Among clinical specialties, rheumatology has been at the epicentre of COVID-19 since the earliest phases due to five pivotal observations, spanning from insights into the disease pathogenesis to organisational opportunities
As of 10 May 2020, there were reports of over 4 million cases of SARS-coronavirus-2 disease (COVID-19) worldwide with 218,000 cases diagnosed in Italy, one of the most affected countries especially in the first three months of the pandemics.1 Cases of pneumonia of unknown origin were first reported from the Hubei Province in China and later defined COVID-19 in association with the infection by SARS-coronavirus-2. Approximately 20% of cases develop severe respiratory symptoms and may require invasive or non-invasive ventilatory support with variable mortality rates.
Two hospitals from the Humanitas Group that we represent (that is, Humanitas Clinical and Reseach Hospital and Cliniche Humanitas Gavazzeni) are located in two of the highest-impact cities (Rozzano and Bergamo, respectively) in Northern Italy and were designed with a strong surgical vocation. While both organisations were significantly affected by the pandemics, the Humanitas Clinical and Research Hospital is the larger Institution and had to develop organisational changes rapidly. By 8 March 2020, all non-emergency admissions and outpatient visits were suspended. In fact, between 1 March and 17 May 2020, a total of 736 COVID-19 patients were admitted to the Humanitas Clinical and Research Hospital; of these, 482 were dismissed and 165 patients died, mostly due to respiratory failure.
The treatments proposed for COVID-19 remain merely supportive as the main cause of death is in fact a severe acute respiratory distress syndrome2 with biochemical features resembling acute inflammation, including a progressive increase in C-reactive protein, ferritin, interleukin-6, and D-dimer.3 Based on the viral aetiology and the hyperinflammatory state, proposed agents to treat COVID-19 have included immunosuppressants such as glucocorticoids,4 anakinra,5,6 and baricitinib,7 immune modulators such as hydroxychloroquine,8 and direct antivirals,9 cumulatively with unconclusive results. Our effort in treating a large number of patients in Bergamo and Rozzano is mirrored by one of the earliest and largest studies on the use of tocilizumab, a monoclonal antibody targeting the interleukin-6 receptor, to treat inflammation in COVID-19.10 In an ancillary study, we addressed the issue of predicting the response to tocilizumab in patients with COVID-19 and utilised, for the first time, a supervised machine learning approach of artificial intelligence and we are currently validating our observations (unpublished data).
The five reasons that make rheumatology a privileged point of observation on COVID-19
Among clinical specialties, rheumatology has been at the epicentre of COVID-19 since the earliest phases due to five pivotal observations, spanning from insights into the disease pathogenesis to organisational opportunities. These observations, indeed, well represent the challenges provided by the new condition and our responses may suggest new ways to address these challenges in other areas.
First, our understanding of the pathogenesis and treatment of rheumatic diseases has been central to understand the uncontrolled amount of literature on COVID-19. In late April 2020, it was estimated that the COVID-19 literature had grown to more than 31,000 papers since January, the biggest explosions of scientific literature ever.11 We have discussed that SARS-Cov-2 triggers a vigorous inflammatory response, as represented by the high levels of interleukin-6, especially in older subjects, and this is similar to what observed in the chronic inflammation associated with rheumatological conditions, particularly rheumatoid arthritis.12 Nearly all anti-rheumatic drugs, that is, tocilizumab, glucocorticoids, anakinra, and hydroxychloroquine, among others, have been proposed to treat COVID-19. It has been hypothesised that patients with rheumatic diseases who were already receiving these medications might be at either higher or lower risk of developing a severe infection, based on the apparent opposing factors of the ongoing immunosuppression versus a potential protective effect of the drugs.
The second issue is that patients with immune-mediated chronic diseases, including rheumatic conditions such as arthritis (that is, rheumatoid or psoriatic arthritis, ankylosing spondilitis) or connective tissue diseases (that is, systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis, and myositis) had to be considered as fragile individuals that had to be strongly advised to avoid being infected by SARS-Cov-2. To address these two questions, we analysed the data from the Humanitas Immuno Center, which coordinates the clinical and research activities of gastroenterologists dedicated to inflammatory bowel diseases, dermatologists dedicated to psoriasis and atopic dermatitis, allergologists, and rheumatologists. Out of approximately 10,000 patients being followed for such immune-mediated inflammatory diseases, we identified only 41 patients who had COVID-19 infection and evaluated the factors associated with a more severe respiratory impairment or death. Our data showed that comorbidities, particularly hypertension, diabetes, obesity and chronic lung disease, were the factors increasing the risk of hospitalization and the need of oxygen supplementation while supporting using extra caution when patients were receiving glucocorticoids. Our most important conclusion, however, was that an ongoing biologic therapy is not associated with a worse pattern of COVID-19 infection,13 as also confirmed in other Italian cohorts.14
The third issue is that rheumatic diseases are largely viewed as non-emergency conditions and this has led to the cancellation of nearly all the scheduled outpatient appointments during the COVID-19 pandemics. In the case of the Humanitas Clinical and Research Hospital, a total of 544 rheumatological outpatient visits took place between 1 March and 17 May 2020, compared with 2759 performed in the same period of 2019, with an 80% decrease. At the same time, six out of nine physicians from the Division of Rheumatology were dedicated full time to attending inpatients, particularly within the COVID-19 wards, and coordinating the investigational use of anti-rheumatic drugs. Starting 17 May 2020, we could re-open non-emergency services and 1100 patient visits were rescheduled between 1 June and 1 September, 2020. The rescheduling had to consider the new rules of outpatient physical presence in the hospital (which limited the efflux to the premises and thus required a longer time allocated for each visit) as well as the previously scheduled appointments, thus requiring a dedicated task by our Operations division.
Fourth, there was the need to reach out to patients with rheumatic diseases to address their numerous questions regarding the need to continue or withdraw chronic treatments or the possible shortage of the anti-rheumatic treatments that were in use for COVID-19. Since the earliest phases of the pandemics, we received a growing number of inquiries by patients from our Division or being followed at other hospitals, especially asking whether they could continue taking their rheumatological medications or should withdraw. The Italian Society of Rheumatology was one of the first National societies to provide a clear guidance against stopping medications, based on the assumption that an inflammatory flare would have been characterized by the need for strong immunosuppression and thus a higher risk from COVID-19 infection.15 Together with four other academic Rheumatology Centres in the Lombardy region, we signed a letter to all patients which was disseminated by the local patient support organisation (ALOMAR) to prevent patients from stopping their treatments in the absence of signs of COVID-19. The Italian recommendations were then followed by the same messages provided by the American College of Rheumatology and the European League Against Rheumatism (EULAR). At a local level, a dedicated telephone line was activated to answer the patients questions and an average of 20 calls was received daily. The Divisional email address also continued to be accessible for patients to send inquiries and all messages were answered within the same day. Of note, we became aware of a very small number of cases in which patients could not find their usual medications due to a COVID-19-related shortage, which could be expected due to the widespread use of hydroxychloroquine for example to treat or prevent the infection, an assumption that was not supported by experimental data. The hospital pharmacy was proactive at contacting patients receiving biologics to provide the home delivery of refills.
Fifth, and last, considering the chronic nature of rheumatic diseases and the often non-invasive evaluations, rheumatology might be an ideal playing field to experiment the potential of teleconsultations. While physical examination remains crucial to the rheumatology practice, the natural history of chronic inflammatory diseases includes phases of activity (flares) alternating with phases of remission or low disease activity. In the former case, the therapeutic target is not reached and a tight control of patients, with frequent visits requiring physical examination, is recommended. However, if the patient condition is under acceptable control (very low or minimal disease activity or remission) visits can be scheduled with lower frequency. In these cases, teleconsultations represent an ideal option to minimise the risk related to hospital visits and reduce the inconvenience of long commuting, particularly for patients living in other regions throughout Italy. During the COVID-19 pandemics, one rheumatologist from our group started teleconsultations one day a week with very encouraging, yet preliminary, results. We envision that an integrated approach using telemonitoring of disease activity through a dedicated app that is being developed for our patients and the possibility of teleconsultation would be an ideal method to select the patients eligible for this new tool. The availability of such monitoring app would be also central to a more accurate real-time monitoring of infectious events, including COVID-19, in patients with chronic diseases.
What rheumatologists learned or should have learned from the pandemic
The COVID-19 pandemic hit our hospitals very hard and affected the practice of medicine and rheumatology significantly. As we were all involved at different levels in the care of patients with COVID-19 without abandoning patients with chronic diseases, we learned several lessons that will impact our future practice:
- Immunology is key to medicine, well beyond chronic inflammatory diseases; as well represented by the use of immunomodulators in COVID-19, we should never overlook the role of the immune system in the development of disease;
- Rheumatological patients are well aware of the possible implications of their disease and the ongoing treatments; informing patients and making timely recommendations available is crucial in the management of a health crisis such as the COVID-19 pandemics;
- Patients with immune mediated inflammatory diseases know how to behave in a storm; we have observed very few treatment discontinuations and very few cases of COVID-19 among our patients;
- Patients with rheumatic diseases need to have a quick and reliable access to the rheumatologist to obtain information in case of symptoms of infection, as well as other issues which primary care physicians prefer not to address;
- Logistical difficulties in getting biologics (distributed by hospital pharmacies) or other drugs (that is, hydroxychloroquine) due to the requests for COVID-19 need to be foreseen and overcome with innovative processes, such as the home delivery of drugs, which allow continuity of treatment and reduce the need for hospital access;
- A new paradigm is needed for the long-term care of patients with rheumatological diseases; chronic diseases with an intermittent activity are ideal settings to establish a combination of telemonitoring, teleconsultations, and physical examination when needed;
- New tools, including artificial intelligence, an organisational effort from hospital administration to adapt, and a data-driven approach to new scenarios, are key to the appropriate treatment of chronic diseases in a setting of limited resources and uncertainty.
- Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins. 2020.
- Zhao D et al. A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias. Clin Infect Dis 2020;Mar 12.
- Zhou F et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020;395:1054–62.
- Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473–5.
- Aouba A et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann Rheum Dis 2020;79(10).
- Cavalli G et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2(6):E325–E331.
- Cantini F et al. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J Infect 2020;81:318–56.
- Geleris J et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;382(25):2411–18.
- Cao B et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787–99.
- Canziani LM et al. Interleukin-6 receptor blocking with intravenous tocilizumab in COVID-19 severe acute respiratory distress syndrome: A retrospective case-control survival analysis of 128 patients. J Autoimmun 2020;102511.
- Brainard J. New tools aim to tame pandemic paper tsunami. Science 2020;368:924–5.
- Rodriguez Y et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun 2020;102506.
- Allocca M et al. Clinical course of COVID-19 in 41 patients with immune-mediated inflammatory diseases: Experience from humanitas center, Milan. Pharmacol Res 2020;160:105061.
- Fredi M et al; Brescia Rheumatology C-SG. COVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case-control study. Lancet Rheumatol 2020;2:e549–e56.
- Ceribelli A et al. Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy. J Autoimmun 2020;109:102442.
Carlo Selmi MD PhD
Humanitas Clinical and Research Center IRCCS, Rozzano, Milan
Humanitas University, Department of Biomedical Sciences,
Pieve Emanuele, Milan
Humanitas Clinical and Research Center IRCCS, Rozzano, Milan
Humanitas Clinical and Research Center IRCCS, Rozzano, Milan