EXCELLENT PROGNOSIS of RHEUMATIC MANIFESTATIONS FOLLOWING COVID-19 VACCINATION: 7 MONTHS FOLLOW-UP DATA

Background: It is well established that severe forms of SARS-CoV2 infection can induce a massive cytokine storm, which may disrupt the immune system stability and conceivably stimulate the development of reactive manifestations through a molecular mimicry process. Likewise, anti-COVID-19 vaccines, which have so far proved an excellent tolerability and safety profile, are able boost the immune response via different biologic technologies and adjuvant combinations possibly facilitating, in predisposed subjects, the onset of infammatory or even autoimmune manifestations. Objectives: We report a case series of suspected rheumatic adverse events following immunization (AEFI) associated with anti-COVID-19 vaccine. We focused our attention on the prognosis of these patients by analysing their available follow-up data. Methods: We included patients evaluated at frst-aid rheumatologic consultancy and at rheumatologic outpatient and inpatient clinic at Padua University Hospital between May and September 2021 presenting with new-onset rheumatic manifestation or a fare of an underlying rheumatic disease within 30 days after receiving an anti-COVID-19 vaccine dose. Inclusion and exclusion criteria were in accordance with the World Health Organization guidelines for AEFI surveillance. All patients were re-evaluated in January 2022: telemedicine or face-to-face visit. Response to therapy was classifed as complete, good or absent according to the clinician's judgment based on clinical examination, patient's reporting and analysis of laboratory data. Results: We identifed 30 cases of suspected rheumatic AEFI reported in Table 1. Comprehensively the most common manifestations were infammatory arthritis (40.0%), rheumatic polymyalgia (26.7%) and adult-onset Still disease (13.3%). Among patients with an underlying rheumatic disease we recorded an AOSD fare, a rheumatoid arthritis fare with involvement of hands proximal inter-phalangeal joints, one case of wrist arthritis in a patient with psoriatic arthritis, one of aortitis in a patient with large vessels vasculitis, one case of polyarthritis in undifferentiated connective tissue disease and a nephritis fare in a patient with systemic lupus erythematosus. Treatment for the suspected AEFI was based on systemic glucocorticoids (GC) alone (63.3%), systemic GC plus IL-1R antagonists (13.3%), non-steroidal autoinfammatory drugs (13.3%), intra-articular GC (6.6%), colchicine (3.3%) and non-steroidal anti-infammatory drugs (13.3%). At last follow-up contact (7.8±1.5 months) 26 patients (89.6%) were classified as complete responders. Eleven of them (42.3%) withdrew therapy without experiencing recurrence of disease manifestation. One patient with lupus nephritis had a proteinuric flare after the first BNT162b dose;he showed an initial good response to increased glucocorticoid therapy but had a new 24h proteinuria increase at second follow-up visit three months later requiring implementation of immunosuppressive therapy. Another patient with AOSD was in remission at last FU visit in December 2021 but required hospitalization in January 2022 for disease relapse due to a suspected gastrointestinal infection. Finally, one patient hospitalized for a seronegative polyarthritis after the first BNT162b dose achieved complete remission at last available contact (one month after hospital discharge) but was then lost in follow-up. Conclusion: After a mean follow-up of 7.8±1.5 months nearly all of patients showed a complete/good response to standard therapy and about half of them withdrew the treatment without losing the remission status.

EFFICACY of ULTRA-LOW DOSE RITUXIMAB for REMISSION MAINTENANCE THERAPY in ANCA-ASSOCIATED VASCULITIS

Background: Rituximab (RTX) achieved high remission-induction and sustained maintenance rates for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1], [2]. However, RTX is an expensive medication, which may potentially lead to serious side effects. Defning the best dose regimen for maintenance in AAV is still an unmet need. Objectives: The aim of the present study is to compare the effects of ultra-low dose RTX (500 mg or 1000 mg once per year) to standard low dose RTX (500 or 1000 mg twice per year) as remission-maintenance therapy in AAV patients. Methods: We included consecutive AAV patients (classifed as GPA and MPA [3]) referring to four different Rheumatology centers in Italy. We assessed all AAV patients who successfully achieved disease remission (BVASv3=0) with conventional RTX or cyclophosphamide regimens and have been subsequently treated with RTX for maintenance of remission. All included patients received at least three maintenance infusions with either 1000 mg or 500 mg, twice per year (standard low dose) or once per year (ultra-low dose). After a period of 18 months, we assessed the remission rate, damage (VDI), glucocorticoids intake, ANCA status, B-cells depletion and serum IgG levels. Results: From January 2011 to December 2021, 83 AAV patients (mean age 51±16, 49.4% female, 95.2% ANCA positive, 65.8% anti PR3, 34.2% anti MPO), 61 classifed as GPA and 22 MPA, achieved complete disease remission with conventional RTX induction regimen. After 7 [6-9] months, 29.9% patients started maintenance treatment with ultra-low dose RTX (once per year), while 70.1% patients with standard low dose (twice per year), for 18 months. No signifcant differences at baseline were noted between patients receiving ultra-low dose when compared to those treated with conventional low-dose. At the end of observation period, a disease fare was observed in 22.7% of the low-dose group, and 21.2% in those treated with the standard dose (p=0.881). Relapse-free survival was comparable between the two group (log-rank p=0.818, Figure 1). When comparing AAV patients treated with ultra-low dose regimen to those treated with low-dose, no differences were noted in negative ANCA rate (72.2% vs 67.1%, p=0.262), ANCA titer (0 [0-7.8] vs 0 [0-50] UI/mL, p=0.232), B-cells depletion rate (70.6% vs 75%, p=0.725), mean serum IgG (811 [146-922] vs 680 [429-861] mg/dL, p=0.367), mean daily glucocorticoid dosage (2.5 [0-5] vs 3.75 [0-5] mg/d, p=0.647), VDI (4 [1-5] vs 2 [1-4], p=0.098), hypogammaglobulinaemia rate (31.8% vs 36.5%, p=0.697) and deaths (4.5% vs 5.8%, p=0.831). Although not signifcant, patients treated with ultra-low dose had lower severe infection rate (10.5% vs 26.8%, p=0.154). Notably, in the all cohort 5 deaths were related to COVID19 pneumonia. Conclusion: Reduced exposure to RTX was not associated with an impaired efficacy of maintenance therapy in patients with AAV. Remission maintenance with ultra-low dose RTX is a safe and more cost-effective option.

LONG-TERM SURVEY STUDY of the IMPACT of COVID-19 on SYSTEMIC AUTOIMMUNE DISEASES. LOW DEATH RATE DESPITE the INCREASED PREVALENCE of SYMPTOMATIC INFECTION. ROLE of PRE-EXISTING INTERSTITIAL LUNG DISEASE and ONGOING TREATMENTS

Background: Patients with autoimmune systemic diseases (ASDs) can be counted among frail populations as regards the predisposition to COVID-19 due to the frequent visceral organ involvement and comorbidities, as well as the ongoing immunomodulating treatments. Objectives: Our long-term multicenter telephone survey prospectively investigated the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients during the frst 3 pandemic waves. Methods: A large series of 3,918 ASD patients (815 M, 3103 F;mean age 59±12SD years) was consecutively recruited at the 36 referral centers of COVID-19 & ASD Italian Study Group. In particular, ASD series encompassed the following conditions: rheumatoid arthritis (n: 981), psoriatic arthritis (n: 471), ankylosing spondylitis (n: 159), systemic sclerosis (n: 1,738), systemic lupus (172), systemic vasculitis (n: 219), and a miscellany of other ASDs (n: 178). The development of COVID-19 was recorded by means of telephone survey using standardized symptom-assessment questionnaire (1). Results: A signifcantly increased prevalence of COVID-19 (8.37% vs 6.49%;p<0.0001) was observed in our ASD patients, while the cumulative death rate revealed statistically comparable to the Italian general population (3.65% vs 2.95%;p: ns). In particular, among the 328 ASD patients complicated by COVID-19, 57 (17%) needed hospitalization, while mild-moderate manifestations were observed in the large majority of individuals (83%). In addition, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular manifestations. Interestingly, a signifcantly higher COVID-19-related death rate was observed in systemic sclerosis patients compared to the Italian general population (6.29% vs 2.95%;p=0.018). Other adverse prognostic factors to develop COVID-19 were the patients' older age, male gender, pre-existing ASD-related interstitial lung involvement, and chronic steroid treatment. Conversely, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a signifcantly lower prevalence of COVID-19 compared to those without (3.58% vs 46.99%;p=0.000), as well as the chronic administration of low dose aspirin in a subgroup of SSc patients (with 5.57% vs without 27.84%;p=0.000). Conclusion: The cumulative impact of COVID-19 on ASD patients after the frst 3 pandemic waves revealed less severe than that observed during the frst phase of pandemic (1), especially with regards to the death rate that was comparable to the Italian general population in spite of the increased prevalence of complicating COVID-19 in the same ASD series. Ongoing long-term treatments, mainly csDMARDs, might usefully contribute to generally positive outcomes of in this frail patients' population. Of note, a signifcantly increased COVID-19-related mortality was recorded in only SSc patients' subgroup, possibly favored by pre-existing lung fbrosis. Among different ASD, SSc deserves special attention, since it shares the main pathological alterations with COVID-19, namely the interstitial lung involvement and the endothelial injury responsible for diffuse microangiopathy. Besides SSc, the patients' subgroups characterized by older age, chronic steroid treatment, pre-existing interstitial lung disease, and/or impaired COVID-19 vaccine response (1-3), may deserve well-designed prevention and management strategies.

LONG-TERM OUTCOMES of COVID-19 VACCINATION in PATIENTS with RARE and COMPLEX CONNECTIVE TISSUE DISEASES: AN AD-INTERIM ANALYSIS of ERN-RECONNET VACCINATE STUDY

Background: Since the COVID-19 vaccination campaign was launched all over Europe, there has been general agreement on how benefts of SARS-CoV2 vaccines outweigh the risks in patients with rare connective tissue diseases (rCTDs). Yet, there is still limited evidence regarding safety and efficacy of such vaccines in these patients, especially in the long-term. For this reason, in the framework of ERN-ReCONNET, an observational long-term study (VACCINATE) was designed in order to explore the long-term outcome of COVID-19 vaccination in rCTDs patients. The consent form was developed thanks to the involvement of the ERN ReCONNET ePAG Advocates (European Patients Advocacy Group). Objectives: To evaluate the safety profile of COVID-19 vaccination in rCTDs patients and the potential impact on disease activity. Primary endpoints were the prevalence of adverse events (AEs) and of disease exacerbations post-vaccination. Secondary endpoints were the proportion of serious adverse events (SAEs) and adverse events of special interest for COVID-19 (adapted from https://bright-oncollaboration.us/wp-content/uploads/2021/01/SO2-D2.1.2-V1.2-COVID-19- AESI-update-23Dec2020-review-fnal.pdf) Methods: The frst ad-interim analysis of the VACCINATE study involved 9 ERN-ReCONNET Network centres. Patients over 18 years of age with a known rCTD and who received vaccine against COVID-19 were eligible for recruitment. Demographic data and diagnoses were collected at the time of enrolment, while the appearance of AEs and potential disease exacerbations were monitored after one week from each vaccination dose, and then after 4, 12 and 24 weeks from the second dose. A disease exacerbation was defned as at least one of the following: new manifestations attributable to disease activity, hospital-ization, increase in PGA from previous evaluation, addition of corticosteroids or immunosuppressants. Results: A cohort of 300 patients (261 females, mean age 52, range 18-85) was recruited. Systemic lupus erythematosus (44%) and systemic sclerosis (16%) were the most frequent diagnoses, followed by Sjogren's syndrome (SS,12%), idiopathic infammatory myositis (IMM,10%), undifferentiated connective tissue disease (UCTD,8%), mixed connective tissue disease (MCTD,4%), Ehlers-Dan-los's syndrome (EDS,4%), antiphospholipid syndrome (APS,2%). AEs appearing 7 days after the frst and second doses were reported in 93 (31%) and 96 (32%) patients respectively, mainly represented by fatigue, injection site reaction, headache, fever and myalgia. Otitis, urticaria, Herpes Simplex-related rash, stomatitis, migraine with aura, vertigo, tinnitus and sleepiness were reported with very low frequency. Less than 2% of patients experienced AEs within 24 weeks from the second dose. No SAEs or AEs of special interest were observed in the study period. There were 25 disease exacerbations (8%), 7 of which severe. The highest number of exacerbations was observed after 4 weeks from the second dose (12 within week 4, 6 within week 12 and 7 within week 24). Disease exacerbation was most frequent in patients with EDS (33%) and MCTD (25%). Conclusion: This preliminary analysis shows that COVID-19 vaccination is safe in rCTDs patients. AEs appear most often early after vaccination and are usually mild. Disease exacerbations are not frequent, but can be potentially severe and tend to occur most frequently within the frst month after vaccination. Exacerbations can also occur 3-6 months after vaccination, although a causal relationship with the vaccination remains to be established. Our present data underline the importance of long-term observational studies.

SARS-COV-2 COURSE and OUTCOME in PATIENTS with SYSTEMIC AUTOINFLAMMATORY DISEASES (SAID) TREATED with IL-1 INHIBITORS and COLCHICINE

Background: The spread of COVID-19 had a strong impact in north-east Italy especially during 2020 and in the frst months of 2021. Patients affected by rheumatological disorders are at high risk of infections due to immunosuppressant therapies and a clear immunological imbalance. However, some anti-cytokines such as IL-1 inhibitors proved to be effective in curbing the cytokine storm, frequent feature of severe COVID-19. Objectives: We assessed the SARS-CoV-2 clinical course in 28 patients affected by autoinfammatory diseases, referring to the Autoinfammatory Outpatient Clinic of Padova University;in particular we observed if patients undertaking IL-1 inhibitors (group-1) had a diverse outcome compared to those not on anti-IL-1 drugs (group-2). Methods: Through telephone or e-mail consultancy, 28 patients (18 females, mean age 39.5±15), confrmed to have contracted COVID-19 between March 2020 and January 2022. Twelve patients (42.8%) were affected by periodic fevers (FMF/TRAPS), 10/28 (35.7%) had Adult-Onset Still's Disease, 3/28 (10.7%) had Undiffer-entiated Autoinfammatory Diseases, while 2/28 (7.1%) were affected by BehÇet Disease and one patient had Schnitzler Syndrome. 12 out of 28 patients (42.8%) were undertaking IL-1 inhibitors;8/28 (28.5%) were in therapy with colchicine;2 patients were in therapy with methotrexate and abatacept respectively, and 6/28 (21.4%) received no therapy. All were diagnosed with COVID-19 after molecular nasopharyn-geal swab performed either for the presence of symptoms or close contact with a positive subject. 5/28 patients had the infection after receiving the second vaccine shot, two after the booster dose. All the others had COVID-19 before the vaccine injection. GraphPad5 was used for statistical analysis and Fisher's test was applied. Results: COVID-19 clinical course was benign in 27 out of 28 patients (96.4%);a total of 29 infections were counted due to a case of re-infection;2 patients discontinued the therapy;all the others continued their medications (92.8%). Two patients (7.1%) of the entire cohort were hospitalized, one died. Regarding the major symptoms (fever ≥ 38 C°, cough/respiratory or gastro-intestinal symptoms) no difference was noticed between group-1 and group-2 (p=0.449);despite group-1 required less symptomatic therapy than group-2, the difference was not signifcant (p=0.471). Table 1 summarizes the clinical features exhibited by the patients and the therapies undertaken during the infection. Conclusion: Despite the low sample size, our study is of interest since it proves that the inhibition of IL-1 with both anakinra or canakinumab and the employment of colchicine, an important infammasome regulator, may curb the hyperinfammation typical of COVID-19. Given the promising results obtained with anti-IL-1 and colchi-cine in treating severe COVID-19, it is conceivable a 'protective' role of these drugs in preventing a massive cytokine release. Unsurprisingly, none of our patients but one, had a severe course or fatal outcome after SARS-CoV-2 infection.

The added value of a European Reference Network on rare and complex connective tissue and musculoskeletal diseases: insights after the first 5 years of the ERN ReCONNET

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients. It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

COVID-19 in Italian patients with rheumatic autoimmune systemic diseases: Results of a nationwide survey study

Background: SARS-CoV-2 infection poses a serious challenge for patients with rheumatic autoimmune systemic diseases (ASD), characterized by marked immune-system dysregulation and frequent visceral organ involvement. Objectives: To evaluate the impact of COVID-19 pandemic in a large series of Italian patients with ASD. Methods: Our multicenter telephone survey (8-week period, March-April 2020) included a large series of 2,994 patients (584 M, 2,410 F, mean age 58.9±13.4SD years) with ASD followed at 34 tertiary referral centers of 14 regions of northern, central, and southern Italian macro areas, characterized by different prevalence of SARS-CoV-2 infection. According to currently used criteria, COVID-19 was classified as definite COVID-19 (signs or symptoms of COVID-19 confirmed by positive oral/nasopharyngeal swabs at PCR testing) or highly suspected COVID-19 (signs or symptoms highly suggestive of Covid-19, but not confirmed by PCR testing due to limited availability of virological tests in that period). The results were analyzed performing the Odds Ratio by Java-Stat 2-way Contingency Table Analysis. Results: The main findings of the survey study revealed a significantly increased prevalence of COVID-19 in: a.the whole series of ASD patients (definite Covid-19: 22/2994, 0.73%;p=0.0007;definite COVID-19 plus highly suspected Covid-19: 74/2,994, 2.47%;p<0.0001) when compared to Italian general population of COVID-19 infected individuals (349/100000 = 0.34%;data from Italian Superior Institute of Health;h t t p s : / / w w w . e p i c e n t r o . i s s . i t / e n / c o r o n a v i r u s / sars-cov-2-national-surveillance-system). b.the subgroup of patients with connective tissue diseases or systemic vasculitis (n = 1,901) compared to the subgroup of inflammatory arthritis (n = 1,093), namely rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis (definite Covid-19: 19/1,901, 0.99%, vs 3/1,093, 0.27%;p=0.036;definite COVID-19 plus highly suspected Covid-19: 69/1,901, 3.6%, vs 5/1,093, 0.45%;p<0.0001) c.the subgroup of patients with pre-existing interstitial lung involvement (n = 526) compared to those without (n = 2,468) (definite Covid-19: 10/526, 1.90%, vs 12/2,468, 0.48%;p=0.0015;definite COVID-19 plus highly suspected Covid-19: 33/526, 6.27%, vs 41/2,468, 1.66%;p<0.0001). Of interest, the prevalence of COVID-19 did not correlate with presence/absence of different comorbidities, mainly diabetes, cardio-vascular and/or renal disorders, as well as of ongoing treatments with biological DMARDs;while patients treated with conventional DMARDs showed a significantly lower prevalence of COVID-19 compared to those without. COVID-19 was more frequently observed in the patients' populations from northern and central compared to southern Italian macro area with lower diffusion of pandemic. Clinical manifestations of Covid-19, observed in 74 patients, were generally mild or moderate;4/9 individuals requiring hospital admission died for severe pneumonia. Conclusion: The prevalence of COVID-19 observed in ASD patients during the first wave of pandemic was significantly higher than that observed in Italian general population;moreover, the actual prevalence of COVID-19 might be underestimated due to the high number of mild variants as well as the possible clinical overlapping between these two conditions. Patients with ASD should be invariably regarded as 'frail patients' during the pandemic course, considering the risk of worse outcome in the acute phase of Covid-19, as well as the potential long-term effects of viral infection. The statistically significant association of COVID-19 with connective tissue diseases/ systemic vasculitis, as well as with pre-existing interstitial lung involvement, suggests the presence of distinct clinico-pathological ASD subsets, characterized by markedly different patients' vulnerability to SARS-CoV-2 infection.

SARS-CoV2 serology screening in spondyloarthritis patients in north-Eastern Italy: A pilot study

Background: Serology could help defining the real extent of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) diffusion in the population, especially in individuals considered at higher risk of SARS-CoV2 infection (COVID-19), such as Spondiloarthritis (SpA) patients undergoing immunosuppressive therapy or health care workers (HCW). In fact, COVID-19 detection is complicated by the fact that many patients can be asymptomatic. In these cases, it has also been suggested that a weaker immune response might be elicited. In this context, the role of anti-cytokine targeted therapy -commonly used as treatment in SpA-is uncertain, as it is not clear whether it is detrimental or protective towards severe disease forms. Objectives: The aim of the study was to explore the potential role of serology in detecting previous contact with SARS-CoV2 in SpA patients and HCW, and compare the frequency of positive findings with a control population. Methods: Consecutive patients affected by axial or peripheral SpA, classified according to Assessment of SpondyloArthritis international Society (ASAS) criteria and undergoing cytokine-targeted therapy, as well as HCW and controls from the pre-COVID-19 era (control group, 2015) were recruited. In SpA patients, disease activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) and Disease Activity Score on 28-joint-count (DAS28). Sera from all patients were analysed through chemiluminescent analytical system (CLIA) for the presence of IgG and IgM anti-SARS-CoV2. Patients with a positive serological test (either IgM or IgG) additionally underwent real time Polymerase Chain Reaction (RT-PCR) in nasopharyngeal swabs in order to test for active infection. In SpA patients, serology was repeated after 3 months. Data across the 3 groups were compared by ANOVA or Chi-square, while comparison between 2 groups were conducted by Wilcoxon signed rank test or Chi-Square, for continuous and categorical data respectively. P ≤ 0.05 were considered as significant. Results: A total of 396 patients were recruited: 200 SpA, 95 HCW and 101 healthy controls. SpA patients were mostly (54%) males, with mean age 49.6 ±14.7 years, and all were treated with anti-TNFα (78%), anti-IL-17 (9%) and anti-IL-23 drugs (7%), or small molecules (6%). Their disease activity level was moderate-low as assessed by ASDAS (1.95 ±0.98) and DAS28 (2.33 ±2.02). Among HCW and controls, 35% and 62% were male, with mean age 46.7 ±12.9 and 50.6±10.6 respectively. Positive serology (IgM or IgG, or both) was found in 12.5% SpA patients, 8.4% HCW, 0% controls (p=0.001). Among these, IgM titres were higher in the SpA group than in HCW (2.76±2.94 versus 0.80±0.67 KU/L, p= 0.016), while IgG mean titres were lower in the SpA group than in HCW (0.88±3.18 KU/L versus 1.05±0.88, p= 0.035). SpA patients with positive serology more frequently reported COVID-19 like symptoms than those with negative serology (20% vs 4%, p=0.009) and 2 had COVID-19 as confirmed by RT-PCR, none with a severe disease course. None of the HCW reported symptoms or tested positive by RT-PCR. In the SpA patients, at 3 months, the mean IgM titre decreased from 2.76±2.93 to 2.38±2.95 (p=0.001), while the IgG titres decreased from 0.89±3.25 to 0.31±0.87 (p=ns). Interestingly, the IgM or IgG titer at a single-patient level did not seem to change much in terms of absolute value (Figure 1), except in one patient, with documented COVID-19 (positive RT-PCR), in whom IgG level even decreased at 3 months. Conclusion: Serology revealed that exposure to COVID-19 in SpA patients, as well as HCW, was higher than expected based on reported symptoms. Targeted anti-cytokine therapy could act as a protective factor for a severe disease course in SpA patients. However, in this population, IgG and IgM titres did not change in a clinically significant manner at 3 months, and patient did not seem to develop an immune profile consistent with durable response. This result could be due to a weaker immune response in mild infections, but further studies are w rranted to clarify the pathophysiology beyond these observations.

Oncology clinical trials' management in Italy during the covid-19 emergency: Challenges and improving opportunity

Background: The global COVID-19 pandemic has adversely affected all aspects of clinical care and it has not spared even clinical trials on cancer. Indeed the need to adopt precautionary measures for the containment of COVID-19 infection have affected the access of cancer patients in clinical trials. The devastating effects of this global crisis have also negatively impacted the work of our Oncology Unit which has so far conducted more than 120 phase I-III studies. Method: We faced numerous challenges with conducting clinical trials due to COVID-19. In order to contain infection all the actor involved had to apply several precautions. Pharmaceutical companies, no-profit Sponsors, CROs and either our organization have applied or extended smartworking in order to continue their activities related to clinical trials but monitoring visit on site were suspended. When possible remote monitoring visits have been performed. Start initiation visit for new trial, for which it is essential the presence on site, were strongly postponed. Ethics Committee evaluation of clinical trials or substantial amendments have suffered inevitable strong delays nearly to 3 months because they had to adapt their activities also with organize their meetings by web-conferences. Only access to compassionate use was ever granted. Results: At site particular attention was needed in the enrollment of new patients in the trials evaluating the risk/ benefits ratio. For each patient the possible postponement of access to receive treatment has been assessed on the basis of the relationship between the risks, for the patient and the community related to access to the site, and the expected benefits of the treatment itself. The closure of several Hospital Units due to spread of contagion and limited availability of ancillary services caused the interruption of enrollment in clinical trials. Conclusions: Our clinical research activity during the pandemic has suffered negative repercussions but we think that what happened could be an useful opportunity to improve and transform clinical trial conduction system for example by simplifying the study design, optimizing the number of on-site monitoring visits and reducing patient's access to the hospital.

Being a nurse in medical oncology during the covid19 epidemic

Background: Until February 21, 2020, Covid 19 was a disease known exclusively in China. Since that date, our working life has changed considerably. The number of cancer patients has not changed and their needs have always been fulfilled without interruption. Our department has not stopped its activity and the staff have been exposed to the risk of contagion because patients were not able to access the preventive tampon. Method: Our department has followed the regional and internal directives issued by the Health Department in conjunction with those issued by the Istituto Superiore di Sanita. The staff have protected themselves with PPE such as masks of different types, gloves, sanitization and body temperature monitoring. The same protection methods have been used for patients. In order to avoid our patients' unchecked access to the department, a doorbell has been installed to signal their arrival. We have granted the correct social distancing in the waiting rooms and the shifting in the therapy rooms. Because of the absence of a secretary in our department the staff has had to deal also with the several telephone calls, that in tis period have increased further. Our patients in oral treatment have received medications to continue their treatment for a longer period (two months), all the chemotherapy cycles with a second day (e.g. Folfox-4) have been converted into a single day (Folfox-6 and so on). Periodic checks have been postponed after medical evaluation. Results: During the months of March to May, 1589 chemotherapy cycles were performed. In the same period 49 patients were discharged from the hospital ward. Just first or emergency visits were granted. Conclusions: Our workload has not been reduced. Patients were welcomed with new rules. No one has complained about our organizational changes. In a high turnout department like ours, this has been a stressful period for our staff, because in addition to the infectious risk from Covid the nursing and administrative workload have both increased. The volunteer staff to whom the reception is usually delegated remained at home and so did the psychological and nutritional support. From a psychological point of view, this period was not without emotional consequences. None of the staff fell ill, while some of 44 cancer patients tested positive were discovered during our work. 21 of them died.

What about a medical oncology unit during the Covid19 pandemic Activity maintained thanks to timely decisions?: Sondrio's experience

Background: On February 21, 2020 the first Italian Covid19 patient was diagnosed. From that day the pandemic begins, which spreads with an impressive growth. The Oncology Unit Director has responsibilities, which obliged him to execute orders dropped by the Hospital Management in a top-down manner. Above all, he has direct responsibilities towards his collaborators and patients. It's not allowed to entrench behind the sentence: I've no provisions. For this reason, it is necessary to deal with the emergency with clinical intelligence, notwithstanding specific provisions. Method: Since March 9, the Sondrio's Medical Oncology team received specific provisions from its Director, more restrictive than that developed by the hospital summarized in:-obligation to measure body temperature (BT) before leaving home-light protection during work: surgical mask, gloves, cap.-complete protection in case of suspect Covid19 patient-placement of active treatments on at least 2 distinct time slots to avoid gatherings.-sanitization of the chairs after each patient-from 3 April 2020 obligation for all staff to use KN95 masks, purchased directly.-obligation for each patient: o to stay at home if BT > 37.5 ° C. o to monitor BT at home before going out. o to detect BT before entering in day hospital. o it's always forbidden to have accompanying persons. o at least surgical mask o to disinfect hands using gloves Results: With the provisions, no one became infected during work in the last 3 months. Only 1 nurse was Covid+, due to her husband. By contrast, 44 patients were Covid+ and 21/44 have died. 3/44 were diagnosed as Covid19 + as hospitalized patients. These data testifies our daily risk. No patient produced written complaints to the hospital management for our new rules. Discussion: In Sondrio's Province there've been 1,480 infections. Almost 400/1,480 were health employers, a doctor has died. The most serious pandemic of the last 50 years was managed initially with a lack of tampons, delay in the use of serology, ostracism towards the use of personal protective equipment. The provisions of Oncology Unit Director ensured:-protection of staff-guaranteed treatment for all patients At 31 May 2020, the out-inpatients hospitalization activity was comparable to 2019. We used our knowledge for them without deserting. On 9 April and 9 May, 2020 all staff underwent rapid qualitative serological tests purchased directly by our decision. All were negative.

Volunteering and complementary services in oncology during the covid-19 emergency

Background: Volunteering in oncology has been a wellknown and consolidated reality for decades. Alongside this fundamental component, complementary services that deal with providing image consultancy, wigs and onco-aesthetic services to women who undergo oncological surgery and chemotherapy treatments, have been integrated for years Material (patients) and methods: In the context of the emergency we are going through, within the containment measures of the covid-19 pandemic, volunteering and complementary services have been suspended. Volunteers are people who for sensitivity devote their time to those who are experiencing a situation of suffering. They follow a specific training path and their activity is supervised by the psychoncologist. Despite their absence, enhancement of the group and their role, they have been supported through periodic supervisions conducted by the psycho-oncologist online and through the creation of a chat that represents a physical and psychological space for the group. Technology has made it possible to keep the group united by making each member perceive a sense of continuous belonging overcoming physical distances. The members of the group remained in constant contact with each other and with the operators of the department. The supervision activity also continued with the onco-aesthetics operators who remained in contact with Medical staff and offered their availability through telephone consultations on body image care. Body image is related to a positive self-image in female patients who undergo surgery or body changes for chemotherapy treatments. Results: Despite the social distancing measures and the removal of the volunteers from the department the group and its internal dynamics have been preserved. The use of technology in this context ensured the cohesion of the group, the members actively participated in overcoming the limits of physical distance. Conclusions: Nobody knows how this emergency will evolve and when it will be possible to return to normal. During the upcoming months the group of volunteers can keep their motivation and their investment in oncology services alive and it will be important to keep on working on their involvement and internal cohesion. Patients who are going through a difficult time and who need moments of 'normalcy' along their oncological care pathways know how precious the presence of volunteers is.

Post-COVID-19 arthritis: a case report and literature review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the novel pathogen responsible for the coronavirus disease 19 (COVID-19) outbreak. Researchers and clinicians are exploring the pathogenetic mechanisms of the viral-induced damage and growing interest is focusing on the short-term and long-term immune-mediated consequences triggered by the infection. We will focus on post-SARS-CoV2 infection arthritis which may arise as a new pathological condition associated with COVID-19. In this article, we describe a case of acute oligoarthritis occurring 13 days after a SARS-CoV2 severe pneumonia in a middle-aged Caucasian man and we go over a brief review of the current available literature. We hypothesize that molecular mimicry might be the basic immunological mechanism responsible for the onset of COVID-19-related arthritis based on the current knowledge of SARS-CoV2 and on the known pathogenetic mechanism of viral-induced arthritis.

Management of refractory skin lupus

Management of refractory skin lesions in patients with lupus erythematosus involves combinations of local measures and systemic agents requiring adjustment to activity and development of the disease. The treatment options are fairly similar for the different cutaneous manifestations;however, no drugs have been licensed specifically for the treatment of skin lesions in this disease. Therefore, the aim of the European guideline was to achieve a broad consensus on treatment strategies for patients with cutaneous lupus erythematosus (CLE) by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). Standard treatment of CLE includes preventive measures such as smoking cessation and photoprotection. Ultraviolet (UV) A and B light is one of the most important risk factors for CLE, clearly documented by photoprovocation studies in large patient cohorts. In the past years, several trials have been performed to investigate the preventive effect of sunscreens in patients with UV-induced CLE. A randomised controlled trial demonstrated that the application of a broadspectrum sunscreen with a high protection factor prevents UVinduced skin lesions under standardised conditions. First-line treatment options in CLE include topical corticosteroids or calcineurin inhibitors. Currently available topical calcineurin inhibitors (0.03% and 0.1% tacrolimus ointment, 1% pimecrolimus cream) have been licensed for the use in patients with atopic dermatitis. The major advantage of these agents is their better safety profile when compared to topical corticosteroids. A multicentre, randomised, double-blind, vehicle-controlled trial showed significant improvement for oedema and erythema of CLE lesions using 0.1% tacrolimus ointment compared to the vehicle. In patients with disfiguring and widespread disease, systemic agents need to be applied. The first-line systemic treatment is antimalarials, such as hydroxychloroquine, chloroquine or quinacrine, which are particularly recommended in patients with a high risk of scarring and/or the development of systemic disease. In addition, systemic corticosteroids are recommended as first-line treatment in highly active and/or severe CLE. Second- and third-line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy-refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B-cell- or interferon alpha-targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE. In 2011, the monoclonal antibody belimumab, a B lymphocyte stimulator-specific inhibitor, was introduced for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. Currently, a validated skin score is used to confirm the efficacy of belimumab on mucocutaneous manifestations. In summary, there is a high unmet need for new therapeutic strategies, such as B-cell- or interferon-targeted agents, focusing on cutaneous manifestations in lupus erythematosus. Therefore, innovative designs of randomised controlled trials are warranted to develop new therapeutic options for patients with refractory skin manifestations in this disease. Case 1: 40-year-old man with SLE and painful erythemato-violaceous lesions Marzia Caproni A 40-year-old man was diagnosed with systemic lupus erythematosus (SLE) in 2013 based on photosensitivity, Raynaud's phenomenon, positive direct Coombs test, ANA, antidsDNA, Sm, Ro, La, RNP antibodies and low complement, followed by malar rash and discoid lesions on the ears. He started hydroxychloroquine (HCQ) 400 mg/day, nicotinamide 500 mg/day, topical corticosteroids and calcineurin inhibitors with benefit, followed by reactivation of malar rash, w rsening of immunological parameters, proteinuria and lupus nephritis two years later. Prednisone 25 mg/day and mycophenolate mofetil (MMF) 640 mg/day were added with good clinical and laboratory control. In March 2018 he was hospitalised because of suspected macrophage activation syndrome triggered by cytomegalovirus and MMF was withdrawn. As lupus reactivated, in May 2018 he restarted MMF 320 mg/day with prednisone 25 mg/day and HCQ 200 mg/ day. In August 2018, rituximab was administered because of the development of sensory neuropathy with no improvement, thus he underwent intravenous immune globulin treatment with control. In 2020, he developed painful erythemato-violaceous lesions associated with small bullae and ulcers on the distal phalanges of the fingers and toes and of the tip of the nose. Skin lesions were consistent with chilblain lupus. Topical corticosteroid was added. Systemic treatments were replaced by belimumab. Discussion Points • Specific and non-specific skin manifestations during SLE course • Cutaneous lupus erythematosus (CLE) guidelines • Chilblain lupus: differential diagnosis at the time of Covid-19 Case 2: 35-year-old female with SLE and erythemato-desquamative plaques Marzia Caproni A 35-year-old female was diagnosed with SLE in 2013 on the basis of discoid lesions of the face and head, photosensitivity, ANA positivity, lymphadenopathy, hypocomplementemia, leukopenia, low-grade fever and diffuse arthralgias. Comorbidities included Hashimoto's thyroiditis and fybromyalgia under L-tyroxine, baclofen and escitalopram treatment. She started HCQ 400 mg/day and prednisone 25 mg/day, tapering to 5 mg/day with initial control. After 2 years of treatment arthralgias worsened as well as skin lesions and laboratory findings. On examination, atrophic painful plaque of the scalp and erythemato-desquamative plaques on the face were revealed. Topical and IV corticosteroids were added without improvement. Patient also underwent methotrexate, cyclosporine, mycophenolate, rituximab and azathioprine treatment without improvement. We introduced mepacrine 100 mg/day with skin lesion improvement. Due to the difficulty in finding the drug, the patient stopped the treatment with reactivation of the skin manifestations and systemic involvement. We started belimumab 660 mg IV with HCQ 400 mg/day, prednisone 5 mg/day, azathioprine 50 mg/day and duloxetine 60 mg/day with control. Discussion Points • Discoid lupus erythematosus: clinical and histopathological findings • CLE guidelines: topical treatments of discoid lupus erythematosus • CLE guidelines: mepacrine in recalcitrant cutaneous lupus erythematosus • Belimumab and skin lesions in SLE.

SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in northeast Italy: A cross-sectional study on 916 patients.

BACKGROUND: Whether patients with autoimmune rheumatic diseases (ARD) have a higher risk for SARS-CoV-2 infection (COVID-19) and how SARS-CoV-2 pandemic impacts on adherence to therapy has not been fully elucidated. We assessed the rate and clinical presentation of COVID-19, and adherence to therapy in a large cohort of patients with ARD followed-up in a tertiary University-Hospital in Northeast Italy. METHODS: Between April 9th and April 25th, 2020, after SARS-CoV-2 infection peak, a telephone survey investigating the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), and idiopathic inflammatory myopathies (IIM) was administered. Demographics, disease activity status, therapy, occupational exposure, and adherence to social distancing advise were also collected. RESULTS: 916 patients (397 SLE, 182 AAV, 176 SSc, 111 RA, 50 IIM) completed the survey. 148 patients developed at least one symptom compatible with COVID-19 (cough 96, sore throat 64, fever 64, arthromyalgias 59, diarrhea 26, conjunctivitis 18, ageusia/hyposmia, 18). Among the 916 patients, 65 (7.1%) underwent SARS-CoV-2 nasopharyngeal swab (18 symptomatic and 47 asymptomatic), 2 (0.21%) tested positive, a proportion similar to that observed in the general population of the Veneto region. No deaths occurred. 31 patients (3.4%) withdrew ≥1 medication, mainly immunosuppressants or biologics. Adoption of social distancing was observed by 860 patients (93.9%), including 335 (36.6%) who adopted it before official lockdown. CONCLUSIONS: COVID-19 incidence seems to be similar in our cohort compared to the general population. Adherence to therapy and to social distancing advise was high.

The amount of cytokine-release defines different shades of Sars-Cov2 infection.

The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.