Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice

Abstract

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Full text

Vol.:(0123456789)
Indian Journal of Gastroenterology
https://doi.org/10.1007/s12664-023-01507-9
GUIDELINES
Tofacitinib use inulcerative colitis: Anexpert consensus forday‑to‑day
clinical practice
RupaBanerjee1 · VishalSharma2· RajendraPatel1· AnuraagJena3· ParthaPal1· NaliniRaghunathan1·
AjayKumar4· AjitSood5· AmarenderS.Puri6· BhabhadevGoswami7· DevendraDesai8· DhanushMekala1·
G.N.Ramesh9· G.V.Rao1· KiranPeddi10· MathewPhilip11· ManuTandon1· ShobnaBhatia12·
ShubhankarGodbole1· SumitBhatia13· UdayC.Ghoshal14· UshaDutta2· VandanaMidha5· V.G.MohanPrasad15·
D.NageshwarReddy1
Received: 13 October 2023 / Accepted: 13 December 2023
© Indian Society of Gastroenterology 2024
Abstract
Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the
appropriate use of advancedtherapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase
inhibitor, in ulcerative colitis. Tofacitinib is a usefulagent for the induction and maintenance of remission in ulcerative colitis. It can
be used in the setting of biological failure or even steroid-dependent andthiopurine refractory disease. Typically, the induction dose
is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can
be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular
co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous
malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where
feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib
may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to
tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute
severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.
Keywords Herpes zoster· Inflammatory bowel disease· Janus kinase· Tofacitinib· Tuberculosis· Ulcerative colitis·
Upadacitinib
Summary ofstatements
Uses of tofacitinib forulcerative colitis
• Tofacitinib can be used as an advanced therapeutic option
in patients with moderate to severe ulcerative colitis (UC).
• Tofacitinib is a reasonable option for patients with UC
who do not respond to first-line biologic therapy.
• Limited evidence suggests that tofacitinib can be consid-
ered in patients not responding to first-line drugs such as
5-aminosalicylic acid (5-ASA), thiopurines and steroids
in UC (biologic naïve).
• The usual induction dose of tofacitinib in adults is 10mg BD.
• Patients on tofacitinib induction for moderate-severe UC
should be assessed for clinical response and remission at
the end of eightweeks.
• If there is no response at eightweeks of tofacitinib, an addi-
tional eightweeks of extended induction therapy may be
considered, only if the patient has not worsened clinically.
• If a patient on tofacitinib does not demonstrate a clinical
response by week 16, it should be considered a failure of
tofacitinib therapy.
• In patients with clinical response to induction regimen,
dosage for maintenance should be 5mg BD, which
should be started by 16weeks.
• If a patient loses response to 5mg twice daily dose after
de-escalation from 10mg BD, the dose can be escalated
back to 10mg twice daily.
Extended author information available on the last page of the article

Indian Journal of Gastroenterology
• In patients who achieve remission only on a higher tofaci-
tinib (10mg twice daily), de-escalation to 5mg twice
daily should be considered.
Pre-therapy checks
• Tofacitinib should be avoided or used with caution in
patients with leukopenias or low platelet counts, cardio-
vascular comorbidity, active infections, risk factors for
venous thromboembolism or previous malignancy.
• Baseline testing for complete blood count, liver and
kidney functions and lipid profile should be done prior
to starting tofacitinib.
• The risk for thromboembolism should be assessed.
• Testing for hepatitis B should be performed prior to
starting tofacitinib.
• Standard vaccinations for patients with inflammatory
bowel disease, including herpes zoster, should be con-
sidered prior to starting tofacitinib.
Latenttuberculosis
Tofacitinib may be associated with a risk of reactiva-
tion of latent tuberculosis (TB)—the risk is higher with
higher doses and in TB endemic regions.
Patients should be tested for latent TB infection (history
of past TB, contact with TB, chest X-ray, interferon
gamma release assay [IGRA], and tuberculin skin test)
prior to initiating tofacitinib.
Computed tomography of the chest prior to starting
tofacitinib may be considered on a case-to-case basis.
Where possible, latent TB infection (LTBI) treatment
should be completed before starting tofacitinib.
Tofacitinib should not be used in individuals diagnosed
with active TB.
Concomitant initiation of tofacitinib with the treatment
of LTBI may be done if the need for tofacitinib is con-
sidered emergent. In such cases, combined therapy with
rifampicin and isoniazid may be considered.
Special populations
• Tofacitinib should be avoided in the elderly population
if other options are available due to the increased risk
of adverse events.
• The use of tofacitinib in elderly patients is associated with
a higher risk of herpes zoster at higher doses (10mg BD).
• There is insufficient data to recommend the routine use
of tofacitinib in children with UC, although safety has
been demonstrated in rheumatological indications.
• It is advisable to avoid the usage of tofacitinib in patients
with a recent history of stroke or myocardial infarction
or those with pre-existing congestive cardiac failure.
• Tofacitinib is likely to cross the placenta during preg-
nancy and is excreted in breast milk—it should be
avoided during conception and pregnancy.
• It is recommended to use contraception during treatment
and four to sixweeks after the last dose of tofacitinib.
• Breastfeeding should be avoided while the patient is on
tofacitinib.
• Paternal and newborn outcomes are safe with paternal
exposure to tofacitinib.
Background
Inflammatory bowel disease (IBD) has been on the rise
in previously low-incidence regions of the Asia–Pacific
region, including India, over the last few decades. Manage-
ment globally has evolved beyond the traditional 5-amino-
salicylates, steroids and immunomodulators into the early
and more frequent use of advanced therapies. The advent
of biologics revolutionized the treatment with improved
outcomes, including complete mucosal and histologic
remission. However, there are challenges with biologics
including primary and secondary loss of response, require-
ment of infusion centres, risks of adverse events, need for
therapeutic drug monitoring (TDM), and, of course, high
cost especially in resource-deficient countries [1].
More recently, the “small molecules” have entered the
therapeutic arena of IBD. These “small molecular drugs
(SMDs)” have the ability to cross biological barriers, mod-
ulate different biological targets and importantly have oral
bio-availability. The primary advantages of these small
molecules are their low immunogenicity, ease of use (oral
drug) and easy storage. On the other hand, there are con-
cerns about potential side effects such as infections and
cardiovascular events [2].
The small molecule tofacitinib has recently been
approved for moderate to severe ulcerative colitis(UC) in
India. Tofacitinib is an oral, rapidly acting Janus kinase
(JAK) inhibitor, which inhibits mainly JAK1, JAK3 and
JAK2 to a lesser extent and may suppress signaling of
multiple pro-inflammatory cytokines such as interleukin
(IL) − 2, − 4, − 7, − 9, − 10, 15 and 21, interferon (IFN)-α or
γ [3]. Drugs such as upadacitinib and filgotinib are selec-
tive JAK1 inhibitors. This selective inhibition could lead to
possibly lower adverse events of herpes zoster infection and
thrombotic events [4].
There are unique challenges to the use of these immu-
nosuppressants in the Indian context. There is a lack of
awareness on the efficacy and the side effects of tofacitinib.
Moreover, there is always a concern of indiscriminate usage
being an easily available oral drug (generics available in
India), which is much cheaper than biological therapies. The
COVID pandemic created challenges in managing biological

Indian Journal of Gastroenterology
infusions, which required hospital visits and therefore, there
is a contemporary interest in advanced oral therapies [5, 6].
There is an unmet need for well-defined practice guidelines
primarily for routine clinical practice.
Methodology
We formed an expert group to develop best practice state-
ments that would be an educational tool useful for the
practicing physician in the care of UC. This would also
allow optimal positioning of tofacitinib and biologics
in the treatment algorithms. We realized that the avail-
able practice guidelines in western countries could not
completely meet the specific needs of the Asia-Pacific
region, including India. The high risk of infectious dis-
eases including TB together with the low resource settings
with lack of medical insurance pose challenges unique to
the region. We noticed inconsistencies between different
guidelines and doubts about certain recommendations such
as the use as a first-line advanced therapy.
The aim was to educate readers on the principles of tofac-
itinib and review literature, especially that arising from this
region. The lack of local data in certain domains is high-
lighted and avenues for further research are proposed.
A systematic literature review was conducted to identify
available evidence to support each statement. The literature
search was conducted in English language publications
indexed in the MEDLINE, EMBASE and the Cochrane
Trials Registry databases and limited to those in human
subjects. All relevant literature assembled by the literature
review team (RB, VS, RP, AJ, PP) was circulated among
experts. Additionally, regional and international consensus
statements and guidelines on UC were examined. Literature
from the Asia-Pacific region was of particular interest. For
many statements, the evidence has been extrapolated from
rheumatology or from observational data and therefore, the
current guidance is based on low-quality evidence. For the
dosing strategy (dose, duration), randomized controlled tri-
als in UC are available and provide high-quality evidence.
Therefore, a formal assessment of the quality of assessment
and strength of recommendation was not made.
A steering committee (RB, VS, RP, AJ) generated a list of
statements including available published literature. A face-
to-face meeting of the entire expert group was then held and
each of the statements was discussed in view of the avail-
able evidence and experience in the Indian/Asian context.
Every expert put the statement and discussed the literature
supporting that. Each of the statements was assigned to one
expert after the circulation of literature. The initial statement
was made by one expert and later discussed in a meeting.
All edits and modifications were incorporated. Later, the
modified statements were again shared for input to the expert
group members (all authors). All authors agreed to state-
ments in this current form.
The statements were grouped into the following topics in
relation to tofacitinib use:
1. Indications and dosage
2. Monitoring and assessment of patients on therapy
3. Pre-start checklist
4. Latent TB testing and management
5. Safety data and concerns
6. Use in special populations
7. Use in pregnancy and lactation
8. Positioning of tofacitinib in current treatment algorithm
Use oftofacitinib inulcerative colitis:
Indications, dosage, ecacy
Tofacitinib (TOFA) is indicated for the management of
moderate to severe UC. The standard recommended dose is
10mg twice a day for eightweeks, which can be extended
up to 16weeks for the induction of remission. OCTAVE
induction trials showed that clinical remission occurred with
a higher frequency in patients on 10mg BD as compared to
placebo. On achievement of remission, a dose of 5mg twice
a day can be used for themaintenance of remission as shown
by the OCTAVE sustain trial. In case of loss of response, the
dose can be increased to 10mg twice a day. Patients with
previous biologics exposure may need a 10mg twice a day
dose for a longer duration [7–9].
TOFA has also been used in patients with acute severe
UC and refractory pyoderma gangrenosum in recent case
series [10, 11]. In acute severe UC, a higher dose was used
(30mg/day) for a short period instead of the usual induction
dosing of 20mg/day for moderate to severe UC.
Moderate tosevere ulcerative colitis
In the OCTAVE induction trials, the primary endpoint of
therapy was remission at eightweeks. Clinical remission
was defined as a total Mayo score ≤ 2 with no subscore > 1
and rectal bleeding subscore = 0 [12]. The key second-
ary endpoint of therapy was mucosal healing, which was
defined as Mayo endoscopic subscore ≤ 1. The rates of
remission for 10mg tofacitinib at eightweeks were 18.5%
in the OCTAVE 1 trial and 16.6% in the OCTAVE 2 trial,
respectively. The clinical response rate at eightweeks was
59.9% in OCTAVE 1 and 55% in OCTAVE 2 for 10mg
dosage. The rates of mucosal healing at eightweeks
were 31.3% in the OCTAVE 1 trial and 28.4% in the
OCTAVE 2 trial [12]. An extended induction of another
eightweeks helped in the achievement of clinical response

Indian Journal of Gastroenterology
in 52.2% of patients who did not achieve clinical response
to eightweeks of 10mg twice daily tofacitinib therapy
(delayed responders) [13]. The induction therapy acts as
early as threedays of tofacitinib for the reduction in symp-
toms in moderate to severe active UC [14]. There was a sig-
nificant reduction in stool frequency score, rectal bleeding
score and total number of bowel movements by 72hours
of therapy. The clinical response at eightweeks of tofaci-
tinib in biologic naive was similar to biologic experienced
patients (OR 1.59 [95% CI: 0.54–4.63]) [15].
For the maintenance (OCTAVE Sustain) trial, the primary
endpoint of therapy was remission at 52weeks. The rates of
remission were 34.3% for a 5mg tofacitinib dose and 40.6%
for 10mg tofacitinib. Sustained clinical response at 52weeks
was seen in 59.4% with 45.7% mucosal healing for 10mg
tofacitinib dose and 37.4% for 5mg tofacitinib dose [12].
Following drug interruption, the median time to treat-
ment failure was 169 (94–179) days for induction remitters
and 123 (91–168) days for induction responders but non-
remitters. The efficacy was recaptured in 60.6% of induction
remitters and 42.4% of induction responders but non-remit-
ters [16]. Among patients who lost response to 5mg twice
daily reduced maintenance dosage, the dose escalation led
to 64.9% of patients recapturing clinical response and 49.1%
went into remission at 12months [17]. Table1 summarizes
the various studies reporting on the use of tofacitinib in
ulcerative colitis [12, 17, 18, 20–29].
Acute severe colitis
Multiple case studieshave proven the benefit of tofacitinib
in acute severe colitis [30]. The dose of tofacitinib at 10mg
thrice daily for an initial threedays should be used in patients
with acute severe ulcerative colitis (ASUC). A systematic
review including Indian data suggested that tofacitinib could
be an effective rescue therapy for steroid-refractory ASUC
[31]. In pooled data from 134 patients, a six-month colec-
tomy-free survival was noted in about 80% patients [32]. A
recent randomized controlled trial (RCT) suggested that a
combination of tofacitinib with intravenous steroids improved
the steroid responsiveness [33]. A similar RCT is ongoing
(CTRI/2022/11/047186). It would be interesting to see if these
improved response rates are not at the cost of any increase in
adverse effects although most RCTs are typically underpow-
ered for adverse effects [34].
De‑escalation oftofacitinib
In the RIVETING trial, 140 patients (tofacitinib 10mg twice
daily for more than two years and in stable remission > 6months)
were randomized to tofacitinib 5 or 10mg twice a day. The
primary outcome (disease in remission at six months) was met
in,77.1% (5mg) and 90.0% (10mg) of patients, respectively.
Smaller differences comparing groups with baseline endoscopic
subscores of 0 and 1 (9.8% and 21.1%), and groups with and
without prior anti-TNF failure (17.4% and 9.5%, respectively)
were noted [21].
Ulcerative colitis withextraintestinal
manifestations
Patients of UC with extraintestinal(EIM) manifestations
(EIMs) in the OCTAVE trials reported either improvement
or no change in arthritis from baseline after tofacitinib ther-
apy [35]. This was associated with similar rates of clinical
response and remission as compared to those patients with-
out EIM in the OCTAVE trials.
Pre‑start checklist andsafe use oftofacitinib
There are significant concerns regarding toxicity and possible
adverse effects of tofacitinib [17, 19]. Careful selection of
patients can mitigate therapy-related risks to a considerable
extent.
A complete blood count (CBC) at the start of therapy
and while on therapy is suggested since tofacitinib may
be associated with the risk of cytopenia [36]. Minor liver
function derangements are recognized but do not typically
require cessation of therapy.
Pre-therapy assessment should encompass the evaluation
of individuals who are at a higher risk of adverse effects.
This includes a history of previous malignancy, heart dis-
ease, venous thrombosis or associated risk factors. In such
situations, it may be appropriate to avoid using tofacitinib
or treat the modifiable risk factors before starting tofacitinib
[37].
Testing for hepatitis B and latent TB should be done
prior to starting tofacitinib as with biological agents. Vac-
cinations, as recommended for IBD patients, should be up
to date. In particular, the herpes zoster vaccine should be
considered in patients of IBD as JAK inhibitors increase
the risk of herpes zoster [38]
The suggested checklist for the safe use of tofacitinib
is shown in Table2.
Monitoring foradverse eects
In a real-world cohort study conducted in six US centers,
adverse events occurred in 15.7% of patients during therapy
with an incidence rate (IR) of 27.2/100 person-years (PY)
of follow-up [39].

Indian Journal of Gastroenterology
Monitoring during therapy is therefore necessary and
includes both clinical and laboratory parameters.
Clinical monitoring
Patients on tofacitinib need to be monitored clinically
for response to therapy and for any adverse effects. This
includes infections such as urinary tract infection (UTI),
nasopharyngitis and upper respiratory infections [12].
Screening and monitoring for major adverse cardiovascular
events (MACE), malignancies or thrombosis associated with
both regimens of tofacitinib are to be carried out periodically
by the treating physician [40]. Clinical examination should
include periodic skin checks, looking for anemia, lymphad-
enopathy and signs of deep vein thrombosis (DVT).
Laboratory monitoring
Baseline and periodic tests such as CBC, peripheral smear, ESR,
C-reactive protein (CRP), liver function test (LFT) and lipid pro-
file at four, 12 and 24weeks need to be performed. Changes
in liver enzymes, lipid profile, hemoglobin, absolute neutrophil
count (ANC) and/or absolute lymphocyte count (ALC) should
prompt appropriate action. As per the approved label, lipid levels
should be monitored four to eightweeks after the start of therapy
and lipid-lowering agents should be started as required.
In cases of MACE, a switch of therapy or alternate ther-
apy may be considered.
In cases of prior history of VTE, pro-thrombotic work-up
and treatment of predisposing factors may be considered.
Tofacitinib should be avoided in child C cirrhosis and a half
dosage considered in child B cirrhosis.
Table 1 Efficacy of tofacitinib in clinical trials and real-world studies
Clinical trials
Study Dose Duration at Clinical
response
Clinical remission Endoscopic remission
Sandborn etal., 2012, [18]
(Phase II study)
10mg BD  8weeks 61% 48% 67%
Sandborn etal., 2017 [12]
(OCTAVE 1 and 2)
10mg BD  8weeks 59.9%, 55% 18.5%, 16.8% 31.3%, 28.4%
Sandborn etal., 2017 [12]
(OCTAVE SUSTAIN)
10mg BD 52weeks 61.9% 40.6% 45.7%
Sandborn etal., 2022 [19]
(OCTAVE OPEN)
10mg BD
16weeks
12months 52.2% 44.6% 56.8%
Sands etal., 2020 [17]
(OCTAVE OPEN)
10mg BD post-non-remission
on 5mg BD maintenance
12months 64.9% 49.1% 57.9%
 5mg BD post-remission on
10mg BD maintenance
12months 84.1% 74.6% 81.5%
Colombel etal., 2022, [20]
(OCTAVE OPEN)
 5mg BD in remission
post-OCTAVE SUSTAIN
12months 77.5% 68.3% 73.9%
Vermeire etal., 2021 [21]
(RIVETING)
10mg BD post-
remission > 2years
 6months 95.7% 90% 91.4%
 5mg BD post-
remission > 2years
 6months 84.3% 77.1% 80%
Real-world studies
 Biemans etal., 2020 [22] (ICC
Registry)
10mg BD for 8weeks followed
by 5mg BD
24weeks 45.5% 29% 36.4%
 Honap etal., 2020, [23] (LEO
IBD Consortium)
10mg BD for 8weeks followed
by 5mg BD
24weeks 53% 44%
 Ungaro etal., 2019, [24] 10mg BD  8weeks 61% 55%
 Chaparro etal., 2021, [25]
(ENEIDA Registry)
10mg BD 16weeks 57% 32%
 Taxonera etal., 2022, [26]
(real-world studies meta-analysis)
10mg BD  8weeks 62.1% 34.7% 48.3%
12–16weeks 64.2% 47% 45.3%
 6months 50.8% 38.3%
12months 41.8%
 Avni-Biron etal., 2022, [27] 10mg BD  8–16weeks 47.6% 20.6%
 Long etal., 2023 [28] (TOUR) 10mg BD  8weeks 61.5% 42.7%

Indian Journal of Gastroenterology
Skin check for herpes zoster lesions is to be carried out
periodically by the physician.
Safety data onTOFA (rheumatology
experience)
The concerns for the safety of JAK inhibitors have been
raised since the launch of these drugs for rheumatological
diseases. Tofacitinib received FDA approval for use in RA
in 2012. Soon after, Pfizer, the manufacturer was asked by
the American FDA to conduct a post-marketing clinical
trial (ORAL surveillance trial) to address concerns regard-
ing the increased risks of cancers, major adverse cardio-
vascular events (MACE) and serious infections [41]. This
trial included RA patients > 50years on methotrexate, with
at least one added cardiovascular risk factor. Patients were
randomized in a 1:1:1 manner with tofacitinib 5mg or 10mg
BD or anti-TNF (tumor necrosis factor) inhibitor [41, 42].
The interim analysis from an ongoing safety trial in RA
patients found that patients on tofacitinib 10mg BD dosage
had a high incidence of pulmonary embolism and a higher
number of overall deaths. This led to the FDA mandating
switching all patients on 10mg BD tofacitinib to 5mg BD
dose and issuing a black box warning [42]. The final ORAL
trial results did not meet the non-inferiority criteria and the
risks of MACE and cancers were higher with tofacitinib as
were the numbers of other adverse events when compared to
the anti-TNF group [41]. This resulted in an FDA black box
warning regarding the use of JAK inhibitors for the treat-
ment of chronic inflammatory conditions.
Safety data oftofacitinib inulcerative colitis
It is important, however, to highlight that the safety data for
tofacitinib in UC patients in trials and real-world studies
have been consistently reassuring [21, 31, 32].
The primary safety data of tofacitinib in UC comes from
the OCTAVE clinical program and the now-concluded
OCTAVE Open study [19, 43]. Outcomes/adverse events
were calculated as incidence rates (IR) (unique patients with
events/100 patient-years) for treatment duration for three up
to sevenyears of follow-up [19].
More than 80% of patients received tofacitinib 10mg BD
dosage at enrollment in this trial. The study concluded that
serious infections, malignancies and venous thromboembolic
events were infrequent and the safety profile was consistent
with that observed in previous analyses from the OCTAVE
clinical program [19, 43]. The data from the OCTAVE clini-
cal program and open studies show that tofacitinib has an
acceptable safety profile in UC patients. This is in sharp
contrast with similar data from the ORAL surveillance data
in RA patients, which showed an increase in overall deaths,
MACE and cancers with tofacitinib [19, 41].
Of note, all DVT (one event) and PE events (five events,
0.7%) in OCTAVE open were in the tofacitinib 10mg BD
group [19]. The data so far has not suggested an increased
Table 2 Suggested checklist for the safe use of tofacitinib
TB tuberculosis, ANC absolute neutrophil count
Parameter Baseline When to repeat
Hemogram Yes
Avoid use if significant cytopenia
4–8 weekly
Stop if absolute neutrophil or lymphocyte count < 500
If ANC < 1 000, may stop or reduce the dose
Lipid profile Yes 4–8weeks, 6months
Treat dyslipidemia as per standard guidelines
Liver function tests Yes 4–8weeks and then 3 monthly
Most aminotransferase elevations are transient and resolve
Renal function tests Yes Yearly
Creatine kinase May consider May consider
Clinical relevance of creatine kinase elevations is uncer-
tain
Reversible with stopping therapy
Hepatitis B HBsAg and anti-HBc
Venous thrombosis Potential risk factors—hospitalization, smoking, elderly,
underlying malignancy, oral contraceptive use, significant
comorbidities
Cardiovascular risks Assess for smoking, hyperlipidemia, hypertension, diabetes
mellitus and address/control of these
Latent TB testing Perform before starting Yearly while on therapy

Indian Journal of Gastroenterology
incidence of thromboembolic events with the usage of tofaci-
tinib in UC and the IRs have been comparable to those already
reported in literature for patients with UC [44, 45]. With the
exception of a higher IR for herpes zoster (HZ) (7.7%), the
safety of tofacitinib in OCTAVE open was similar to that
reported for other approved UC therapies, including biologics
[40]. Recent real-world data on the safety of tofacitinib similar
to clinical OCTAVE program is reassuring [26]. Taxonera
etal. in a recent systematic review and meta-analysis reported
safety outcomes in 15 studies, including 972 patients, with a
455-patient-years exposure. The IR for serious adverse events
(SAE) was 8.9 patients/100 patient-years [26].
The only consistent finding across studies has been a
higher incidence of HZ infection related to tofacitinib use.
In 13 studies, there were 32 events of HZ in 952 patients
[26]. In fact, the IR for HZ was 6.9 patients per 100 patient-
years, which was higher than OCTAVE open of 4.1. In
the real world, unlike clinical trials, a majority of patients
were already exposed or had failed biologics before being
started on tofacitinib. Prior exposure to biologics or failure
to respond to biologics has been postulated to be a risk fac-
tor for the development of HZ in the integrated analyses
of infections throughout the global tofacitinib UC clinical
program [46]. None of the studies reported major adverse
cardiovascular events or thromboembolic complications,
which is similar to the data from OCTAVE trials [19, 26].
Another real-world study evaluating the safety of tofacitinib
in a cohort of 260 UC patients reported two venous thrombo-
embolisms [39]. Both cases had several predisposing factors
for thromboembolic events alongside UC and were receiving
tofacitinib 10mg twice daily dosage [39]. This is similar
to OCTAVE open, where thromboembolic events occurred
only in patients taking higher dosage [19, 26, 39].
Overall, tofacitinib has shown a consistent and acceptable
safety profile so far in UC patients in clinical trials and real-
world data [23]. However, there are red herrings of increased
major cardiovascular events, thromboembolism, cancers and
deaths in rheumatology trials, especially with higher dosages.
This has to be kept in mind while prescribing to UC patients,
especially high-risk groups including the elderly and patients
with malignancies and comorbidities. We need more data to
define cardiovascular and other risks in the IBD population.
Tofacitinib andrisk ofinfections
Serious and sometimes fatal infections due to bacterial,
mycobacterial, invasive fungal, viral or other opportunistic
pathogens have been reported in patients receiving tofaci-
tinib. Incidence rates (95% CIs) for tofacitinib 5 and 10mg
twice daily in phase-III trials were 3.02 (2.25, 4.05) and 3.00
(2.24, 4.02), respectively [47]. Patients should be closely
monitored for the development of signs and symptoms of
infection during and after treatment with tofacitinib. Treat-
ment should be interrupted if a patient develops a serious
infection, an opportunistic infection or sepsis.
The patient is advised to report on the occurrence of any
new symptom immediately. Symptom-based work for spotting
complications is carried out on an SOS basis.
It has been reported that the risk of HZ is higher in immune-
mediated inflammatory diseases and IBD patients have a
higher risk in general for the development of HZ with a higher
risk in Crohn’s disease than UC [48, 49]. In IBD, the IR ranges
from 6.67 to 9.2 cases per 1000 PY [50, 51]. Many IBD treat-
ments such as the use of corticosteroids, immunomodulators
and biologics (anti-TNF drugs) are also associated with higher
incidence rates of HZ [52].
JAK inhibitors are associated with higher risks of HZ
in immune-mediated inflammatory diseases as per a recent
meta-analysis [53]. An immune response to HZ uses the
JAK signal transducer and activator of transcription path-
ways, especially type I and II (20). This explains the higher
incidence of HZ with pan-JAK inhibitors like tofacitinib. It
remains to be seen, whether selective JAK inhibitors such
as filgotinib and upadicitinib will confer a lower risk of HZ
than tofacitinib.
There has been a consistent and definite risk of devel-
oping HZ infection with the usage of tofacitinib in RA
and UC patients in nearly all reported literature [54, 55].
In tofacitinib, being a pan-JAK inhibitor, the risks of HZ
are postulated to be higher [54]. Pooled data from previous
tofacitinib UC clinical programs showed an elevated risk of
HZ in patients receiving tofacitinib; a majority of cases were
non-serious, cutaneous and limited in their distribution. HZ
events in the OCTAVE clinical program in patients with UC
were generally non-serious and a majority of cases did not
warrant permanent discontinuation of the drug. There were
65 patients with an event of HZ, most of whom were able to
either continue tofacitinib treatment (n = 44) or temporarily
stop/reduce their tofacitinib dose (n = 16) [54]. OCTAVE
Open extension study showed similar high IRs for HZ (non-
serious and serious), both in the tofacitinib 5 and 10mg BD
groups [19].
In terms of management, studies have shown that
amajority of patients are able to continue or resume
tofacitinib treatment. However, a temporary drug dis-
continuation may be considered. Winthrop etal. recently
described > 90% of HZ cases did not require drug discon-
tinuation. HZ events were generally non-complicated and
manageable with standard antiviral treatment [56]. To
summarize, HZ infection is uncommon with tofacitinib;
however, events observed across all indications tend to be
non-complicated and can typically be managed without
permanent discontinuation of therapy.

Indian Journal of Gastroenterology
Prevention ofHZ infection
A recombinant zoster vaccine, Shingrix (GlaxoSmithKline,
London, UK) has been approved by the FDA since 2017
for the prevention of HZ and its complications among
adults > 50years [57]. The US ACIP also recommended it
in 2018 for adults > 50years. It is administered as an intra-
muscular injection in two doses two to sixmonths apart. The
efficacy and immunogenicity of the vaccine are more than
95% with a good safety profile [58]. In 2017, the American
College of Gastroenterology clinical guidelines for IBD
recommended that patients older than 50years, including
those immunosuppressed, should be recommended HZ vac-
cination [59].
Another live zoster vaccine Zostavax (Merck Sharp and
Dohme, Kenilworth, NJ, USA) an attenuated form of VZV
has been approved for the prevention of HZ and its complica-
tions in adults > 60years by the US Food and Drug Admin-
istration (FDA) since 2006 [60]. It is administered as a sin-
gle-dose subcutaneous with an efficacy of more than 60% in
the age group > 60years of age [60]. Live zoster vaccine is
contraindicated in patients with primary and acquired immu-
nodeficiency states, immunosuppressive therapy, including
high-dose corticosteroids, active untreated tuberculosis and
pregnancy [60]. We suggest that vaccination with recombi-
nant vaccine should be considered prior to initiating tofaci-
tinib, especially in high-risk groups (elderly). Although vac-
cination is suggested, the recombinant vaccine is costly at
present. Additionally, all patients with UC and > 50years
should be vaccinated by the two-dose standard vaccination
for HZ to prevent infection with the use of advanced therapies
including anti-TNFs, which can also increase the risk.
Latent TB testing andmanagement prior
tostarting tofacitinib
Although the initial trials of tofacitinib in UC did not
show evidence of TB reactivation, there is evidence of an
increased risk in rheumatoid arthritis [19, 61–64]. In gen-
eral, the same guidelines as for infliximab can be followed.
Evidence from a mouse model also suggested an increase
in mycobacterial replication and heightened risk of TB reac-
tivation with the use of tofacitinib [65]. Tuberculosis has
been reported as a common opportunistic infection in RA
patients on tofacitinib [62]. There is also evidence to suggest
that the underlying high TB endemicity of the geographic
region is an important risk factor for tuberculosis with tofac-
itinib use [62, 64]. The risk of tuberculosis is also higher
with higher doses considering that the dose of tofacitinib is
usually higher in UC [66].
However, there are only a few case reports of tuberculo-
sis with the use of tofacitinib in patients with UC possibly
because most of the tofacitinib use so far has been only in
low endemic regions [67, 68]. However, given the reports of
TB reactivation in the setting of other autoimmune condi-
tions, high TB endemicity in India and higher induction dose
in UC, patients being started on tofacitinib should undergo
screening and treatment for latent TB.
There is no direct evidence to suggest the appropriate
screening modality prior to tofacitinib initiation in ulcera-
tive colitis. The 2015 ACR Guideline for Rheumatoid
Arthritis suggests that the pre-tofacitinib screening in rheu-
matoid arthritis should be similar to other biologics [31].
In a recent study from India, the use of stringent screening
(with computed tomography of the chest) and treatment
resulted in a decline in TB cases with anti-TNF use [69]. It
is unclear if a similar stringent strategy is warranted with
tofacitinib.
If there is evidence of LTBI, the treatment should ide-
ally be done prior to initiation of tofacitinib. Rifampicin
may reduce the levels of tofacitinib and compromise clini-
cal efficacy [70, 71]. Therefore, when immediate initia-
tion of tofacitinib is warranted clinically, a combination of
rifampicin and isoniazid may be preferable because isoniazid
may increase the levels of tofacitinib.
Tofacitinib inspecial populations
The general guidelines for the management of UC in four
distinct special populations are considered:
Elderly patients, children, patients with coronary artery
disease (CAD) and those with past or current history of
venous thromboembolism (VTE).
1. Elderly: As per the WHO definition age > 65 is arbi-
trarily defined as elderly. In India according to the law,
age > 60years is considered a senior citizen. The effi-
cacy of tofacitinib for theinduction of remission and
maintenance of remission was established by the Octave
I, II and Octave sustain trials [12, 13]. The mean age
of patients in these two trials (Octave 1476 and Octave
2479 patients) was 41years with an SD of 14 and
13years, respectively. Assuming that the age distribu-
tion followed the Gaussian pattern, it would be reasona-
ble to assume that a significant proportion of the patients
were elderly. Of the 1157 patients evaluated for adverse
events, severe adverse events occurred in 144 (12.4%).
Studies in both RA and UC suggest that the risk of HZ
is higher in elderly patients possibly due to their lower
immune status. Based on studies in RA, it was shown
that elderly patients with at least one risk pre-existing

Indian Journal of Gastroenterology
cardiac risk factor were more prone to major adverse
cardiac events (MACE). Thus, caution needs to be
advised in prescribing tofacitinib in elderly patients. To
date, however, there have been no clinical trials that have
compared the efficacy and safety of tofacitinib in elderly
vs. non-elderly populations. A recent study showed that
tofacitinib could be safely given in elderly patients with-
out therisk of thromboembolic manifestation by either
reducing the dose or concomitant anti-thrombotic ther-
apy [72]. On the contrary, a study showed an increased
risk of zoster and malignancies in the elderly cohort
receiving tofacitinib [73].
2. Pediatric population: Limited data is available on the
efficacy and safety of tofacitinib in the pediatric popula-
tion. In one small study of 21 patients aged < 21years,
the clinical response rate at 12weeks was 43%. At
52weeks, 7/17 patients were in steroid-free clinical
remission. Colectomy was necessary in eight of the 21
(38%) patients. Considering that these patients had pedi-
atric onset UC (A1) disease which has an aggressive
course, a sizeable proportion of patients were able to
avoid colectomy in the short-term [74]. A study of 17
children showed a good clinical response and steroid-
free disease course in seven patients with tofacitinib at
52weeks [74]. A retrospective series of 15 Irish children
showed clinical remission in eight patients with tofaci-
tinib [75]. Another study of hospitalized 11 children of
refractory UC showed that eight patients could avoid
colectomy at three months [76]. A small case series
of four patients demonstrated clinical and endoscopic
remission in three patients without any serious adverse
events [77]. One patient with refractory colitis was man-
aged with a high dose of tofacitinib successfully [78].
Given the limited experience of usage of tofacitinib in
the pediatric UC age group, no definite recommenda-
tions can be given until more data is available.
3. Coronary artery disease: Tofacitinib causes a reversible
and dose-dependent increase in the level of total choles-
terol, high-densitylipoprotein(HDL) and low-density
lipoprotein (LDL). In September 2021, the FDA issued
a Black Box warning for tofacitinib, as it was associated
with a higher risk of sudden death due to stroke and
acute myocardial infarction in patients with rheumatoid
arthritis [79]. The overall incidence ratio for sudden
death is, however, small < 0.5/100 patient-years and is
mainly in patients > 50years with at least one risk factor.
Thus, the drug is best avoided in patients with a recent
history of stroke or MI or underlying congestive car-
diac failure. Serious cardiovascular adverse events were,
however, not reported in any of the OCTAVE studies for
UC [19].
Tofacitinib inpregnancy andlactation
The position statements on the usage of tofacitinib in preg-
nancy and lactation are based on a small number of stud-
ies, prescriber information from the drug manufacturer and
indirect evidence from the usage in non-IBD patients such
as rheumatoid arthritis. Pregnant women and feeding moth-
ers are excluded from large clinical trials of tofacitinib in
IBD due to the lack of safety data. Though there is no data
to prove or disprove, it is reasonable to assume that being a
small molecule, tofacitinib will cross the placenta.
In a large study of 9815 patients with rheumatoid arthri-
tis/psoriasis, 1821 female patients of child-bearing age were
enrolled. Of these, 47 women became pregnant, including 33
who received tofacitinib monotherapy, 13 who received com-
bination therapy with methotrexate and one patient whose
therapy was still blinded. One congenital pulmonary valve
stenosis, seven spontaneous abortions and eight medical ter-
minations were identified but no fetal deaths were reported.
The remaining 25 women had healthy newborns [80].
Asmany as 1157 patients (including 301 women of
childbearing age) with 1612.77 patient-years of tofacitinib
exposure were included in the tofacitinib UC interventional
studies. Twenty-five cases of pregnancy were reported (11
cases of maternal and 14 cases of paternal exposure were
identified). Outcomes were 15 healthy babies, no fetal or
neonatal deaths, no congenital malformations, two sponta-
neous abortions and one medical termination [81]. Tofaci-
tinib is teratogenic in animals and contraindicated in patients
planning for pregnancy as per the original manufacturer
(Xiejanz, Prescribing information 2018).
If tofacitinib is to be stopped during pregnancy, a washout
of at least one week before planned conception is advised
as its half-life is 3.2hour. The manufacturer’s recommenda-
tion is to use effective contraception during treatment and
for four to sixweeks after the last dose of tofacitinib [82].
Higher concentrations (× 2) of tofacitinib are seen in milk
than serum of lactating rats and it is likely to be the same
among humans. So until further data, the recommendation
is to avoid breastfeeding for 18hours after the last dose of
tofacitinib [29]
No effect on sperm quality, motility and concentration
was noted among rats exposed to much higher doses of
tofacitinib than humans. Pregnancy and newborn outcomes
among patients with paternal exposure to tofacitinib are the
same as that of the general population [82]
The evidence on the usage of tofacitinib in pregnant
women and breastfeeding mothers is subjected to the follow-
ing limitations: a small number of studies, limited number
of pregnancies, short exposure and brief follow-up. There
are no control groups for the pregnant group receiving

Indian Journal of Gastroenterology
tofacitinib. Often there is a lack of consideration of poten-
tial confounders (disease activity, smoking, alcohol, con-
comitant medications). Most societies advise to consider a
contraindication during pregnancy.
Positioning TOFA inthecurrent treatment
algorithm
In IBD therapy, infliximab triggered a revolution in 1999,
which was followed by adalimumab, golimumab, first bio-
similar infliximab, vedolizumab, tofacitinib, upadacitinib,
ustekinumab, risankizumab, guselkumab, ozanimod and
other JAK inhibitors. In India, the available molecules
include two anti-TNF agents/biosimilars, vedolizumab
ustekinumab and tofacitinib. Due to the high cost of biologi-
cals (and even biosimilars), many patients cannot afford it.
They have side effects due to profound immunosuppression.
More than half the patients discontinue biologicals due to
primary non-response or secondary loss of response due to
the development of antibody formation.
Tofacitinib has the advantage of oral administration and
low cost in the Indian context compared to the biologicals.
Being a small molecule, there is no risk of development
of antibodies to tofacitinib. On the other hand, the drug
has potentially serious side effects such as pulmonary
thromboembolism, lipid abnormalities and risks of herpes
zoster.
Therefore, a judicious usage balancing efficacy and safety
is needed for optimum patient care [83]. On the other hand,
the cost of tofacitinib (Generic: Rs29,000 per year of treat-
ment) is cheaper than biologicals (Infliximab biosimilar:
Rs360,000 per year of treatment) in India because of the
availability of generics and would serve as a good option for
patients of LMIC [84].
A network meta-analysis showed in patients with previ-
ous exposure to anti-TNF drugs, ustekinumab and tofacitinib
were ranked highest for the induction of clinical remission
[85]. They were found to be superior to vedolizumab and
adalimumab. The network study by Lasa etal. showed tofac-
itinib was ranked highest for the maintenance of steroid-free
remission in randomized trial responders [86].
Recommendations fromvarious guidelines
Multiple recent guidelines are from the British Society of
Gastroenterology (BSG), American Gastroenterological
Association (AGA), American College of Gastroenterol-
ogy (ACG) and European Crohn’s and Colitis Organisation
(ECCO) for medical management of moderate to severe UC
[7, 87, 88]. However, there are very limited head-to-head
Fig. 1 Algorithm suggested for tofacitinib administration in moderate to severe ulcerative colitis

Indian Journal of Gastroenterology
trials and primarily data from network meta-analysis have
been used.
In the updated guidelines, AGA recommended using inf-
liximab, adalimumab, golimumab, vedolizumab, tofacitinib
or ustekinumab over no treatment. The use of tofacitinib
should be restricted to the setting of a clinical or registry
study in view of the black box warning. Tofacitinib or
ustekinumab is recommended only for patients with pri-
mary/secondary loss of response to anti-TNFs.
The ACG and the recent 2022 ECCO guidelines [87, 88]
on the other hand have recommended TOFA as a first-line
drug for ulcerative colitis after careful consideration against
black box warnings such asincreased risk of serious cardi-
ovascular-related events (e.g. heart attack, stroke), cancer
(e.g. lymphoma, lung cancer), thrombosis and death with
the use of TOFA as compared to anti-TNF.
Relevance totheIndian practice
In India, biological agents are unaffordable for many patients
with moderate to severe UC. Tofacitinib can be considered
as a first-line drug in these patients. However, patients must
be selected carefully in view of their side effect profile. There
is upcoming evidence that supports the use of tofacitinib as
a first-line therapy. A recent multi-centre Indian experience
suggests that 70% of the patients achieved clinical remis-
sion with tofacitinib and around 60% were in remission at
six months [89]. There are similar unpublished data from
other India centers (Banerjee R). In a randomized ORCHID
study comparing steroids to tofacitinib in moderately active
UC, tofacitinib was similarly effective in achieving clinical
remission and response at eightweeks [90]. Therefore, there is
emerging evidence that tofacitinib could be used in anti-TNF
unexposed Indian patients. There is evidence of some adverse
effects, especially herpes zoster and tuberculosis (24, 71, 72).
The risk of HZ can now be mitigated by the recent availability
of the Shingrix vaccine in India. Though a costly vaccine, the
risks associated with HZ can be avoided.
Future studies reporting on tofacitinib experience in the
Indian population may shed more light on the real risks,
especially in relation to infections.
Keeping serious adverse events in mind and in line with
FDA warnings as well, the expert panel suggested avoidance of
tofacitinib in with other cardiovascular risk factors, those who
develop a malignancy and those with a known malignancy
other than a successfully treated non-melanoma skin cancer.
The following algorithm is suggested (Fig.1) for tofaci-
tinib administration in moderate to severe UC.
In conclusion, the statements for the effectiveness of
tofacitinib for moderate to severe UC in the current scenario
have been laid down by a panel of experts. In particular, the
usage of tofacitinib in India has also been highlighted and
can serve as a useful guide for clinicians during practice.
Data availability Not applicable.
Declarations
Competing interests RB, VS, RP, AJ, PP, NR, AK, AS, ASP, BG, DD,
DM, GNR, GVR, KP, MP, MT, SB, SG, SuB, UCG, UD, VM, VGMP
andDNR declare that they have no conflict of interest.
Ethics approval and consent to participate Not applicable.
Consent for publication Not applicable.
Disclaimer The authors are solely responsible for the data and thecon-
tents of the paper. In no way, the Honorary Editor-in-Chief,Editorial
Board Members, the Indian Society of Gastroenterology or the printer/
publishers are responsible forthe results/findings and content of this
article.
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Authors and Aliations
RupaBanerjee1 · VishalSharma2· RajendraPatel1· AnuraagJena3· ParthaPal1· NaliniRaghunathan1·
AjayKumar4· AjitSood5· AmarenderS.Puri6· BhabhadevGoswami7· DevendraDesai8· DhanushMekala1·
G.N.Ramesh9· G.V.Rao1· KiranPeddi10· MathewPhilip11· ManuTandon1· ShobnaBhatia12·
ShubhankarGodbole1· SumitBhatia13· UdayC.Ghoshal14· UshaDutta2· VandanaMidha5· V.G.MohanPrasad15·
D.NageshwarReddy1
* Rupa Banerjee
dr_rupa_banerjee@hotmail.com
1 Department ofMedical Gastroenterology, Asian Institute
ofGastroenterology, Mindspace Road, Gachibowli,
Hyderabad500032, India
2 Postgraduate Institute ofMedical Education andResearch,
Sector-12, Chandigarh160012, India
3 IMS andSUM Hospital, K8, Kalinga Nagar,
Bhubaneswar751003, India
4 BLK Institute ofDigestive Science, BLK-Max Super
Speciality Hospital, Pusa Road, NewDelhi110005, India
5 Dayanand Medical College andHospital, Civil Lines, Tagore
Nagar, Ludhiana141001, India
6 Medanta Hospital, CH Baktawar Singh Road, Medicity,
Islampur Colony, Sector 38, Gurugram122001, India
7 Dispur Hospital, Dispur, Manik Nagar, Guwahati781006,
India
8 Hinduja Hospital, 8-12, Swatantryaveer Savarkar Road,
Mahim West, Mahim, Mumbai400016, India
9 Aster Hospital, Kuttisahib Road Cheranelloor, South
Chittoor, Kochi682027, India
10 Yashoda Hospitals, 6-3-905, Raj Bhavan Road, Matha Nagar,
Somajiguda, Hyderabad500082, India
11 Lisie Institute ofGastroenterology, Cochin, Lisie Hospital
Road, North Kaloor, Kaloor, Ernakulam682018, India
12 National Institute ofMedical Sciences, Kalwad Kalan and
Khurd, Jaipur303121, India
13 Paras Hospitals, Sec-43, Sushant Lok, Gurugram122002,
India
14 Apollo Institute ofGastrosciences andLiver, Apollo
Multispecialty Hospitals, 58, Canal Circular Road, Kadapara,
Phool Bagan, Kankurgachi, Kolkata700054, India
15 VGM Hospital, 2100, Trichy Road, Coimbatore641005,
India