DISCUSSION
Our retrospective cohort study reveals that, during the firsts weeks of
the SARS-CoV-2 outbreak in Spain (March 2020), individuals with IMIDs
exposed to biologic and synthetic DMARDs presented a lower risk of
hsCOVID-19 symptoms than individuals with IMIDs unexposed to these
treatments. Previous preliminary observations also support our findings
[15-17]. These results underline the interest of starting clinical
trials with compounds that decrease immunological responses to evaluate
their possible efficacy in minimizing the progression of the disease.
The three families of monoclonal antibodies approved to treat rheumatoid
arthritis are directed against IL-6, B lymphocyte surface protein CD20
and TNFα, three targets of potential protective compounds for hsCOVID-19
symptoms. TNFα, IL-6 and B lymphocytes have been reported to play a
crucial role in the inflammatory cascade taking place days before the
manifestation of the most severe forms of SARS-CoV-2 infection [10],
and in the physiopathological processes leading to rheumatoid arthritis
[18]. In the present study, TNF-α antagonists were the most abundant
biologic DMARDs and showed a 50% reduction in the relative risk of
hsCOVID-19 symptoms. Nevertheless, our cohort included a limited number
of patients treated with two important groups of immunomodulatory
compounds, IL-6 (52 patients) and B lymphocyte antagonists (42
patients). Interestingly, none of these 94 patients showed hsCOVID-19
symptoms, which agrees with the reported efficacy of the IL-6
antagonists tocilizumab [19] and sarilumab (unpublished
observations) in COVID-19 treatment, and with the protective effect of
IL-6 antagonists shown in a cross-sectional recent study [17].
Regarding synthetic DMARDs, although their global effect was protective
(RR=0.62; 95%CI 0.43, 0.91), our results point that not all synthetic
DMARDs would play a protective role against the appearance of hsCOVID-19
symptoms. On the one hand, methotrexate was the most abundant synthetic
DMARD and presented a 30% reduction in the RR of hsCOVID-19 symptoms.
Among individuals exposed to leflunomide (N=111) only 5 presented
hsCOVID-19 symptoms. Interestingly, leflunomide produces a stronger and
widespread decrease in pro-inflammatory ILs than classical DMDARDs, such
as methotrexate with limited effects in ILs expression [20]. On the
other hand, the exposure to chloroquine/hydroxychloroquine was not
associated with a statistically significant protective effect of
hsCOVID-19 symptoms (RR=0.76; CI95% 0.36, 1.62). These compounds have
been widely used to treat COVID-19, although their benefit/risk was
questioned due to the side-effects and moderate efficacy in disease
progression, in agreement with our results. Accordingly, clinical trials
have been now withdrawn due to the recently reported decreased
in-hospital survival associated with increased risk of ventricular
arrhythmia during hospitalization [12-13].
The severity of COVID-19 symptoms shows clear sex differences with more
severe cases and higher mortality reported in men than women [9].
Similar sex differences were revealed in the outcome of influenza A
virus infections probably mediated by the impact of sex steroid hormones
in immune responses [21]. Although the studied population was not
sex-balanced (1592 women vs 902 men) our analyses stratified by
sex also revealed potential sex differences in the effects of several
immunomodulatory compounds. Indeed, anti-TNFα compounds show higher
protective effects in women (RR=0.33, 95%CI 0.17, 0.64) than in men
(RR=0.76, 95%CI 0.41, 1.43). Although a possible sex influence in the
therapeutic effects of anti-TNFα compounds is controversial, a better
prognosis of ulcerative colitis has been reported in women treated with
infliximab, an anti-TNFα monoclonal antibody [22]. Sex differences
were also revealed in our study in glucocorticoid effects. Taken into
account the high variability of the doses of glucocorticoids used in
these patients [23] and the differential effects depending on dose
exposure [24], we have stratified glucocorticoid treatment in low
(≤10 mg of prednisone or equivalent) and high doses (>10
mg). Women exposed to low glucocorticoids doses had a reduced RR of
hsCOVID-19 symptoms (RR=0.72, 95%CI 0.42, 1.22), whereas high doses
produce the opposite effect (RR=1.62, 95%CI 0.75, 3.52). Considering
the high availability and safety profile of low doses of
glucocorticoids, it would be of interest to evaluate the potential use
of such low doses in women as a potential treatment in early periods of
SARS-CoV-2 infection to prevent disease progression.
In spite of the potential beneficial effects of biological and synthetic
DMARDs, those patients receiving a combination of both groups of
compounds (n=298) show enhanced incidence of hsCOVID-19 symptoms
(RR=4.30, CI95% 2.0, 9.3). The strong immunosuppression that should
result by the combination of these treatments and the severity of the
diseases targeted by these drug combinations may explain this
paradoxical effect. Indeed, previous studies have reported that more
patients experienced infectious adverse events when increasing doses of
synthetic DMARDs were combined with anti-TNFα compounds [25, 26]. In
addition, the main reason for combining both treatments is related to
the lack of efficacy in these particular patients [27], which could
also have influenced our results.
Finally, we made a sub-analysis of patients aged 60 or older taking into
account their worse prognosis of the disease [7]. Biological DMARDs
showed the same protective effect in both groups of patients
(RR<60=0.47 and
RR>60=0.47), although the subgroup of
anti-IL6/12/17/23 ILs showed higher effects in patients under 60
(RR=0.36) than in older patients (RR=0.77). Synthetic DMARDs effects
were higher in patients aged 60 or older (RR=0.48) than in younger
individuals (RR=0.77). In contrast, protective effects of low doses of
glucocorticoids were higher in women under 60 (RR=0.50) than in older
women (RR=0.91) underlying the potential interest of this treatment in
this particular population.
The results obtained here may be interpreted in the light of the
following limitations. First, taking into account that the main interest
of our study was focused on the early stages of COVID-19 pandemic in
Spain, we included patients showing hsCOVID-19 symptoms due to the
scarcity of COVID-19 tests that for ethical reasons were only reserved
to patients showing more severe disease symptoms. Indeed, large cohorts
of patients with mild symptoms and confirmed COVID-19 tests were not
available in Spain at these early moments. Therefore, we and others
[17] have used a similar research strategy based on patients showing
hsCOVID-19 symptoms as the unique possible research approach available
to perform this kind of early studies in Spain on the protective effects
of medication pre-exposure. It is also important to underline that the
symptoms were recorded from 14 days before the COVID-19 alarm was
announced in Spain (March 16th) when patients could be supposed to
protect themselves more if they are at risk. Therefore, this potential
self-protection would not represent any possible bias for the
interpretation of our results considering the time schedule of our
symptoms recording. Second, the indications for each treatment not only
depend on the underlying pathology, but also on the specific clinical
manifestations of each patient, and some of the indications are risk
factors of COVID-19 [28]. Given the heterogeneity of the studied
treatments and underlying pathologies, it is difficult to analyse all
the factors that could cause confounding by indication. However, RR
estimates of hsCOVID-19 symptoms after propensity score matching with
some of the covariates that predict receiving anti-TNFα and other
treatments were similar than RR estimates in the unmatched sample
(Supplementary Table 6). The slightly different RRs found with these
treatments matching the above mention covariates suggest that some of
these IMID may represent an increased risk for hsCOVID-19 symptoms.
Indeed, these particular comorbidities have been reported to increase
COVID-19 susceptibility [29]. Furthermore, patients receiving these
immunomodulatory treatments have an enhanced propensity to bacterial
infection [29] that could eventually provide manifestations similar
to hsCOVID-19 symptoms. In spite of this possible bias that would impair
the results obtained with these treatments, we have obtained promising
RRs with these compounds that suggest significant protective effects on
COVID-19 symptoms.
In summary, our results report that pre-exposure to DMARDs does not
enhance the incidence of COVID-19 symptoms. In contrast, we identify
specific DMARDs with different immune-depressor mechanisms that decrease
hsCOVID-19 symptoms incidence with potential sex differences. These
results underline the interest of starting clinical trials in women with
anti-TNFα compounds in early periods of SARS-CoV-2 infection to evaluate
their possible efficacy in minimizing the severity of COVID-19
progression. We have also revealed protective effects of low doses of
glucocorticoids in women, which may also open new possibilities for low
cost and safe early COVID-19 treatment mainly considering the current
progression of the disease in countries with limited health resources.
Interestingly, the protective effects of anti- IL6/12/17/23 compounds
were mainly revealed in patients younger than 60, which underlies the
need of an appropriate patient stratification for optimizing the results
of the future clinical trials. The protective effects reveal with these
immunomodulatory compounds may open novel therapeutic strategies to
avoid serious COVID-19 manifestations, future deaths and, ultimately,
the collapse of the health system.
Acknowledgements: We thank all patients who participated in the
study, Gemma Vilagut (PhD) for her guidance and support on the
statistical analysis and Mònica Gratacós (PhD) for translating the
clinical protocol into English, for English language support and
proofreading of the manuscript. The Covidmar Study Group members are:
Hospital del Mar, Barcelona: Selene Labrada, Miguel Mejía-Torres
(Rheumatology Service) and Irene Carrión-Barberà, Carolina Pérez-García,
Fabiola Ojeda, Tarek Carlos Salman-Monte, Josep Blanch-Rubió
(Rheumatology Service & IMIM-Hospital del Mar Medical Research
Institute) collected data and provided care for study patients;
IMIM-Hospital del Mar Medical Research Institute: Luciano Polino, Laura
Triginer, Anna Ribes (Cell Research on Inflammation and Cartillage
Research Group, Inflammatory and Cardiovascular Processes Program)
collected data; Maria-Victòria Puig (Integrative Pharmacology and
Systems Neuroscience Research Group, Neurosciences Research Program &
IMIM-Hospital del Mar Medical Research Institute); contributed to
analysis design; Parc Sanitari Pere Virgili, Barcelona: Maria Teresa
Martí Vila, Maria Luisa Perez Miras (CAP Vila Olímpica) collected data;
Universitat Pompeu Fabra, Barcelona: Beltrán Álvarez-Pérez, Araceli
Bergadà-Martínez, Pablo Calvé Alba Calvet-Pavón, Mireia Carcolé, Laura
Domingo-Rodríguez, Alejandra Escudero-Lara, Lorena Galera-López, Jolita
Jančytė, Marta Linares-López, Sara Martínez-Torres, Antonio
Ortega-Álvaro, Andrés Ozaita, Sheila Piedra-Barrull, Dulce Real-Muñoz,
Maria Sanchis-Ollé, Clara Seira Oriach, Miquel-Àngel Serra, Anna
Vázquez-Oliver (Laboratory of Neuropharmacology, Department of
Experimental and Health Sciences & IMIM-Hospital del Mar Medical
Research Institute) collected data.
Competing interests : All authors have completed the ICMJE
uniform disclosure form at www.icmje.org/coi_disclosure.pdf, and
declare: the submitted work was supported by the Hospital del Mar;
outside the submitted work, NSD has received funding from Centro de
Información Cerveza y Salud (CICS); AG has received research grants or
consulting fees from Astrazeneca and Bioiberica S.A.U., RM has received
research grants or consulting fees from Aelis, Almirall, Boehringer
Ingelheim, BrainCo, Esteve, Ferrer, GlaxoSmithKline, Grünenthal, GW
Pharmaceuticals, Janus, Lundbeck, Pharmaleads, Phytoplant, Rhodes,
Sanofi, Spherium, Union de Pharmacologie Scientifique Appliquée, Upjohn,
and Uriach; JM has received grants or consulting fees from Procare
Health Iberia S.L, Esteve, Labhra, Bioibérica S.A.U, Grunenthal Pharma
S.A, Pfizer, OPKO Heath Spain S.L.U and Roche Pharma S.A. LT, JL-O, PN,
EM-G and RdlT declare no competing interests.
Funding : “Ministerio de Ciencia, Innovación y Universidades”
(#AEI-SAF2017-84060-R FEDER to RM, #DPI2016-80283-C2-2-R),
“Ministerio de Sanidad, Servicios Sociales e Igualdad”
(#RD16/0017/0020 & #PNSD-2017I068 to RM, #PI18/00059 to TCS-M) and
“Generalitat de Catalunya” (#2017-SGR-669 & #ICREA-Acadèmia 2015 to
RM, #2017-SGR-138 to RdlT). NSD is recipient of predoctoral fellowship
#2019-DI-47 from the DIUE-AGAUR of the “Generalitat de Catalunya”.
There is not a private sponsor for this study.
Ethical approval : The observational study was approved by the
Parc de Salut Mar Ethical Committee on Clinical Studies (ref. 2020/9246)
before it started, and was monitored by the Clinical Trial Unit of
Rheumatology Service at Hospital del Mar. Due to the nature of the study
(all the data are completely anonymous), the importance of immediate
results, and their implication for the treatment of the SARS-COV-2
pandemic, it is not planned to obtain informed consent from the
participants. The Clinical Protocol and the STROBE checklist are
attached as Supplementary files (see Supporting Information).
Data availability : Requests to access data should be addressed
tojmonfort@parcdesalutmar.cat.
Deidentified individual participant data (including data dictionary)
will be available to medical researchers by request in accordance with
local registration and ethical approval when the article has been
published until 30/4/2030. All proposals requesting data access will
need to specify an analysis plan and will need approval of the
scientific board before any data can be released.
The lead author (RM) affirms that the manuscript is an honest, accurate,
and transparent account of the study being reported; that no important
aspects of the study have been omitted; and that any discrepancies from
the study as planned and registered have been explained
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