Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

Tixagevimab/cilgavimab for the prevention of COVID-19 in vaccine-refractory patients with autoimmune diseases: a prospective cohort study.

OBJECTIVES: To investigate the effects of passive immunization with the anti-SARS-CoV-2 monoclonal antibodies tixagevimab/cilgavimab on humoral responses and on COVID-19 outcomes in vaccine-refractory patients with immune-mediated inflammatory diseases (IMID) at high risk of severe COVID-19. METHODS: A prospective cohort study was performed on a cohort of high-risk vaccine-refractory IMID patients treated with a single dose of tixagevimab/cilgavimab (150 mg/150 mg). COVID-19 outcomes as well as serum and salivary anti-SARS-CoV-2 IgG were assessed at baseline and for at least 6 months. Results were compared with an untreated high-risk vaccine-refractory IMID population. Standardised incidence ratios (SIR) of COVID-19 compared with the general population were calculated for both groups. RESULTS: 38 high-risk IMID patients received tixagevimab/cilgavimab and were compared with 114 untreated high-risk IMID controls. Serum anti-Spike IgG increased to 6.6 OD (SD: ±0.8) at day one and remained positive up to month 6 (6.3 ± 1.4 OD). Salivary anti-Spike IgG peaked at month 2 (1.6 ± 1.1 OD)) and decreased from month 3 (0.8 ± 0.3 OD)). No severe or extended infection was observed in the tixagevimab/cilgavimab group. Compared with the general population, the SIR of COVID-19 in treated patients was 0.76 (95% CI: 0.24-1.58) despite the increased risk profile. The SIR of the control group was 1.51 (1.07-2.02), corresponding to a significantly increased incidence. CONCLUSIONS: Passive immunization with tixagevimab/cilgavimab is safe and effective in inducing anti-SARS-CoV-2 immunity and potentially in preventing COVID-19 in high-risk vaccine-refractory IMID patients. These data provide a proof of concept for the use of monoclonal antibodies as a preventative strategy against SARS-CoV-2 in vulnerable populations.

Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus.

OBJECTIVES: To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE. METHODS: In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up. RESULTS: A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3-23.3) years for cases and 12.4 (IQR 7.2-13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%). CONCLUSION: In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography.

OBJECTIVE: To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. METHODS: We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. RESULTS: We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. CONCLUSION: MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.

Serum Interleukin-36 α as a Candidate Biomarker to Distinguish Behçet's Syndrome and Psoriatic Arthritis.

Behçet's syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α-a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases-to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.

Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease.

OBJECTIVES: To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. METHODS: Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. RESULTS: 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. CONCLUSIONS: Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.

Advanced neural networks for classification of MRI in psoriatic arthritis, seronegative, and seropositive rheumatoid arthritis.

OBJECTIVES: To evaluate whether neural networks can distinguish between seropositive RA, seronegative RA, and PsA based on inflammatory patterns from hand MRIs and to test how psoriasis patients with subclinical inflammation fit into such patterns. METHODS: ResNet neural networks were utilized to compare seropositive RA vs PsA, seronegative RA vs PsA, and seropositive vs seronegative RA with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1 coronal and axial fat-suppressed contrast-enhanced (CE), and T2 fat-suppressed axial sequences were used. The performance of such trained networks was analysed by the area under the receiver operating characteristics curve (AUROC) with and without presentation of demographic and clinical parameters. Additionally, the trained networks were applied to psoriasis patients without clinical arthritis. RESULTS: MRI scans from 649 patients (135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were fed into ResNet neural networks. The AUROC was 75% for seropositive RA vs PsA, 74% for seronegative RA vs PsA, and 67% for seropositive vs seronegative RA. All MRI sequences were relevant for classification, however, when deleting contrast agent-based sequences the loss of performance was only marginal. The addition of demographic and clinical data to the networks did not provide significant improvements for classification. Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that a PsA-like MRI pattern may be present early in the course of psoriatic disease. CONCLUSION: Neural networks can be successfully trained to distinguish MRI inflammation related to seropositive RA, seronegative RA, and PsA.

At the Heart of Eosinophilic Granulomatosis with Polyangiitis: into Cardiac and Vascular Involvement.

PURPOSE OF REVIEW: To provide an overview of existing literature on pathogenetic and clinical aspects of cardiac and vascular involvement in eosinophilic granulomatosis with polyangiitis (EGPA). RECENT FINDINGS: In EGPA, cardiac and vascular involvement are more common than previously thought. However, no international recommendations on the topic are available yet. Herein, we summarize the existing evidence on the topic and propose a diagnostic approach for cardiac involvement in EGPA. The prevalence of cardiovascular involvement in patients with EGPA varies greatly among published studies, ranging between 3.1-18.7% for occlusive arterial disease, 5.8-30% for venous thrombosis and 17-92% for heart involvement. Cardiac involvement in EGPA is associated with high mortality even though manifestations are heterogeneous. In principle, every anatomical structure of the heart can be involved, and EGPA-related heart disease may be completely asymptomatic at first. A careful diagnostic work-up for early detection and prompt treatment initiation is therefore required. While cardiac manifestations are more common in anti-neutrophil cytoplasmic antibodies (ANCA)-negative patients, arterial and venous thrombotic events are not linked to ANCA status but correlate closely with disease activity and accumulate at disease onset. Thrombotic events (mainly venous) are considerably more frequent in EGPA than in the general population contributing substantially to morbidity and highlighting the importance of developing specific prevention strategies for patients who are diagnosed with EGPA.

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

OBJECTIVES: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. RESULTS: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. CONCLUSIONS: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.

Prevalence and clinical course of SARS-CoV-2 infection in patients with Behçet's syndrome.

OBJECTIVES: We aimed to assess the prevalence of SARS-CoV-2 infection among Behçet's syndrome (BS) patients, evaluating the possible association between demographic and clinical features and the risk of infection. Moreover, we aimed to evaluate the possible association between BS disease activity and treatment, and the risk of SARS-CoV-2 infection. METHODS: A survey was conducted on BS patients followed at the Behçet's Centre of the Careggi University Hospital, Florence, Italy. We further evaluated the possible association between BS disease activity and treatment, and the risk of SARS-CoV-2 infection. RESULTS: Out of 335 BS patients contacted, fourteen cases of SARS-CoV-2 were identified between April 1st, 2020 and February 9th, 2021, suggesting a prevalence of SARS-CoV-2 infection among BS patients of 4.2%, in line with the data of the general population in Italy (4.4%). When comparing clinical features between SARS-CoV-2 cases and matched SARS-CoV-2 negative BS patients, we found that the presence of different disease manifestations did not significantly differ between the two groups. SARS-CoV-2 cases and controls were also comparable in terms of immunosuppressive therapy, with the only exception of corticosteroids (71.4% vs. 35.7%, p=0.030), whose daily dose was significantly higher in cases than controls [5mg/day (IQR 0-10,) vs. 0 mg/day (IQR 0-5), p=0.005], suggesting that the right timing of usage and the more appropriate dosage of corticosteroid are a key question for the better management of these patients. CONCLUSIONS: Based on our results, patients with BS do not seem to be at a greater risk of SARS-CoV-2 infection or severe complications compared with the general population.

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study.

OBJECTIVE: To evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet's phenotype resistant to conventional and biologic treatment. METHODS: A multicentre retrospective study was performed on 15 patients with a mucosal and articular phenotype of Behçet's syndrome fulfilling the International Criteria for Behçet's Disease and refractory to treatment with colchicine, disease-modifying antirheumatic drugs and at least one antitumour necrosis factor-α agent. Minimum follow-up was set at 6 months. Six patients with a polyarticular involvement were treated with secukinumab 300 mg/month, while all other cases received secukinumab 150 mg/month. Dose increase from 150 to 300 mg per month and shortening of administration frequency were allowed for poor disease control. Response evaluation was based on the number of oral ulcers in the previous 28 days and Disease Activity Score-28 for articular manifestations. RESULTS: At 3 months of follow-up, nine (66.7%) patients achieved a response (complete or partial), and this proportion further increased to 86.7% at 6 months, 76.9% at 12 months, 90.0% at 18 months and 100.0% after 24 months. Notably, all patients who started with secukinumab 300 mg/month achieved complete response by month 6. Seven (46.7%) patients could achieve a response only after switching to a higher dosage. CONCLUSIONS: Our study suggests that secukinumab at a dose of 150 and 300 mg per month is safe and effective for the long-term treatment of patients with Behçet's syndrome with a mucosal and articular phenotype refractory to previous treatments. Notably, secukinumab 300 mg/month resulted in superior complete mucosal and articular responses with no serious or dose-related adverse effects.

IL-1 Inhibitors in the Treatment of Familial Mediterranean Fever: Treatment Indications and Clinical Features in a Large Real-World Cohort.

Background: The accruing evidence about the efficacy of anti-IL-1 agents in Familial Mediterranean Fever (FMF) patients led to their widespread off-label use. Therefore, identifying precise indications and clinical characteristics of IL-1i-warranting patients are important. This study investigated the clinical characteristics and treatment indications of patients with FMF requiring interleukin 1 inhibition therapy (IL-1i). Methods: Hospital records of FMF patients attending a tertiary care center at the Department of Rheumatology, University of Health Sciences, Basaksehir Cam and Sakura City Hospital were retrospectively analyzed. Data on symptoms and disease manifestations, age of symptom onset, time to diagnosis, MEFV variants, type of treatment, and their indications were collected. Results: Between June 2020 and March 2023, 312 FMF patients were identified. The mean age at the onset of symptoms was 14.0, and the mean time to diagnosis was 11.9 years. In total, 87.1% of patients were receiving colchicine monotherapy, while the remaining 11.8% warranted IL-1i. Clinical symptoms and flare manifestations did not show a significant difference between the two groups. However, patients receiving IL-1i started having symptoms at younger age (11.5 vs. 14.5, p = 0.042) and time to diagnosis was longer (18.2 vs. 11.0, p < 0.01). M694V homozygosity was more common in patients receiving IL-1i. Indications for patients receiving IL-1i were colchicine resistance (8.0%), secondary amyloidosis (5.1%), and colchicine intolerance (2.2%). Conclusions: This study shows that a subset of FMF patients, particularly those with a more severe phenotype with an earlier disease onset and M694V homozygosity, require IL-1i treatment despite the overall good efficacy and tolerability of colchicine, primarily due to colchicine resistance, intolerance, or complications such as amyloidosis.

Metabolic and molecular imaging in inflammatory arthritis.

It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called 'metabolic imaging' tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively.Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation.Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.

Anatomical pattern of entheseal and synovial fibroblast activation in patients with psoriasis and its risk of developing psoriatic arthritis.

OBJECTIVES: To assess the presence and anatomical distribution of activated fibroblasts in the joints and entheses of patients with psoriasis with arthralgia and to test how fibroblast activation visualised by 68gallium-labelled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04)-positron emission tomography (PET)/CT correlates with clinical tenderness, musculoskeletal ultrasound findings and progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study in patients with psoriasis and arthralgia who underwent clinical and ultrasound evaluation and whole-body PET/CT imaging with 68Ga-FAPI-04. 68Ga-FAPI-04 uptake at synovial and entheseal sites was assessed by maximal standardised uptake values (SUVmax) and PET/CT Joint Index (JI); logistic regression models were used to investigate its correlation with clinical and ultrasound findings. Survival analyses were performed on patients with at least 6 months of follow-up. RESULTS: 36 patients with psoriasis were enrolled. 68Ga-FAPI-04 uptake was found in 318 (7.9%) joints and 369 (7.3%) entheses in 29 (80.6%) participants, with a mean SUVmax (SD) of 3.2 (1.8) for joints and 2.9 (1.6) for entheses. Large joints and the lower limbs were predominantly affected. A significant positive relationship was found between 68Ga-FAPI-04-PET/CT signal intensity and the 68 tender joint count (SUVmax: p<0.001; PET/CT-JI: p<0.001) and tender entheses count (SUVmax: p<0.001; PET/CT-JI: p=0.002). No correlations were found with ultrasound findings (SUVmax: p=0.969; PET/CT-JI: p=0.720). Patients with relevant synovio-entheseal 68Ga-FAPI-04 uptake showed a statistically significant higher risk of developing PsA (p=0.02), independent of ultrasound findings. CONCLUSIONS: Patients with psoriasis presenting with arthralgia show localised signs of resident tissue activation in joints and entheses, which are associated with higher risk of developing PsA.