DISCUSSION
In our study, tofacitinib in addition to standard of care therapy did
not reduce the composite end-point of invasive mechanical ventilation or
death among hospitalised patients with moderately severe COVID-19. Most
patients had signs of systemic inflammation, that is, persisting fever
and/or elevated CRP. The primary end-point was not met both in patients
requiring oxygen supply at the time of tofacitinib initiation and those
with normal oxygen saturation. In multivariate Cox regression analysis
adjusted for inverse propensity score weighting, the addition of
tofacitinib to the standard of care therapy improved outcomes neither in
hypoxic patients nor in those receiving no supplemental oxygen.
In both groups, analysis of the composite end-point rates
non-significantly favoured tofacitinib. The percentages of patients who
started mechanical ventilation or died during hospitalisation in the
tofacitinib and control groups were 12.5% vs. 14.1%, respectively,
among patients who required respiratory support, and 1.7% vs. 4.4%,
respectively, in those with normal oxygen saturation. These differences
could be related to the use of glucocorticoids that was two- to
three-fold higher in the tofacitinib groups. The RECOVERY trial showed
the efficacy of dexamethasone in reducing mortality only among
hospitalised patients with more severe COVID-19 [4]. However, a
favourable effect of glucocorticoids on the course of COVID-19 might
also be present in cases with signs of excessive inflammatory response,
even in the absence of hypoxia at the time of hospitalisation.
In the ACTT-2 trial, the beneficial effects of the combination treatment
with baricitinib and remdesivir included a 1-day shorter time to
recovery and a greater improvement in clinical status as assessed on the
ordinal scale [10]. In contrast, we did not evaluate the time to
clinical improvement or recovery, since we could not validate these data
that were collected retrospectively for control patients. The assessment
of time to recovery was even more challenging in patients with normal
oxygen saturation. Therefore, the hard end-points of death or invasive
ventilation seemed to be more suitable criteria of efficacy for our
non-randomised clinical study.
The use of glucocorticoids was prohibited by the protocol of the ACTT-2
trial, although these medications were permitted for standard
indications including septic shock and acute respiratory distress
syndrome. In the ACTT-2 study, dexamethasone was administered to only
6.0% of patients in the baricitinib group. On the contrary, systemic
glucocorticoids were used in 82% of patients who were enrolled in the
tocilizumab arm of the RECOVERY study. Addition of tocilizumab to
glucocorticoids resulted in 20% reduction in the risk of all-cause
mortality, whereas this benefit was not seen in patients who did not
receive glucocorticoids [7]. These findings suggest that in patients
with COVID-19 tocilizumab and probably other immunomodulators should be
considered in addition to glucocorticoids, particularly in those who do
not respond to initial anti-inflammatory therapy or present with severe
or progressive disease. In our study, 31.2% of patients received
intravenous dexamethasone. Addition of tofacitinib to glucocorticoids
was associated with a more than two-fold reduction in the occurrence of
the composite end-point of death or mechanical ventilation compared to
controls among patients with low oxygen saturation (12.9% vs. 28.2%).
Both the need of mechanical ventilation and all-cause mortality rates
were lower in the tofacitinib group. However, the differences between
the two groups were not significant, probably as a result of limited
number of enrolled patients. The incidence of the primary and secondary
end-points was low in patients with normal oxygen saturation and did not
differ between the two groups. Tofacitinib was well tolerated in the
studied population and was discontinued in only 5.4% of patients.
Our findings are in contrast with the results of the STOP-COVID Trial,
in which treatment with tofacitinib compared to placebo resulted in a
lower cumulative incidence of death or respiratory failure through day
28 (risk ratio, 0.63; 95% CI, 0.41 to 0.97; p = 0.04) and reduction in
the proportional odds of having a worse score on the eight-level ordinal
scale (0.54, 95% CI, 0.27 to 1.06) at day 28, whereas the difference in
the mortality rates between the tofacitinib and placebo groups did not
reach statistical significance [11]. A higher rate of
glucocorticoids administration (78.5%) and a higher dose of tofacitinib
(10 mg twice daily) are the possible explanations of the better outcomes
of JAK-inhibitor use in the STOP-COVID Trial.
Our study has several limitations. First, we could not account for
confounders inherent to the study design, although we adjusted the
baseline model for inverse propensity score weighting. Control patients
were selected randomly from the population of COVID-19 patients who were
hospitalised during the first wave of the pandemic in Russia.
Nevertheless, selection biases cannot be ruled out. Second, the
statistical power of our study was limited, particularly among patients
with normal oxygen saturation given the low incidence of events.
However, we evaluated tofacitinib’ efficacy in a relatively large sample
of patients with COVID-19.
In summary, tofacitinib in addition to standard of care therapy did not
reduce the risk of invasive mechanical ventilation or death in patients
with moderately severe COVID-19. Analysis of the composite primary
end-point and the secondary end-points favoured tofacitinib,
particularly among patients with low oxygen saturation who received
intravenous dexamethasone. However, all the differences between
tofacitinib users and controls were not significant.