The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET

Abstract

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.

Full text

COVID-19 is an infectious disease caused by
SARS- CoV-2, a newly discovered coronavirus.
In March 2020, the WHO declared the
COVID-19 outbreak to be a pandemic and as
of 17 November 2020, the WHO had reported
more than 54 million confirmed cases
and more than 1 million confirmed deaths
attributable to the disease1.
The COVID-19 pandemic has had a
considerable effect on different aspects
and needs of patients with rare diseases,
highlighted the many challenges faced by
these patients as well as their families and
caregivers during the pandemic2, including
the interruption of routine medical care
and rehabilitation therapies as well as
many psychological barriers related both
to isolation and to fear of infection with
SARS- CoV-2 when receiving care in
hospitals.
These same challenges can be readily
related to autoimmune diseases, in which
the rate and mechanisms of COVID-19
transmission have raised many concerns
among scientists and patients, especially
considering the well- known susceptibility
of these patients to infections owing to their
altered immune systems and to the use of
immunosuppressive therapies3,4.
In parallel, owing to the so- called
deleterious ‘cytokine storm’ that might
explain the rapid worsening of some patients
with COVID-19, some of the most common
DMARDs, such as hydroxychloroquine,
baricitinib, corticosteroids and tocilizumab,
have been used in clinical trials for
patients with COVID-19 who have
hyperinflammation5,6. Thus, clinicians
caring for patients with rheumatic diseases,
as specialists in inflammation and the use
of these drugs, have naturally been at the
front line in treating COVID-19 in many
cases. The interest in DMARDs has indeed
helped to elucidate some of the pathogenetic
mechanisms underlying COVID-197–9, but it
has also caused tensions and, in some cases,
shortages in the supply of some DMARDs
(in particular hydroxychloroquine)10,11.
COVID-19 has also affected the
management and treatment of patients with
rheumatic and autoimmune diseases during
the COVID-19 emergency. Publications
reporting these effects have described
challenges to provision of care, management
of clinical trials and the psychological state of
patients and their carers12,13.
These challenges are particularly relevant
in the case of rare and complex connective
tissue and musculoskeletal diseases (rCTDs),
in which knowledge related to diagnosis,
treatment and complications is often limited
and expertise is scattered. rCTDs comprise
a large number of diseases and syndromes,
including hereditary conditions, rare
systemic autoimmune diseases and complex
of rare and complex diseases, first on the
risk of SARS- CoV-2 infection for people
affected by these conditions, and also on the
management of care and treatment during
(and after) this global health emergency.
Thepreliminary results of a Europe- wide
survey organized by Rare Barometer
(an initiative of the European Organisation
for Rare Diseases), which was aimed
at collecting the opinions, experiences
The impact of COVID-19 on rare and
complex connective tissue diseases:
the experience of ERN ReCONNET
RosariaTalarico, SilviaAguilera, TobiasAlexander , ZahirAmoura,
AnaM.Antunes, LaurentArnaud , TadejAvcin, LorenzoBeretta,
StefanoBombardieri, GerdR.Burmester, SaraCannizzo, LorenzoCavagna,
BenjaminChaigne, AlainCornet, NathalieCostedoat- Chalumeau,
AndreaDoria, AlessandroFerraris, RebeccaFischer- Betz, JoãoE.Fonseca,
CharissaFrank, AndreaGaglioti, IlariaGaletti, JürgenGrunert,
VeraGuimarães, EricHachulla, FredericHoussiau, LucaIaccarino,
ThomasKrieg, MarteenLimper, FransiskaMalfait , XavierMariette,
DianaMarinello , ThierryMartin, LisaMatthews, MarcoMatucci- Cerinic,
AlainMeyer, CarlomaurizioMontecucco, LucMouthon, UlfMüller- Ladner,
SimonaRednic, VascoC.Romão, MatthiasSchneider, VanessaSmith,
AlbertoSulli, FarahTamirou, DomenicaTaruscio, AnnaV.Taulaigo,
EnriqueTerol, AngelaTincani, SimoneTicciati, GiuseppeTurchetti,
P.Martinvan Hagen, JacobM.van Laar, AnaVieira,
JeskaK.deVries- Bouwstra, MaurizioCutolo and MartaMosca
Abstract | During the COVID-19 pandemic, the need to provide high- level care for
a large number of patients with COVID-19 has affected resourcing for, and limited
the routine care of, all other conditions. The impact of this health emergency is
particularly relevant in the rare connective tissue diseases (rCTDs) communities,
as discussed in this Perspective article by the multi- stakeholder European
Reference Network on Rare and Complex Connective Tissue and Musculoskeletal
Diseases (ERN ReCONNET). The clinical, organizational and health economic
challenges faced by health- care providers, institutions, patients and their families
during the SARS- CoV-2 outbreak have demonstrated the importance of ensuring
continuity of care in the management of rCTDs, including adequate diagnostics
and monitoring protocols, and highlighted the need for a structured emergency
strategy. The vulnerability of patients with rCTDs needs to be taken into account
when planning future health policies, in preparation for not only the post- COVID
era, but also any possible new health emergencies.
PERSPECTIVES
Nature reviews
|
Rheumatology

systemic autoimmune diseases, and are
characterized by the complexity of their rare
and diverse clinical phenotypes (for example,
neurological involvement in systemic lupus
erythematosus, or cryoglobulinaemia or
lymphoma in Sjögren syndrome). rCTDs
have a tremendous impact on the health and
well- being of patients around the world;
they affect individuals by limiting their
acti vities, affect societies by contributing
to health- care costs, work loss, disability
pensions, early retirement and the need for
social support, and confer a considerable
burden in relation to morbidity and
mortality14,15.
In order to address considerations
specific to rare and complex diseases, the
EC (European Commission) has promoted
the creation of 24 European Reference
Networks (ERNs; see related links); the
ERN on Rare and Complex Connective
Tissue and Musculoskeletal Diseases (ERN
ReCONNET; see related links) is aimed
at improving the management of rCTDs
including antiphospholipid syndrome,
Ehlers–Danlos syndromes, idiopathic
inflammatory myopathies, IgG4- related
diseases, mixed connective tissue diseases,
relapsing polychondritis, Sjögren syndrome,
SLE, systemic sclerosis and undifferentiated
connective tissue diseases across the
EU(European Union).
The ERN ReCONNET’s network of
health- care providers (HCPs) currently
comprises 26 full members from eight EU
countries: Belgium, France, Germany, Italy,
Netherlands, Portugal, Romania and Slovenia,
and 13 affiliated partners from an additional
10 countries. This Perspective article presents
the point of view of the ERN ReCONNET
and was conceived and authored by
ERN ReCONNET HCP representatives,
European Patient Advocacy Group (ePAG)
representatives, members of the steering
committee and of the external scientific
advisory board as well as representatives of
the EC. Considering the complexity of the
COVID-19 pandemic, in this article we aim
to assess the effects of the health emergency
on rCTD communities during the initial
phase of the pandemic, bringing together
input from multiple stakeholders within the
ERN ReCONNET, representing patients,
families, caregivers, expert clinicians,
researchers and health economists.
Moreover, we also discuss organizational
and health economic considerations related
to rCTDs in the context of COVID-19,
which could be useful for the design of
specific health- care plans in the context of
possible future health emergencies. Finally,
we outline the support provided by ERN
ReCONNET and other institutions during
the first phase of the pandemic, as well as
introducing possible contributions that ERN
ReCONNET could provide in the future
phases of managing COVID-19.
Effects of COVID-19 on rCTD care
The COVID-19 pandemic and the health
emergency it has given rise to have had a
substantial effect on numerous dimensions
of health care, especially in the countries
where the outbreak first emerged, which
for Europe was Italy and Spain. Hospitals
and HCPs had to face the unprecedented
challenge of fighting against an unknown
virus while caring for a tremendous number
of patients with COVID-19 in need of
high- level care. Consequently, there was
a dire need to concentrate resources for
the care of patients with COVID-19, thus
affecting the resources dedicated to the
management of all the other conditions
and limiting the performance of routine
care. The impact of the COVID-19 crisis on
health care as well as on patients, families
and caregivers was particularly relevant in
the rCTDs communities, in which the main
challenges were related to the clinical and
organizational aspects of care10,16–18. In the
following paragraphs, we discuss the main
effects of COVID-19 on rCTDs from the
perspective of clinicians, patients, health
economists and institutions, all of whom are
included in the ERN Re CONNET.
Effects on clinical management
Registries of patients with rCTDs and
COVID-19. During the initial phase of
thepandemic, more specifically during
the first months of 2020, the effect of
SARS- CoV-2 on patients with rCTDsbecame
an important clinical concern. Specifically,
this concern focused on two essential
clinical questions: are patients with rCTDs
at a higher risk of contracting SARS- CoV-2,
and, if they are infected, do they have a
worse prognosis than those without rCTDs?
In order to collect the evidence needed to
answer these questions, several initiatives
were launched across the globe, including
the COVID-19 Global Rheumatology
Alliance (REF.19 and related links) and
the EULAR COVID-19 Rheumatology
Database (see related links), as well as
national registries that are collecting data
of patients with rheumatological diseases
and SARS- CoV-2 infection, such as the
registry launched by the Italian Society
of Rheumatology20. Preliminary data
from these registries suggest that use
of conventional DMARDs (including
hydroxychloroquine) is neutral, chronic
use of corticosteroids at doses above
10 mg per day is deleterious and the use of
biologics (especially TNF inhibitors) could
be protective21,22. Moreover, data from the
newly established registries also demonstrate
that paediatric patients with rCTDs are at
a much lower risk of acquiring clinically
significant COVID-19 infection than
patients over 61years old23.
Recommendations for the management of
rCTDs in the context of COVID-19. For
the rheumatology community, EULAR
has made a notable contribution with the
publication of provisional recommendations
for the management of rheumatic and
musculoskeletal diseases (including
most of the diseases covered by the ERN
ReCONNET) in the context of SARS-
CoV-2 infection24. The document provides
useful overarching principles, including
the fact that so far there is no evidence
that rheumatic patients are at a higher
risk of contracting SARS- CoV-2 or of
having a worse prognosis once infected.
Inaddition, the recommendations state that
the treatment plan should be continued
in rheumatic patients who do not have
suspected or confirmed diagnosis of
COVID-19 and that the postponement of
face- to- face rheumatological consultations
should be considered on the basis of stability
of the disease and of the tolerability of the
treatments. Useful considerations were
also provided by the World Scleroderma
Foundation and answered the main clinical
questions regarding SARS- CoV-2 infection
and patients with SSc25.
The effects of the COVID-19 pandemic
within ERN ReCONNET. Through internal
discussions, the ERN ReCONNET has
identified and prioritized a number of
clinical and organizational challenges
(FIG.1). Specifically, patients with rCTDs
and the health- care professionals treating
them have experienced numerous clinical
challenges during the pandemic, most
frequently limitations to completing the
diagnostic process and performing routine
follow- up and monitoring. These challenges
arose mainly from the limitations imposed
by the measures necessary for prevention
and control of SARS- CoV-2 transmission,
including the closure of some clinics
and/or the reorganization of services, which
impeded face- to- face consultations. These
limitations have often delayed the definition
of the most appropriate treatment plans
based on the diagnosis and on the disease
activity of patients with rCTDs. Asreported
by the ERN ReCONNET HCPs, in order
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to avoid the risk of contagion among
patients in the hospital setting as much as
possible, clinicians have also opted — when
considered appropriate — to switch from
infusion to subcutaneous therapies, so that
patients could reduce their visits to the
hospital.
Still to be clarified, among many
other issues, is whether the process
for the screening of patients prior to
commencement of immunosuppressive
therapy should be updated, taking into
consideration the possibility of a positive test
for SARS- CoV-2 infection (by swab and/or
serology). In particular, it remains to be
confirmed whether systematic SARS- CoV-2
screening needs to be incorporated into
existing protocols, in order to avoid the
hazardous consequences of starting a new
biologic therapy in patients with undisclosed
infection8. From the above considerations,
it seems clear that the pandemic has
had a considerable effect on the clinical
management of rCTDs and that its influence
will continue in the coming months and
even years. The period of disruption will
probably be prolonged both because the
pandemic is continuing to affect health- care
systems at present, and subsequently
patients with rCTDs might still encounter
barriers and challenges to the provision
of the care they need. For these reasons,
thecare of patients with rCTDs duringthe
post- pandemic era should be carefully
planned and implemented, profiting from
the experience gained during the health
emergency.
Effect on organization of care
The pandemic has put HCPs under
enormous pressure, and has made
health- system collapse a real risk, owing to
the need to provide care for patients affected
by COVID-19. As the ERN ReCONNET
HCP and ePAG representatives can
attest, health- care professionals treating
patients with rCTDs have faced numerous
organizational challenges during the
pandemic (FIG.2).
Heads of units, hospital managers and
health- care professionals have joined forces
in order to reorganize the services of whole
hospitals, to ensure adequate resources for
COVID-19 units while maintaining, when
and if possible, essential health services
for patients with rCTDs. Many ERN
ReCONNET HCPs had to cope with the
fact that some of their staff were reassigned
to COVID units and in some cases units
treating patients with rCTDs were even
converted into COVID units; they have
also faced shortages and tensions in the
provision of medicines and of personal
protective equipment. As the rate of new
cases has slowed across Europe, in most
rCTD units the staff have returned from
COVID units, although patient flow for
inpatient and outpatient activities has had
to be reorganized in order to enable social
distancing and to limit the risk of contagion
as much as possible. Many of these
challenges are still being faced by rCTD
units during the current second wave of the
pandemic.
Organizational challenges caused bythe
pandemic have frequently interrupted
the care provided to patients with rCTDs,
including the suspension of inpatient
and outpatient clinics, or provision of
infusion therapies. ERN ReCONNET
HCPs and ePAGs have also had to manage
requests from a large number of patients
for information on their risk of being
infected because of their disease or to
their treatments, and have needed to use
telemedicine to provide routine services
instead of face- to- face evaluations or
to identify patients for whom direct
assessments cannot be postponed26.
Although the ERNs are already quite
experienced in terms of eHealth owing
to the usage of the Clinical Patient
Management System (CPMS; see related
links), a web- based secure platform used
by all ERNs for the virtual discussion
ofclinical cases across borders, the use of
telemedicine in routine clinical practice is
still being implemented in many health- care
systems. However, the limitations imposed
by the pandemic have enabled health- care
professionals to activate, within a very
short time frame, different initiatives
related to telemedicine, such as telephone
and video consultations and issuing
prescriptions electronically. Many of these
initiatives were also reimbursed by various
health- care systems in Europe27,28. The use
of telemedicine during the pandemic has
revealed the potential of this approach in the
routine follow- up of patients even beyond
the pandemic; clearly, this experience could
be translated into a wider, harmonized and
systematic usage of telemedicine across
Europe, benefiting patients, health- care
professionals and institutions.
Effects on patients with rCTDs
Besides clinicians and health- care
professionals, the COVID-19 pandemic has
heavily affected the community of patients
with rCTDs. The patient- centred approach
of ERN ReCONNET has encouraged the
ERN ReCONNET ePAG representatives to
discuss together the effects of the pandemic
on patients with rCTDs across Europe.
During the pandemic, patients affected
by rCTDs have had to deal with many more
complex situations than healthy people,
owing to the fact that many of them are
treated using immunosuppressive therapy
and that lung involvement is a common
manifestation in rCTDs11,29. The (in)
Clinical challenges
Limitations on the
diagnostic process and
routine monitoring of
patients with rCTDs
Managing infection risk
in patients starting a
new immunosuppressive
therapy
Impossibility
of performing
face-to-face
evaluations
Disease relapse
due to patients
suspending therapies
autonomously
Switching route of
administration of
therapies from infusion to
subcutaneous injection
Managing infection risk
in patients already
taking immunosuppressive
therapies
Limited access to
some drugs for
rCTDs (e.g.
hydroxychloroquine)
Fig. 1 | Clinical challenges faced by patients and health-care providers during the COVID-19
pandemic. Discussions within the European Reference Network on Rare and Complex Connective
Tissue and Musculoskeletal Diseases (ERN ReCONNET) have identified a number of clinical challenges
faced by patients with rare connective tissue diseases (rCTDs) and the health- care professionals treat-
ing them during the COVID-19 pandemic. Some concerns relate to the fear and/or consequences
of these patients contracting COVID-19, whereas others reflect changes to clinical protocols
implemented to prevent or control SARS- CoV-2 transmission in clinics.
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Rheumatology
PersPectives

voluntary lockdown also had a substantial
influence on the quality of life and daily
activities of these patients because of a
shift to teleworking, the need to coordinate
24- h family life or the loss of fundamental
support from caregivers, particularly for
those patients living alone. At the same time,
patient organizations (such as the Federation
of European Scleroderma Associations
(FESCA); see related links) had to suspend
their routine activities while making great
efforts to provide psychological support
via telephone or online assistance. The
challenges faced by patients with rCTDs
might be easily related to the fact that
patients affected by rCTDs are, even in
routine scenarios, at an increased risk of
infection and the fear of contagion has
often increased the need for psychological
support for patients with rCTDs. Patients
experiencing isolation and fear have,
in fact, expressed the need to maintain
thepsychological support service after the
pandemic as well.
Moreover, as mentioned above, regular
access to medical advice and continuity
of care for non- COVID-19 patients have
been disrupted as hospitals have become
COVID-19 units and concerns for the
safety of patients emerged. As mentioned
above, the safety of patients with rCTD
patients was, and still is, particularly
important because of their vulnerability;
protecting these patients from the risk
of contagion should remain apriority.
The use of different telemedicine tools,
even though they have not always been
part of an established system, has played
a crucial role in compensating for the
discontinuation of routine care, by
providing an additional service for patients
unable to attend hospital. Dispensation
of hospital medications or treatments has
been replaced by community pharmacy
delivery or alternative treatment methods
when possible, and access to emergency
rooms has been regulated toavoid contact
with potentially contagious patients.
Post- COVID, maintaining the delivery
of hospital medicines via community
pharmacies, secure access to emergency
rooms and the possibility of at- home
management of therapies is anticipated
to have a positive impact on the quality
of life and on the economic burden of
patients. A CPMS- like teleconsultation
platform should be developed to enable
interactions between patients and clinicians
and guarantee safe data management; by
doing this, the lessons learned during the
pandemic would deliver a positive benefit
for patients.
Another important consideration for
patients with rCTDs during the pandemic
is related to the fact that some rCTDs are
treated with hydroxychloroquine. Reports
of the potential of hydroxychloroquine30 as
a treatment for COVID-19 (REF.7) created an
increased demand that led to supply gaps
in many countries, causing anxiety and
fear among patients who rely on the drug.
Asurvey performed in one European rCTD
community highlighted that only 44% of
patients with ‘on label’ hydroxychloroquine
use obtained on- the- spot delivery of their
drug in early April, and 6.7% experienced
a delay of 2 weeks or more31. ERN
ReCONNET ePAGs have actively engaged
with several patient groups to monitor
the availability of the drug, to monitorthe
prescription and distribution rules in
different countries, and to obtain emergency
supply routes direct from the manufacturer,
in order to assist and reassure the patient
community.
Organizational considerations
The COVID-19 pandemic has raised
a number of organizational and health
economic considerations related to the
management of rCTDs. Pertinent questions
are summarized in BOX1 and potential
solutions are discussed in this section.
Ensuring continuity of care
The challenges and risk of health- care
system collapse experienced during the
COVID-19 pandemic have highlighted,
among other things, how essential it is
to maintain continuity in the provision
of care, especially for the managementof
rare diseases. Interruption of the care
provided to patients with rCTDs and other
rare diseases was in fact one of the most
frequent health problems experienced by
patients and health- care professionals.
For this reason, it is worth considering
whether potential future emergencies
could threaten health- care systems and
services and challenge the maintenance
of adequate care. From an organizational
point of view, the COVID-19 outbreak
challenged coordination strategies, making
it difficult to balance the need for a rapid
responseto COVID-19 while ensuring
provision of essential health services to
patients with rCTDs. As suggested in the
preliminary operational guidance document
developed by the WHO32, the identification
of context- relevant essential services is
crucial to prioritizing and maintaining
care delivery during an outbreak, with, for
example, the creation of disease- specific
structured care pathways and well- designed
patient flow (that is, screening, triage
and targeted referral). This guidance
Organizational challenges
Interruption
of care for
patients
with rCTDs
↑ Patient requests
for information
about infection
risk
Prioritization of
essential and/or
emergency
health services
Provision of
SARS-CoV-2 tests
prior to procedures
or hospitalization
in a rCTD unit
Provision of
telemedicine
services instead
of face-to-face
evaluations
Reassignment of
health-care
professionals to
COVID-19 units
Reorganization of
patient flow through
clinics to accommodate
social distancing
requirements
Uncertainty in the
availability and
supply of some drugs
for rCTDs (e.g.
hydroxychloroquine)
?
Fig. 2 | Organizational challenges faced by health-care clinics during the COVID-19 pandemic.
Health- care systems are under sometimes severe strain owing to the need to care for patients with
COVID-19, which has had a knock- on effect for the management of other patients, including those
with rare connective tissue diseases (rCTDs). Health- care providers within the European Reference
Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET)
have faced many organizational challenges during the pandemic, many of which have arisen as a
consequence of restrictions imposed on clinics in order to prevent and control SARS- CoV-2
transmission.
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provides operational suggestions that
could represent the basis for emergency
strategies if applied and adopted in the
arena of rare and complex diseases and
supported by the experience, expertise
andinfrastructures of the ERNs. Addressing
the challenges associated with maintaining
essential health services with the support
of ERN ReCONNET could greatly benefit
rCTD communities, by enabling the needs
specific to rCTDs and by considering and
implementing the priorities of clinicians,
hospital managers, patients and other
stakeholders in future plans.
Integrating eHealth tools
The limitation of face- to- face consultations
enabled the widespread application of
eHealth and telemedicine tools, such
as video and telephone consultations.
During the COVID-19 health emergency,
eHealth and telemedicine have been
and will continue to be valuable tools
for monitoring patients with rare and
complex diseases in order to identify
andprioritize patients needing immediate
care. Although face- to- face evaluation
and clinical examination remain essential
in the management of rCTDs, eHealth
and telemedicine tools could facilitate
optimization of care (for example,
improving the monitoring of adherence
to treatment, self- monitoring of disease
activity, enabling communication with
general practitioners, etc.), especially if
integrated with medical devices such as
apps for mobile phones and wearable
devices. In order to implement effective and
appropriate eHealth and telemedicine tools,
EU- wide initiatives could be developed
not only to create tools to be used across
different rare diseases, but also to ensure
their usage in different (both emergency and
routine) health- care scenarios. In addition,
existing EU reimbursement schemes could
be adapted and adopted to ensure the
recognition of these crucial services across
Europe. In this regard, the experience and
knowledge gained in recent years by the
ERN ReCONNET might be particularly
precious in the planning of future eHealth
and telemedicine initiatives and policies for
rCTDs, especially considering that the ERNs
represent a model to ensure adequate and
equitable access to care and treatment across
different countries, mainly by sharing the
knowledge and expertise of their members
and patient representatives.
Planning for future emergencies
The unprecedented emergency precipitated
by the COVID-19 pandemic has
highlighted the strengths and weaknesses
of our organizations and of our health- care
policies. During an emergency, priorities—
necessarily — change. However, as
discussedin this paper, this reprioritization
risks under- diagnosis (or missed diagnoses),
under- treatment or missed treatment,
inadequate monitoring, or simply delays
to health- care procedures. Preparation
is required in order to avoid the negative
health and economic implications for rCTDs
arising from COVID-19 and potential
future emergencies, which we suggest can
be done along two directions. The first
direction is to continue to increase the
awareness of all the relevant stakeholders
(policy- makers, hospital managers, national
authorities, patients’ organizations etc.)
about the relevance of rCTDs and their
health- related, organizational and economic
burden. Rare and complex diseases,
and rCTDs in particular, should always
occupy an important place in the agenda
of health- care policy makers, and the
expense — continuous and systematic —
allocated to health care in this area should
be considered an investment and not a
cost33. The second direction is to invest in
cross- border European infrastructure for the
management of rare and complex diseases,
which will already be in place for when
emergencies happen. ERN ReCONNET,
and ERNs in general, represent a common
platform that can be relied on in both
‘ordinary’ and ‘extraordinary’ times to
ensure that patients are not neglected, even
when priorities are redefined during an
emergency. Continued investment in and
upgradingoftheseinfrastructures by the
EC and its member states will ensure that
they are robust when new emergencies
arise, thus helping to minimize the negative
health, organizational and economic
implications for the management of rare
and complex diseases.
Institutional support
Institutions, including the ERNs, can
provide support to clinicians and patients
with rCTDs in the COVID-19 era in several
different ways. In this section, we outline
how the EC, ERNs (particularly ERN
ReCONNET) and related organizations have
responded to the pandemic and contributed
to rCTD communities.
The European Commission response
Since the very beginning of the pandemic,
the EC has been coordinating a common
European response in order to reinforce
public health sectors and mitigate the
socioeconomic ramifications in the EU34.
The EU response to the SARS- CoV-2
outbreak included closure of the EU’s
external borders to limit transmission of
the virus, the introduction of ‘green lanes’
(border crossing routes established to
ensure the free circulation of goods within
the EU), the promotion of research into
COVID-19 and granting access to the
RescEU stockpile of medical equipment and
the EU Solidarity Fund (see related links).
Among the many initiatives promoted in
the EU, the EC launched the COVID-19
Clinical Management Support System
(CMSS)35 in March 2020 as a tool to enable
health- care professionals involved in
handling the COVID-19 crisis across the
EU (including the UK) and the European
Economic Area to exchange information and
consult with colleagues about the treatment
and management of COVID-19, facilitate
the clinical decision- making process and
improve training, similar to theERN
approach. The CMSS consists of the
COVID-19 Clinicians Network (a database
of clinicians treating COVID-19), a central
helpdesk and a web- conferencing system for
online conferences and webinars35. So far,
several health- care professionals from many
HCPs have connected to the COVID-19
Clinicians Network. Virtual discussions
are also taking place in the framework of
the CMSS and training webinars are being
organized on COVID-19 and rare and
complex diseases. These initiatives clearly
show how EU- wide initiatives can contribute
to the improvement of care and knowledge,
topics that are particularly important inthe
management of both COVID-19 andrCTDs.
Box 1 | Organizational and health economic considerations
The organizational and health economic challenges faced by health- care providers, institutions,
patients and their families during the COVID-19 pandemic highlight important questions to be
considered regarding the future management of rare connective tissue diseases (rCTDs).
•How should care be reorganized to guarantee continuity in the provision of care, especially for
patients with rCTDs?
•How can eHealth and telemedicine be integrated into health- care systems following the
experience of using these approaches during the COVID-19 pandemic?
•How can we prevent the negative health and economic implications of COVID-19 and future
emergencies for the care of patients with rCTDs?
Nature reviews
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Rheumatology
PersPectives

COVID-19 and the ERNs
The know- how and experience of the ERNs
with respect to sharing of knowledge,
networking and education provided a
valuable model for the development of
the CMSS initiative. In particular, the
implementation of the CPMS provided
the background for the EC to develop
and establish the CMSS and the related
COVID-19 Clinicians Network.
Many ERNs have also supported the
EC’s Directorate- General for Health and
Food Safety (DG SANTE; the department
responsible for EU policy on food safety
and health and for monitoring the
implementation of related laws) with the
organization of a series of free webinars on
COVID-19, which are contributing expertise
and knowledge gathered on COVID-19 and
rare and complex diseases. The live webinars
organized since April 2020 explore a range
of themes across various diseases, such as
the use of anti- epileptic drugs in patients
with COVID-19, providing remote care for
patients with rare bone diseases during the
pandemic, COVID-19 and intensive care
medicine, and the impact of COVID-19 on
people living with a rare disease. In addition,
most ERNs are also setting up targeted
initiatives related to COVID-19 and their
individual disease areas. All webinars are
publicly available on the EC website, as is
a regularly updated list of the various ERN
initiatives36.
ERN ReCONNET initiatives
Considering the substantial impact of
the COVID-19 outbreak within rCTD
communities and the need for reliable
information on COVID-19 and rCTDs
(amid ‘fake news’ and inaccurate sources),
ERN ReCONNET has developed a series of
relevant initiatives. Since the beginning of
the pandemic, a specific section of the ERN
ReCONNET website has been dedicated
to the COVID-19 pandemic37 in order to
provide a comprehensive list of reliable and
authoritative resources to inform and update
patients and health- care professionals
on COVID-19- related topics. This
section includes extensive resources from
organizations, including scientific societies
(EULAR and national rheumatological
societies), the EC and the European
Organisation for Rare Diseases.
ERN ReCONNET has also endorsed
recommendations for patients with
rheumatic musculoskeletal diseases issued
by Fai2R (see related links), the French
health- care network for rare autoimmune
and autoinflammatory diseases38.
These recommendations emphasize the
importance of continuing treatment
plans and provide useful information
on how to act in the case of contact with
someone who has tested positive for
SARS- CoV-2 or in the case of symptoms
ascribable to the virus. Following the ERN
ReCONNET’s endorsement of the Fai2R
recommendations, the ERN ReCONNET
ePAGs have supported both the Fai2R
and the ERN ReCONNET by providing
translations of the documents issued by
Fai2R (“Recommendations for patients
suffering from rheumatic musculoskeletal
diseases” and “How to live better during
this containment period”) in 16 different
languages, which are published on the ERN
ReCONNET website, together with the
English and French versions developed by
Fai2R39. Starting from the translations, the
ERN ReCONNET also created infographics
(also available in 16 languages) to be shared
with the rCTD communities on social media
platforms. This strong collaboration among
ePAG representatives and their network of
patients, the Fai2R and ERN ReCONNET
demonstrates that joining efforts can really
have a positive influence, especially on the
lives of patients, for whom the translations
provide access to useful information on
COVID-19 and their disease in their own
language.
The scarcity of information on rCTDs
and COVID-19 has also motivated ERN
ReCONNET to promote the organizationof
educational activities and dissemination
of updates for patients and health- care
professionals on these topics from the
point of view of a European network40,
including a series of webinars. The initiatives
organized to date also serve to focus
attention on rCTDs despite the pandemic,
highlighting the added value of the ERN
ReCONNET even during a global health
emergency and representing good practice
applicable outside the ERN scenario as well.
Considering the acute need for guidance
and specific information on COVID-19and
rCTDs, and that the ultimate goal of
the ERN ReCONNET stakeholders and
institutions is to improve the care of patients
with rCTDs in Europe, more initiatives will
be organized by ERN ReCONNET on these
topics, both for patients and for health- care
professionals, in order to provide a tangible
contribution to rCTD communities.
CNMR initiatives
Another example of institutions providing a
rapid and useful response to the COVID-19
pandemic is the Italian National Rare
Diseases Centre (CNMR; see related links)
formally established within the National
Institute of Health (Istituto Superiore di
Sanità; ISS) in 2008; the CNMR is the central
coordination body of the Italian national
network for rare diseases. The CNMR
carries out scientific research and public
health activities related to rare diseases, at
both the national and the international level.
Considering the high number of
COVID-19 cases that occurred in Italy
at the beginning of the outbreak in Europe41,42,
the CNMR has worked intensively on a
number of activities and initiatives related
to COVID-19 and rare diseases. The CNMR
formed a task force dedicated to rare
diseases and COVID-19, involving experts
in rare diseases both internal and external
to the ISS. The task force has coordinated
a series of weekly webinars43 dedicated to
general public health issues related to the
pandemic, as well as to specific aspects
of rare diseases in relation to COVID-19,
involving the WHO, national and regional
institutions, CNMR centres of expertise,
ERNs (including ERN ReCONNET, as
well as ERNs for rare endocrine conditions
(ENDO- ERN), rare haematological diseases
(ERN- EuroBloodNet), rare neurological
diseases (ERN- RND) and others), ePAGs
and Italian patients’ associations. The
CNMR task force has also developed
several guidance documents44 that provide
recommendations and support for the
management of several rare conditions
during the COVID-19 pandemic, including
Kawasaki disease and acute multisystem
inflammatory syndrome in children and
adolescents. In addition, the CNMR task
force, together with the Italian federation
of rare disease associations (UNIAMO),
organized a national survey to explore the
effects of COVID-19 on Italian patients
with rare diseases, the results of which were
presented in a webinar. The main difficulties
faced by patients and their caregivers include
problems regarding both health care and
social health support during the pandemic,
as well as a substantial unmet need for
information. Most relevant, more than
half of the survey’s respondents reported
challenges in accessing follow- up care.
Conclusions
The COVID-19 pandemic has brought
many challenges to the already vulnerable
communities of patients with rCTDs.
However, many of these challenges can be
translated into positive lessons to be applied
in the post- COVID era.
One of the main positives to emerge from
the pandemic is surely the use of eHealth
and telemedicine in the provision of care
to patients with rCTDs. The experience
www.nature.com/nrrheum
PersPectives

gained during the pandemic, building
on theprevious knowledge obtained
throughthe use of CPMS by ERNs, has
highlighted the need to integrate eHealth
and telemedicine into routine clinical
practice as a tool to improve and optimize
the management of rCTDs. Inmany
cases, the alternation of telemedicine
and face- to- face evaluation could in fact
be considered when disease activity is
stable, enabling patients to avoid the
unnecessary burden of travelling, as
well as its related costs and social and
work- related disadvantages. Therefore, it
is desirable that telemedicine and eHealth
should be taken into consideration in
future health policies and planning, to
enable their successful integration into the
health- care services provided to patients
with rCTDs. Importantly, such policies
could also promote the optimization and
implementation of consultation between
general practitioners and clinicians caring
for patients with rCTDs.
In addition, the clinical and
organizational challenges faced during the
pandemic demonstrate how important
it is to ensure the continuity of adequate
diagnostic and monitoring protocols in the
management of rCTDs. At present, we do not
know whether the pandemic and the related
lockdown might have indirectly influenced
the exacerbation of the disease in some
patients with rCTDs or contributed to delays
in diagnosis; only observation in the coming
months is likely to provide potentially
useful information. What we do know is
that, because new health emergencies might
occur in the future, a specific and structured
emergency strategy could be developed for
the management andcare of rCTDs, as well
as for other rareand complex conditions.
The vulnerability and the specific needs
of patients with rCTDs must, in fact, be
taken into account when planning future
health policies, in preparation for not only
the post- COVID era, but also any possible
new health emergencies. To this end, the
contribution of ERNs to the development
of such strategies could add important
value, supporting scientific societies and
policymakers in providing for the needs
and priorities of the Europe- wide rCTD
communities.
RosariaTalarico1, SilviaAguilera2, TobiasAlexander
3,
ZahirAmoura4, AnaM.Antunes5, LaurentArnaud
6,
TadejAvcin7, LorenzoBeretta8, StefanoBombardieri9,
GerdR.Burmester3, SaraCannizzo1,10,
LorenzoCavagna11, BenjaminChaigne12, AlainCornet13,
NathalieCostedoat- Chalumeau12, AndreaDoria14,
AlessandroFerraris15, RebeccaFischer- Betz16,
JoãoE.Fonseca17, CharissaFrank18, AndreaGaglioti1,
IlariaGaletti19, JürgenGrunert20, VeraGuimarães21,
EricHachulla22, FredericHoussiau23,
LucaIaccarino14, ThomasKrieg24, MarteenLimper25,
FransiskaMalfait
26, XavierMariette27,
DianaMarinello
1, ThierryMartin28,
LisaMatthews29, MarcoMatucci- Cerinic30,
AlainMeyer6, CarlomaurizioMontecucco11,
LucMouthon12, UlfMüller- Ladner31 , SimonaRednic32,
VascoC.Romão17, MatthiasSchneider16,
VanessaSmith33, AlbertoSulli34, FarahTamirou23,
DomenicaTaruscio35, AnnaV.Taulaigo5,
EnriqueTerol36, AngelaTincani37, SimoneTicciati1,
GiuseppeTurchetti10, P.Martinvan Hagen38,
JacobM.van Laar25, AnaVieira39,
JeskaK.deVries- Bouwstra40, MaurizioCutolo3
and MartaMosca1,41 ✉
1Rheumatology Unit, Azienda Ospedaliero Universitaria
Pisana, Pisa, Italy.
2Spanish Association for Antiphospholipid Syndrome
(SAF España), Elche, Spain.
3Department of Rheumatology and Clinical Immunology,
Charité University Medicine Berlin, Berlin, Germany.
4Department of Internal Medicine, Hospital
Pitié- Salpêtrière, Assistance Publique Hôpitaux de
Paris, French National Referral Center for SLE and
APS, Paris, France.
5Auto- immune Disease Unit, Hospital de Curry Cabral,
Centro Hospitalar de Lisboa Central, EPE,
Lisbon, Portugal.
6Service de rhumatologie, Hôpitaux Universitaires de
Strasbourg, Centre National de Référence des
Maladies Systémiques et Auto- immunes Rares
Grand- Est Sud- Ouest (RESO), Strasbourg, France.
7Department of Allergology, Rheumatology and Clinical
Immunology, University Children’s Hospital, University
Medical Centre Ljubljana, Ljubljana, Slovenia.
8Referral Center for Systemic Autoimmune Diseases,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico di Milano, Milan, Italy.
9University of Pisa, Pisa, Italy.
10Institute of Management, Scuola Superiore Sant’Anna,
Pisa, Italy.
11Department of Rheumatology, IRCCS Policlinico San
Matteo Foundation, Pavia, Italy.
12Service de Médecine Interne, Hôpital Cochin, Centre
de Référence Maladies systémiques Autoimmunes
Rares d’Ile de France, Assistance Publique- Hôpitaux de
Paris (AP- HP), Université de Paris, Paris, France.
13Lupus Europe, Brussels, Belgium.
14Rheumatology Unit, Department of Medicine,
University of Padova, Padova, Italy.
15Medical Genetics Laboratory, Molecular Medicine
Department, San Camillo Forlanini Hospital, Sapienza
University, Rome, Italy.
16Department of Rheumatology, University Hospital
Düsseldorf, Heinrich- Heine- University Düsseldorf,
Düsseldorf, Germany.
17Rheumatology Department, Hospital de Santa Maria,
Centro Hospitalar Lisboa Norte, Lisbon Academic
Medical Centre, Lisbon, Portugal.
18Flemish Association for Hereditary Connective Tissue
Disorders, Koersel, Belgium.
19Federation of European Scleroderma Associations
(FESCA), Milan, Italy.
20Deutsche Ehlers- Danlos Initiative e.V., Furth,
Germany.
21Liga Portuguesa Contra as Doenças Reumáticas,
Lisbon, Portugal.
22Département de Médecine Interne et Immunologie
Clinique, Centre de Référence des Maladies
Systémiques et Auto- Immunes Rares du Nord- Ouest
(CERAINO), LIRIC, INSERM, Univ. Lille, CHU Lille,
Lille, France.
23Department of Rheumatology, Cliniques
Universitaires Saint- Luc, Brussels, Belgium.
24Department of Dermatology, Universitätsklinikum,
Cologne, Germany.
25Department of Rheumatology and Clinical
Immunology, University Medical Center Utrecht,
Utrecht University, Utrecht, Netherlands.
26Center for Medical Genetics, Ghent University
Hospital, Ghent, Belgium.
27Université Paris- Saclay, INSERM, CEA, Centre de
recherche en Immunologie des infections virales et des
maladies auto- immunes; AP- HP. Université
Paris- Saclay, Hôpital Bicêtre, Rheumatology
Department, Le Kremlin Bicêtre, Paris, France.
28Clinical immunology department, Hôpitaux
Universitaires de Strasbourg, Centre National de
Référence des Maladies Systémiques et Auto- immunes
Rares Grand- Est Sud- Ouest (RESO), Strasbourg, France.
29Relapsing Polychondritis Awareness and Support,
Worcester, UK.
30Division of Rheumatology and Scleroderma Unit,
Department of Clinical and Experimental Medicine,
AOU Careggi, University of Florence, Florence, Italy.
31Department of Rheumatology and Clinical
Immunology, Kerckhoff Klinik, Justus Liebig University
of Giessen, Bad Nauheim, Germany.
32Department of Rheumatology, Emergency County
Teaching Hospital, Cluj- Napoca, Romania.
33Department of Rheumatology, Ghent University
Hospital Department of Internal Medicine,
Ghent, Belgium.
34Research Laboratory and Academic Division of Clinical
Rheumatology, Department of Internal Medicine, IRCCS
Polyclinic Hospital San Martino, University of Genoa,
Genoa, Italy.
35National Centre for Rare Diseases, Istituto Superiore
di Sanità, Rome, Italy.
36Directorate- General for Health and Food Safety,
European Commission, Brussels, Belgium.
37Rheumatology and Clinical Immunology Unit,
ASST- Spedali Civili and University of Brescia,
Brescia, Italy.
38Department of Internal Medicine and Immunology,
Erasmus MC, Rotterdam, Netherlands.
39Liga Portuguesa Contra as Doenças Reumáticas,
Núcleo Síndrome de Sjögren, Lisbon, Portugal.
40Department of Rheumatology, Leiden University
Medical Center, Leiden, The Netherlands.
41Rheumatology Unit, University of Pisa, Pisa, Italy.
✉e- mail: ern.reconnet@ao- pisa.toscana.it
https://doi.org/10.1038/s41584-020-00565- z
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Acknowledgements
This publication was funded by the European Union’s Health
Programme (2014–2020).
Author contributions
R.T., S.C. and D.M. researched data for the article. R.T., S.C.
L.C., B.C., A.C., D.M., M.C. and M.M. made substantial contri-
butions to discussion of the content. R.T., S.A., A.C., C.F., I.G.,
J.G., V.G., D.M., L.M., D.T., G.T., A.V. and M.M. wrote the arti-
cle. R.T., S.A., T.A., Z.A., A.M.A., L.A., T.A., L.B., S.B., G.R.B.,
S.C., L.C., N.C.- C., A.D., A.F., R.F.- B., J.E.F., A.G., E.H., F.H., L.I.,
T.K., M.L., F.M., X.M., D.M., T.M., M.M.- C., A.M., C.M., L.M.,
U.M.- L., S.R., V.C.R., M.S., V.S., A.S., F.T., D.T., A.V.T., E.T., A.T.,
S.T., G.T., M.P.v.H., J.M.v.L., J.K.d.V.- B., M.C. and M.M.
reviewed/edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
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