Editorials
for timely access to outpatient therapeutics and
support the proof of concept for pursuing oral
prodrugs of remdesivir’s active metabolite. Rapid
emergence of variants with adaptive mutations
in the spike protein can result in escape from
vaccines and monoclonal antibodies, whereas
antiviral agents, given the absence of variation in
their viral target, are likely to maintain activity,
reinforcing the value of antivirals such as rem-
desivir in curtailing the pandemic.10 If Covid-19
is here to stay, our focus on prevention through
vaccines remains a priority, but therapeutic op-
tions to keep vulnerable patients out of the hospi-
tal are an important tool in the armamentarium.
Disclosure forms provided by the authors are available with
the full text of this editorial at NEJM.org.
From the Department of Pharmacy Practice and Science, Uni-
versity of Maryland School of Pharmacy (E.L.H.), and the Insti-
tute of Human Virology, University of Maryland School of Med-
icine (S.K.), Baltimore.
This editorial was published on December 22, 2021, at NEJM.org.
1. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-
COV2, a neutralizing antibody cocktail, in outpatients with
Covid-19. N Engl J Med 2021;​384:​238-51.
2. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab
as monotherapy or in combination with etesevimab on viral load
Risks and Benefits of Janus Kinase Inhibitors
in Rheumatoid Arthritis — Past, Present, and Future
Jasvinder A. Singh, M.B., B.S., M.P.H.
The Food and Drug Administration (FDA) man-
dated a safety study to be performed because of
possible safety signals detected for the Janus
kinase (JAK) inhibitor tofacitinib. As Ytterberg
et al. report in this issue of the Journal, the Oral
Rheumatoid Arthritis Trial (ORAL) Surveillance
was a 4-year randomized, open-label, noninferi-
ority, postauthorization, safety end-point trial,
in which patients with active rheumatoid arthri-
tis despite methotrexate treatment who were 50
years of age or older and had at least one addi-
tional cardiovascular risk factor were randomly
assigned in a 1:1:1 ratio to receive oral tofacitinib
at a dose of 5 or 10 mg twice daily or a subcuta-
neous tumor necrosis factor (TNF) inhibitor
(etanercept or adalimumab).1
The risks of major adverse cardiovascular
events (MACE) and cancers (excluding nonmela-
noma skin cancer [NMSC]) were higher with the
combined tofacitinib doses than with a TNF in-
n engl j med 386;4  nejm.org  January 27, 2022
The New England Journal of Medicine
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
in patients with mild to moderate COVID-19: a randomized
clinical trial. JAMA 2021;​325:​632-44.
3. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the
treatment of Covid-19 — final report. N Engl J Med 2020;​383:​
1813-26.
4. WHO Solidarity Trial Consortium. Repurposed antiviral
drugs for Covid-19 — interim WHO Solidarity trial results. N Engl
J Med 2021;​384:​497-511.
5. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesi-
vir plus standard of care versus standard of care alone for the
treatment of patients admitted to hospital with COVID-19 (Dis-
CoVeRy): a phase 3, randomised, controlled, open-label trial.
Lancet Infect Dis 2021 September 14 (Epub ahead of print).
6. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to
prevent progression to severe Covid-19 in outpatients. N Engl J
Med 2022;​386:​305-15.
7. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with
severe COVID-19: a randomised, double-blind, placebo-controlled,
multicentre trial. Lancet 2020;​395:​1569-78.
8. Caraco Y. Phase 2 results from a randomized, controlled,
phase 2/3 trial evaluating molnupiravir for treatment of COVID-19
in non-hospitalized adults (MOVe-OUT). Presented at the 31st
European Congress of Clinical Microbiology and Infectious Dis-
eases (ECCMID), Vienna, July 9–12, 2021.
9. Anderson TS, O’Donoghue AL, Dechen T, Mechanic O, Ste-
vens JP. Uptake of outpatient monoclonal antibody treatments
for COVID-19 in the United States: a cross-sectional analysis.
J Gen Intern Med 2021;​36:​3922-4.
10. Callaway E. Heavily mutated omicron variant puts scientists
on alert. Nature 2021;​600:​21.
DOI: 10.1056/NEJMe2118579
Copyright © 2021 Massachusetts Medical Society.
hibitor, and the noninferiority of tofacitinib was
not shown, with hazard ratios of 1.33 (95%
confidence interval [CI], 0.91 to 1.94) for MACE
and 1.48 (95% CI, 1.04 to 2.09) for cancers. The
researchers estimated that during 5 years of
treatment, 113 and 55 patients would need to be
treated with tofacitinib at a dose of 5 mg twice
daily rather than with a TNF inhibitor to result
in one additional MACE and cancer, respectively.
Efficacy was similar in all three trial groups
with respect to multiple patient-centered and
clinical outcomes.
What do these results mean? Rheumatoid
arthritis is associated with an increased risk of
MACE.2 The use of TNF inhibitors3 and other
traditional and biologic disease-modifying anti-
rheumatic drugs (DMARDs)4 to treat rheumatoid
arthritis is associated with a reduced risk of
MACE, presumably through a reduction in inflam-
mation. The most relevant estimates for MACE
387
 The n e w e ng l a n d j o u r na l
in patients with rheumatoid arthritis come from
two real-world observational studies that used
data from United Healthcare (United States) from
2003 through 20125 and the Health Improve-
ment Network (United Kingdom) from 1994
through 20106 and a randomized, noninferiority
trial comparing tocilizumab (an antibody to the
interleukin-6 receptor) with etanercept in 3080
patients over a mean of 3.2 years.7 The incidence
rates were 1.42, 1.21, and 1.82 (with tocilizumab)
per 100 person-years, respectively. The incidence
rates of MACE in ORAL Surveillance were 0.91,
1.05, and 0.73 per 100 patient-years with tofaci-
tinib at a dose of 5 mg twice daily, tofacitinib at
a dose of 10 mg twice daily, and a TNF inhibitor,
respectively.
ORAL Surveillance showed higher risks of
MACE and cancer with tofacitinib than with a
TNF inhibitor. This is a cause for concern and
caution with its current and future use to treat
rheumatoid arthritis. To my knowledge, no clear
mechanism of action is evident or proven cur-
rently for this safety signal. Some of the differ-
ence in MACE risk between tofacitinib and a
TNF inhibitor in ORAL Surveillance may be due
at least partially to a greater reduction in cardio-
vascular risk with a TNF inhibitor than with
tofacitinib. The nonuse of conventional DMARDs
in this trial prevents an assessment of this hypoth-
esis. Whether the excess MACE risk associated
with the choice of tofacitinib over the choice of
a TNF inhibitor is attributed to the fact that a
TNF inhibitor reduced the risk of MACE relative
to tofacitinib or whether tofacitinib increased the
risk of MACE (i.e., as compared with placebo)
cannot be determined from this trial; however,
it does not change the risk–benefit analysis in
choosing between the two drugs with regard to
the risk of MACE.
Rheumatoid arthritis increases the risk of
cancer.8 The difference in cancer risk between
tofacitinib and a TNF inhibitor in ORAL Surveil-
lance is more difficult to understand. Cancer is
listed as a black-box label warning for TNF in-
hibitors. The use of TNF inhibitors to treat rheu-
matoid arthritis may be associated with a slight-
ly increased risk of NMSC or melanoma9 but is
not associated with an overall increase in cancer
risk.10 The trial indicates that this risk is higher
with tofacitinib than with a TNF inhibitor. This
finding makes tofacitinib a nonpreferred drug
for patients with rheumatoid arthritis with cur-
rent or previous cancer or those at risk for can-
388 n engl j med 386;4  nejm.org  January 27, 2022
The New England Journal of Medicine
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
cer. Risk factors for cancer in patients with
rheumatoid arthritis are less well understood,
and incidence rates vary widely. Long-term pop-
ulation-level studies and large safety trials are
needed to examine the cancer risk among pa-
tients with rheumatoid arthritis that is attribut-
able to rheumatoid arthritis, DMARDs, or coex-
isting conditions and to examine whether cancer
risk differs according to the type of DMARD.
What are the clinical implications of these
findings? Recently, the FDA issued the black-box
warning not just for tofacitinib but also for upa-
dacitinib and baricitinib, the two other JAK in-
hibitors for which increased risks of MACE and
cancer are considered to be class effects. The
FDA also changed the indications for tofacitinib
and upadacitinib from incomplete response to
methotrexate to incomplete response to a TNF
inhibitor. In patients with rheumatoid arthritis
who have an incomplete response to methotrex-
ate and have active disease, a TNF inhibitor will
be preferred to tofacitinib for a new start, espe-
cially in persons 65 years of age or older. If pa-
tients strongly prefer or are only willing to take
an oral DMARD and if the patient is 50 to 64
years of age, a detailed patient–provider discus-
sion of the risks associated with tofacitinib as
compared with TNF inhibitors and shared deci-
sion making are needed before choosing tofaci-
tinib as the treatment option. JAK inhibitors are
among important oral treatment options for
rheumatoid arthritis.
To whom do these results not apply? The re-
sults of ORAL Surveillance do not apply directly
to the following subpopulations of patients with
rheumatoid arthritis: those younger than 50 years
of age, those 50 years of age or older but with
no additional cardiovascular risk factors, and
those with an incomplete response to or unac-
ceptable side effects from a TNF inhibitor.
Treating rheumatoid arthritis with an effec-
tive DMARD is critically important. The use of
DMARDs to treat rheumatoid arthritis reduces
pain; improves function, quality of life, and pro-
ductivity; reduces joint destruction and disabil-
ity; and decreases systemic inflammation. The
increase in risk with tofacitinib as compared
with TNF inhibitors must be balanced against
patient preferences for oral medication.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Medicine Service, Veterans Affairs Medical Center,
and the Department of Medicine, School of Medicine, and the
 Editorials

Division of Epidemiology, School of Public Health, University
of Alabama at Birmingham — both in Birmingham.
1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and
cancer risk with tofacitinib in rheumatoid arthritis. N Engl J
Med 2022;​386:​316-26.
2. Choy E, Ganeshalingam K, Semb AG, Szekanecz Z, Nurmo-
hamed M. Cardiovascular risk in rheumatoid arthritis: recent
advances in the understanding of the pivotal role of inflamma-
tion, risk predictors and the impact of treatment. Rheumatology
(Oxford) 2014;​53:​2143-54.
3. Roubille C, Richer V, Starnino T, et al. The effects of tu-
mour necrosis factor inhibitors, methotrexate, non-steroidal anti-
inflammatory drugs and corticosteroids on cardiovascular events
in rheumatoid arthritis, psoriasis and psoriatic arthritis: a sys-
tematic review and meta-analysis. Ann Rheum Dis 2015;​74:​480-9.
4. Singh S, Fumery M, Singh AG, et al. Comparative risk of
cardiovascular events with biologic and synthetic disease-modi-
fying antirheumatic drugs in patients with rheumatoid arthritis:
a systematic review and meta-analysis. Arthritis Care Res
(Hoboken) 2020;​72:​561-76.
5. Liao KP, Liu J, Lu B, Solomon DH, Kim SC. Association be-
tween lipid levels and major adverse cardiovascular events in
rheumatoid arthritis compared to non-rheumatoid arthritis pa-
tients. Arthritis Rheumatol 2015;​67:​2004-10.
6. Ogdie A, Yu Y, Haynes K, et al. Risk of major cardiovascular
events in patients with psoriatic arthritis, psoriasis and rheuma-
toid arthritis: a population-based cohort study. Ann Rheum Dis
2015;​74:​326-32.
7. Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of
tocilizumab versus etanercept in rheumatoid arthritis: a ran-
domized controlled trial. Arthritis Rheumatol 2020;​72:​31-40.
8. Mellemkjaer L, Linet MS, Gridley G, Frisch M, Møller H,
Olsen JH. Rheumatoid arthritis and cancer risk. Eur J Cancer
1996;​32A:​1753-7.
9. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic
and biological DMARDs: a systematic literature review inform-
ing the 2013 update of the EULAR recommendations for manage-
ment of rheumatoid arthritis. Ann Rheum Dis 2014;​73:​529-35.
10. Askling J, van Vollenhoven RF, Granath F, et al. Cancer risk
in patients with rheumatoid arthritis treated with anti-tumor
necrosis factor alpha therapies: does the risk change with the
time since start of treatment? Arthritis Rheum 2009;​60:​3180-9.
DOI: 10.1056/NEJMe2117663
Copyright © 2022 Massachusetts Medical Society.

The Price of Freedom from Tricuspid Regurgitation

Joanna Chikwe, M.D., and Mario Gaudino, M.D.

Progressive tricuspid regurgitation is common, tation, or death — occurred less frequently in

particularly in patients undergoing mitral-valve
surgery. Severe tricuspid regurgitation decreases
survival and quality of life due to right ventricu-
lar dysfunction, congestive hepatopathy, and renal
failure. The tricuspid valve can easily be repaired
during mitral-valve surgery, and consensus guide-
lines recommend concomitant repair of mild or
moderate tricuspid regurgitation with annular
dilatation of 4.0 cm or more.1 However, these
recommendations are based on mostly observa-
tional data, and controversy surrounds the most
effective strategy, which contributes to wide varia-
tion in practice: concomitant tricuspid repair
rates at cardiac surgery programs in the United
States range from under 5% to more than 75%.2
Consequently, the results of the trial by Gam-
mie and colleagues that are reported now in the
Journal are timely and welcome.3 In this multi-
center trial, 401 patients with moderate tricus-
pid regurgitation or annular dilatation who were
undergoing mitral-valve surgery were randomly
assigned to undergo either mitral surgery alone
or mitral surgery plus tricuspid annuloplasty (TA).
The primary end point — a composite of reop-
eration for tricuspid regurgitation, progression of
tricuspid regurgitation by two grades from base-
line or the presence of severe tricuspid regurgi-
the surgery-plus-TA group than in the surgery-
alone group (3.9% vs. 10.2%, P = 0.02). This dif-
ference was driven by progression to severe tri-
cuspid regurgitation, which occurred less often
in patients who underwent TA (0.6% vs. 5.6%).
However, more permanent pacemakers were
implanted after TA (14.1% vs. 2.5%). Essentially,
concomitant TA during mitral surgery in 20 pa-
tients prevented severe tricuspid regurgitation in
about 1 patient, at the price of permanent pace-
maker implantation in approximately 2 patients
over 2 years. The planned 5-year follow-up may
better delineate the clinical effect of severe tri-
cuspid regurgitation after isolated mitral sur-
gery, as compared with pacemaker placement
after concomitant TA.
Other useful observations can be made from
these high-quality, prospective data. First, severe
tricuspid regurgitation was not associated with
worse clinical symptoms or quality of life at
2 years. This finding suggests that an aggressive
approach to TA in high-risk patients with limit-
ed life expectancy is probably not warranted.
Similarly, the results challenge guideline recom-
mendations to perform surgery in patients with
lesser grades of tricuspid regurgitation, since
almost none of these patients had progression to

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Copyright © 2022 Massachusetts Medical Society. All rights reserved.