Tofacitinib for the treatment of psoriasis and …eprints.whiterose.ac.uk/135283/3/Tofacitinib%20for%20the...4.4 Tofacitinib in the treatment of psoriatic arthritis Two phase 3 studies
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This is a repository copy of Tofacitinib for the treatment of psoriasis and psoriatic arthritis..
White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/135283/
Version: Accepted Version
Article:
Berekmeri, A, Mahmood, F, Wittmann, M orcid.org/0000-0003-2328-4926 et al. (1 more author) (2018) Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert reviewof clinical immunology, 14 (9). pp. 719-730. ISSN 1744-666X
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In recent years several new treatment options have become available for the treatment
of psoriatic arthritis (PsA), with biological therapies revolutionising the market.
However, parenteral administration potentially restricts the use of biologics,
highlighting the need for new, effective and safe oral therapies. Although tofacitinib (5
mg BID or once daily 11 mg extended release tablets) has been recently approved by
FDA for the treatment of PsA approval has been denied for use in moderate-to-severe
plaque psoriasis. The range of new oral treatments in skin psoriasis is currently limited
to the small molecule phosphodiesterase-4 inhibitor, apremilast. However, with JAK
inhibitors including tofacitinib proving successful in dermatology phase II trials for
alopecia areata (AA) and vitiligo, it is likely to become available for those indications
due to lack of efficient alternative therapies.
All of the above mentioned dermatology trials demonstrated the superiority of both
tofacitinib 5 and 10 mg BID versus placebo in the treatment of moderate-to-severe
plaque type psoriasis. Nevertheless, tofacitinib 10 mg BID was more effective
compared to the 5mg BID dosage, producing results in a shorter time period and
having a greater proportion of patients achieve PASI75, PASI90 and PGA responses,
albeit at the cost of more adverse events. However, rapid regression of the disease
occurs upon cessation of treatment [15, 17, 19]. Yet, the OPT Retreatment study
indicates that the majority of patients effectively regain response to tofacitinib following
a single interruption, results which are reassuring as treatment interruption (due to
poor compliance, pregnancy, infections, surgery) is not unusual in clinical practice.
Having said that, the study also proved continuous treatment to be better than
interrupted treatment in optimal disease control [17]. This is in line with previous
observations in the treatment of psoriasis [28], however, it has not yet been
established whether the long-term continuous use of tofacitinib is safe (33 months
being the longest treatment period examined within the Pivotal and LTE studies). The
combination of tofacitinib 5 mg, BID with MTX, as approved for the treatment of RA,
could also be a future option in the management of plaque psoriasis, especially if
associated with PsA. In the Pivotal Retreatment study no rebound phenomena have
been experienced [18], however it is not fully clear if tofacitninib can produce rebound
phenomena upon withdrawal as reported for CsA. Similar to CsA the effect on T cell
suppression is strong but rapidly reversible.
17
Both rheumatology studies have shown significantly higher ACR20 responses for each
dose of tofacitinib compared to placebo at month 3. Improvements in both trials were
observed with tofacitinib as early as week 2. Patients in OPAL Beyond had failed one
or more TNF inhibitors, implying that they had disease which was resistant to
treatment, and yet 50-60% had an ACR20 response to treatment with tofacitinib by the
end of the study. Both studies used the ACR composite measure, which is validated
for rheumatoid arthritis but not PsA. It could also be argued that ACR20 as a primary
endpoint is a relatively low target to assess for efficacy. The higher targets of ACR50
and ACR70 were achieved apart from ACR70 in the OPAL Beyond study. When
composite endpoint measures of disease specific for PsA (such as the Psoriatic
Arthritis Disease Activity Score and Composite Psoriatic Disease Activity Score) are
applied to the results of the OPAL trials both doses of tofacitinib showed improvements
compared with placebo at 3 months [29]. This demonstrates that tofacitinib improves
measures that assess across all domains of PsA.
The safety of tofacitinib has a number of issues. Altogether the rate of malignancies
was low across studies. Data taken from RA patients treated with tofacitinib (first
approved indication for the drug) showed that the overall malignancy rate and type
remain stable over time with increased tofacitinib exposure [30] and the risk is similar
to that of available non-biological and biological DMARDs. However, in the LTE
studies the numerical incidence rate of specific malignancies (especially NMSC) was
higher for tofacitinib 10 mg than with biologics used in RA (etanercept, certolizumab,
tocilizumab) [31]. Targeted screening based on the personal and family history of
patients, and on use of previous therapies such as UVB, should be considered in high
risk patients before tofacitinib administration. Long term data from registries would be
needed to examine the malignancy risk with tofacitinib.
The high incidence of HZ infection in both PsA and psoriasis patients treated with
tofacitinib, especially in Japanese population, is also of some concern. The identified
risk factors for HZ in tofacitinib treated patients include: asian race, increased age,
higher dose and prior biologic exposure [32]. Vaccination against HZ prior to starting
the drug may be considered. Patients should at least be counselled about the risk of
HZ when being initiated on treatment. The current vaccine available is a live vaccine,
although an inactivated vaccine has recently been developed and approved for use
by the CDC. According to the summary product characteristics for tofacitinib it is not
18
recommended that live vaccines be given concurrently with the drug, but should be
administered preferably at 4 weeks prior to drug initiation or in accordance with
vaccination guidelines in reference to immunosuppressive medications [33].
Downregulated molecules are believed to have an impact on persistent viral infection
control (i.e. IL-21) raising slight concerns regarding the risk of slow viral diseases of
the central nervous system – although there is no current data supporting this concern.
No cases of tuberculosis were observed in either study, although all patients would
have been screened for TB prior to entering the study and those positive would have
been filtered out. It would be prudent to screen patients for TB prior to starting the drug
until further safety data becomes available.
The increased cardiovascular morbidity in psoriasis and psoriatic arthritis is well
recognised. For this reason, the cardiovascular risk profile is an important
consideration for tofacitinib use as studies have shown elevations in lipid values.
However, values increased up to month 3, and then apparently stabilised. The use of
tofacitinib in high risk patient groups needs further evaluation. The association of
tofacitinib with lipid lowering agents, such as statins, may increase the safety of JAKs
but additional attention to the hepatic enzymes would be recommended. The modest
rise in CK levels seen with this drug may also be worth noting both in the context of
statin use and if acute cardiovascular events do occur. Monitoring patients on
tofacitinib with regular blood tests, including full blood count, liver enzymes, CPK, and
lipid profile would be recommended.
Many immunosuppressive drugs have adverse effects on the neutrophil count. It
would be prudent for clinicians to monitor neutrophil counts whilst patients are taking
JAK inhibitors as tofacitinib can cause neutropenia. Haemoglobin levels can be also
reduced although severe anaemia was not reported in the pivotal studies.
The oral formulation of tofacitinib improves patients’ convenience, independence and
compliance to treatment and reduces health care costs associated with parenteral
administration. Clinicians and patients prefer a drug for psoriatic arthritis to treat all the
different clinical domains of the disease. It would seem that this is true with tofacitinib
for skin, dactylitis and enthesitis, recognising the methodological and statistical
difficulties that were encountered. For rheumatologists treating psoriatic arthritis a key
question with regards to tofacitinib use would be where would its use fall in a treatment
19
algorithm? At what stage during the treatment pathway should tofacitinib be used for
maximal benefit? Currently clinicians move from conventional synthetic disease
modifying drugs to TNFi inhibitors, possibly switching to an alternative biologic or
apremilast if there are contraindications to TNFi. The choice of an alternative to TNFi
will depend on a number of factors, including patient preference, the presence of co-
morbidities and predominant domain involved. For example, if a patient has psoriasis
as the predominant domain an IL17 inhibitor may be the drug of choice, or an IL12/23
inhibitor if there are safety issues. Tofacitinib will be an important drug for those who
prefer oral therapies and it may be positioned alongside apremilast in the hierarchy,
although it appears to have slightly better efficacy on the articular manifestations than
apremilast. OPAL Beyond showed that tofacitinib was effective in patients who had
failed one or more biologic DMARD previously (both TNF-I & other biologic agent),
suggesting that it was an effective treatment in patients with difficult to treat disease.
OPAL Broaden examined the use of tofacitinib in patients who had failed to respond
to synthetic DMARD, using adalimumab as an active comparator. However, although
the authors state that there was no apparent difference between drug performance,
the study was not powered as a head-to-head study. Long term use in practice,
strategy and head to head trials will prove informative.
Unique bone changes occur in psoriatic arthritis, including both bone loss (erosions
and osteolysis) and bone formation (particularly juxta-articularly but also as periostitis).
These changes can develop in the same patient, even in the same digit, consisting a
paradox of this disease. The effect of tofacitinib on RANKL and IL22 may have an
important role in this respect, particularly with regard to bone loss, but larger and
longer studies with appropriate imaging will be required to demonstrate these
changes.
Tofacitinib is unlikely to be licensed for treating psoriasis alone but it may be used in
circumstances where there in concomitant musculoskeletal disease, as indicated
above. Tofacitinib is also of potential use in other skin disorders such as alopecia
areata so may be available in the dermatology area for that condition. However, the
lower dose regime of 5mg bid has less impressive efficacy on psoriasis compared to
conventional drugs such as methotrexate and certainly compared to biologic drugs.
Given the likely pricing of tofacitinib this makes the lower dose less attractive for
treating psoriasis. It is worth noting the beneficial results of tofacitinib on nail psoriasis
20
especially as this clinical feature is refractory to conventional treatments and can
impact significantly on quality of life [34, 35, 36]. Tofacitinib is greatly efficient in the
reduction of itching, with ameliorations seen as soon as following the first day of
treatment.
In summary, tofacitinib is an interesting new drug for the treatment of psoriatic disease.
It may be of particular interest for those patients refusing injection therapies and in
those with multiple molecular pathways affected by their genetic background and
maintaining disease activity. Different from CsA and MTX the effect of tofacitinib on
tissue cells relevant for psoriatic disease manifestations may be stronger and more
direct.
7 Five-year view
What place will tofacitinib take in the treatment of psoriasis and psoriatic arthritis over
the next 5 years? It is difficult to see tofacitinib achieving approval for treating psoriasis
at the 5mg bid dose and there are safety concerns, as noted by the FDA, of the more
effective 10mg bid dose. In due course other JAK inhibitors may come to market for
treating psoriasis. From the point of view of psoriatic arthritis many patients prefer an
oral drug and a drug that can improve all aspects of their disease while having minimal
side effects (particularly nausea) will be a welcome addition to the therapeutic array.
However, experience with the drug in practice and emerging data on persistence and
safety from registries will be required before the drug can be fully recommended.
Dosing is important – 5mg bid is associated with less adverse effects and will be the
dose of choice for psoriatic arthritis. The order in which the drug will be used in practice
will need further investigation, both in practice and clinical trials. Combination therapy
will also require consideration in certain, difficult to treat, patients and the safety of
such combinations will require careful monitoring. Head to head studies will emerge
so that the rheumatology community can assess the comparative efficacy and safety
of tofacitinib. Such studies will also inform the cost benefit issues which are of
particular importance where limited resources exist. With the eventual introduction of
cheaper generic forms of this drug then cost benefit issues will change and it is
possible to envisage a time when generic tofacitinib is the first disease modifying drug
to be used in psoriatic arthritis. There is no doubt that this class of drugs is here to
stay and we can expect other members of this drug class to appear for treating both
psoriasis and psoriatic arthritis.
21
Key issues
The JAK/STAT signaling pathway plays a fundamental role in cytokine messaging, therefore it has become an interesting therapeutic target in several immune mediated, inflammatory diseases;
Tofacitinib is an oral JAK inhibitor, first approved for the treatment of RA, which is now investigated for the treatment of moderate-to-severe plaque psoriasis and PsA;
The OPAL Broaden and OPAL Beyond phase III studies demonstrated the clinical efficacy of tofacitinib in the treatment of PsA;
Tofacitinb has recently received FDA approval (December 2017) for the treatment of PsA, administered p.o. 5 mg BID or as an extended release tablet 11 mg OD.
Tofacitinib approval has previously been rejected (October 2015) by the FDA for the treatment of moderate-to-severe plaque psoriasis;
Multiple dermatology phase III trials (OPT Pivotal 1 and 2; OPT Retreatment) have demonstrated the efficacy and short term safety of tofacitinib treatment in plaque psoriasis, with tofacitinib 10 mg BID administration proven to be the most effective dosage.
As more phase III study data becomes available regarding the efficacy and short term safety of tofacitinib in the treatment of plaque psoriasis, there is a higher chance that tofacitinib will receive FDA approval upon resubmission for this indication.
Long term safety concerns regarding malignancy, serious infection and viral reactivation still exist, especially with the 10 mg BID dosage, therefore there is a need for drug registries to evaluate the long term safety profile.
References
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(**)
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