Alberto Cauli

Background/Objectives: This study aimed to evaluate whether liver stiffness (LS), as assessed by transient elastography (TE), is increased in patients with systemic sclerosis (SSc) and to identify the factors associated with LS. Methods: In this exploratory cross-sectional study, the LS value and the prevalence of LS ≥ 5.3 and LS ≥ 7.5 kPa in 94 SSc patients and 50 healthy controls (HCs) were compared by univariate and multivariate analyses (adjusted for age and sex). TE was performed using FibroScan^® and LS values were expressed in kPa. Clinical and laboratory variables were analysed as factors potentially associated with LS, LS ≥ 5.3 kPa and LS ≥ 7.5 kPa, in exploratory analyses adjusted for a pre-specified set of confounders. Results: Among the 94 SSc patients, 79 (84%) were female; median age was 59 (49–70) years, and median disease duration was 8 (3–13) years. LS was significantly higher in SSc patients than in HCs in both univariate (5.12 ± 1.95 vs. 4.18 ± 0.98 kPa, p < 0.001) and multivariate analyses (β = 0.289, p = 0.001), with a higher prevalence of LS ≥ 5.3 kPa (40.4% vs. 10.0%, adjOR 6.85, p = 0.001) and LS ≥ 7.5 kPa (11.7% vs. 0%, p = 0.009). Only a limited number of factors were associated with LS abnormalities: telangiectasias (β = 0.222, p = 0.044) and glutamic–oxaloacetic transaminase (GOT) (β = 0.278, p = 0.012) for LS, and GOT (adjOR 1.082, p = 0.020) and anti-centromere antibodies (adjOR 4.09, p = 0.017) for LS ≥ 5.3 kPa. In univariate analysis, LS ≥ 7.5 kPa was associated with pulmonary hypertension (p = 0.049), pre-capillary pulmonary hypertension (p = 0.011), and GOT (p = 0.032); no multivariate model was fitted because of the few events. Conclusions: SSc patients show increased LS values and a higher prevalence of both LS ≥ 5.3 kPa and LS ≥ 7.5 kPa than HCs, easily detectable by TE. These findings are exploratory and require confirmation in larger cohorts to determine whether increased LS in SSc reflects hepatic fibrosis and whether it carries clinical and prognostic implications.

Objective: To investigate the demographic and clinical features of systemic sclerosis (SSc) patients with anti-U1RNP antibodies using the European Scleroderma Trials and Research (EUSTAR) database, a phenotype less well-defined in SSc than other more commonly associated antibodies. Methods: SSc patients fulfilling classification criteria with available data on anti-U1RNP antibodies were analyzed. Clinical characteristics were collected when the status of anti-U1RNP antibodies was first recorded and patients positive/negative for anti-U1RNP antibodies were compared by univariable analysis. Associations between anti-U1RNP status and organ involvement were assessed by multivariable logistic regression. Multiple imputation used for missing data. Results: A total of 8391 patients were eligible for this analysis, among which 408 (4.9%) were positive for anti-U1RNP antibodies. By multivariable analysis, anti-U1RNP antibodies were confirmed independently associated with younger age at disease onset (OR 0.96, 95% CI 0.95 to 0.97), synovitis (OR 1.82, 95% CI 1.20 to 2.77), pulmonary hypertension on echocardiography (OR 2.13, 95% CI 1.41 to 3.20), proteinuria (OR 2.25, 95% CI 1.29 to 3.93), lower mRSS (OR 0.95, 95% CI 0.93 to 0.98) and elevated ESR (OR 1.48, 95% CI 1.03 to 2.12). There was a negative association with White patients (OR 0.25, 95% CI 0.17 to 0.37). Conclusion: This is the largest cohort of SSc patients positive for anti-U1RNP antibodies reported. It defines a distinct clinical phenotype, with predilection for non-white race, younger disease onset, more inflammatory and musculoskeletal, cardiopulmonary or renal involvement. The detection of anti-U1RNP antibodies in SSc patients might be helpful for risk stratification in clinical practice.

Objectives: To assess the effectiveness of canakinumab (CAN) in controlling clinical and laboratory inflammation by achieving complete control of cardinal disease manifestations and full normalization of laboratory inflammatory markers. Methods: Data were obtained from the international AutoInflammatory Disease Alliance (AIDA) network registry, dedicated to monogenic autoinflammatory diseases. The assessment included both retrospective and prospective real-world data. Results: In total, 158 FMF patients treated with CAN were enrolled. Complete clinical-laboratory response was observed in 45.6% of patients at 3 months, 58.6% at 12 months and 55.2% at the last follow-up, after a mean treatment duration of 45 months. Partial response occurred in 16.5%, 12.5% and 16.8% at the same timepoints, respectively. Complete absence of clinical manifestations was observed in more than 80% of patients at each timepoint. Inflammatory markers normalized significantly by the 3-month assessment. The probability of achieving and maintaining complete response and full laboratory control appeared higher in patients reaching these outcomes by 3 months, although it remained substantial in other patients as well. Complete response was associated with a relapsing-remitting disease course and fewer annual attacks. Nearly all patients maintained stable organ damage scores, and therapy discontinuation due to inefficacy was rare (≤6%). Conclusion: CAN is effective in achieving rapid and sustained clinical and laboratory control in FMF, including stringent endpoints of complete response. Early effectiveness may favour better long-term outcomes, but delayed achievement of complete response and full laboratory control is not uncommon. This study confirms CAN as an effective, and durable therapeutic option in FMF.

Objectives: In the perspective of an increasingly widespread application of precision medicine in rheumatoid arthritis (RA), this study aimed to compare efficacy and safety of ultrasound-guided synovial biopsy (US-SB) performed in an experienced rheumatology and community hospital setting. Methods: A post hoc analysis of R4RA, STRAP and STRAP-EU trials was performed, comparing US-SB performed in a radiology department of a community hospital without experience in RA (n = 14), versus a rheumatology academic centre with a high expertise in RA management and US-SB (n = 16). Suitability of specimens for histological and transcriptomic analysis (tissue and RNA quality) was analyzed as the main outcome. Results: Demographic and clinical features of the two patients’ groups were similar, except of disease duration (p < 0.05). No differences were recorded regarding site and ultrasound of the biopsied joint. Suitability for histological (% of gradable tissue) and transcriptomic analysis (RIN >3) was similar in the two cohorts (both 85.7% vs. 87.5%, p = 0.88). Proportion of gradable biopsies in total (59.2% vs. 59.5%, p = 0.96) and for each patient (52% vs. 56.15%, p = 0.77), were similar in both cohorts. Adverse events were rare (two in community hospital cohort, one in rheumatology cohort, p = 0.54), none considered severe. Seven patients in the community hospital experienced mild or severe pain, only two referred the same in the rheumatology cohort (p = 0.04). Conclusions: US-SB can be safely and effectively performed in a community hospital without experience in RA. A larger diffusion of this technique could allow to pursuit a tailored approach also in ordinary rheumatology outpatient clinics.

Background/Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory condition that primarily affects the musculoskeletal system and skin. While biologic and targeted synthetic DMARDs have improved treatment, many patients still fail to achieve remission. Combining conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) with biologic (b) DMARDs or targeted synthetic (ts) DMARDs shows no added benefit over monotherapy with IL-17, IL-23 inhibitors, or JAK inhibitors, unlike TNFi, which benefit from csDMARD co-administration. Guselkumab (GUS) and risankizumab (RKZ) target IL-23 with high specificity. RCTs (DISCOVER 1 and 2, COSMOS) have confirmed GUS efficacy regardless of methotrexate (MTX) use, though liver toxicity was higher with MTX. Real-world data on GUS remain limited, with gaps in understanding its long-term effectiveness and drug survival. The aim of this study is to assess the following three points within a multicenter Italian real-life cohort of PsA patients treated with guselkumab (GUS) and followed for 12 months: (1) effectiveness and safety of GUS; (2) drug retention rate (DRR) and reasons for discontinuation; (3) impact of comorbidities on achieving minimal disease activity (MDA). Methods: This study utilized data from the GISEA registry, which includes centers in different parts of Italy (north, center, south, and islands), and included patients aged 18 and older diagnosed with PsA according to the CASPAR criteria. Results: Data on 170 PsA patients treated with GUS were collected. In the first 6 months, a prompt mean percentage improvement in all clinimetric indexes was observed compared to the baseline. At 6-month follow-up, ACR 20 was reached by 60% of patients, ACR 50 by 30%, ACR 70 by 15%, MDA by 28%, and DAPSA < 14 by 50% of patients in the overall group. Significant differences were found in the rate of ACR 50 in the bDMARD-naive group (50%) compared to one bDMARDs non-responder (NR) (8%) (p = 0.021). At 12-month follow-up, a notable gap was observed in the rate of patients reaching MDA between bDMARD-naive (60%) and one bDMARDs NR (22%) (p = 0.035) and between bDMARD-naive (60%) and ≥2 bDMARDs NRs (22%) (p = 0.024). By using multivariate binary logistic analysis, the predictors of reaching MDA at 12-month follow-up were naive bDMARDs (OR: 7.9, 95% CI: 1.3–44.8, p = 0.019) and a higher value of pGA at baseline (OR: 1.1, 95% CI: 1–1.5; p = 0.046). The presence of comorbidities, including fibromyalgia and obesity, did not seem to affect the reaching of MDA. At 12-month follow-up, the GUS retention rate was 76%, with a mean survival time of 10.5 months ± 0.2 (95% CI: 10–10.9). No significant differences in GUS survival time were found among bDMARD-naive, one bDMARDs NR, and ≥2 bDMARDs NR patients (in the latter, regardless of the previous mechanism of action: TNFi or other mechanism), as well as between patients treated with GUS in monotherapy and those treated in combination with csDMARDs. A low rate (17%) of discontinuation was found due to both primary NR and secondary NR. The high safety of GUS was recorded. In fact, discontinuation due to adverse events (all definable as minor) was observed in just 4% of patients. By using COX regression multivariate analysis, the factors associated with higher GUS discontinuation risk were a more severe baseline PASI (HR: 1.05, 95% CI: 1–1.1, p = 0.038) and higher baseline ESR (HR:1.06, 95% CI: 1–1.03, p = 0.05). Conclusions: Good performance of GUS was observed in both biologic-naive patients and those with failure of previous bDMARDs (regardless of the mechanism of action of the previous drug: TNFi or non-TNFi), presenting good persistence in therapy even when used as a third mechanism of action. Its high safety profile allows the use of GUS even in particularly complex patients.

Objective: Patient global assessment (PtGA) is a patient-reported outcome (PRO) that reflects a patient's judgment of their health/disease activity (DA). The objective of this systematic literature review was to assess the psychometric properties of PtGA in psoriatic arthritis (PsA).Methods: Research articles reporting the assessment of psychometric properties of PtGA in PsA, listed in PubMed and extracted according to the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 and the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) terminology, were selected. Validity was assessed for comprehensiveness (content), correlation with other DA instruments (construct), and with quality of life measurements (criterion). A metaanalysis regarding construct validity was performed. Correlations between PtGA variations and other indices' variations (external responsiveness) and PtGA variations after treatment (internal responsiveness) were collected. Data on the formulation of PtGA and its discordance with physician global assessment (PGA) were also collected.Results: Of 60 articles analyzed (comprising 17,453 patients), 44 were observational studies and 16 were trials. PtGA was assessed through 27 different formulations. In all the retrieved studies, PtGA assessed DA, and in 3 studies, PtGA was assessed as a variable of global health status. The correlation between PtGA and PROs was strong (ρ > 0.50), whereas with other DA indices and PGA, it ranged from weak to moderate (ρ 0.20-0.50). Three studies described a positive discordance (PtGA > PGA). Responsiveness, assessed in 24 studies, showed a strong correlation with joint count index variations (ρ 0.51-0.52).Conclusion: PtGA is a valid and responsive tool in PsA. Correlations were higher with PROs and weaker with DA composite indices and PGA. PGA was usually scored lower than PtGA. A standardized formulation of PtGA would be useful.

Aiming to identify the potential challenges in the classification of musculoskeletal manifestations in patients with psoriasis (PsO), this study analyzed the outcomes of a cross-sectional rheumatologic assessment of 1057 PsO patients. In total, 209 had a previous diagnosis of psoriatic arthritis (PsA). Out of the remaining 848 subjects, 293 (35%) were classified as suspected PsA cases according to the rheumatologist’s judgment and/or Early PsA Screening Questionnaire score (EARP) ≥ 3. However, only 14% received a PsA diagnosis, 49% had a PsA-alternative diagnosis, and the remaining 37% had nonspecific arthralgias. Most of the newly diagnosed PsA patients had a symptoms duration ≥1 year (72%) and moderate disease activity (55%) with active oligoarthritis (85%), dactylitis, or enthesitis (35%) as the most frequent clinical pattern. The most frequent PsA-alternative diagnoses were osteoarthritis and fibromyalgia (44% and 41%). The only factors with significant (p < 0.05) utility in discriminating PsA from other diseases and nonspecific arthralgias were young age and EARP score with a history of morning stiffness, swollen joints, or dactylitis. These results demonstrated a high prevalence of suspected musculoskeletal symptoms in PsO patients, with, however, only a small proportion due to PsA. Close collaboration between the dermatologist and rheumatologist plays a crucial role in the differential diagnosis of PsA, as well as in monitoring nonspecific arthralgias for the potential transition to overt PsA.

The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition.

Aim. To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. Methods. All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (p = 0.034 and p = 0.028, respectively). Conclusions. Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.