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Background:Subglottic Stenosis (SGS) is a rare and possibly life-threatening manifestation of Granulomatosis with Polyangiitis (GPA) carrying a significant risk of mortality and morbidity. Few data are available in the literature on SGS optimal treatment and the risk factors for relapses are currently unknown. Interim results of the STOP GPA study about GPA-related SGS are reported here.Objectives:The aim of the STOP-GPA study is to assess the clinical profile and response to treatment in a European cohort of SGS patients and to identify possible risk factors for relapse.Methods:Patients with GPA-related SGS referred to tertiary care centres from 1980 to 2023 were included in this retrospective observational, multicentre study. Collected variables and covariates included age at diagnosis, sex, BVAS, ANCA status at GPA onset, SGS treatment, SGS relapse was defined as the need for endoscopic dilation or as a new onset dyspnoea with confirmed calibre reduction via bronchoscopy or CT scan. Relapse rates were compared via Chi square test, while t test was employed for continuous predictors. We compared the efficacy of different treatments between relapsing and non-relapsing SGS patients. Time to relapse was compared via log rank test.Results:In this study, 31 patients (12 males, 19 females, median age 43) were included. Median BVAS at GPA diagnosis was 10 (8 – 13), while ANCA were positive in 19 patients (64.5%, 10% MPO and 68.4% PR3), (in four patients ANCA specificity was not available); 12 patients (38.7%) had SGS at GPA diagnosis while 19 (61.3%) developed SGS as a subsequent manifestation (median time of 61 months, IQR 26-103). Other baseline characteristics of patients at SGS onset are reported in Table 1.Twenty-three patients (74.2%) received immunosuppressive induction treatment for the first SGS, while 5 were treated with endoscopic dilation, 2 with laser-therapy and 1 with glucocorticoids (GCs) local infiltration. Specifically, cyclophosphamide (CYC) induction regimen was followed by DMARDs maintenance in 6 patients (19%), while Rituximab (RTX) induction and maintenance in 9 (29%) patients. In 8 patients (16%) DMARDs were used as monotherapy. At the first SGS episode, 16 (51.6%) underwent endoscopic dilation. All patients were treated with oral GCs (median GC dose 37.5mg, IQR 25-50 mg). Fifteen (48%) had SGS relapses, with a median time to relapse of 22.3 months (12.7 – 67.2). Nine patients (29.0%) experienced more than one SGS relapse (median number of relapses: 3). Notably, patients experiencing SGS relapse were significantly younger (31 vs 48 years old, p < 0.05) and experienced SGS earlier in disease course compared with non-relapsers (median time to SGS 29 vs 49 months, p = 0.05). There were no differences in relapse rate according to the ANCA status. In respect of medical therapy, patients treated with either RTX or CYC showed a trend towards lower relapse rate compared to dilation alone (44% vs 84%, p =0.09). Notably, patients who received induction treatment and maintenance with RTX had a trend toward longer time to relapse compared to CYC plus DMARDs and endoscopic dilation alone (p=0.1). The three-year relapse rate in RTX, CYC plus DMARDs, and dilation alone was 23%, 38%, and 64%, respectively (Figure 1).Conclusion:These preliminary data indicate that younger SGS patients may require tighter follow-up due to a higher likelihood of relapse and that RTX treatment is associated with a trend towards lower relapse rate. Endoscopic dilation alone is inferior to systemic treatment. Larger patient accrual will be pivotal to further assess the natural history of this difficult-to-treat condition.REFERENCES: NIL.Figure 1.Three-year relapse-free survival stratified by treatment strategyAcknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundMepolizumab is an anti-interleukin-5 (IL-5) agent approved for EGPA at the dose of 300 mg every 4 weeks. However, from real-life studies, evidence is accruing of its comparable effectiveness at “asthma-dose” of 100 mg every 4 weeks. The preferred approach at our center is to start mepolizumab 300 mg/4 weeks and to reduce to 100 mg/4 weeks once remission is achieved (Birmingham Vasculitis Activity Score - BVAS=0), asthma is controlled (Asthma Control Test – ACT >20), eosinophil count is normalized and glucocorticoids are withdrawn (step-down approach).ObjectivesTo assess the long term-efficacy of step-down treatment with mepolizumab in EGPA.MethodsWe reviewed medical charts of patients with EGPA treated with mepolizumab from April 2014 to December 2022. We divided patients by homogeneous dosing schedule and compared disease activity and characteristics at baseline and over time.ResultsWe treated 38 patients for a median follow up of 38 months (IQR 29-53). Seven patients underwent a step-up approach (starting with mepolizumab 100 mg/4w and subsequent switching to mepolizumab 300 mg/4w in case of failure). Among them, only 1 patient (17%) needed a dose increase due to uncontrolled respiratory symptoms. Mepolizumab 300 mg/4w was started in 31 patients allowing a step-down in 9 (29%), without any patient having to increase the dose again. Both subgroups of the step-down strategy showed significant reduction in terms of BVAS, ACT, serum eosinophils and daily prednisone dose at last follow-up. At the same time presented a high proportion of nasal exacerbations (33 vs. 9% p=0.31). [Table 1]ConclusionIn our experience, a step-down approach with mepolizumab in EGPA is reasonable and allows to safely reach the low-dose regimen in a great proportion of patients. Nasal polyps are the new challenge for physicians treating EGPA in an age where a steroid-free remission is an achievable target.Table 1STEP-UP STRATEGYSTEP DOWN STRATEGY100 ->100100 ->300300 ->100300 ->300N° of patients (%)6 (16%)1 (2%)9 (24%)22 (58%)Sex (female)4 (67%)1 (100%)7 (78%)10 (5 %)Median age at the starting of MEPO59 (57-72)4852 (50-58)56 (49-64)START of MEPODisease duration at MEPO start90,5 (51,25-165)14450 (21-91)75 (34-108)ACT22 (19-25)1019 (15-19)19 (14,5-25)BVAS4,5 (3,3-5,8)42 (2-3)3,5 (2-5)EOS550 (365-697,5)400600 (390-665)590 (400-1040)PDN dose5 (3,7-5)255 (5-7,5)8,75 (5-23,75)asthma exac./6 months before MEPO start0,5 (0-1)41 (1-1,5)1 (0-3)n° of patients treated with immunosuppressants3 (50%)1 (100%)7 (78%)15 (68%)END of F-UPTotal months of FUP33 (22-40)4648 (38-89)33 (12-50)ACT25 (25-25)1325 (25-25)**25 (25-25)**BVAS1,5 (0,25-3,5)50 (0-2)**0 (0-2)**EOS77,5 (56,25-95)*30075 (48-108)**40 (0-100)**PDN dose0 (0-0)7,50 (0-0)**0 (0-2,5) **n° of pts experienced asthma exac0 (0%)1 (100%)1 (11,1%)4 (18%)n° of pts experienced ENT exac0 (0%)1 (100%)3 (33,3%)2 (9%)n° of pts experienced non respiratory EGPA exac0 (0%)00 (0%)4 (18%)n° of pts treated with immunosuppressants2 (33,3%)1 (100%)3 (33,3%)14 (64%)ACT: Asthma Control Test; BVAS: Birmingham Vasculitis Activity Score; EOS: eosinophils;EXAC: exacerbation; F-UP: follow-up; MEPO: mepolizumab; PDN: prednisone; PTS: patients; *:p < 0.05 for START vs END analysis, ** p<0.01 for START vs END analysisREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Systemic lupus erythematosus (SLE) is a multi-organ disease characterised by generalised immune dysfunction. Patients with SLE are more susceptible to infections and higher rates of SLE flares are observed following infectious stimuli (1, 2). Little is known about the qualitative impact of infections on SLE phenotype.Objectives:To assess potential clinical differences between infection-triggered (ITF) and other SLE flares (OF).Methods:A retrospective review of prospectively collected data from >300 patients with SLE was performed. Disease activity was estimated through the SLE disease activity index 2000 (SLEDAI-2K) and the British Isles Lupus Assessment Group (BILAG) 2004 index, damage with the SLE International Collaborating Clinics/American College of Rheumatology Damage index (SDI). DAS-28 was used quantitate arthritis activity. Remission was surrogated by the Lupus Low Disease Activity State (LLDAS) algorithm. Included patient records consisted in couples of consecutive visits showing progression from LLDAS fulfillment to LLDAS loss. Visit couples were divided according to the association vs non-association of recent infections requiring antimicrobial treatment and/or absence from work. Clinical, laboratory and treatment features along with patient history data were compared at inter- and intraindividual level between the two groups. Anti-double stranded DNA antibody titres (ADNA) were recorded in a 0-4 discrete scale. Data are expressed as median (interquartile range), unless otherwise specified.Results:Out of 134 visit couples from 114 patients, 38 were ITF. Viral infections were 11/38. ITF involved one or two BILAG domains in 80% of cases, the most frequent being haematological (61%), mucocutaneous (24%) musculoskeletal 34% and renal (18%) domains. Cardiopulmonary manifestations were numerically less frequent in ITF than OF (0/38 vs 9/96; p=0.060). Although no difference was found in the frequency of musculoskeletal manifestations, ITF were characterised by higher DAS-28 scores [2.6 (2.3-4.1), n=12] than OF [2.0 (1.6-2.7), n=47;p=0.024]. Accordingly, intraindividual comparisons showed higher DAS-28 scores during ITF than during OF (10/11 vs 1/11; p=0.004). Compared to OF, viral IF were associated with lower ADNA titres [0 (0-0) vs 2 (0-3);p=0.046) and a lower frequency of complement consumption (2/11 vs 52/96; p=0.029) along with higher creatinine levels [1.2 (0.8-1.3) vs 0.8 (0.7-0.9)];p=0.016]. No differences were found in flare treatment profiles between ITF and OF.Conclusion:Preliminary data from a monocentric cohort apparently indicate that ITF, especially of viral origin, are associated with distinct clinical and serological phenotypes. This evidence suggests the existence of diverging pathophysiological mechanisms sustaining SLE activity under different conditions, which might benefit for personalized treatments.REFERENCES:[1] Danza A, et al., Lupus. 2013[2] Joo YB, et al., Scientific Reports. 2021Acknowledgements:NIL.Disclosure of Interests:Giuseppe Alvise Ramirez Astrazeneca (lessons), Astrazeneca, GSK (advisory boards), Astrazeneca (financial support for publication), Chiara Calabrese: None declared, Gabriele Domenico Gallina: None declared, Luca Moroni Astrazeneca (lessons), Astrazeneca, GSK (advisory boards), Astrazeneca (financial support for publication), Enrica Bozzolo: None declared, Marco Matucci-Cerinic: None declared, Lorenzo Dagna: None declared

Background:Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterised by significant morbidity. Corticosteroids are the mainstay of treatment but also associate with damage accrual, with evidence suggesting high risk even with short exposures to naïve subjects [1]. Current guidelines suggest a target prednisone dose ≤5mg/day to minimize its detrimental impact [2]. Little is known about the effectiveness of this target in patients with long-standing disease [3].Objectives:To assess whether short-term exposure to high-dose corticosteroids affects damage accrual in patients with SLE flares after diagnosis.Methods:We performed a retrospective analysis of prospectively collected data of 206 patients with SLE followed-up from January 2015 to December 2023. Inclusion criteria were: 1) SLE with a flare after remission from the onset manifestations; 2) availability of ≥2 visits after flare acknowledgement. Patients unable to reduce prednisone dose to ≤5mg/day throughout the follow-up were categorised as high-dose group and compared to the remainder patients (low-dose group). Demographics, SLE clinical history, baseline diseases features, and organ involvement were evaluated. We used Cox regression to estimate the cumulative damage progression rate in the two groups. Organ involvement was assessed with the British Isles Lupus Assessment Group (BILAG) index. Disease activity was also quantitated with the SLE disease activity index 2000 (SLEDAI-2K) along with a 0.0-3.0 physician global assessment scale (PGA). Damage was assessed with the SLE International Collaborating Clinics/American College of Rheumatology Damage index (SDI). Data are expressed as mean ± standard deviation (SD), unless otherwise specified.Results:The study sample consisted in 129 patients (63%) receiving low-dose and 77 (37%) high-dose prednisone. There were no significant differences in terms of sex, age and disease duration between groups. Compared to patients treated with low-dose steroids, patients in the high-dose group had a higher prevalence of skin manifestations, especially of alopecia and cutaneous vasculitis in their history, along with a higher frequency of cardiac involvement and lymphadenopathy (Table 1). The mean disease duration at time of flare was 11±8 years in the high-dose group and 15± 9 years in the low-dose group. Patients in the high-dose group at SLE flares had a higher SLEDAI-2k (7 ± 6 vs 3 ± 2, p<0.001) PGA scores (1.5±0.8 vs 0.5±0.4, p<0.001) compared to the low-dose group. In patients with high-dose prednisone, SLE flares at presentations were characterised by prominent activity in the renal (21% vs 16%, p=0.006), mucocutaneous (31% vs 14%, p=0.003), and constitutional BILAG domain (10% vs 3%, p=0.030) compared to patients in the low-dose group. Over time, patients in the high-dose group had a higher risk of SDI progression compared to patients treated with lower steroid doses (HR=2.55, 95% CI, 1.17 to 5.53; p=0.02; Figure 1. SDI progression occurred early in the treatment course, with an estimated 12% vs 3% 24-month damage accrual incidence in the high- and low-dose group, respectively.Conclusion:Patients with long-standing SLE treated with prednisone doses >5mg/day are characterised by broader disease extent and rapidly accrue damage even with relatively short exposure to corticosteroids, consistent with observations in reacent-onset subjects [1]. Prednisone doses ≤5mg/day significantly minimise, although do not abate damage accrual in patients with longstanding SLE.REFERENCES:[1] Floris A, et al., RMD Open. 2022[2] Fanouriakis A, et al., Ann Rheum Dis. 2023[3] Gerosa M, et al., J Clin Med. 2022Figure 1.Kaplan-Meier survival curves for SDI progressionAcknowledgements:NIL.Disclosure of Interests:None declared.

Background:Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disease characterised by eosinophilia and small-vessel inflammation. Thromboembolism is a relatively common complication of small-vessel vasculitides, including EGPA. Eosinophils are endowed with a significant thrombogenic potential, possibly due to their ability to cause endothelial damage and activate the coagulation cascade by expressing tissue factor. Modulation of interleukin 5 (IL5) is effective in controlling systemic eosinophilic inflammation. Little is known about the potential impact of anti-IL5 agents on thromboembolism.Objectives:To assess whether treatment with mepolizumab (MPZ, an anti-IL5 monoclonal antibody) affects thromboembolism rates in patients with EGPA.Methods:We retrospectively reviewed the clinical and treatment history of 81 consecutive patients with EGPA. We investigated whether patients had experienced one or more thrombotic events, and gathered details about the timing and type of the first event. We also recorded whether patients did or did not receive MPZ and the timeframe of exposure to the drug. Patients exposed to MPZ were analysed before and during MPZ treatment. Disease activity and chronic damage were assessed with the Birmingham vasculitis activity score (BVAS) version 3 and the Vasculitis Damage Index (VDI), respectively. Data are expressed as median (interquartile range) unless otherwise specified.Results:Of 81 patients with EGPA, 57 were and 24 were not exposed to MPZ. Exposure to MPZ started after 61 (29-150) months from disease onset and was observed for 45 (14-48) months. Eighteen patients experienced 21 thrombotic events. The most frequent were deep vein thrombosis (n=7), followed by myocardial infarction (n=4), endocardial thrombosis (n=4), retinal thrombosis (n=3) and stroke (n=3). Six events (33%) occurred at disease onset, while the remainder occurred after 46 (12-133) months. Thrombotic event incidence rates were 1.1/100 person-years (95%CI=0.1-4.0) in-MPZ and 2.6/100 person-years (95%CI=1.5-4.3) off-MPZ. By excluding pre-exposure observations, patients never exposed to MPZ had a higher rate of thrombotic events (n=9/24) compared to patients receiving MPZ (n=2/57; HR=6.7, 95%CI=1.4-33.3, p=0.018). When pre-exposure records were combined with non-exposures, a similar trend was still observed (HR=4.2, 95%CI= 0.9-20; p=0.062). Compared to patients without thrombosis, patients with thrombosis had higher BVAS scores at EGPA onset [12 (10-14) vs 8 (6-13); p=0.042] and a higher frequency of heart involvement (63% vs 12%; p<0.001). No other associations were found with distinct organ involvement or damage accrual.Conclusion:Treatment with MPZ was associated with a low frequency of thrombotic events, consistent with clinical trials and real-life studies [1-3]. Dampening eosinophilic inflammation through MPZ might contribute to reduce the risk of thrombotic events in patients with EGPA [4], especially at later disease stages. Further studies are needed to validate these findings and obtain insights on potential mechanistic implications of IL5 modulation towards haemostasis.REFERENCES:[1] Wechsler ME, et al., N Engl J Med. 2017.[2] Bettiol A, et al., Arthritis Rheumatol. 2022.[3] Ishii T, et al., Mod Rheumatol. 2023.[4] Bettiol A, et al., Eur Respir J. 2021.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Systemic lupus erythematosus (SLE) is a multi-organ disease characterised by generalised immune dysfunction and dominated by autoimmunity. High-grade systemic inflammation, resembling autoinflammatory (AI) disorders might complicate and overlap with the classical lupus phenotype (1, 2). Patients with these characteristics amid the spectrum of SLE constitute an ill-defined subgroup despite a potentially higher risk of morbidity and mortality.Objectives:To characterise the clinical profile and long-term SLE outcomes of patients with AI features within a monocentric SLE cohort.Methods:By reviewing the clinical characteristics of about 300 patients with SLE we identified a group of subjects with AI features (AIG), meeting the following criteria: 1) fever without infection or with incomplete antibiotic response, lasting more than two weeks and/or resistant to 0.5mg/kg prednisone-equivalent steroid therapy; 2) history of non-infectious fever ≥40°C or 3) of Macrophage Activation Syndrome (MAS); 4) erythrocyte sedimentation rate (ESR) higher than 75mm/h in at least three consecutive visit, 5) C-reactive protein higher than twice the upper level of normality in at least three consecutive visits, excluding infections; 6) ferritinaemia higher than 600 ng/ml despite 0.5mg/kg prednisone-equivalent steroid therapy. We collected demographic, clinical and treatment data from a series of 140 consecutive patients without these criteria, which constituted a Control Group (CG). Damage accrual was measured with the SLE International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).Results:Thirteen subjects met the inclusion criteria for AIG. The main AI manifestations were non infectious and/or steroid resistant fever longer than two weeks (n=8, 62%) followed by persistent ESR (n=7, 54%). MAS, persistent CRP and Ferritin elevation had a prevalence of 31% (n=4) each. Five subjects (39%) had concomitant SLE and AI onset (Table 1). Compared to the CG, SLE patients in the AIG had a significant higher proportion of constitutional symptoms (77% vs 38%, p=0.032), including fever (92% vs 16%, p<0.001), as expected. Gastrointestinal symptoms were also more frequent in the AIG compared to CG (31% vs 2%, p<0.001). A lower antiphospholipid antibody prevalence was found in AIG, especially with regard to anticardiolipin antibodies (0% vs 32%; p=0.015). No other differences were identified in terms of demographics, clinical and treatment features among the two groups. AIG patients with SLE had a higher risk of SDI progression over time compared to CG patients (HR 5.2, 95%C.I. 1.4-19.5 p=0.012; Figure 1).Conclusion:AI features constitute an uncommon, yet clinically significant aspect of the broad spectrum of SLE manifestations. SLE patients with AI manifestations show a distinct clinical profile and accrue damage more rapidly compared to patients without these clinical characteristics. These data highlight a still unmet need in the care of patients with SLE and suggest that unique pathogenic events occur in patients with AI features, which might insufficiently be tackled by current diagnostic and treatment strategies.REFERENCES:[1] Gavand PE, et al., Autoimmun Rev. 2017[2] Mahajan VK, et al., World J Clin Cases. 2023Acknowledgements:NIL.Disclosure of Interests:Giovanni Benanti: None declared, Giuseppe Alvise Ramirez Astrazeneca (lessons), Astrazeneca, GSK (advisory boards), Astrazeneca (financial support for publication), Costanza Vitellaro: None declared, Chiara Calabrese: None declared, Serena Nannipieri: None declared, Luca Moroni Astrazeneca (lessons), Astrazeneca, GSK (advisory boards), Astrazeneca (financial support for publication), Enrica Bozzolo: None declared, Marco Matucci-Cerinic: None declared, Lorenzo Dagna: None declared.

BackgroundAlthough several studies report a high incidence of pulmonary manifestations in SLE, lung involvement is often underestimated in SLE clinical assessment [1]. This is also mirrored by the absence of pulmonary manifestations other than pleurisy in the old and new classification criteria for SLE [2]. Moreover, limited evidence on the management of SLE-related pulmonary manifestations is available.ObjectivesTo assess prevalence and clinical impact of the spectrum of SLE-related pulmonary manifestations and their association with patient autoantibody profiles in a large SLE cohort and to describe the effectiveness of different therapeutic approaches in distinct clinical settings.MethodsPatients followed at the Lupus Clinics of ASST G. Pini-CTO and San Raffaele Hospital (Milan, Italy) were enrolled. Data regarding demographics, disease characteristics, autoantibody profile, pulmonary manifestations, damage accrual and treatment were collected. The following types of lung involvement were recorded: pleurisy, acute lupus pneumonitis, interstitial lung disease (ILD), alveolar haemorrhage, pulmonary embolism, arterial pulmonary hypertension and shrinking lung syndrome.ResultsOf the 471 SLE patients enrolled, we identified 78 patients (16.5%) displaying at least one pulmonary manifestation. Epidemiological data on each manifestation are reported in Table 1. Pleurisy was the most common pulmonary manifestations and manifested at disease onset in most cases (56%).Patient home environment (urban vs countryside) did not seem to impact the risk of developing lung disease. Damage accrual was relevant, as 2/3 of patients displayed at least 1 point increase in SLICC Damage Index (SDI) after the onset of lung involvement in comparison to baseline. All patients received at least one steroid course. Immunosuppressive treatment choices and efficacy differed among distinct manifestations: only half of the patients with pleurisy received immunosuppression, mainly azathioprine, with 100% of improvement, while 80% of cases of ILD received immunosuppression, predominantly mycophenolate, with a 50% risk of non-response.By comparing demographics and clinical characteristics among cases and controls, we found a significantly lower median age at disease onset (p=0.002) and a higher frequency of male sex (18% vs 9%; p=0.07), joint involvement (p=0.02) and constitutional symptoms (p=0.02) in patients with lung involvement, while no differences were observed in the autoantibody profile, including anti-dsDNA and anti-ENA autoantibodies.ConclusionOur study confirms that, in addition to the known epidemiological burden of pleurisy, other types of pulmonary involvement can complicate the disease course and contribute to damage accrual. In particular, ILD can frequently occur and respond to immunosuppressants in only half cases. Consistent with the association of lung involvement with increased morbidity, higher-risk categories for severe disease such as males and subjects with early-onset SLE were more represented among patients with pulmonary manifestations.References[1] Amarnani R, et al. Front. Med. 2021; 7:610257.[2] Aringer M, et al. Ann Rheum Dis. 2019; 78:1151-1159.[3] Smith EMD, Clin Immunol. 2019; 209:108274.[4] Ryu S, et al. Lupus Sci Med. 2017;):e000221.Table 1.Demographic and disease characteristics of SLE patients with lung involvementDemographics and clinical characteristicsFemales, n (%)65 (83)Age at diagnosis (years): median (IQR)29 (22 – 39)Disease duration (years): mean ±DS19 ± 12Subjects with >0 and >1 point SDI increase from baseline: n (%)48 (61.5); 26 (33)Lung involvementN (%)immunosuppressive therapy, %Pleurisy61 (78)49Acute pneumonitis4 (5)100ILD15 (19)80PAH6 (8)50Pulmonary embolism4 (5)50Shrinking lung1 (1)100Alveolar hemorrage4 (5)100Acknowledgements:NIL.Disclosure of InterestsMaria Gerosa: None declared, Giuseppe Alvise Ramirez: None declared, Lorenza Maria Argolini: None declared, Isabella Scotti: None declared, Carolina Artusi: None declared, Luca Moroni: None declared, Enrica Bozzolo: None declared, Maria Rosa Pellico: None declared, Ludovica Cavallo: None declared, Lorenzo Dagna: None declared, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB,

Background:Avacopan is a new orally administered drug approved for the treatment of ANCA-associated vasculitis (AAV).Objectives:The aim of this study was to assess efficacy, safety and impact on quality of life associated with the use of avacopan in a real cohort of patients from Italian Rheumatology Units.Methods:The prospective collection of clinical data commenced in May 2022, and encompassed patients with either GPA or MPA, including those with newly diagnosed or relapsing diseases, who initiated avacopan therapy. For each patient the Italian AAV-PRO questionnaire was completed every 3 months.Results:Twenty-four patients were included: 17 GPA (16/17 c-ANCA/PR3+; 1/17 p-ANCA/MPO+), 7 MPA (6/7 MPO+; 1/7 ANCA negative). The median age of patients was 60 (IQR 52-63) years, with 58% being women. One-third of the patients (8/24) initiated avacopan following a new diagnosis of AAV. Patients treated after a relapse (16/24) had a median disease duration of 8.5 (IQR 7-14) years and prior treatments with RTX (75%), CYC (50%), MTX (25%), AZA (18.8%), MMF (12.5%). At avacopan initiation, BVASv3 and VDI were 9 (IQR 5-20) and 3 (IQR 1-4), respectively. The main disease manifestations included renal involvement (75%), with 12/18 having rapidly progressive glomerulonephritis, and pulmonary involvement (46%), with 5/11 experiencing hemorrhagic alveolitis. Avacopan was administered in combination with RTX in all patients, preceded by CYC IV in 5 patients. Two out of 12 patients with rapidly progressive glomerulonephritis also underwent plasmapheresis. At the baseline, the median corticosteroid (CS) dose was 25 mg/day (IQR 7-41). For patients with renal involvement, the median baseline creatinine and proteinuria values were 1.9 mg/dL (IQR 1.6-2.8) and 1140 mg/24h (IQR 300-2400), respectively. Sixteen out of 18 patients had microhematuria. At 12 weeks, 75% of patients had achieved clinical remission, with 28% being steroid-free. The median CS dose had decreased to 5 mg/day (IQR 2-5) (p-value <0.001). The median creatinine and proteinuria values had reduced to 1.6 mg/dL (IQR 1.2-2.1) (p-value=0.029) and 300 mg/24h (IQR 100-1223) (p-value=0.014), respectively. Only eight out of 18 patients still presented with microhematuria (p-value=0.005). During the observation period (median follow-up duration: 26 weeks [IQR 22.5-52]), avacopan was suspended 8 times, primarily due to infectious and adverse events (AEs): respiratory infections (50%), urinary tract infections (12.5%), diarrhea (12.5%), planned surgery (12.5%), and difficulty dispensing the drug (12.5%). Two clinical relapses were reported at weeks 26 and 52, necessitating the resumption of CS and RTX plus CS, respectively. One death at week 65 due to a fungal infection was registered. Finally, a progressive reduction in AAV-PRO questionnaire scores was observed from baseline to week 12 (Figure 1).Conclusion:The addition of avacopan to AAV induction therapy allows for a significant reduction in CS in the early weeks of treatment, with a good safety profile and positively impacting the perception of patients’ quality of life.REFERENCES:[1] Jayne DRW et al, Avacopan for the Treatment of ANCA-Associated Vasculitis, N Engl J Med, 2021.Figure 1.Graphic representation of responses to the AAV-PRO_ita questionnaire divided into the three domains at baseline and at week 12.Acknowledgements:NIL.Disclosure of Interests:None declared.

Scaffolds derived from natural polysaccharides are very promising in tissue engineering applications and regenerative medicine, as they resemble glycosaminoglycans in the extracellular matrix (ECM). In this study, we have prepared freeze-dried composite scaffolds of chitosan (CHT) and hyaluronic acid (HA) in different weight ratios containing either no HA (control) or 1%, 5%, or 10% of HA. We hypothesized that HA could enhance structural and biological properties of CHT scaffolds. To test this hypothesis, physicochemical and biological properties of CHT/HA scaffolds were evaluated. Scanning electron microscopy micrographs, mechanical properties, swelling tests, enzymatic degradation, and Fourier transform infrared (FTIR) chemical maps were performed. To test the ability of the CHT/HA scaffolds to support chondrocyte adhesion and proliferation, live–dead and MTT assays were performed. Results showed that CHT/HA composite scaffolds are noncytotoxic and promote cell adhesion. ECM formation was further evaluated with safranin-O and alcian blue staining methods, and glycosaminoglycan and DNA quantifications were performed. The incorporation of HA enhanced cartilage ECM production. CHT/5HA had a better pore network configuration and exhibited enhanced ECM cartilage formation. On the basis of our results, we believe that CHT/HA composite matrixes have potential use in cartilage repair.

Background:Anifrolumab (ANI) is a fully human monoclonal antibody against the type I interferon receptor that has recently been approved for the treatment of moderate to severe Systemic Lupus Erythematosus (SLE) as an add-on treatment to standard of care. Data from randomized controlled trials have demonstrated its efficacy and safety, but real-world data are still limited, especially regarding the impact of this new drug on patients’ quality of life (QoL).Objectives:To evaluate the effect of ANI therapy on QoL and disease burden in a multicentric cohort of refractory SLE patients.Methods:Consecutive adult SLE patients (2019 EULAR/ACR criteria) were prospectively enrolled at ANI prescription. Data on demographic features, medical history, previous therapies and SLICC-DI were collected from clinical charts at enrolment. Patients’ assessments were performed at the first ANI infusion and subsequently after one, three and six months of treatment. At each time-point, the clinical evaluation included SLEDAI-2K, SLE-DAS, Physician Global Assessment, number of tender and swollen joints and cutaneous activity and damage assessed using the Cutaneous LE Disease Area and Severity Index (CLASI-A for activity and -D for damage). Patients’ perspective was assessed by self-administration of validated Patient Reported Outcomes (PROs): Lupus Impact Tracker (LIT) to assess the overall impact of SLE on patients’ QoL, Functional Assessment of Chronic Illness Therapy – Fatigue scale (FACIT-F) to measure self-reported fatigue and its impact on daily activities and, in a subgroup of patients with mucocutaneous involvement, Skindex-16 which is a specific PRO to investigate the impact of the skin disease in symptom, emotional and functioning spheres.Results:Twenty-five patients (96% female, 92% Caucasian) with a median age of 45 years (IQR 37-58) and a median disease duration of 11 years (IQR 7.5-21.5) were enrolled. In the whole cohort, 24 patients (96%) had a history of articular involvement, 23 (92%) of mucocutaneous involvement, 16 (64%) of haematological involvement, 7 (28%) of lupus nephritis, 5 (20%) of serositis and 4 (16%) of neuropsychiatric involvement. At baseline, 23 patients (92%) were on concomitant steroid therapy (median prednisone daily dose 7.5 mg, IQR 5-10), 19 (76%) on hydroxychloroquine and 23 (92%) on immunosuppressive treatment (10 methotrexate, 9 mycophenolate mofetil, 3 azathioprine, 1 cyclosporine). Active disease manifestations at the time of ANI prescription were in most cases mucocutaneous (18/25, 72%), followed by articular (10/25, 40%) and haematological (5/25, 20%) involvement.As reported in Table 1, after ANI start, all the disease activity measures showed a progressive improvement over time. A significant correlation was observed between LIT and joint count and Skindex-16 and CLASI-A at baseline (r≥0.464, p≤0.026 for LIT; r≥0.731, p≤0.04 for Skindex-16). During follow-up, LIT and Skindex-16 exhibited progressively and significantly improved scores, while no changes were observed in FACIT-F scores. Notably, Skindex-16 was significantly improved as early as 4 weeks after the first drug infusion (symptoms p=0.028, emotions p=0.03, functioning p=0.05), while LIT reached statistical significance after 12 weeks of treatment (p=0.046), maintaining in both cases the result achieved over time (Figure 1).Conclusion:Our preliminary data show that ANI not only allows a rapid clinical improvement of SLE activity, but also of QoL as shown by the significant amelioration of PROs from the very first months of treatment. Further long-term studies on larger cohorts are needed to confirm and corroborate these results.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.