key: cord-308184-w8ewm8ve authors: Sarzi-Puttini, Piercarlo; Marotto, Daniela; Antivalle, Marco; Salaffi, Fausto; Atzeni, Fabiola; Maconi, Giovanni; Monteleone, Giovanni; Rizzardini, Giuliano; Antinori, Spinello; Galli, Massimo; Ardizzone, Sandro title: How to handle patients with autoimmune rheumatic and inflammatory bowel diseases in the COVID-19 era: An expert opinion date: 2020-05-05 journal: Autoimmun Rev DOI: 10.1016/j.autrev.2020.102574 sha: doc_id: 308184 cord_uid: w8ewm8ve • A correct patient risk stratification is of paramount importance for the proper management of economic and human resources. • It's fundamental to prioritize clinical trials evaluating dosing, prophylaxis, and treatment with immunosuppressant in COVID-19 in order to avoid either an overuse and a treatment shortage. • Future controlled studies may highlight in our patients a potential preventive role of immunosuppressant therapies in the development of severe forms of Covid-19. • Despite the overall risk of infection in rheumatic and gastroenterological diseases a conclusive association between these diseases and COVID −19 remains questionable. Since December 2019, the new coronavirus infections COVID-19 has spread like a rising tide overwhelming the world. This unabated spread led the World Health Organisation (WHO) to classify it as a pandemic on March 11,2020 a global public health emergency that will also have serious social and economic repercussions [1] . The last time the WHO declared a pandemic was for H1N1 swine flu in 2009. At the time of writing, COVID-19 has killed more than 30,100 people and, unfortunately, this number will continue to rise. While awaiting the development and distribution of a vaccine, scientists around the world are racing against time in the search for possible therapeutic strategies based on those used in previous health emergencies [2] . Everyone, from governments to clinicians and entire populations, feels disoriented before this unknown enemy, and so scientific societies have been drawing up constantly updated guidelines in a bid to aid physicians caring for patients with autoimmune rheumatic and inflammatory bowel disease [3] [4] [5] [6] [7] [8] [9] . The highly contagious and phenotypically diverse SARS-CoV-2 virus has a direct impact on everybody's daily life, particularly in the case of already vulnerable patients [10] . Preliminary recommendations regarding changes in the treatment of the patients with autoimmune diseases attending our rheumatology and gastroenterology units. Patients with rheumatic and inflammatory bowel diseases (IBDs) may be at higher risk of infection [6, 7, 11, 12] . Disease activity, co-morbidities, immunosuppressive drugs including glucocorticoids (GCs), disease-modifying antirheumatic drugs (DMARDs), conventional synthetic (csDMARDs), biological (bDMARDs), targeted synthetic DMARDs (tsDMARDs), and the biological agents currently available for treating patients with IBD are all considered risk factors for infective complications. In addition, there are the risks inherent to the individual diseases and their treatments. The overall risk is increased if more than one of these drugs are taken, therefore preventing infections is a crucial part of the management of rheumatic and gastroenterological patients [13] [14] [15] [16] [17] . For example, before starting tumour necrosis factor (TNF)-α blocking agents or biological agents in general, QuantiFERON-tb is required for the diagnosis of latent or active tuberculosis, and it is Rheumatological diseases and IBD are immune disorders that are associated with an increased risk of developing opportunistic and community-acquired infections such as respiratory virus infections. They are therefore also at risk of high co-morbidity and mortality rates, particularly those receiving immunosuppressive therapy [11, 12, 16] . This has raised concerns about the potential risk of COVID-19 infection in IBD patients (particularly those who are taking immunosuppressants or biological drugs) because of the high morbidity and mortality rates observed in the old and frail with co-morbidities. However, to the best of our knowledge, the only data concerning the risk of SARS-CoV-2 infection in IBD patients come from just one study [19] , and there are no data concerning the risk in rheumatic patients. The observational study of IBD patients was carried out in Wuhan, China, during the peak of the outbreak (between January 1,2020 and February 8,2020) involved 318 patients with a mean age of 39 years who answered a questionnaire covering concerns about their clinical condition and disease relapses. As a result of the early warning and strict preventive measures, none of the patients developed any significant clinical manifestation of COVID-19 infection, not even those being treated with corticosteroids (12.6%), immunosuppressants (11%) and biological agents (6%), or those with co-morbidities. At the end of the study period, none of them reported any significant respiratory symptoms or other clinical manifestations attributable to viral infection, and none had a confirmed diagnosis of COVID-19. An international pediatric and adult registry designed to monitor and report the outcomes of [ 24] . Unfortunately, there are no data concerning the risk of relapse of IBD and related symptoms in patients with SARS-CoV-2 infection but, given that worsening symptoms or relapsing IBD are usually characterised by diarrhoea, nausea, vomiting and fever, these may mimic and hide a COVID-19 manifestation. As this could be misinterpreted as a pure relapse, it would be appropriate to investigate other more specific symptoms of COVID-19, such as headache, dyspnoea, or changes in smell and taste before planning an examination or treating such patients. At the time of writing, Italy has the third highest number of COVID-19 cases after USA and Spain It is essential to promote the basic protective measures against COVID-19 recommended by the WHO for everybody [25] :  Stay at home and follow the directions of the local health authority;  Maintain social distancing of at least two meters from anyone;  Wash hands frequently and thoroughly with soap and water or clean them using an alcoholbased hand rub;  Avoid touching the eyes, nose and mouth  Practice respiratory hygiene by covering the mouth and nose with a bent elbow or tissue when coughing or sneezing (and immediately dispose of the used tissue);  Seek medical care early if symptomatic. In addition, people should be educated to wear a mask in order to avoid infecting other people, avoid public toilets, and use gloves for shopping and all other outside activities. Given the speed at which the pandemic is evolving, all of our patients have been asked to keep themselves informed and been told that our units would provide them with behavioural indications that will enable them to comply fully with all of the provisions issued by the Italian government and regional institutions. All patients should be warned not to discontinue or reduce their treatment without consulting their rheumatologist unless they have specific symptoms. The first challenge for rheumatologists is to decide whether to interrupt or continue a treatment: although it is true that the treatment is designed to control disease activity, it is also undeniable that the same treatment may expose patients, such other infection, to an increased risk for COVID-19. It is known that infections are a major concern in patients with overt inflammatory arthritis as they can contribute to disease flares [26] . One prospective cohort study of patients with inflammatory polyarthritis showed that the risk of hospitalisation because of infection is 2-4 times higher than in the healthy population [27] . Similarly, an analysis by the US CORRONA registry of rheumatoid arthritis (RA) patients has shown that each 0.6 unit increase in the 28-joint Disease Activity Score (DAS28) corresponds to a 25% increase in the rate of infections requiring hospitalisation and a 4% increase in the rate of outpatient infections [28]. J o u r n a l P r e -p r o o f Although there are no published data supporting it, we prefer to discontinue the use of rituximab (RTX) infusions because of the related risk of infections. RTX is a monoclonal antibody that acts by binding the CD20+ surface antigen, thus leading to the depletion of CD20-positive B cells. It was originally approved for the treatment of a broad variety of hematological disease such as B-cell lymphoma, but it has been increasingly used in various autoimmune diseases in which B cells are thought to play a key role, and is now also approved for the treatment of severe active RA and granulomatosis with severe active polyangitis and microscopic polyangitis. In addition to infections. which remain a major concern for patients receiving RTX, another rare but potentially fatal complication associated with RTX infusion is cytokine release syndrome (CRS), a life-threatening condition generated by uncontrolled immune activation that leads to multi-organ failure and eventually death [29] . COVID-19 can induce such a "cytokine storm" [2, [30] [31] [32] of over-active effector T cells and the bulk production of pro-inflammatory cytokines, thus leading to acute lung injury (ALI) and ARDS [33] . Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in autoimmune diseases. Given its increased risk of opportunistic infections and potential haematological alterations such as leukopenia and thrombocytopenia we prefer to discontinue it although, at now, there aren't data supporting it [34, 35] . Another important and much debated issue is how to deal with the use of corticosteroids, which do not seem to add any benefit in terms of the clinical outcome of COVID-19, and may actually slow virus clearance. We therefore consider it appropriate to reduce their administration to the minimum effective dose, but not below 5-10 mg of prednisone per day. A great tumult arose about the use of NSAIDs after the French Minister of Health''s statement advising against the use of ibuprofen in patients with COVID-19. The European Medicines Agency (EMA) has reiterated that up to now there is no scientific evidence of a link between ibuprofen and the worsening of COVID-19, although the situation will have to be monitored over time [36] . We believe that it is best to be prudent and that it is up to each individual rheumatologist to choose which NSAID or analgesic to use for each specific case. We therefore recommend their use on demand, albeit for as short a time as possible. A recent study found that chloroquine, a long used antimalarial drug, had a potent in vitro antiviral effect in a COVID-19 assay by increasing the endosomal pH required for virus/cell fusion and J o u r n a l P r e -p r o o f interfering with the glycosylation of cell receptors, thus adding to its well-known immunemodulating action [37] . Chloroquine is being considered for inclusion in the next versions of the guidelines for the prevention, diagnosis and treatment of COVID. 19 [3] . Although the available data do not suggest that there is a specific risk of SARS-CoV-2 infection and morbidity in IBD patients receiving immunosuppressive treatment, it is known that opportunistic infections have deleterious effects on such patients, which suggests that the risks and benefits of the treatment should be balanced before continuing its administration. There is evidence showing that IBD patients have impaired innate mucosal immunity, but they should not be considered as having altered immunocompetence per se. The current guidelines recommend screening patients who have to start immunosuppressive or biological therapy for some, but not all viruses: for example, screening for HBV, HCV and HIV is recommended, but screening for herpes simplex virus (HSV), patients should be vaccinated against VZV using inactivated vaccine before starting any immunomodulatory therapy because of the greater risk of developing severe viral infection [12] . Given that there is no vaccine or specific treatment for COVID-19, it seems that the only preventive measure that could be taken is to discontinued immunosuppressive treatment while bearing the associated risks in mind. There are no data that contraindicate the use of oral or rectal mesalazine, which can and should be continued if it is already being used. Although the Chinese experience suggests that the short-term use of low-dose steroids (≤0.5-1 mg/kg for seven days) may be beneficial in controlling overwhelming inflammation and cytokinerelated lung injury as much as possible, it is better to avoid systemic steroids, especially if they are Any patient who develops symptoms of any infection such as fever, cough and/or shortness of breath should be tested (pharyngeal and/or nasal swab, sputum, bronchoalveolar lavage fluid) and given medical care. As SARS-CoV-2 preferentially proliferates in type II alveolar cells, a higher positive rate of nucleic acids is found in the lower respiratory, and so a specimen taken from this area is to be preferred. However, an initial negative test should be repeated on subsequent days because peak viral shedding occurs 3-5 days after disease onset. In the case of a positive test, immunosuppressive treatment with traditional DMARDs other than chloroquine or hydroxychloroquine, biological DMARDs (bDMARDs), small molecules, and biological agents for IBD should be discontinued throughout the course of the infection. We believe that a temporary suspension of even one month does not worsen disease activity, whereas, at now, given the well-known infectious risk relating to these therapies, continuing immunosuppressive therapy would lead to the possibility of a rapid evolution of the infection. We resume biological agents after patients have undergone two negative tests and their full blood counts, creatinine, bilirubin, albumin, LDH, AST/ALT, CK, CRP, IL-6, troponin T and ferritin levels, pro-thrombin (INR) and lipid profiles have normalized. Our prudent attitude, guided by current scientific evidence on immunosuppressant infectious riskrelated, does not preclude the possibility that future data will instead highlight the protective role of these therapies in the development of severe forms of Covid-19 [43] . In accordance with the provisions of the Italian government and regional institutions, all deferred medical services were suspended except for those required for urgent clinical conditions (within three days) and those that could only be delayed for ten days. Consequently, all of the scheduled clinical and instrumental evaluations of stable patients in regular follow-up were re-scheduled, although is still possible for patients to interact with their dedicated rheumatology and gastroenterology team via phone interviews and social networks, thus making it possible to monitor their clinical condition [44] . They can also send in the results of routine laboratory tests and report any problems with their clinical condition or current therapies. Electronic intensive care unit (e-ICU) monitoring programs, which allow nurses and physicians to monitor the status of sicker patients are ideal, but patients who report symptoms suggesting a recurrence are preferably assessed by means of a telephone interview in order to clarify the severity of the episode and make therapeutic decisions [45] . Patients complaining symptoms suggesting a severe relapse are invited to visit the hospital (while strictly complying with all of the necessary procedures) with the aim of assessing the need for hospitalization, and the consequent diagnostic and therapeutic procedures. Patients on the surgical list were contacted by our reference surgeon and re-scheduling was considered, while ensuring a non-COVID path for urgent interventions. The following procedures were defined for patients enrolled in controlled clinical trials: -they can only be admitted to hospital if they are being treated with intravenously administered drugs; -if they are being treated with subcutaneous drugs and unpostponable visit is planned, the Sponsor is asked to have the drug delivered to their home; -the possibility of carrying out laboratory tests at trusted laboratories close to each patient's home is verified. The de novo enrolment of patients with rheumatic disease and/or IBD is continued only if the study drug is the only therapeutic alternative. For the more than 1000 patients administered biological drugs at our rheumatology and gastroenterology units, the following general measures have been taken: -they are received by a nurse who provides them with an alcohol solution for hand cleansing, a mask and gloves; -they then undergo the planned outpatient examination by a doctor from the rheumatology or gastroenterology team; -infusions are administered in special rooms with armchairs separated by more than one meter (as mortality is higher among elderly patients [46] , they are allocated single rooms in order to avoid any other possible contact); -if necessary, the time interval between infusions is extended. In the case of subcutaneous biological therapies, Lombardy's regional government has activated alternative means of delivering the medicines for home use in order to limit the need for patients Lombardy but unable to attend a regional hospital for objective reasons, the ATS schedules the collection of drugs from the hospital pharmacy and their delivery to each patient's home by a courier; in the case of patients resident, domiciled or simply present in the territory of the ATS who are being treated at a hospital outside Lombardy and for whom movement is not recommended, the ATS coordinates with hospital facilities in Lombardy in order to guarantee the continuation of the therapeutic program. Some recent studies have reported that chloroquine has an antiviral effect on COVID-19 assays, and chloroquine and its analogue hydroxychloroquine are well known to rheumatologists. 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