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E Wiesik-Szewczyk, M OlesinskaInstitute of Rheumatology, Department of Connective Tissue Diseases, Warsaw, PolandAbstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology, and the limited available therapeutic options for this disease, are frustrating to both clinicians and patients. However, recent advances in the understanding of disease mechanisms have given rise to numerous studies on specific approaches to SLE treatment. Rituximab, the first chimeric, mouse-human monoclonal antibody which is directed against CD20, seems to be a new therapeutic option. The purpose of this review is to explain the current clinical evidence on the therapeutic use of rituximab in adult SLE patients. Two randomized clinical trials with rituximab (the EXPLORER and LUNAR studies) failed to prove efficacy of this drug on SLE. Ongoing data analysis continues to explain the reasons behind why this treatment fails to work. However data from open source and observational studies contrast with clinical trials results. The global analysis of this data supports the off-label use of rituximab in subsets of SLE that are refractory to standard treatment.Keywords: B cells, systemic lupus erythematosus, rituximab, off-label use, clinical trials

Aleksandra Kucharczyk,1 Ewa Więsik-Szewczyk,1 Anna Poznańska,2 Karina Jahnz-Różyk1 1Department of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defence, Military Institute of Medicine, Warsaw, Poland; 2Department of Population Health Monitoring and Analysis, National Institute of Public Health – National Institute of Hygiene, Warsaw, PolandCorrespondence: Ewa Więsik-SzewczykDepartment of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defence, Military Institute of Medicine, Szaserów 128, Warsaw 01-141, PolandTel/ Fax +48 261 816 581Email ewa.w.szewczyk@gmail.comIntroduction: Omalizumab is a high-cost therapy recommended for the treatment of severe allergic asthma.Objective: To find clinical parameters that are related to the sustained response to omalizumab.Patients and Methods: This retrospective, real-life, 4-year follow-up was provided in Poland between March 2013 and May 2019. The success of omalizumab was assessed based on composed subjective and objective criteria. Simple/multiple regression analyses were performed to search for predictors of the response to omalizumab.Results: A total of 989 severe allergic asthma patients were referred for omalizumab therapy, of whom 854 patients were considered eligible for treatment. At weeks 16 and 52, omalizumab was successful in 84% and 91% of patients, respectively. Treatment effectiveness was maintained up to the 4-year follow-up. Four predictors of the response to omalizumab were found at week 16 and two at week 52. The results at week 16 may be used as predictors of success at week 52 based on the model including baseline FEV1% and change in ACQ-7 and miniAQLQ score at week 16: the area under the ROC curve equals 0.746 [95% CI: 0.672– 0.820].Conclusion: Omalizumab therapy is very effective, with this efficacy sustained after 4 years of treatment. Success of the therapy can be predicted from the baseline FEV1% and clinical improvement (based on ACQ-7 and miniAQLQ scores) at week 16.Keywords: allergic asthma, anti-IgE, biologics, personalized therapy

Ewa Więsik-Szewczyk,1 Anna Felis-Giemza,2 Mirosław Dziuk,3 Karina Jahnz-Różyk1 1Department of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine in Warsaw, Warsaw, Poland; 2Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland; 3Department of Nuclear Medicine, Military Institute of Medicine in Warsaw, Warsaw, PolandCorrespondence: Ewa Więsik-SzewczykDepartment of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Military Institute of Medicine in Warsaw, Szaserów 128 01-141, Warsaw, PolandTel/Fax +48 261 816 581Email ewa.w.szewczyk@gmail.comAbstract: A 32-year-old-man, with a history of chronic urticaria from the age of 27, diagnosed with an adult-onset Still’s disease and received a low dose of glucocorticoids, methotrexate and tocilizumab. Despite the long-term combined treatments, he suffered from chronic urticaria, low-grade fever and bone pain. He was found to have high inflammatory markers, hypogammaglobulinemia, monoclonal IgM – kappa light chain in serum and increased radiotracer uptake in the whole bone scintigraphy. No pathological variants for monogenic autoinflammatory diseases were present in the genome exome sequencing. These investigations confirmed the diagnosis of Schnitzler syndrome, which is an exception before the age of 35. Switching from tocilizumab to interleukin 1 receptor inhibitor, anakinra led to a full clinical response and normalisation of inflammatory markers. Patients with a history of fever and chronic urticaria are routinely tested for monoclonal gammopathy in the context of malignancy, but it should also be considered as a sign of the autoinflammatory syndrome. The Schnitzler syndrome and the adult-onset Still’s disease share common features, so the diagnosis requires a thorough investigation to establish an optimal treatment. In the diagnostic algorithm, monoclonal gammopathy is usually considered red flag for malignancy but might be overlooked as a criterion of Schnitzler syndrome, particularly in young adults. We confirm that the interleukin 1 inhibitor should be the first line of therapy in Schnitzler syndrome, and in the presented case we found it more effective than the interleukin 6 blockade. The main goal of this paper is to increase awareness of Schnitzler syndrome among health care professionals. We aim to present features which can be helpful in differential diagnosis.Keywords: chronic urticaria, monoclonal gammopathy, tocilizumab, anakinra, autoinflammation

Objective: We aimed to evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still disease. We also aimed to assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly., Methods: A multicenter, observational, prospective study was designed including patients included in the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale Adult-Onset Still Disease Study Group and the Autoinflammatory Disease Alliance Network Still Disease Registry. Patients were assessed to see if the variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whatever the clinical course, and/or macrophage activation syndrome, a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis., Results: A total of 597 patients with Still disease were assessed (mean ± SD age 36.6 ± 17.3 years; male 44.4%). The systemic score, assessed as a continuous variable, significantly predicted the life-threatening evolution (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.07-1.42; P = 0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR 3.36; 95% CI 1.81-6.25; P < 0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR 1.68; 95% CI 1.48-2.67; P = 0.031) and lung disease (OR 2.12; 95% CI 1.14-4.49; P = 0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations., Conclusion: The clinical utility of the systemic score was shown in identifying Still disease at a higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted., (© 2024 American College of Rheumatology.)

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The clinical relevance of human leukocyte antigen (HLA) subtypes such as HLA-B51 on Behçet's disease (BD)-related uveitis and non-infectious uveitis (NIU) unrelated to BD remains largely unknown., Methods: Data were prospectively collected from the International AIDA Network Registry for BD and for NIU. We assessed differences between groups (NIU unrelated to BD and positive for HLA-B51, BD-related uveitis positive for HLA-B51 and BD-related uveitis negative for HLA-B51) in terms of long-term ocular complications, visual acuity (VA) measured by best corrected visual acuity (BCVA), anatomical pattern, occurrence of retinal vasculitis (RV) and macular edema over time., Results: Records of 213 patients (341 eyes) were analyzed. No differences in complications were observed ( p  = 0.465). With regard to VA, a significant difference was detected in median BCVA ( p  = 0.046), which was not maintained after Bonferroni correction ( p  = 0.060). RV was significantly more prevalent in NIU-affected patients who tested positive for HLA-B51, irrespective of the systemic diagnosis of BD ( p  = 0.025). No differences emerged in the occurrence of macular edema ( p  = 0.99)., Conclusions: Patients with NIU testing positive for HLA-B51 exhibit an increased likelihood of RV throughout disease course, irrespective of a systemic diagnosis of BD. The rate of complications as well as VA are comparable between NIU cases unrelated to BD testing positive for HLA-B51 and uveitis associated with BD. Therefore, it is advisable to perform the HLA-B typing in patients with NIU or retinal vasculitis, even in the absence of typical BD features.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF., Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression., Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p =0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p =0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (β1 = 0.039, 95% CI. 0.001-0.071, p =0.02), the age at the diagnosis (β1 = 0.048, 95% CI. 0.039-0.085, p =0.006), the age at the enrolment (β1 = 0.05, 95% CI. 0.007-0.068, p =0.01), the number of attacks per year (β1 = 0.011, 95% CI. 0.001- 0.019, p =0.008), the use of biotechnological agents (β1 = 1.77, 95% CI. 0.43-3.19, p =0.009), the use of anti-IL-1 agents (β1 = 2.089, 95% CI. 0.7-3.5, p =0.002)., Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vitale, Caggiano, Tufan, Ragab, Batu, Portincasa, Aragona, Sota, Conti, De Paulis, Rigante, Olivieri, Şahin, La Torre, Lopalco, Cattalini, Maggio, Insalaco, Sfikakis, Verrecchia, Yildirim, Kucuk, Kardas, Laymouna, Ghanema, Saad, Sener, Ercan Emreol, Ozen, Jaber, Khalil, Di Ciaula, Gaggiano, Malizia, Affronti, Patroniti, Romeo, Sbalchiero, Della Casa, Mormile, Silvaroli, Gicchino, Çelik, Tarsia, Karamanakos, Hernández-Rodríguez, Parronchi, Opris-Belinski, Barone, Recke, Costi, Sfriso, Giardini, Gentileschi, Wiesik-Szewczyk, Vasi, Loconte, Jahnz-Różyk, Martín-Nares, Torres-Ruiz, Cauli, Conforti, Emmi, Li Gobbi, Biasi, Terribili, Ruscitti, Del Giudice, Tharwat, Brucato, Ogunjimi, Hinojosa-Azaola, Balistreri, Fabiani, Frediani and Cantarini.)

Introduction: The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment., Methods: Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent., Results: No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response ( p  =0.62), partial response ( p  =0.61), treatment failure ( p  >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy ( p  =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use ( p  =0.34), daily glucocorticoid dosage ( p  =0.47), or concomitant methotrexate dosage ( p  =0.43) at the last assessment during CAN treatment., Conclusion: Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vitale, Caggiano, Sfikakis, Dagna, Lopalco, Ragab, La Torre, Almaghlouth, Maggio, Sota, Tufan, Hinojosa-Azaola, Iannone, Loconte, Laskari, Direskeneli, Ruscitti, Morrone, Mayrink Giardini, Panagiotopoulos, Di Cola, Martín-Nares, Monti, De Stefano, Kardas, Duran, Campochiaro, Tomelleri, Alabdulkareem, Gaggiano, Tarsia, Bartoloni, Romeo, Hussein, Laymouna, Parente de Brito Antonelli, Dagostin, Fotis, Bindoli, Navarini, Alibaz-Oner, Sevik, Frassi, Ciccia, Iacono, Crisafulli, Portincasa, Jaber, Kawakami-Campos, Wiesik-Szewczyk, Iagnocco, Simonini, Sfriso, Balistreri, Giacomelli, Conti, Frediani, Fabiani and Cantarini.)

Objective: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease., Methods: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease., Results: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments., Conclusions: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Beckground: Despite the recent advances in the field of autoinflammatory diseases, most patients with recurrent fever episodes do not have any defined diagnosis. The present study aims at describing a cohort of patients suffering from apparently unexplained recurrent fever, in whom non-radiographic axial spondylarthritis (SpA) represented the unique diagnosis identified after a complete clinical and radiologic assessment., Materials and Methods: Patients' data were obtained from the international registry on Undifferentiated Systemic AutoInflammatory Diseases (USAIDs) developed by the AutoInflammatory Disease Alliance (AIDA) network., Results: A total of 54 patients with recurrent fever episodes were also affected by non-radiographic axial SpA according to the international classification criteria. SpA was diagnosed after the start of fever episodes in all cases; the mean age at the diagnosis of axial SpA was 39.9 ± 14.8 years with a diagnostic delay of 9.3 years. The highest body temperature reached during flares was 42°C, with a mean temperature of 38.8 ± 1.1°C. The most frequent manifestations associated to fever were: arthralgia in 33 (61.1%) cases, myalgia in 24 (44.4%) cases, arthritis in 22 (40.7%) cases, headache in 15 (27.8%) cases, diarrhea in 14 (25.9%) cases, abdominal pain in 13 (24.1%) cases, and skin rash in 12 (22.1%) cases. Twenty-four (44.4%) patients have taken daily or on-demand non-steroidal anti-inflammatory drugs (NSAIDs) and 31 (57.4%) patients have been treated with daily or on demand oral glucocorticoids. Colchicine was used in 28 (51.8%) patients, while other conventional disease modifying anti-rheumatic drugs (cDMARDs) were employed in 28 (51.8%) patients. Forty (74.1%) patients underwent anti-tumor necrosis factor (TNF) agents and 11 (20.4%) were treated with interleukin (IL)-1 inhibitors. The response to TNF inhibitors on recurrent fever episodes appeared more effective than that observed with anti-IL-1 agents; colchicine and other cDMARDs were more useful when combined with biotechnological agents., Conclusion: Signs and symptoms referring to axial SpA should be inquired in patients with apparently unexplained recurrent fever episodes. The specific treatment for axial SpA may lead to a remarkable improvement in the severity and/or frequency of fever episodes in patients with unexplained fevers and concomitant axial SpA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vitale, Caggiano, Silva, Oliveira, Ruscitti, Ciccia, Vasi, Tufan, Lopalco, AlMaghlouth, Sota, Wiesik-Szewczyk, Gaggiano, Giardini, Spedicato, Ragab, Iannone, Balistreri, Frassi, Hernández-Rodríguez, Fabiani, Falsetti, Di Meglio, Frediani, Mazzei, Rigante, Faria and Cantarini.)

This study aims to describe musculoskeletal manifestations (MSM) in children with Behçet's syndrome (BS), their association with other disease manifestations, response to therapy, and long-term prognosis. Data were retrieved from the AIDA Network Behçet's Syndrome Registry. Out of a total of 141 patients with juvenile BS, 37 had MSM at disease onset (26.2%). The median age at onset was 10.0 years (IQR 7.7). The median follow-up duration was 21.8 years (IQR 23.3). Recurrent oral (100%) and genital ulcers (67.6%) and pseudofolliculitis (56.8%) were the most common symptoms associated with MSM. At disease onset, 31 subjects had arthritis (83.8%), 33 arthralgia (89.2%), and 14 myalgia (37.8%). Arthritis was monoarticular in 9/31 cases (29%), oligoarticular in 10 (32.3%), polyarticular in 5 (16.1%), axial in 7 (22.6%). Over time, arthritis became chronic-recurrent in 67.7% of cases and 7/31 patients had joint erosions (22.6%). The median Behçet's Syndrome Overall Damage Index was 0 (range 0-4). Colchicine was inefficacious for MSM in 4/14 cases (28.6%), independently from the type of MSM (p = 0.46) or the concomitant therapy (p = 0.30 for cDMARDs, p = 1.00 for glucocorticoids); cDMARDs and bDMARDs were inefficacious for MSM in 6/19 (31.4%) and 5/12 (41.7%) cases. The presence of myalgia was associated with bDMARDs inefficacy (p = 0.014). To conclude, MSM in children with BS are frequently associated with recurrent ulcers and pseudofolliculitis. Arthritis is mostly mono- or oligoarticular, but sacroiliitis is not unusual. Prognosis of this subset of BS is overall favorable, though the presence of myalgia negatively affects response to biologic therapies. ClinicalTrials.gov Identifier: NCT05200715 (registered on December 18, 2021)., (© 2023. The Author(s).)

Objective: The present manuscript aims to describe an international, electronic-based, user-friendly and interoperable patient registry for monogenic autoinflammatory diseases (mAIDs), developed in the contest of the Autoinflammatory Diseases Alliance (AIDA) Network., Methods: This is an electronic platform, based on the Research Electronic Data Capture (REDCap) tool, used for real-world data collection of demographics, clinical, laboratory, instrumental and socioeconomic data of mAIDs patients. The instrument has flexibility, may change over time based on new scientific acquisitions, and communicate potentially with other similar registries; security, data quality and data governance are corner stones of the platform., Results: AIDA project will share knowledge and expertise on mAIDs. Since its start, 118 centers from 24 countries and 4 continents have joined the AIDA project. Fifty-nine centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 337 users (122 Principal Investigators, 210 Site Investigators, 2 Lead Investigators, and 3 data managers). The Registry collects baseline and follow-up data using 3,748 fields organized into 21 instruments, which include demographics, patient history, symptoms, trigger/risk factors, therapies, and healthcare information for mAIDs patients., Conclusions: The AIDA mAIDs Registry, acts both as a research tool for future collaborative real-life studies on mAIDs and as a service to connect all the figures called to participate. On this basis, the registry is expected to play a pivotal role in generating new scientific evidence on this group of rare diseases, substantially improving the management of patients, and optimizing the impact on the healthcare system. NCT05200715 available at https://clinicaltrials.gov., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gaggiano, Vitale, Tufan, Ragab, Aragona, Wiesik-Szewczyk, Ait-Idir, Conti, Iezzi, Maggio, Cattalini, Torre, Lopalco, Verrecchia, Paulis, Sahin, Insalaco, Sfikakis, Marino, Frassi, Ogunjimi, Opris-Belinski, Parronchi, Emmi, Shahram, Ciccia, Piga, Hernández-Rodríguez, Pereira, Alessio, Naddei, Olivieri, Giudice, Sfriso, Ruscitti, Gobbi, Kucuk, Sota, Hussein, Malizia, Jahnz-Różyk, Sari-Hamidou, Romeo, Ricci, Cardinale, Iannone, Casa, Natale, Laskari, Giani, Franceschini, Sabato, Yildirim, Caggiano, Hegazy, Marzo, Kucharczyk, Khellaf, Tarsia, Almaghlouth, Laymouna, Mastrorilli, Dotta, Benacquista, Grosso, Crisafulli, Parretti, Giordano, Mahmoud, Nuzzolese, Musso, Chighizola, Gentileschi, Morrone, Cola, Spedicato, Giardini, Vasi, Renieri, Fabbiani, Mencarelli, Frediani, Balistreri, Tosi, Fabiani, Lidar, Rigante and Cantarini.)

Objective: The aim of this paper is to present the AutoInflammatory Disease Alliance (AIDA) international Registry dedicated to Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, describing its design, construction, and modalities of dissemination., Methods: This Registry is a clinical, physician-driven, population- and electronic-based instrument designed for the retrospective and prospective collection of real-life data. Data gathering is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain real-world evidence for daily patients' management. The Registry may potentially communicate with other on-line tools dedicated to VEXAS syndrome, thus enhancing international collaboration and data sharing for research purposes. The Registry is practical enough to be easily modified to meet future needs regarding VEXAS syndrome., Results: To date (April 22 nd , 2022), 113 Centers from 23 Countries in 4 continents have been involved; 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) are currently able to access the registry for data entry (or data sharing) and collection. The Registry includes 4,952 fields organized into 18 instruments designed to fully describe patient's details about demographics, clinical manifestations, symptoms, histologic details about skin and bone marrow biopsies and aspirate, laboratory features, complications, comorbidities, therapies, and healthcare access., Conclusion: This international Registry for patients with VEXAS syndrome will allow the achievement of a comprehensive knowledge about this new disease, with the final goal to obtain real-world evidence for daily clinical practice, especially in relation to the comprehension of this disease about the natural history and the possible therapeutic approaches. This Project can be found on https://clinicaltrials.gov NCT05200715., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vitale, Caggiano, Della Casa, Hernández-Rodríguez, Frassi, Monti, Tufan, Telesca, Conticini, Ragab, Lopalco, Almaghlouth, Pereira, Yildirim, Cattalini, Marino, Giani, La Torre, Ruscitti, Aragona, Wiesik-Szewczyk, Del Giudice, Sfikakis, Govoni, Emmi, Maggio, Giacomelli, Ciccia, Conti, Ait-Idir, Lomater, Sabato, Piga, Sahin, Opris-Belinski, Ionescu, Bartoloni, Franceschini, Parronchi, de Paulis, Espinosa, Maier, Sebastiani, Insalaco, Shahram, Sfriso, Minoia, Alessio, Makowska, Hatemi, Akkoç, Li Gobbi, Gidaro, Olivieri, Al-Mayouf, Erten, Gentileschi, Vasi, Tarsia, Mahmoud, Frediani, Fares Alzahrani, Laymouna, Ricci, Cardinale, Jahnz-Rózyk, Tosi, Crisafulli, Balistreri, Dagostin, Ghanema, Gaggiano, Sota, Di Cola, Fabiani, Giardini, Renieri, Fabbiani, Carrer, Bocchia, Caroni, Rigante and Cantarini.)

Objective: This paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs)., Methods: This is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions and potentially communicate with other similar tools; this platform ensures security, data quality and data governance., Results: The focus of the AIDA project is connecting physicians and researchers from all over the world to shed a new light on heterogeneous rare diseases. Since its birth, 110 centers from 23 countries and 4 continents have joined the AIDA project. Fifty-four centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 179 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry is collecting baseline and follow-up data using 3,769 fields organized into 23 instruments, which include demographics, history, symptoms, trigger/risk factors, therapies, and healthcare information access for USAIDs patients., Conclusions: The development of the AIDA International Registry for USAIDs patients will facilitate the online collection of real standardized data, connecting a worldwide group of researchers: the Registry constitutes an international multicentre observational groundwork aimed at increasing the patient cohort of USAIDs in order to improve our knowledge of this peculiar cluster of autoinflammatory diseases. NCT05200715 available at https://clinicaltrials.gov/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Della Casa, Vitale, Lopalco, Ruscitti, Ciccia, Emmi, Cattalini, Wiesik-Szewczyk, Maggio, Ogunjimi, Sfikakis, Tufan, Al-Mayouf, Del Giudice, Aragona, La Torre, Sota, Colella, Di Cola, Iacono, Mattioli, Jahnz-Rózyk, Joos, Laskari, Gaggiano, Abbruzzese, Cipriani, Rozza, AlSaleem, Yildirim, Tarsia, Ragab, Ricci, Cardinale, Korzeniowska, Frassi, Caggiano, Saad, Pereira, Berlengiero, Gentileschi, Guerriero, Giani, Gelardi, Iannone, Giardini, Almaghlouth, Kardas, Ait-Idir, Frediani, Balistreri, Fabiani, Rigante and Cantarini.)

Objectives: To investigate survival of IL-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective., Patients and Methods: Multicentre retrospective study analysing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analysed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation., Results: Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated DRR of IL-1 inhibitors at 12, 24 and 48 months of follow-up was 75.8%, 69.7% and 51.1%, respectively. Patients experiencing an adverse event had a significantly lower DRR (P=0.019). In contrast, no significant differences were observed between biologic-naïve patients and those previously treated with biologic drugs (P=0.985). Patients carrying high-penetrance mutations exhibited a significantly higher DRR compared with those with low-penetrance variants (P=0.015). Adverse events were the only variable associated with a higher hazard of treatment withdrawal [hazard ratio (HR) 2.573 (CI: 1.223, 5.411), P=0.013] on regression analysis. A significant glucorticoid-sparing effect was observed (P<0.0001)., Conclusions: IL-1 inhibitors display an excellent long-term effectiveness in terms of DRR, and their survival is not influenced by the biologic line of treatment. They display a favourable safety profile, which deserves, however, a close monitoring given its impact on treatment continuation. Special attention should be paid to molecular diagnosis and mutation penetrance, as patients carrying low-penetrance variants are more likely to interrupt treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient's daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.

Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies., Experimental Design: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency., Results: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10 -5 ). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); P < 0.0001]., Conclusions: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer., (©2020 American Association for Cancer Research.)

Facilitated subcutaneous immunoglobulin (fSCIG) replacement therapy is the latest method of IgG administration; however, real-life data are limited. We retrospectively analyzed the everyday experience of fSCIG administration, particularly, the method used to switch from intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) to fSCIG and the dosing modifications required. Of the 39 adult patients with primary immunodeficiency (PID) who received fSCIG, 34 remained on the therapy at the end of the study. The median observation time was 18 (range, 3-24) months. Two patients were IgG-treatment-naïve; 23 had previously received IVIG and 14 had received SCIG. In 25 cases, a non-ramp-up dosing mode was used to switch to fSCIG (including two half-monthly doses given biweekly in 14 cases, and full monthly doses given in 11 cases), a ramp-up mode was used in six cases; other methods were used in eight cases. The median IgG trough level at baseline was 7.9 g/L ( n = 38), 7.9 g/L ( n = 32) at Month 6, 9.0 g/L ( n = 30) at Month 12, 8.6 g/L ( n = 22) at Month 18, and 9.0 g/L ( n = 11) at Month 24. No serious bacterial infections or hospitalizations due to PID complications occurred. At the end of the study, 24 patients (71%) received fSCIG every 4 weeks, six (18%) received fSCIG every 3 weeks, and four (12%) received fSCIG biweekly. In conclusion, our study provides real-life evidence of clinical efficacy of personalized fSCIG treatment when switching from prior immunoglobulin replacement using various switching modes and dosing frequencies., (Copyright © 2020 Wiesik-Szewczyk, Sołdacki, Paczek and Jahnz-Różyk.)

Cytokines are implied in polymyositis/dermatomyositis (PM/DM) pathogenesis. Our aim was to evaluate the serum levels of interleukin-15 (IL-15), soluble receptors for IL-2 (sIL-2R) and TNF-alpha type 1 receptor (sTNF-R1) in PM/DM patients and their relation to disease activity and clinical symptoms. Thirty-eight patients who met definite or probable criteria of Bohan and Peter for DM/PM were included into the study. Results in patients with active (41 observations) and inactive disease (24 observations) were compared with control (15 subjects). The median level of IL-15 was 47.6 ± 170 pg/ml in active patients, 25.15 ± 240 pg/ml in inactive and 28.5 ± 28.89 pg/ml in controls. We demonstrated significant differences between active patients and controls in levels of IL-15 (0.016, 95%CI 1.39-57.1). The median level of sIL-2R was 314 ± 388, 235.3 ± 269 and 144.3 ± 152.9 pg/ml, and the median level of sTNF-R1 was 350 ± 388; 294.7 ± 204.7; 209.5 ± 105.9 pg/ml in active, inactive and control subjects, respectively. There were significantly higher serum levels of these cytokines in active patients than in control subjects (for sIL-2R P = 0.05, CI95% 0.4-331; and sTNF-R1 P = 0.031, CI95% 15.1-321.5). The interleukin levels did not differ between inactive patients and controls. Elevation of IL-15, sIL2-R and sTNF-R1 in active patients provides preliminary evidence for the activation of inflammatory response during PM/DM flares. Further studies may be needed to explain the mechanisms driving these diseases.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology and limited available therapeutic options frustrating both clinicians and patients. However, recent advances in the understanding of disease mechanisms have given rise to numerous studies on specific approaches to SLE treatment. The purpose of this review is to explain the rationale for new treatments and results of the first clinical studies. We will focus on agents which deplete B cells (anti-CD20, anti-CD22), block cytokines (TNF α, Il 6), inhibit B/T cells interaction (CTLA-4Ig, anti-CD40L), or are even expected to reconstruct physiologic immunotolerance. Although preliminary results seemed promising, two randomized clinical trials with rituximab (EXPLORER and LUNAR study) failed to prove efficacy. Data analysis continues to explain the reasons. Trial design, subject population, limitations of the outcome measure instrument and site qualification have been questioned. Future studies are likely to focus on specific organ involvement or treatment combinations with other immunosuppressive agents.

The objective of this study is to evaluate efficacy and safety of influenza vaccine in systemic lupus erythematosus (SLE) patients. We studied SLE patients and healthy subjects immunised with inactivated influenza vaccine. Efficacy was measured by comparing humoral response to vaccine antigens between groups. Safety was monitored by SLEDAI and serological markers. Subjects attended visits at baseline and on post-vaccination weeks 4 and 12. We enrolled 62 SLE patients and 47 healthy subjects. In post-immunisation week 4, anti-haemagglutinin antibody titres rose in the patient group at least 6.23-fold, compared to 11.90-fold among controls (P < or = 0.05). The seroconversion rate range was 53-56% among patients and 72-85% among controls (P < 0.05 for strains H1N1 and H3N2, NS for strain type B). The seroprotection rate ranged between 62% and 73% and between 90% and 98% in the patient and control group, respectively (P < 0.05). In post-vaccination week 12, the antibody titre was higher at least 3.86-fold in the patient group and 7.65-fold among controls. The seroconversion rate range was 32-40% among patients and 64-70% among controls, while the seroprotection rate ranged between 43% and 50% and between 79% and 94%, respectively (P < 0.005 for three strains). We identified one severe and six mild to moderate SLE exacerbations by week 12. The anti-nuclear antibodies and anti-double-stranded DNA titres grew by post-immunisation week 4 (P < 0.05). The post-vaccination response was weaker in SLE patients compared to healthy subjects. Immunisation did not change underlying disease activity.

Systemic sclerosis is a multi-system disease characterized by skin fibrosis and visceral involvement. The course of disease is unpredictable, sometimes stable for years sometimes rapidly progressive, leading to death during months. Prognosis is limited by internal organ involvement. Nowadays leading cause of death is interstitial lung fibrosis and pulmonary arterial hypertension. In this paper we present two subsets of systemic sclerosis: limited and diffuse and newly proposed classification for early systemic sclerosis, including objective documentation of Raynaud's phenomenon and systemic sclerosis-type naifold capillary pattern or presence of selective auto-antibodies (anti-centromer or anti-Scl 70). We describe clinical symptoms, internal organ involvement and tools to its detection, with use of HRCT, Doppler echocardiography, spirometric gas transfer (DLCO). We present current approach to staging the disease according to parameters proposed by Medsger et al. involving general symptoms, Raynaud's phenomenon severity, Rodnan skin score, musculoskeletal symptoms, lung, heart and kidney involvement. Factors related to scleroderma renal crisis are presented, to provide clinical evaluation of patients at risk of this complication.

This paper presents progress in management of systemic sclerosis, with respect of EULAR recommendation. In the first part we present efficacy of overall immunosupresive treatments and preliminary data of autologous stem cell transplantation based on randomized clinical trials. The second part concerns a treatment specific for target organs: Raynaud's phenomenon, alimentary tract involvement, interstitial lung disease, pulmonary arterial hypertension and scleroderma renal crisis. Despite intensive investigations disease modifying drug therapy is still unknown, but specific organ treatment increase survival and improve health related quality of life.

Introduction: Antibodies against ribosomal P protein (anti-P) are detected predominantly in patients with systemic lupus erythematosus (SLE). However, the data on their frequency and clinical relevance remain inconclusive., Objectives: The aim of the study was to assess the frequency as well as clinical and serological relevance of anti-P autoantibodies in Polish patients with SLE and to determine the significance of these antibodies in the diagnosis of SLE., Patients and Methods: Anti-P antibody levels were measured in the sera of 100 SLE patients using an enzyme-linked immunosorbent assay and Western blotting. All patients underwent a routine clinical and laboratory evaluation. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score., Results: Anti-P antibodies were detected in 14 of 100 patients. When compared to anti-P-negative patients, this group was characterized by earlier onset of SLE, higher disease activity, more frequent occurrence of fever and facial erythema, decreased serum levels of complement, and elevated levels of alanine and aspartate aminotransferases. In 2 cases, anti-P antibodies were the only serological marker of SLE detected in these patients., Conclusions: SLE with the presence of anti-P antibodies is characterized by an early onset and high disease activity.

Controversies regarding the safety and efficacy of immunization in patients with SLE have persisted for over 60 years. However infections are the main threat in these patients. There are concerns that immunization may cause SLE exacerbation. Evidence from prospective trials suggests that inactivated vaccines are probably safe in patients with stable or inactive disease. Live vaccines are contraindicated in immunocompromised hosts and patients on high dose steroids. Data regarding efficacy of vaccinations are scarce, mainly concerning influenza and pneumoccocal vaccine. Majority of patients have appropriate immunological response, but there are group without serological response after immunization. Risk factors for impaired response are not clear. In same cases it seems reasonable to assess protective antibody titer post vaccination. In this review we would like to present data concerning safety and efficacy of vaccines in patients with SLE to help doctor to decide when vaccination is advisable and when should be avoided.

Pregnancy in patients with systemic lupus erythematosus (SLE) is considered a high-risk pregnancy. It is complicated by preeclampsia, premature labour and miscarriage more frequently than in the general population. Improved prognosis depends on low disease activity during conception and on appropriate medical care (SLE activity monitoring, selection of therapy safe for the mother and the developing foetus, advances in neonatology). Because symptoms of physiological pregnancy and SLE exacerbation are similar, their correct interpretation is essential for skin lesions, arthralgias, arterial hypertension or results of laboratory tests: proteinuria, thrombocytopenia or leucopenia observed in the patient. In order to standardise the assessment of SLE activity during pregnancy, scores of this activity are used. In the past, scores validated on non-pregnant populations (including male patients) were used: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus Activity Measure (SLAM), European Consensus Lupus Activity Measurment (ECLAM). Only recently have SLE activity scores been introduced that are specific for pregnant women: Lupus Activity Index In Pregnancy (LAI-P), Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI), modified--Systemic Lupus Activity Measure (m-SLAM) and a visual three-grade score modified--Physician Global Assessment (m-PGA). So far, only scores LAI-P and m-PGA have been validated. According to the LAI-P score, clinical data are divided into 4 groups. Group 1 includes mild clinical symptoms, group 2--symptoms of involvement of internal organs, group 3 pertains to modifications of treatment and group 4 to laboratory parameters. Point values are ascribed to individual parameters depending on their intensity.

The idiopathic inflammatory myopathies are a heterogeneous group of diseases that can involve various systems. Antibodies directed against aminoacyl-tRNA synthetases, such as anti-Jo-1 antibodies, are strongly associated with a syndrome which consists of myositis, interstitial lung disease (ILD), arthritis and Raynaud's phenomenon. Forty-one patients with various forms of idiopathic inflammatory myopathies were assessed: 14 patients with anti-Jo-1 antibodies and 27 patients without anti-Jo-1 antibodies as a control group. We retrospectively analysed clinical symptoms, treatment and outcome in both groups. Patients with anti-Jo-1 antibodies more often had ILD (64.2 vs. 11.1%), arthritis (64.2 vs. 18.1%) and Raynaud's phenomenon (38 vs. 0%). Patients without the anti-Jo-1 antibody presented worse muscle strength and more frequently myalgia (37 vs. 21%), cutaneous rash (18.5 vs. 7%), heliotrope rash (29% vs. 7%) and periungueal changes (22 vs. 0%) than the anti-Jo-1-positive patients. Outcome was good in both groups. Improvement was achieved in the 14 (100%) Jo-1 positive patients, and in 25 (92.5%) controls. Two (7.5%) patients from control group achieved remission.

In recent years new potential therapies of systemic lupus erythematosus, called biological therapies, have been developed. These agents influence some immunological reactions, essential for genesis of systemic lupus erythematosus, ie. T cells and B cells activation, antibodies production, cytokines and complement components activation. Pathogenic basis of using these therapies, their safety and efficacy assessment have been presented.

Wegener's granulomatosis is a necrotizing vasculitis with heterogenous initial symptoms what may still cause diagnostic problems. We present analysis of initial symptoms of 14 patients with Wegener's granulomatosis to evaluate their value in early diagnosis. Involvement of kidneys as well as upper and lower airways may suggest the diagnosis. Acute onset with intensified general symptoms may provoke more intensive diagnostic procedures and the diagnosis can be established earlier. In patients with non-acute onset the diagnosis may be delay, in some cases a few years after the first symptoms.