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Background:Immunocheckpoint inhibitors (ICIs) revolutionized cancer therapy due to their efficacy on long-term survival. The most employed drugs are directed against CTLA-4 and PD1/PDL-1, whose main role is to stimulate immune system and enhance antitumour response, regulating T-cellular response[1]. However, this uncontrolled and non-selective immune response may lead to different immune-related adverse events (irAEs) [2]. Rheumatic toxicity has an overall incidence of about 10%. The most frequent manifestation is the joint involvement (5-7%), including inflammatory arthralgia, arthritis, polymyalgia rheumatica (PMR)-like syndrome (ir-arthritis phenotype). Glucocorticoids (GCs) represent the first line therapy; conventional and biologic disease modifying anti-rheumatic drugs (cs- and bDMARDs) are employed in most severe cases to reduce GCs but the impact on oncological outcome is debated [3,4].Objectives:to describe a monocentric cohort of oncologic patients (pts) with ir-arthritis phenotype toxicity and to analyse the role of an early use of cs- and bDMARDs on oncological outcome.Methods:retrospective analysis of oncologic pts with ir-arthritis phenotype followed from January 2019 to November 2023. Pts with a pre-existing rheumatic disease (pRD) were included. The severity of irAEs was established according to the Common Terminology Criteria for Adverse Events (CTCAE). The chi-square/Fisher’s test and the t-test were applied to evaluate association between different variables (age, cancer type, first line ICI, pRD, therapies) and oncological outcome in terms of progression or not. The Charlson index (CCI) was used to assess the influence of comorbidities on the overall outcome.Results:31 pts (21 males) with a mean age of 69.5y were included. The most frequent neoplasms were non-small cell lung cancer (35%) and melanoma (19%). The most employed drugs were anti-PD1. Five pts had a pRD (3 PMR, 1 rheumatoid arthritis and 1 psoriatic arthritis) and were treated with methotrexate (MTX) or hydroxychloroquine (HCQ) at the beginning of ICI. The mean (±standard deviation, SD) time to irAEs onset was 17 weeks (±23) with severity grade G2/G3 in the large majority (90%) and with a median follow-up of 15 months (IQR: 5-23). Twelve pts developed PMR-like syndrome, 12 arthritis, 7 inflammatory arthralgia. All pts with pRD relapsed. All pts started GCs (mean initial dose PN-eq 30 mg and mean cumulative dose PN-eq 1.3 g), in 20 pts ICI was transiently interrupted. Due to recurrence of irAEs during two-month GC tapering, a csDMARD or an IL6 inhibitor was started in 15 and 5 pts, respectively (Table 1). During the follow-up, 14 pts had an oncological progression and/or died, while 17 had a stable disease or a partial/complete response. An association between csDMARD use and no cancer progression was noted (p= 0.045) (Table 2). At last follow-up, all pts were recovered from irAEs.Conclusion:In our cohort, an early introduction of DMARDs showed to be effective in counteracting irAEs, sparing GC, without negatively affecting the oncological outcome.REFERENCES:[1] Weinmann, S. C. & Pisetsky, D. S. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatol. Oxf. Engl. 58, vii59–vii67 (2019).[2] Shen, P. et al. Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy. Front. Med. 8, 762247 (2021).[3] Reid, P. & Cappelli, L. C. Treatment of rheumatic adverse events of cancer immunotherapy. Best Pract. Res. Clin. Rheumatol. 36, 101805 (2022).[4] Kostine, M. et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann. Rheum. Dis. 80, 36–48 (2021).Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Pulmonary involvement (PI) is the second most common extra-glandular manifestation of primary Sjogren Syndrome (pSS) with a prevalence ranging between 10% to 20% significantly impacting patients’ prognosis. According to the EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI), PI encompasses both airways involvement (AD) and interstitial lung involvement (ILD). The clinical, functional, and radiological heterogeneity of pSS-PI, along with the absence of specific recommended treatments, has led to controversial results in literature, particularly related to the outcomes and management of this complication.Objectives:To assess PI prevalence in a tertiary care referral hospital’s pSS cohort and to characterize patients clinically, functionally, and radiologically. Additionally, to establish relationships between pSS-PI symptoms, radiological patterns, pulmonary function tests (PFTs) abnormalities, therapeutic strategies, and outcomes.Methods:pSS patients meeting ACR/EULAR 2016 criteria with concomitant PI defined by ESSDAI pulmonary criteria, observed from 2000 to 2022, were included. Data collected encompassed the duration of lung disease, reported symptoms, PFTs, radiological patterns, and medications. Mortality and pSS-PI progression, accordingly INBUILD trial criteria, were evaluated and any associations between categorical variables were analyzed using the Fisher exact test.Results:23/345 pSS patients exhibit PI (6,6%) with a mean onset age of 53,2±11,6 years. The mean follow-up time from diagnosis of pSS-PI to last assessment is 6,2±6,9 years. 19/23 patients (82,6%) display ILD; 4/23 (17,4%) exhibit AD, demonstrated by air trapping on HRCT. Clinically, at pSS-PI diagnosis, ILDs showed significantly more dyspnea and less persistent cough than ADs (p=0.04; p=0.01, respectively). PFTs at diagnosis, showed in 1/19 ILDs a FVC<80% while none of ADs presented FVC abnormalities; of note, in 10/19 ILDs (52%) and in 4/4 ADs (100%) a DLCO<70% was observed, without a significant difference between the two groups (p=1; p=0.12). Focusing on ILD patterns, NSIP was the most prevalent followed by ground glass opacities, LIP, UIP and OP. Mixed patterns were also observed (i.e., NSIP+OP). Regarding treatment employed: in 0/4 ADs no systemic treatment was used while in ILD an immunosuppression was used in 13/19 (68,4%) patients being azathioprine the preferred drug (6/13; 46%). Examining the outcomes of pSS-ILD patients, no death was registered while a progressive phenotype characterized 2/19 pSS-ILD both with NSIP pattern. No difference in dyspnea (p=0.54), cough (p=0.46), FVC<80% (p=1), DLCO<70% (p=0.47), radiological pattern (NSIP; p=0.21) or therapeutic strategy (immunosuppression vs wait-and-see; p=0.54) was noted in comparison to non-progressive ILDs; no progression or death was seen in AD patients.Conclusion:Pulmonary complications in pSS are extremely heterogeneous involving both interstitium and bronchi, the latter probably underrecognized. Although patients with pSS-ILD are characterized by significant dyspnea, substantial abnormalities in PFTs appear to be rare and are comparable between ILD and non-ILD patients, with reduced DLCO the first functional sign. The broad clinical, functional and radiological variability explains the absence of a common treatment strategy, which is still based on the clinician judgment. Nevertheless, a relatively benign prognosis seems to emerge independently from pSS-PI characteristics and therapeutic strategy used. A better phenotyping will enhance pSS-PI risk stratification guiding optimal and shared therapeutic strategies.REFERENCES:[1] Berardicurti O et al. J Clin Med. 2023;12(7):2586. doi:10.3390/jcm12072586[2] La Rocca G et al. J Clin Med. 2023;12(10):3428. doi:10.3390/jcm12103428Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Hepatitis C virus (HCV) is often associated with autoimmune features and extra-hepatic manifestations. Sicca symptoms are reported in about 30% of the cases. Both HCV and Sjögren’s disease (SjD) are associated with hyperactivation of B-cells and lymphocytic infiltration of salivary and lacrimal glands. About half of HCV-infected patients have focal sialadenitis simulating SjD.Objectives:To study the effect of the direct-acting antivirals (DAAs) on sicca manifestations in HCV-patients and to study the difference between those patients and those with SjD.Methods:This study included 60 patients divided into 3 groups: Group 1 included 20 patients with active HCV and sicca manifestations, Group 2 included 20 patients with HCV without sicca manifestations and Group 3 included 20 patients with SjD. Groups 1 and 2 received treatment with DAAs and were assessed clinically and serologically before and 6 months after finishing treatment. Group 3 was evaluated the same once.Results:After DAAs, all HCV cases had sustained viral response (SVR). Comparing the characteristics of groups 1& 3: Group 1 patients had a statistically higher frequency of rheumatoid factor (RF) (50% vs. 25%), serum cryoglobulins (40% vs. 0%) and polyclonal hypergammaglobulinemia (60% vs. 25%) with p values 0.021, 0.003 and 0.00 respectively compared to group 3. While group 3 patients had higher statistically significant VAS dry eye score, VAS dry mouth score, VAS fatigue, and VAS pain figures (P values 0.000 in all) compared to group 1. Also, group 3 patients had a higher frequency of Anti-Ro (80% vs. 0%) and Anti-La (65% vs. 5%) antibodies (P values <0.001 in both) compared to group 1.Group 1 patients after SVR showed marked statistical improvement in VAS dry eye, VAS dry mouth, VAS fatigue, VAS pain, ESSPRI, and ESSDAI after treatment (P values <0.003, <0.002, <0.016, 0.000, <0.002 and <0.014 respectively). Immunologically there was a statistically significant improvement in RF, and serum Beta 2 microglobulins (β2M) (P values <0.013 and 0.001 respectively). Serum Cryoglobulins were negative in all patients after antiviral treatment (40% pre vs. 0% post).Group 2 patients after SVR showed improvement in serum cryoglobulins after DAAs treatment (15% vs. 0% post). There was no statistically significant improvement in RF (25% vs. 20% post) and IgG (25% vs. 25%) (P values <0.293 and <0.794, respectively).Group 1 patients before DAAs had higher markers denoting hyperactive B-cells (higher RF, cryoglobulins, and β2M) compared to group 2 that improved markedly after SVR. Group 1 showed significant improvement of sicca symptoms and immunological profile after clearance of HCV as well as significant improvement of β2M.Conclusion:Treatment of cases with HCV and sicca manifestations by DAAs is associated with significant clinical and immunological improvement. HCV with sicca manifestations showed higher markers denoting B-cell hyperactivity that improved markedly after HCV clearance. So we recommend longer follow-up for these patients and their prioritization for early treatment. This could halt or delay the risk of lymphoproliferation.The difference between group 1 (before and after SVR) and group 3, supports that they are 2 different diseases, with different characteristic features, as they showed improvement of Sicca symptoms after eradication of HCV. So we suggest that even treated HCV infection should be excluded from the classification criteria for the diagnosis of Primary Sjögren disease (which excluded only active HCV in the current form).REFERENCES:[1] Cacoub P, Buggisch P, Carrión JA, Cooke GS, Zignego AL, Beckerman R et al. Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe. J Viral Hepat. 2018; 25(7):811-7.[2] Alves M, Angerami RN, Rocha EM. Dry eye disease caused by viral infection: [review]. Arq Bras Oftalmol. 2013 Mar-Apr; 76(2):129-32[3] Loustaud-Ratti V, Riche A, Liozon E, Labrousse F, Soria P, Rogez S et al. Prevalence and characteristics of Sjögren’s syndrome or Sicca syndrome in chronic hepatitis C virus infection: a prospective study. J Rheumatol. 2001;28(10):2245-51.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Cryoglobulinemic vasculitis related to primary Sjögren’s syndrome (CV-pSS) is a rare condition, yet it is known to be associated with high disease activity and risk of lymphoma (NHL) in pSS[1]. Data on the impact of age at diagnosis of CV are scarce.Objectives:The aim of this study was to evaluate the impact of age in the frequency of major relapses and clinical response in CV-pSS patients.Methods:Patients with pSS referred to the Rheumatology Unit of Udine and diagnosed with CV from January 2003 to January 2021 were retrospectively collected. The inclusion criteria were the documented positivity of cryoglobulins in pSS patients and the fulfillment of classification criteria of CV[2]. The exclusion criteria were the concomitant HCV and/or HBV infections and asymptomatic cryoglobulinemia. Major relapses were defined as the recurrences of clinical symptoms and signs requiring additional treatment beyond glucocorticoids (GCs).Results:20 pSS patients (90% females) with CV were included. In according to the age of CV diagnosis, patients were divided in three groups: <60years old (7/20), 60-64years old (7/20), and ≥65years old (6/20). The main clinical features at CV onset were purpura (95%), fatigue (75%), arthralgia (70%), peripheral neuropathy (35%), and skin ulcers (10%). All patients had low levels of C4 complement and RF positive, and the median BVASv3 was 4/63 (IQR 3-9). The first line treatments for CV are shown in Figure 1A. During the follow up (median time: 9 years [IQR 5-14]), at least one major relapse occurred in 86% (6/7), 29% (2/7), and 0% of patients in each group (p-value 0.005), respectively (Figure 2). The main manifestation at relapse was the cutaneous and/or nervous involvement. A complete clinical response was achieved in 4/8 relapsing patients with rituximab (RTX) alone. Three out of 8 patients required a combination therapy belimumab (BELI) plus RTX, and one patient received a BTK inhibitor. At last follow-up, the median BVASv3 was 3/33 (IQR 0-3) and patients mainly complained articular and nervous involvement (Figure 1B). A complete immunological response was documented in 29%, 29%, and 50% of patients in each group (p-value=0.716), respectively. Two out of 20 patients developed chronic hypogammaglobulinemia (IgG≤600mg/dL), not complicated by recurrent infections. Concerning the lymphoproliferative risk, nine out of 20 patients experienced NHL in their medical history (4/7, 2/7, 3/6 in each group, respectively). The onset of NHL was closely associated (within ±3years) with the CV onset in 5/9 patients, while it preceded (2/9) or followed (2/9) CV onset with a median time span of approximately ±11 years.Conclusion:In CV-pSS patients, an earlier onset of CV may be correlate with a higher probability of experiencing at least one major relapse despite the treatment. The lymphoproliferative risk in CV-pSS is increased and not influenced by the age at CV diagnosis.REFERENCES:[1] Quartuccio L, Baldini C, Priori R, et al (2017) Cryoglobulinemia in Sjögren Syndrome: A Disease Subset that Links Higher Systemic Disease Activity, Autoimmunity, and Local B Cell Proliferation in Mucosa-associated Lymphoid Tissue. J Rheumatol 44:1179–1183. https://doi.org/10.3899/jrheum.161465[2] Quartuccio L, Isola M, Corazza L, et al (2014) Validation of the classification criteria for cryoglobulinaemic vasculitis. Rheumatol Oxf Engl 53:2209–2213. https://doi.org/10.1093/rheumatology/keu271Figure 1.First-line treatment at onset (A) and at the last follow-up visit (B) of CV patientsFigure 2.Distribution of major relapse in CV patients divided by ageAcknowledgements:NIL.Disclosure of Interests:None declared.

Background:Ultrasound-guided core needle biopsy (US-guided CNB) of major salivary glands represents an innovative diagnostic approach in primary Sjögren’s syndrome (pSS) and related lymphoproliferative complications. This procedure has proven to be safe and well tolerated, with good diagnostic accuracy (1-3).Objectives:to report our updated data on safety, tolerability and diagnostic accuracy of US-guided CNB of major salivary glands on a wider cohort of pSS patients at increased risk for lymphoma.Methods:from September 2019 to October 2023, we included patients with a clinical diagnosis or suspicion of pSS and increased risk for lymphoma. All patients underwent US-guided CNB of major salivary glands, and subsequently monitored for eventual complications (transient if lasting <12 weeks; persistent if ≥12 weeks) at 1, 2 and 12 weeks, through clinical evaluation and a written questionnaire on post-procedural complication and pain Visual Analogue Scale 0-10 (VAS 0-10).Results:US-guided CNB was performed on 57 major salivary glands (8 submandibular glands, 49 parotid glands) in 55 patients. In 22/57 cases no swelling was present at the time of biopsy. During follow-up (mean 26,75 months, SD ±15,4), only 1/57 case of persistent complication and 23/57 cases of transient complications were reported.The only persistent complication was represented by mild auricle paresthesia in the afference territory of great auricular nerve; the same involvement was described in other 2 cases as transient. Of note, no involvement of facial nerve was ever reported.Complications were reported in 10/22 cases with no glandular enlargement at the time of biopsy; in 14/35 cases with glandular enlargement at the time of biopsy, with no statistical difference between the 2 groups (p value 0.7).Mean intraprocedural VAS pain was 1,96 (SD ±2,87); post procedural VAS pain was 0,77 (SD ±1,87). Furthermore, tissue samples were adequate for diagnostic purposes in 54/57 cases (94,7%), allowing also pSS differential diagnosis in 5/57 cases (3 sarcoidosis, 1 IgG4 related disease, 1 chronic sclerosing sialadenitis). Mean gland surface area of histological samples was 26,56 mm2 (SD ±12,35) All updated and detailed results are summarized in the attached Table 1.Conclusion:Expanding upon our previous group of cases enabled us to affirm and reinforce the growing significance of US-guided CNB in pSS patients at higher risk for glandular lymphoma. Notably, this procedure is well-tolerated, safe and exhibits a high level of diagnostic accuracy. Among our cohort, there haven’t been any recorded cases of facial nerve injury following the biopsy procedure. However, there is a possibility of mild and mostly temporary sensory auricular impairment in the afference area of great auricular nerve.REFERENCES:[1] Giovannini I et al., RMD Open, 2022;[2] Zabotti et al., Clin Exp Rheumatol, 2022;[3] Zabotti et al., Rheumatology, 2021.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Spondyloarthritis (SpA) is the most common extraintestinal manifestation in inflammatory bowel disease (IBD). Patients with SpA related to IBD (IBD related SpA) usually develop arthritis after the diagnosis of IBD1. Detecting SpA at an early stage enhances the possibility of achieving complete remission of disease, thereby improving patient care through the use of drugs that could work both for gut and joint.Objectives:i) to determine the sensitivity and the specificity of two questionnaires, the IBd Identification of Spondyloarthritis Questionnaire (IBIS-Q)2 and the DETection of Arthritis in Inflammatory bowel diseases (DETAIL)3, both used to investigate signs and symptoms suggestive of IBD-related SpA. Ii) to describe the clinical phenotype of the undiagnosed IBD related SpA.Methods:Between April and October 2023, both IBIS-q and DETAIL2,3 questionnaire were administered to consecutive IBD outpatients attending the University Hospital of Udine, Italy. During the routine gastroenterology evaluation, patients aged between 18-75 years, affected by Crohn disease (CD) or ulcerative colitis (UC) were asked to fill both the questionnaires. Subsequently, all the patients who completed the questionnaires were referred to a blinded rheumatological evaluation within 2 weeks. Patients with a previous diagnosis of IBD related SpA or other forms of inflammatory arthritis were subsequently excluded. The new IBD related SpA diagnosis was attributed in the case of rheumatological diagnosis and fulfillment of ASAS criteria.Results:A total of 203 patients were initially included in the study, but 26 out of 203 (12.8%) were excluded due to a pre-existing diagnosis of arthritis (Figure 1A). Among the remaining 177 patients, 11 out of 177 (6.2%) were newly diagnosed with IBD related SpA. The DETAIL questionnaire (with a cut-off ≥3) exhibited a sensitivity of 36.66% (95% CI 10.93%-69.21%) and a specificity of 84.34% (95% CI 77.90% to 89.51%) for SpA diagnosis (Figure 1B), while the IBIS-Q questionnaire (cut-off ≥3) demonstrated a sensitivity of 63.64% (95% CI: 30.79-89.07%) and a specificity of 74.10% (95% CI 66.74% to 80.58%) (Figure 1B). Regarding the new cases of IBD related SpA, imaging confirmed enthesitis was the predominant pattern in 8 out of 11 cases (72.7%, 8/8 without concomitant peripheral arthritis), axial involvement in 2 out of 11 (18.2%), and peripheral arthritis in 1 out of 11 (9.1%) (Figure 2). The median duration of musculoskeletal symptoms before the IBD related SpA diagnosis was 6 months.Conclusion:The number of patients with undiagnosed IBD related SpA is low but not negligible and this study underscores how enthesitis, even in the absence of synovitis, could be the initial sign of disease creating a specific challenge in early disease recognition. Furthermore, in our study IBIS-Q exhibited higher sensitivity but lower specificity compared to DETAIL in identifying patients with IBD related SpA.REFERENCES:[1] Rodríguez-Reyna TS et al, 2009 Nov 28;15(44):5517-24. doi: 10.3748/wjg.15.5517.[2] Variola A et al, J Crohns Colitis. 2020 Dec 2;14(12):1680-1686.[3] Benfaremo D et al, J Rheumatol. 2021 Feb;48(2):179-187.Figure 2.Distribution of prevalent pattern of SpA in our cohort.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Cryoglobulinemic vasculitis in primary Sjögren’s syndrome (pSS-CryoVasc) is a specific phenotype marked by B-cell lymphoproliferation and immunocomplex-mediated vasculitis affecting skin, nerves, joints and kidneys. With a prevalence of 3-10% among pSS, pSS-CryoVasc is linked to high clinical and biological disease activity, increased morbidity, and mortality. The link between CryoVasc and pSS involves pronounced B-cell activation, leading to salivary MALT lymphoproliferation and a significantly elevated risk of non-Hodgkin lymphoma (NHL) development. In the context of CryoVasc, Rituximab (RTX) has shown efficacy in controlling lymphoproliferation and associated manifestations. However, its safety, effectiveness, and optimal therapeutic regimen in the specific pSS-CryoVasc subset remain unclear.Objectives:To compare safety and efficacy of two different Rituximab (RTX)-based therapeutic approaches on vasculitic and lymphoproliferative-related disease activity and on Non-Hodgkin Lymphoma (NHL) development in a cohort of patients affected by pSS-CryoVasc.Methods:pSS-CryoVasc patients followed from January 1999 with an active follow-up in August 2023 were selected. 3 groups were identified: 1) Early RTX induction followed by maintenance; 2) Late RTX induction with possible on-demand retreatment; 3) No RTX treatment. For each group it was evaluated from pSS-CryoVasc diagnosis to last assessment: a) changes in disease activity according to the overall ESSDAI score related to vasculitis and lymphoproliferation and to each ESSDAI domain related to the same manifestations; b) the development of NHL; c) the occurrence of persistent hypogammaglobulinemia and serious infections.Results:13 pSS-CryoVasc patients were identified: 1) 5/13 treated earlier with RTX with subsequent maintenance; 2) 5/13 treated late with RTX with possible on-demand retreatment; 3) 3/13 not treated with RTX. A significant decrease in total ESSDAI considering domains related to vasculitic and lymphoproliferative manifestations was highlighted in the two RTX groups, with group 1 showing the most substantial reduction (median -17 vs -4 vs 7; H=6.55; p=0.03). Regarding CV-related ESSDAI domains (cutaneous, PNS, articular) a significant improvement was observed among patients receiving RTX vs patients not receiving RTX (p=0.007; p=0.006; p=0.03; respectively) while no difference was noted between patients receiving the two distinct RTX-based regimens. Considering lymphoproliferative-related ESSDAI domains no improvement was observed between those undergoing RTX and those not undergoing RTX, however, when evaluating the two RTX schemes an improvement in the glandular and nodal ESSDAI was noted in patients of group 1 (p=0.03; p=0.03, respectively). No significant differences among NHL occurrence (p=0.42) or safety concerns (p=1) were observed among the groups.Conclusion:RTX is an effective and safe treatment to control pSS-CryoVasc disease activity with a greater impact when administered early with a subsequent maintenance regimen (Figure 1); whilst an on-demand RTX strategy is sufficient to control vasculitic manifestations, a more aggressive approach is required to control lymphoproliferative disease activity. However, RTX alone cannot affect the possible development of an overt NHL in pSS-CryoVasc (Figure 2). These preliminary findings support the use of RTX in pSS-CryoVasc emphasizing the importance of precise stratification of these patients to ensure them a tailored and effective treatment.REFERENCES:[1] Quartuccio L et al. Cryoglobulinemia in Sjögren Syndrome: A Disease Subset that Links Higher Systemic Disease Activity, Autoimmunity, and Local B Cell Proliferation in Mucosa-associated Lymphoid Tissue. J Rheumatol. 2017;44(8):1179-1183.[2] Quartuccio L, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023;42(2):359-370.Figure 1.Overall ESSDAI reduction...Figure 2.NHL occurrence into the...Acknowledgements:NIL.Disclosure of Interests:None declared.

The ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire is a 29-item disease-specific PRO measure for AAV (1), proving to be valid, reliable, feasible, and able to discriminate among disease states. The purpose of this study is to validate the Italian version of AAV-PRO questionnaire (AAV-PRO_ita). AAV-PRO has been translated in collaboration with Oxford and Bristol University (UK). Then, consecutive Italian-speaking AAV-patients were collected in order to validate the questionnaire. Inclusion criteria are AAV diagnosis (ANCA positivity at least one time and/or biopsy-proven AAV), and age ≥18 years old. Participants completed the AAV-PRO_ita three different times: at baseline, after 5-7 days, and at month 3. Friedman test was applied to verify internal consistency of the questionnaire over time. 27 AAV-patients (16 females, 11 males) were recruited and completed the questionnaire at baseline, after 5-7 days, and at month 3. The main diagnosis was granulomatosis with polyangioitis (GPA) (19/27, 70.4%), following by eosinophilic granulomatosis with polyangioitis (EGPA) (8/27, 29.6%). Mean (SD) BVASv3 was 1 (2) at baseline, and it was unchanged at month 3 in 25/27 (92.6%). The mean age at onset of disease was 54.7±17.3 years and the median disease duration was 51 months (1-3 interquartile range 34-76). Their history was characterized by at least one relapse in 10/27 (37%) patients, at least one hospitalization due to AAV in 19/27 (70.4%), and ESRD in 1/27 (3.7%). At the last follow up, 24/27 (88.9%) of patients were taking an immunosuppressive drug [rituximab (8/24), azathioprine (8/24), methotrexate (7/24) or mycophenolate mofetil (1/24)] and more than two-thirds were also taking glucocorticoids (19/27, 70.3%). Fatigue (item 9) and arthralgia (item 6) were the most important symptoms, and half of the patients (14/27, 51.9%) classified them as “moderate” or “severe”. Nearly one-third of patients (8/27, 29.6%) admitted to being “usually” or “always” concerned about their future (item 19) and long-term therapy (item 29) (Figure 1). Friedman test was not significant (p>0.05), indicating internal consistency of the questionnaire. A large multicentre Italian study has been organized based on this preliminary data coming from the coordinating centre, and it is now recruiting. The results will be soon available by the Italian Vasculitis Study Group. The AAV-PRO_ita is a new disease-specific PRO measure for AAV. It is a self-administered questionnaire and could become an important tool to evaluate health-related quality of life in AAV (2). As in other systemic autoimmune diseases, fatigue and chronic pain represent an unmet need to be addressed by future treatment strategies. [1]J. C. Robson et al., «Validation of the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire», Ann. Rheum. Dis., 2018, vol. 77, n. 8, p. 1157–1164, doi: 10.1136/annrheumdis-2017-212713. [2]L. Quartuccio, et al., «Healthcare and economic burden of ANCA-associated vasculitis in Italy: an integrated analysis from clinical and administrative databases», Intern Emerg Med, July 2020, doi: 10.1007/s11739-020-02431-y. None declared [Display omitted]

Backgroundin primary Sjögren’s syndrome (pSS), salivary epithelial cells show an active role in the initiation and reiteration of the immunomediated damage. Epithelial saliva production is regulated by autonomic stimuli, intracellular calcium and cAMP concentration. The latter controls the action of cystic fibrosis transmembrane conductance regulator (CFTR), whose malfunction is postulated in sicca syndrome and pSS pathogenesis. (1) Forskolin is an activator of CFTR used in organoid swelling test in human salivary-gland derived organoid culture systems. Interestingly, also PDE4 is involved in intracellular cAMP deregulation: PDE4 inhibition might thus stimulate salivary function in pSS. (2-3) To the best of our knowledge, no data on the application of human salivary gland organoids specifically for testing drugs effective on xerostomia in pSS are found in literature.Objectivesto culture vital salivary gland organoids obtained through labial or parotid biopsy of pSS patients; to evaluate the morphological structure and functional capacity of organoids in basal condition and after stimulation with forskolin or PDE4 inhibitor apremilast.Methodssalivary gland tissues were harvested from 5 pSS patients through labial or parotid biopsy. After tissue processation and vital organoids obtainment, swelling essay and cell proliferation tests were performed after forskolin and apremilast application, compared to DMSO-treated controls. Immunohistochemistry evaluation on original salivary gland tissue and corresponding organoids was performed, by testing: alpha-amylase and AQP5 for acinar differentiation; EMA for ductal differentiation; calponin for myoepithelial differentiation and CK5 for basal differentiation; CK14, cKit and CD34 as markers of progenitor/stem cells.Resultsafter application of forskolin or apremilast, we observed organoid swelling after 30 minutes, compatible with positive functional status and enhancement of saliva production. DMSO-treated controls were instead unaffected. In 3 cases apremilast induced proliferation of the organoids (Figure 1). All the cases were positive for CK14, most of the cases for CK5. All the cases were positive for Amylase; its secretion, and thus functional status of organoids, was confirmed by its high concentration in the culture medium. A focal ductal differentiation was found in some cases, highlighted by EMA positivity. The more differentiated EMA positive areas were negative for the staminal marker CK14, showing a sort of “complementary staining”.Conclusionour data confirm that, from pSS epithelium, differentiated cells that escape senescence and vital and functional organoids that recapitulate the development of original salivary glands can be obtained from different target tissues of pSS. The direct stimulating effect of PDE4 inhibitor apremilast on pSS human salivary organoids is reported, opening new perspectives on targeting oral dryness with drugs that combine secretagogue and immunomodulatory effects.References[1]Zeng M et al. Gastroenterology. 2017.[2]Boyd A et al. Biochem J. 2021.[3]Yoshimoto S et al. Dis Model Mech. 2020.Figure 1.results on cell proliferation (upper graphs) and swelling essay (lower graphs) of salivary gland organoids after forskolin or apremilast application.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Recently, avacopan has been approved for the treatment of ANCA-associated vasculitis (AAV). Avacopan is an inhibitor of the C5a-receptor, which plays an important role in chemotaxis and the amplification loop of inflammation in AAV. In the most recent, international guidelines avacopan is recommended as steroid-sparing agents for the management of AAV. Here, we review the clinical trials that have led to demonstrate that avacopan is an effective treatment option in the management of AAV, where it can significantly reduce the cumulative dosage of glucocorticoids (GC). Despite the new guideline recommendations, clear guidance on how to employ avacopan in real-world clinical practice is lacking. We therefore also address in this review the data and clinical experience with avacopan obtained from real-world evidence. Combining preclinical studies, clinical trials, and real-world evidence helps to provide a better position of avacopan for the management of AAV in routine clinical practice, taking advantage of the GC-sparing effects of avacopan as a possible solution for the current challenge of reducing GC-toxicity in AAV patients. Furthermore, we delineate current knowledge gaps and future research areas that need to be addressed.