steroid injection for dactylitis by demonstrating that it involves the resolution of extra-articular inflammation, in particular FT and STO.

Psoriatic Dactylitis: Current Perspectives and New Insights in Ultrasonography and Magnetic Resonance Imaging.

Dactylitis, one of the most typical features of psoriatic arthritis (PsA), is the diffuse swelling of the digits and is determined by the involvement of different anatomic structures, including: the subcutaneous fibrous tissue "accessory pulley" system; flexor tendons, with their related structures; the articular synovium; the small enthesis of the hands. Dactylitis is currently considered both a marker of disease activity and severe prognosis and its importance in PsA is emphasized by the inclusion in the classification criteria of PsA. This review focuses on the role of imaging in the management of PsA patients with dactylitis in clinical practice and in a research setting. Furthermore, imaging could be a valuable tool to assist in unravelling some of the underlying mechanisms of the onset and chronicization of dactylitis in PsA patients.

Short-Term Effect of a New Oral Sodium Hyaluronate Formulation on Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

OBJECTIVE: the aim of this pilot study was to test the short-term effect of oral supplementation with a sodium hyaluronate with a large spectrum of molecular weights (FS-HA®) on the symptoms and functionality of knee osteoarthritis (OA). METHODS: 60 subjects affected by clinical and/or radiological diagnosis of symptomatic knee OA were consecutively enrolled in a randomized, double blind, placebo-controlled, clinical trial. At randomization visit, at day 28 (visit 2), and day 56 (visit 3), the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the Lequesne Functional Index (LFI) and the Visual Analogue Scale (VAS) for pain (VAS-p) were administered to the enrolled patients. Then, patients were asked how many times they used rescue medications (non-steroidal antinflammatory drugs - NSAIDs and/or anti-pain drugs) during the previous 4 weeks. Finally, the range of knee joint motion (ROM) was also instrumentally measured. RESULTS: In FS-HA® treated subjects, VAS-p, pain and total WOMAC score, LFI and ROM significantly improved compared to the baseline values (p < 0.05). At 60 days, the VAS-p and the pain WOMAC score were significantly lower after FS-HA® treatment when compared with placebo as well (p < 0.05). The FS-HA® treated subjects significantly reduced the weekly use of NSAIDs and/or antipain drugs when compared to the placebo-treated ones (p < 0.05). CONCLUSION: the oral supplementation with a FS-HA® characterized by a large spectrum of molecular weight was associated with a short-term improvement in symptomatology and functionality of osteoarthritis-affected knees, and associated with a reduction in the use of NSAIDS and anti-pain drugs.

Targeted synthetic pharmacotherapy for psoriatic arthritis: state of the art.

INTRODUCTION: In recent years, different studies regarding psoriatic arthritis (PsA) have shown the pathogenetic role of dysfunction of signaling pathways involving the phosphodiesterase-4 enzyme and transcription factors or enzymes belonging to the kinase (JAK)-signal family pathway. These also represent the target of several drugs known as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). AREAS COVERED: The authors performed a systematic literature search using the PubMed database, as well as through retrieving data from randomized controlled trials, their post-hoc analysis, and pooled data analysis on the efficacy and safety profile of the PDE4 inhibitor (PDE4i), apremilast, and the inhibitors of JAK (JAKis), tofacitinib, filgotinib, baricitinib, and upadacitinib, in PsA. EXPERT OPINION: In PsA, the PDE4i, apremilast, and the JAKi, tofacitinib, are effective across multiple clinical domains and have an acceptable tolerability profile, thus expanding the treatment options available for PsA patients. Apremilast and tofacitinib show several advantages mainly represented by their oral administration, a fast onset of action, and a short half-life. Data on tsDMARDs in PsA are still limited, and randomized trials and real-life studies are advocated.

Predominant ultrasonographic extracapsular changes in symptomatic psoriatic dactylitis: results from a multicenter cross-sectional study comparing symptomatic and asymptomatic hand dactylitis.

OBJECTIVE: Despite diffuse digital swelling, dactylitis may sometimes be asymptomatic. The objective of this study was to compare the clinical and ultrasonographic features of symptomatic with asymptomatic psoriatic arthritis (PsA) dactylitis. METHODS: One hundred and twenty-five hand dactylitis were evaluated in a multicenter cross-sectional study for the presence of pain, subjective functional limitation, and tenderness (4-points scale) with the calculation of a Leeds Dactylitis Index (LDI) score. Fingers were subsequently investigated using high-frequency ultrasound (US) both in gray-scale (GS) and power Doppler (PD), for the presence and grading of flexor tenosynovitis, soft tissue edema, subcutaneous PD signal (PDUS), extensor tendon involvement, and joints synovitis. Clinical and US characteristics of symptomatic dactylitic fingers were compared with the asymptomatic dactylitic ones. RESULTS: Symptomatic fingers (n = 80) had a significantly lower dactylitis duration compared to asymptomatic fingers (n = 36) (p < 0.001). Values of LDI, patient VAS-pain, and VAS-functional score were significantly higher in fingers with symptomatic dactylitis (p < 0.001 and p = 0.010, respectively). Symptomatic dactylitis had a higher prevalence of flexor tenosynovitis of grade > 2, soft tissue edema and subcutaneous PDUS signal (p < 0.001). Asymptomatic dactylitis showed a greater prevalence of joint synovitis (both in GS and in PD) than symptomatic dactylitis (p < 0.001). CONCLUSIONS: Digital tenderness and pain are linked to US tenosynovitis of grade > 2 and extra synovial abnormalities and conversely asymptomatic dactylitis is associated with joint-based synovitis.Key Points• Digital tenderness and local pain in psoriatic arthritis dactylitis are strongly associated with flexor tenosynovitis of grade> 2, soft tissue edema, and subcutaneous PD signal.• In psoriatic arthritis, asymptomatic dactylitis showed a greater prevalence of joint synovitis than symptomatic dactylitis.• In psoriatic arthritis, ultrasound inflammatory abnormalities are present in about 70% of cold dactylitis which is linked for disease chronicity.• In psoriatic arthritis, the flexor tendon and adjacent soft tissues play a significant role in symptomatic dactylitis.

Musculoskeletal Ultrasound in Monitoring Clinical Response to Treatment in Acute Symptomatic Psoriatic Dactylitis: Results from a Multicentre Prospective Observational Study.

This observational and prospective study evaluated the clinical correlations of sonographic lesions in consecutive psoriatic arthritis (PsA) dactylitis cases. Eighty-three dactylitic digits were evaluated clinically and sonographically before treatment and at one-month (T1) and three-month (T3) follow-up. Clinical evaluation included the Leeds Dactylitis Index-basic (LDI-b) score and the visual analogue scales for pain (VAS-p) and functional impairment (VAS-FI). High-frequency ultrasound with grey scale (GS) and power Doppler (PD) assessed flexor tenosynovitis (FT), soft tissue oedema (STO), extensor tendon paratenonitis, and joint synovitis. There was a statistically significant correlation between the clinical parameters (VAS-p, VAS-FI, and LDI-b) and FT and STO at T1 and T3. We found statistically significant improvement in FT and STO for the cases with clinically meaningful treatment responses (p < 0.001). After a multiple conditional logistic regression analysis, the only variables that correlated with a T1 clinical response were the resolutions of PD FT (OR 15.66) and PD STO (OR 6.23), while the resolution of PD FT (OR 27.77) and of GS STO (OR 7.29) correlated with a T3 clinical response. The clinical improvements of active dactylitis are linked to the regression of sonographic evidence of extracapsular inflammation (particularly FT and STO).

Ultrasonographic Evidence of Predominance of Acute Extracapsular and Chronic Intrasynovial Patterns in 100 Cases of Psoriatic Hand Dactylitis.

OBJECTIVE: To use ultrasonography to study whether the duration of psoriatic dactylitis was associated with different patterns of extracapsular and synovial-based involvement. METHODS: One hundred cases of hand dactylitis from 85 patients with psoriatic arthritis (PsA) were consecutively enrolled in a multicenter cross-sectional study and divided into 2 groups according to dactylitis duration (shorter or longer than the median: 20 weeks). All dactylitis fingers were investigated using high-frequency ultrasound both in greyscale (GS) and power Doppler (PD), evaluating the presence of flexor tenosynovitis, soft tissue edema, subcutaneous PD signal (PDS), extensor tendon involvement, and joint synovitis. RESULTS: Cases with a shorter dactylitis duration (< 20 weeks) had a significantly higher prevalence of GS flexor tenosynovitis of grade > 2, PD flexor tenosynovitis, soft tissue edema, and subcutaneous PDS (p = 0.001, p < 0.001, p < 0.05, and p = 0.001, respectively). However, the presence of synovitis in GS and PD mode (in both cases at proximal interphalangeal level) was more frequent in patients with longer dactylitis duration (p < 0.001). When detected in the chronic form, flexor tenosynovitis was grade 2 or lower. CONCLUSION: In a large cohort of PsA hand dactylitis, we found a predominant extracapsular inflammation (flexor tenosynovitis and soft tissue edema) in early cases and a high prevalence of joint synovitis at proximal interphalangeal level in the chronic form. However, longitudinal imaging studies are needed to clarify these aspects.

Metabolic Syndrome and psoriatic arthritis: considerations for the clinician.

Introduction: Metabolic Syndrome (MetS) is strictly interconnected with systemic inflammation, and increased evidence has described a close link between this condition and Psoriatic Arthritis (PsA).Areas covered: This review summarizes main studies exploring clinical aspects and prevalence of MetS in PsA cohorts. Further, there is accumulating evidence showing shared inflammatory pathways between MetS, its components, and PsA.Expert opinion: The high prevalence of MetS in PsA highlights the need for screening, evaluation, and close monitoring of MetS and its components (namely, diabetes mellitus, obesity, hypertension, and dyslipidemia) in psoriatic patients.Further studies should focus on the pathogenetic link between MetS and PsA. More studies are required to identify appropriate algorithms for the assessment and management of MetS in PsA patients.

Significance of inflammation restricted to adventitial/periadventitial tissue on temporal artery biopsy.

OBJECTIVE: To evaluate the characteristics and significance of inflammation restricted (RI) to the adventitial and/or periadventitial tissue on temporal artery biopsy (TAB). METHODS: We studied a retrospective cohort of 80 patients with RI, extending our earlier series of 39 patients. For comparison purposes, we collected the same data from 254 patients with transmural inflammation (TMI) and 81 TAB-negative patients. A review of the literature was also performed. RESULTS: A final diagnosis of giant cells arteritis (GCA) and/or polymyalgia rheumatica (PMR) was observed in 86% of patients with RI. Compared to TMI, GCA diagnosis was significantly less frequently observed in patients with RI and in those TAB-negative (p < 0.0001), while cranial manifestations were significantly less frequent (p = 0.001) and ESR and CRP values at diagnosis significantly reduced (p < 0.0001). PMR, permanent visual loss, and large vessel involvement at diagnosis were equally present in the 3 subgroups. The median duration of prednisone therapy, the cumulative prednisone dosages, and the relapse and long-term remission rates were similar between patients with GCA-RI and those with TMI. The positive likelihood ratios (LRs) of pathological evidence of RI at TAB for GCA or GCA/PMR diagnoses were 0.88 (CI, 0.61-1.27) and 1.15 (CI, 0.67-1.99), while that of inflammation limited to adventitia was 1.37 (CI, 0.59-3.19) and 3.77 (CI, 0.53-26.72). In the literature review, the positive LR of RI for GCA diagnosis was 0.92 (CI, 0.68-1.25). CONCLUSION: A large part of the patients with RI have GCA/PMR, however, the diagnostic value of RI for GCA diagnosis is not relevant.