Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease caused by
SARS coronavirus 2 (SARS-CoV-2) . The disease was first identified in Wuhan, China
and the WHO was alerted in December 2019. By May 2020, the WHO reported over 4.6 million
confirmed cases in over 200 countries around the globe . Most individuals that
test positive for COVID-19 experience mild symptoms with fever, fatigue and dry cough
as the most common symptoms. However, due to a large number of infected individuals,
there have been over 313,000 deaths worldwide as of 18 May 2020 . As a result of
the widespread disease, many countries have placed limits on travel and social gatherings,
as well as closed schools and nonessential workplaces. The impact of the pandemic
affects everyone, ill and healthy, in all aspects of daily living. This article discusses
how the COVID-19 pandemic may affect rheumatology and dermatology patients with immune-mediated
diseases who are receiving anticytokine or Jak inhibitor therapies.
Safety of immunotherapy in patients with rheumatic diseases during COVID-19
Patients with rheumatic diseases are often on immunosuppressive medications, and both
the disease and the medications contribute to a higher infectious risk, leading to
concerns of increased risk and severe disease with COVID-19 in these patients. The
concerns have resulted in changes in patients’ treatment plans. For example, an email
questionnaire surveying 7061 patients in FORWARD, the US wide registry for rheumatic
disease, received responses from 530 participants, of those, 471 responded to questions
about changes in their rheumatology care in the previous 2 weeks . Of the 197 patients
(out of 471) who reported some change, 14% had made changes to their own medication
list or dose while 11% made such changes based on physician recommendations . The
survey identified the perception of increased risk and potential severity of COVID-19
secondary to taking immunosuppressive medications as a reason for both self-imposed
and physician-approved discontinuation of disease-modifying antirheumatic drugs (DMARDs)
Interestingly, preliminary data suggest that patients with rheumatic diseases treated
with immunosuppressive agents are not at an increased risk for poor outcomes for COVID-19
compared with the general population. For example, of the 458 patients with rheumatic
diseases (56% were on corticosteroids, 44% on conventional synthetic DMARDs and 41%
on biologic DMARDs) interviewed in Tuscany, Italy, only 13 reported symptoms consistent
with COVID-19 . Of those, seven patients were given nasopharyngeal swab and only
one was positive, resulting in a prevalence of 0.22% (0.01–1.21%) which is similar
to that of the general population of Tuscany (0.20% [0.20–0.21%]) . Likewise, a
survey conducted in Milan, Italy, with 123 adult patients with rheumatic diseases
(64.2% were on corticosteroids, 59.3% on conventional synthetic DMARDs and 20.3% on
biologic DMARDs), had only one patient with a positive COVID-19 nasopharyngeal swab,
resulting in an incidence of 0.81% which is comparable with the incidence of 0.62%
seen in the Lombardy region during the same time period . Similarly, a survey of
320 patients with chronic arthritis treated with DMARDs in Pavia, Italy, found that
none of the patients with a confirmed diagnosis of COVID-19 (n = 4) or a highly suggestive
clinical picture (n = 4) or contact with a known COVID-19 patient (n = 5) developed
severe respiratory complications or died .
A study in New York City by Haberman et al. described 86 COVID-19 patients with immune-mediated
diseases and compared the characteristics of those who were hospitalized to those
who were not (ambulatory patients) . The mean age was slightly older in those who
required hospitalization (50 vs 46 years in those who did not) and more males than
females were hospitalized compared with ambulatory patients (50 vs 42%) . Patients
with rheumatoid arthritis (RA) had a higher frequency of hospitalization compared
with Crohn’s, ankylosing spondylitis and psoriasis . Therefore, it is not surprising
that hospitalized patients were more likely to be receiving methotrexate (43%) versus
ambulatory patients (15%) . Those who received hydroxychloroquine (HCQ) had more
hospitalizations (21%) versus ambulatory (7%), likely due to a diagnosis of RA .
This drug did not look protective but there was no comparison to the frequency of
use of HCQ in RA patients who did not develop COVID-19 . Glucocorticoids were more
apt to be prescribed prior to hospitalization than in ambulatory patients (43 vs 15%),
whereas TNF inhibitors were less likely to be received by patients requiring hospitalization
(21 vs 49%) . The numbers on other biologics and JAK inhibitors were too small
to draw any conclusion .
A large multinational case series described the first 600 COVID-19 cases collected
by the COVID-19 Global Rheumatology Alliance and identified risk factors for hospitalization
for COVID-19 in patients with rheumatic diseases . Similar to the findings by Haberman
et al. , the median age was older in those that were hospitalized compared with
nonhospitalized (62 vs 52 years) and more males than females were hospitalized compared
with nonhospitalized patients (33 vs 26%) . Most intriguingly, the report identified
that age >65 years, comorbidities (namely diabetes, hypertension/cardiovascular, lung and
renal diseases), >10 mg/day prednisone-equivalent glucocorticoids were associated
with a higher risk of hospitalization for COVID-19 . Conversely, TNF inhibitors
were associated with a lower odd of hospitalization .
The studies to date have not had fully adequate control groups such as members of
the community with rates of infection for age- and gender-matched people, and medications
comparing those who developed COVID-19 to those who did not to see if certain diseases
have a risk of more frequent infection and if the disease-modifying drugs are a risk,
protective or irrelevant. Also, there could be biases in testing for COVID-19 more
often in patients with immune-suppressive treatment.
Medication shortages & their effect on patients
Many medications commonly used in the treatment of rheumatic diseases are currently
being studied as potential treatments for COVID-19. HCQ and chloroquine were the first
to receive substantial media attention. As a result, shortages of HCQ and/or chloroquine
have been reported on Drug Shortages Canada  and American Society of Health-System
Pharmacists  (as of 11 May 2020). Chloroquine was not available in Canada months
before the pandemic, placing the supply of the medication in a precarious position.
Medication shortage is a complex health problem. Patients have anxiety that they will
run out of medication, especially if it in some way prevents a severe outcome from
COVID-19 infection. A scoping review found an increase in out-of-pocket drug costs,
medication error rates, adverse events, mortality and patient complaints during times
of drug shortage . Thus, experts have expressed concerns over the limited availability
of HCQ and chloroquine for patients with an approved indication such as lupus and
RA [11,12]. Despite the efforts, on 28 March 2020, the US FDA issued an emergency
use authorization for chloroquine and HCQ for the treatment of COVID-19. There are
restrictions detailed in the authorization. Nonetheless, this hasty drug approval
hindered patient adherence to immunosuppressive therapies. In the survey, 10% of the
197 patients who experienced some change in their care reported difficulty with obtaining
their medication, especially HCQ . Furthermore, a survey sent to 531 Canadian rheumatologists
found that of the 134 rheumatologists who completed the survey, 81 (60%) had been
contacted by patients or pharmacies regarding difficulty with HCQ access .
A disruption in maintenance therapy may lead to poorly controlled rheumatic disease,
and high disease activity itself in rheumatic diseases, such as in RA, is associated
with an increased risk of infection . Governments have increased their supply
of HCQ from several manufacturers in response to the shortage. The data of benefit
for antimalarials in COVID-19 infection is sparse and large randomized trials are
needed . In fact, high-dose chloroquine had a higher death rate than low-dose chloroquine
in a randomized controlled trial (RCT) .
Current evidence for the use of chloroquine and HCQ for treatment of COVID-19 remains
limited and inconsistent. Therefore, efforts should be made to ensure that patients
with previously existing medical indications be given priority access to the medication.
The use of HCQ for COVID-19 should be restricted to clinical trials until further
evidence is available.
Immune modulators as COVID-19 treatments
Immunomodulating medications have been in the spotlight during this pandemic. This
is due to the cytokine dysregulation and hyperinflammation seen in some severe COVID-19
Anakinra, an IL-1 inhibitor, has preliminary evidence for its safety and efficacy
in patients with COVID-19. A retrospective cohort study compared the outcomes of 29
patients who received high-dose intravenous anakinra, noninvasive ventilation and
standard treatment to those of the 16 patients who received only noninvasive ventilation
and standard treatment . Clinical improvements at 21 days were shown in 21 (72%)
patients receiving high-dose anakinra and 8 (50%) patients receiving standard treatment
. At 21 days, three (10%) patients receiving high-dose anakinra died versus seven
(44%) patients receiving standard treatment . The immune modulator is currently
being investigated in at least 11 COVID-19 related clinical trials registered on ClinicalTrials.gov.
Multiple IL-6 inhibitors, such as tocilizumab, sarilumab and siltuximab, are also
being investigated as COVID-19 treatments. Tocilizumab has the most preliminary evidence
so far. A retrospective study with 21 patients in China showed that tocilizumab is
effective in reducing mortality in severe and critical COVID-19 patients . Another
retrospective study in China with 15 patients with COVID-19 treated with tocilizumab
suggested that it is a possible treatment option for patients at risk of cytokine
storms . Many more tocilizumab clinical studies are currently underway worldwide.
Data involving siltuximab and sarilumab in COVID-19 are pending peer review or still
Baricitinib, a JAK inhibitor, is predicted to block SARS-CoV-2 receptor-mediated endocytosis
into pulmonary epithelial cells, as well as excessive JAK-dependent cytokine signaling
. An open-label study with 12 patients with oral baricitinib added to ritonavir/lopinavir
therapy showed promising results as all patients improved at 2 weeks and required
no ICU admission . At least, five clinical trials involving baricitinib have been
registered on ClinicalTrials.gov.
TNF inhibitors, such as adalimumab, have also garnered some attention . There
is one study evaluating adalimumab in COVID-19 registered in the Chinese Clinical
Trial Registry 2000030089. Several other biologic and antirheumatic drugs have been
identified to be theoretically helpful in the treatment of COVID-19 including colchicine,
IL-17 inhibitors, IL-12 and IL-12/23 inhibitors, mycophenolate mofetil, azathioprine,
methotrexate, cyclosporine, tacrolimus and other treatments  (accessed on 18 May 2020).
There is speculation that anticytokine therapies used in rheumatology and dermatology
such as IL-17, IL-12/23 and IL-23 inhibitors are safe to use during COVID-19 and may
have some potential benefit theoretically [25,26].
For all these medications, there are currently insufficient data to recommend either
for or against their use for the treatment of COVID-19. Supplementary Table 1 summarizes
potential immune modulator treatments for COVID-19.
The COVID-19 pandemic is a rapidly evolving situation, and information on the topic
is released and revised as the situation unfolds each day. Current evidence shows
that rheumatology patients do not seem to have worse outcomes despite immune suppression.
Many immunomodulating medications are being studied as treatments of COVID-19, which
can lead to negative impacts on the health and wellbeing of patients treated with
immunotherapies secondary to medication shortages. It is important to still follow
steps that have been put in place for years to safeguard proper medication development
and usage. These steps require valid randomized controlled trials for approving medications
and prescribing treatments. As many have expressed previously, immunosuppressive medications
are not without adverse effects and, thus, these medications should be used only with
careful considerations and be allocated to patients who have proven to benefit from
these therapies . There are likely to be long-term consequences for patients with
immune-mediated diseases after COVID-19 including chronic stress/anxiety, depression
and pain, an increase in fibromyalgia and post-traumatic stress disorder and flaring
of immune-mediated diseases in some patients due to financial and health stressors.
Click here for additional data file.