The clinical heterogeneity of adult onset Still's disease may underlie different pathogenic mechanisms. Implications for a personalised therapeutic management of these patients.

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown aetiology usually affecting young adults and manifesting with a clinical triad of spiking fever, arthritis, and evanescent cutaneous rash. AOSD may be considered a highly heterogeneous disease, despite a similar clinical presentation, the disease course may be completely different. Some patients may have a single episode of the disease whereas others may evolve toward a chronic course and experience life-threatening complications. On these bases, to dissect the clinical heterogeneity of this disease, four different subsets were identified combining the manifestations at the beginning with possible diverse outcomes over time. Each one of these derived subsets would be characterised by a prominent different clinical feature from others, thus proposing dissimilar underlying pathogenic mechanisms, at least partially. Consequently, a distinct management of AOSD may be suggested to appropriately tailor the therapeutic strategy to these patients, according to principles of the precision medicine. These findings would also provide the rationale to recognise a different genetic and molecular profile of patients with AOSD. Taking together these findings, the basis for a precision medicine approach may be suggested in AOSD, which would drive a tailored therapeutic approach in these patients. A better patient stratification may also help in arranging specific designed studies to improve the management of patients with AOSD. Behind these different clinical phenotypes, distinct endotypes of AOSD may be suggested, probably differing in pathogenesis, outcomes, and response to therapies.

EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease.

Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing. METHODS: In May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS). Systematic literature reviews were conducted accordingly. RESULTS: The TF based their recommendations on four overarching principles, highlighting notably that sJIA and AOSD are one disease, to be designated by one name, Still's disease.Fourteen specific recommendations were issued. Two therapeutic targets were defined: clinically inactive disease (CID) and remission, that is, CID maintained for at least 6 months. The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors associated to short duration glucocorticoid (GC). MAS treatment should rely on high-dose GCs, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors. A specific concern rose recently with cases of severe lung disease in children with Still's disease, for which T cell directed immunosuppressant are suggested. The recommendations emphasised the key role of expert centres for difficult-to-treat patients. All overarching principles and recommendations were agreed by over 80% of the TF experts with a high level of agreement. CONCLUSION: These recommendations are the first consensus for the diagnosis and management of children and adults with Still's disease.

Short-term effectiveness of guselkumab in psoriatic arthritis patients and suggestive features of axial involvement: results from a real-life multicentre cohort.

OBJECTIVE: To evaluate the short-term effectiveness of guselkumab in patients with psoriatic arthritis (PsA) and suggestive features of axial involvement in a prospective "real-life" multicentre cohort. METHODS: Between June 2022 and June 2023, PsA patients with axial involvement were evaluated if treated at least for 4 months with guselkumab. The effectiveness was evaluated by BASDAI, ASDAS, DAPSA, and achievement of BASDAI ≤ 4, also exploiting predictive factors. In a group of patients, MRI findings on sacroiliac joints were assessed before and after guselkumab administration. RESULTS: Sixty-seven patients with PsA and suggestive features of axial involvement (age 53.4 ± 11.2 years, male sex 26.9%) were treated with guselkumab. After 4 months, a significant reduction of BASDAI, ASDAS, and DAPSA was observed. A ΔBASDAI of -2.11 ± 0.43 was estimated assessing the mean difference values before and after guselkumab administration and 52.2% of patients reached a BASDAI ≤ 4. In 27 patients, MRI findings on sacroiliac joints were assessed before and after guselkumab administration. A reduction of 0.80 or larger of the sacroiliac joint lesion score was observed in the majority of patients (70.3%) based on MRI improvements, paralleling with the clinical response.No life-threatening side effects were recorded; 17.9% of patients reported minor adverse events mainly injection site reactions. CONCLUSIONS: The short-term effectiveness of guselkumab in patients with PsA and suggestive features of axial involvement was shown. Although further studies are needed, our multicentre "real-life" study may suggest the clinical usability of guselkumab in this context.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

The assessment of the drug retention rate of secukinumab in patients with psoriatic arthritis in a real-life multicentre cohort.

OBJECTIVES: We aimed to evaluate the drug retention rate (DRR) of secukinumab, an anti-IL-17A monoclonal antibody, in patients with psoriatic arthritis (PsA) in a real-life cohort, and to assess the impact of comorbidities and patient clinical characteristics on the DRR of secukinumab. METHODS: A retrospective study of prospective followed-up patients was performed to evaluate the DRR of secukinumab on patients with PsA attending the recruiting centres between January 2016 and June 2022. RESULTS: In 207 patients with PsA, a 60-month DRR of secukinumab of 57.0% was estimated (mean time of administration of 21.5±17.1 months). Male gender, age ≥65 years, disease duration ≥5 years and ≥10 years did not influence the DRR of secukinumab. The presence of comorbidities, considering any concomitant disorder, did not affect the DRR of secukinumab. In patients with cardiometabolic multimorbidity, a trend toward a better DRR of secukinumab was recorded. In fact, patients with high blood pressure, dyslipidaemia, and type 2 diabetes showed a trend toward an improved DRR of secukinumab. Furthermore, the presence of obesity did not influence the DRR of secukinumab. Different dosages, previous bDMARDs, and concomitant therapy with csDMARDs did not influence the DRR of secukinumab. CONCLUSIONS: A cumulative 60-month DRR of secukinumab of 57.0% in patients with PsA was retrieved. The presence of cardiometabolic multimorbidity could be associated with an improved DRR of secukinumab, whereas obesity did not affect this feature in our cohort. Previous bDMARDs, concomitant csDMARDs, and different drug dosages could not influence the DRR of secukinumab over time.

Clinical and subclinical atherosclerosis in patients with systemic sclerosis: an observational, multicentre study of GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale).

OBJECTIVES: Conflicting results about clinical and subclinical atherosclerosis in systemic sclerosis (SSc) and the associated risk factors have been reported. Hence, we aimed to determine the prevalence of clinical and subclinical atherosclerosis in a large number of Italian SSc patients and the associated risk factors. METHODS: This study included 613 SSc patients from 11 Italian tertiary Rheumatologic Units. All patients underwent full history taking, clinical examination, and relevant laboratory and radiological investigations. Doppler ultrasonography (US) of the common carotid and upper and lower limbs was performed to measure carotid and femoral intima-media thickness (cIMT and fIMT), and carotid and peripheral atheroma plaques. Doppler US of the brachial artery was performed to measure flow-mediated dilatation (FMD). RESULTS: Patients were mostly women (91.4%) with a median age of 61 years (range, 20-100); a median disease duration of 14 years (range, 0-77) from the onset of the first non-Raynaud's phenomenon (RP); 9.3% had a history of clinical atherosclerosis (9 stable/unstable angina, 21 myocardial infarctions, 24 heart failure, 3 strokes, 8 transient ischaemic attack, 6 intermittent claudication, 10 atrial thrombo-embolism). In 37.1% of patients, subclinical atherosclerosis was detected, after excluding those with a history of clinical atherosclerosis. The prevalence of clinical and subclinical atherosclerosis was higher than that reported by the European Society of Cardiology and observational studies that enrolled Italian healthy individuals as a control group, respectively. CONCLUSIONS: A higher prevalence of clinical and subclinical atherosclerosis was detected in SSc Italian patients and correlated with traditional and SSc-related risk factors.

Clinical correlates of a subset of anti-fibroblast antibodies in systemic sclerosis.

Anti-fibroblast antibodies (AFA) have been reported in systemic sclerosis (SSc) and are known to promote fibroblast activation. Aim of this study was to characterize the fine specificity of AFA and to analyze any correlations with clinical parameters associated to fibrosis. To this end, AFA were affinity-purified from a patient with diffuse cutaneous SSc (dcSSc) and interstitial lung disease (ILD). Panning of a phage display peptide library with purified AFA identified the motif . The peptide p121, bearing the AFA-specific motif, was used in ELISA to screen sera from 186 SSc patients and 81 healthy donors. Anti-p121 Ab serum levels were statistically higher in SSc than in healthy groups, and directly associated with dcSSc, reduced FVC (FVC < 70), and ILD. Given these clinical correlates, this study lays the groundwork for the identification of the antigen recognized by anti-p121 Ab, which might represent a novel therapeutic target for ILD.

COVID-19 and Mixed Cryoglobulinemia Syndrome: Long-Term Survey Study on the Prevalence and Outcome, Vaccine Safety, and Immunogenicity.

PURPOSE: Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. METHODS: The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. RESULTS: A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients' older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). CONCLUSIONS: The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.

Systemic sclerosis and primary biliary cholangitis share an antibody population with identical specificity.

Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC), respectively, and can coexist in up to 25 and 30% of SSc and PBC patients. Here, we evaluated whether anti-centromeric protein A (CENP-A) antibodies cross-react with mitochondrial antigens. To this end, sera from two lcSSc patients (pt1 and pt4), one of them (pt4) also affected by PBC, were used as the source of ACA, previously shown to recognize different groups of amino acids (motifs) in the CENP-A region spanning amino acids 1-17 (Ap1-17). Pt1 and pt4 Ap1-17-specific IgG were purified by affinity-chromatography on insolubilized Ap1-17-peptide column and tested by western blotting with nuclear and cytoplasmic protein extract from HeLa cells. Immunoreactive proteins were identified by mass spectrometry and validated by immunodot. The results showed that affinity-purified SSc/PBC pt4 anti-Ap1-17 and not SSc pt1 anti-Ap1-17 Ab, specifically cross-reacted with the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen in PBC. Sequence homology analysis indicated that the motif A-x-x-P-x-A-P recognized by pt4 anti-Ap1-17 IgG and shared by CENP-A and PDC-E2, is also expressed by some members of the Human Herpesvirus family, suggesting that they may trigger the production of these cross-reacting antibodies.

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis.

BACKGROUND: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. OBJECTIVE: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. METHODS: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. RESULTS: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. CONCLUSION: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.

Fibroblast expression of CD248 may contribute to exacerbation of microvascular damage during systemic sclerosis.

OBJECTIVES: CD248 is a glycoprotein, highly expressed on pericytes and fibroblasts (FBs), that is implicated in the fibrotic process. During angiogenesis, CD248 can promote vessel regression, binding multimerin-2 (MMRN-2). Thus, we investigated the expression of MMRN-2 in systemic sclerosis (SSc)-skin and of CD248 in isolated SSc-FBs. The anti-angiogenic property of CD248+ SSc-FBs was evaluated by co-culturing these cells with healthy control endothelial cells (HC-ECs). The apoptotic effect of CD248 on HC-ECs was evaluated. Finally, the ability of CD248 to prevent activation of VEGF receptor 2 (VEGFR2) was assessed. METHODS: By IF, MMRN-2 was investigated in SSc-skin and CD248 in SSc FBs. The anti-angiogenic property of CD248+ SSc-FBs was evaluated by HC-ECs/SSc-FBs co-cultures. Lentiviral-induced CD248 short-hairpin RNA delivery was employed for loss-of-function studies in SSc-FBs. HC-ECs were cultured in the presence of CD248 to assess apoptosis by IF and VEGFR2 phosphorylation by western blot. RESULTS: MMRN-2 expression was increased in skin SSc-ECs, whereas CD248 expression was increased in SSc-FBs. Functionally, CD248+-SSc-FBs suppressed angiogenesis in the organotypic model, as assessed by the reduction in total tube length of HC-ECs. This anti-angiogenetic behaviour was reversed by CD248 silencing. Furthermore, the presence of CD248 promoted the apoptosis of HC-ECs. Finally, CD248 prevented activation of VEGFR2 by reducing its phosphorylation after VEGF stimulation. CONCLUSION: CD248 was anti-angiogenic in vitro due to a reduction in tube formation and to induction of apoptosis of ECs. Increased expression of CD248 in SSc could contribute to the microvascular rarefaction observed at the tissue level in SSc. Our results suggest a pathogenic role for CD248-MMRN-2 in SSc.

Diagnosis of COVID-19 associated arthritis in patients with or without underlying rheumatic and musculoskeletal disease supported by musculoskeletal ultrasound: a case series from three European centres.

OBJECTIVES: The coronavirus disease 19 (COVID-19) pandemic concerns the field of rheumatology in many ways. Arthritis in conjunction with COVID-19 is increasingly reported. However, clinical data are still limited and there is lack of a detailed characterisation of COVID-19 associated arthritis by musculoskeletal ultrasound (MSUS). This case series reports different forms of COVID-19 associated arthritis supported by MSUS in patients with or without underlying rheumatic and musculoskeletal disease (RMD). METHODS: From March 2020 to July 2021, adult patients (n=10) with arthritis timely related to COVID-19 were assessed in three European centres by clinical and laboratory values and additionally MSUS. RESULTS: In the group without underlying RMD (n=6), two patients presented with polyarticular arthralgia during severe COVID-19, swelling was rarely seen and MSUS demonstrated arthritis only in a few joints affected. The other four patients showed arthritis four to 16 weeks after mild or moderate COVID-19 (without hospitalisation): polyarthritis (n=1), oligoarthritis of the upper and lower limb (n=2), and in one case, late-onset rheumatoid arthritis (LORA) was newly diagnosed. In the group with an underlying RMD (n=4), an increase of disease activity was reported by MSUS during mild and mild-moderate COVID-19. In general, MSUS often presented power Doppler (PD) positive synovitis and tenosynovitis. CONCLUSIONS: In our patients without underlying RMD, arthritides associated with COVID-19 are comparable to the clinical picture of a reactive arthritis (ReA) or other virus-related arthritides (e.g. parvovirus B19). New onset or flares of RMD possibly triggered by COVID-19 are noteworthy.

Association between Patient Acceptable Symptom State and disease activity in psoriatic arthritis is disrupted by confounders, including comorbid fibromyalgia.

OBJECTIVES: Due to the prevalence of fibromyalgia in psoriatic arthritis (PsA) patients, any evaluation about PsA-specific patient-reported outcomes (PROs) should take in account the possible bias related to this comorbidity. Patient acceptable symptom state (PASS) is a patient-reported measure evaluating the acceptable and/or satisfactory level of symptoms in rheumatic diseases, which has been proposed as a disease activity index, in patients with PsA. Thus, this study was designed to analyse if the association between PASS and PsA disease activity may be biased by the presence of comorbid fibromyalgia. METHODS: A multi-centre, cross-sectional, observational study enrolling consecutive PsA participants has been conducted from July 2021 to November 2021. The Disease Activity for Psoriatic Arthritis (DAPSA) was collected; the following formulation of PASS question: 'Think about all the ways your PsA has affected you during the last 48 hours. If you were to remain in the next few months as you were during the last 48 hours, would this be acceptable to you?', was submitted to our participants. RESULTS: Multivariable logistic regressions, adjusted for the presence of fibromyalgia, did not show any significant association between PASS and DAPSA low disease activity, DAPSA as nominal variable (remission, low disease activity, moderate disease activity, high disease activity) and DAPSA as continuous variable. CONCLUSIONS: Our data suggest that fibromyalgia influences the patient's perception of the disease and has a negative impact on PASS status independently of disease activity, thus limiting the utility of this Patient reported outcome in real world clinical practice.

The negative impact of pain catastrophising on disease activity: analyses of data derived from patient-reported outcomes in psoriatic arthritis and axial spondyloarthritis.

OBJECTIVES: Psychosocial factors are recognised as important determinants of pain experience in patients with inflammatory arthritides. Among them, pain catastrophising, a maladaptive cognitive style, observed in patients with anxiety and depressive disorders, garnered specific attention. Here, we evaluated pain catastrophising (PC) and its related domains (Rumination, Magnification, and Helplessness), in psoriatic arthritis (PsA) and axial spondyloarhtiritis (axSpA) participants, to assess its impact on disease activity. Furthermore, we analysed possible correlations of PC-Scale (PCS) with those psychometric domains which have been already related to catastrophisation in patients with chronic pain. Lastly, we aimed to define the relationship between PCS and the different variables included in the composite indices of disease activity. METHODS: A multi-centre, cross-sectional, observational study has been conducted on 135 PsA (age 56 (47-64) years, males/females 40.74/59.26%; Disease Activity in Psoriasic Arthritis (DAPSA) 13.34 (5.21-22.22)) and 71 axSpA (age 49 (37-58) years, males/females 56.34/43.66%; Bath Ankylosing Spondylitis Arthritis Activity (BASDAI) 4.17 (2.1-6.3)) participants. Multivariable regressions and correlations were performed to evaluate the relationship between pain catastrophising and both disease activity and patient-reported outcomes. RESULTS: The adjusted linear regression model showed a positive association between PCS and DAPSA as well as between PCS and BASDAI; PCS negative impacts on the subjective domains of disease activity scores. CONCLUSIONS: This study suggests the role of PC, independently of inflammation, in disease perception and achievement of remission or low disease activity in chronic arthritides.

The hyper-expression of NLRP4 characterizes the occurrence of macrophage activation syndrome assessing STING pathway in adult-onset Still's disease.

To assess stimulator of interferon genes (STING) pathway in patients with adult-onset Still's disease (AOSD) who were complicated or not by macrophage activation syndrome (MAS), evaluating peripheral blood mononuclear cells (PBMCs), and synovial tissues. The relative mRNA expression of key molecules of the STING pathway (i.e. CGAS, NLRP4, PKDC, STING1, XRCC5, and XRCC6) and interferon (IFN)-γ was assessed in PBMCs obtained from patients with AOSD, who were complicated or not by MAS, and healthy controls (HCs). A bulky RNA sequencing was performed in synovial tissues from two patients with AOSD. Finally, the ability of heavy ferritin subunit (FeH) to induce the expression of NLRP4 was evaluated in cultured macrophages. Twenty patients with AOSD were analysed. Out of them, seven patients were complicated by MAS. Assessing mRNA relative expression in PBMCs, STING1, NLRP4, XRCC6, and IFN-γ were significantly expressed in AOSD than HCs. The mRNA relative expression of CGAS, PKDC, and XRCC5 did not differ between patients and HCs. Furthermore, NLRP4 and IFN-γ resulted to be significantly increased in patients with AOSD complicated by MAS than others. By RNA-sequencing analysis, we observed that Nlrp4 gene was significantly up-regulated in patients with AOSD. Following the stimulation with FeH, an increased expression of NLRP4 was observed in cultured macrophages. In conclusion, an increased expression of some key molecules of STING pathway characterized patients with AOSD. In addition, our results suggested that a hyper-activity of NLRP4 may be observed in patients with MAS. Furthermore, FeH increased the expression of NLRP4 in cultured macrophages.

Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Cytokine profile, ferritin and multi-visceral involvement characterize macrophage activation syndrome during adult-onset Still's disease.

OBJECTIVES: To multidimensionally characterize macrophage activation syndrome (MAS) complicating adult-onset Still's disease (AOSD) considering cytokine profile, inflammatory markers and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN)-related pathways in AOSD synovial tissues by a bulky RNA sequencing. METHODS: Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterize circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. RESULTS: Forty consecutive AOSD patients were assessed, 14 complicated with MAS. Paralleling with increases of systemic score and ferritin, MAS patients showed higher levels of IL-1α, IL-1ß, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α and SCF. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ and IL-10. By CyTOF analysis, MAS patients showed an increase of circulating 'classical monocytes' and a reduction of total NK cells. Our assessment showed 3477 IFN-related genes (IRGs) were differently expressed in AOSD synovial tissues. CONCLUSIONS: A multidimensional characterization of AOSD patients suggested that IFN-γ, IL-10, ferritin and systemic score discriminated the occurrence of cytokine storm syndrome associated with MAS. The inflammatory milieu of AOSD and MAS may be related to a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

Novel biomarker for pulmonary vascular disease in systemic sclerosis patients.

OBJECTIVES: In systemic sclerosis (SSc) patients, pulmonary arterial hypertension (PAH), which is preceded by pulmonary vascular disease (PVD), is one the of major causes of morbidity and mortality. Given the higher risk of PAH among anti-CENP antibodies (ACA)+ patients, we previously characterised a subset of ACA+ patients, based on a differential reactivity of their ACA with the phage clone (pc4.2)-expressing peptide 4.2 (p4.2). There was a considerably greater prevalence of a low diffusing lung capacity for carbon monoxide (DLCO), an expression of PVD, among patients with high anti-pc4.2 Ab levels. Here we examine whether a similar clinical subgroup can be identified within a larger cohort of ACA+ patients, using the synthetic p4.2. METHODS: Clinical data and serum samples were collected from 134 ACA+ patients. Sera were screened for reactivity with p4.2 by indirect ELISA. Statistical analyses were performed to define any associations between anti-p4.2 Ab levels and PVD. RESULTS: Kendall's analysis showed that anti-p4.2 Ab were directly associated with both a reduced DLCO and the presence of pulmonary fibrosis (PF). These associations were confirmed by Fisher's exact test. At multivariate analysis, anti-p4.2 Ab was associated to DLCO<70, DLCO≤60, and PF. Moreover, multivariable analysis showed that only the association of anti-p4.2 Ab with DLCO<70, and not with DLCO≤60, was independent of PF. CONCLUSIONS: Anti-p4.2 Ab are able to identify SSc patients at high risk of developing PVD even in the absence of PF. Patients with high anti-p4.2 Ab levels should be strictly monitored for PVD onset and eventually PAH.

Adult-onset Still's disease with elderly onset: results from a multicentre study.

OBJECTIVES: In this study, we aimed at describing the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset. METHODS: A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed. RESULTS: Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p<0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012). CONCLUSIONS: Clinical features of AOSD patients in the elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD.