Discussion
Our retrospective study revealed a considerable high prevalence of
tocilizumab in the tertiary care hospital and the number of patients who
received off-label treatment is 76 out of 167 (45.5%). Takayasu
Arteritis was the most often prescribed off label indication.
The possible reasons why off-label prescription of tocilizumab is common
in our hospital.
Firstly, the difference of approved indications between China and
foreign countries or regions. RA and sJIA are the only two indications
approved by National Medical Products Administration (NMPA). However,
some foreign countries or regions had approved a widely use of
tocilizumab except for RA and sJIA. For instance, Japan approved
Castleman’s Disease (2005.4), polyarticular juvenile idiopathic
arthritis (pJIA) (2008.4), giant cell arteritis (GCA) (2017.8), temporal
arteritis (2017.8). Europe approved pJIA (2013.5), GCA (2018), chimeric
antigen receptor T-cell immunotherapy induced Cytokine release syndrome
(CAR-T induced CRS) (2016). The US approved polyarticular juvenile
idiopathic arthritis pJIA (2013.4), giant cell arteritis (GCA) (2017.5),
CAR-T induced cytokine release syndrome (CRS) (2017.8). Moreover, the
development of clinical skills have surpassed the approval of new
indications. Some unlabelled indications have been recommended by
authoritative guidelines, or its effectiveness has been verified by
systematic reviews or well-designed clinical trials. Last but not least,
the rapid development of biological disease modifying antirheumatic drug
(bioDMARD), their comprehensive use in a variety of rheumatic diseases
have been verified effectiveness with low incidence of drug adverse
reaction. In some cases, traditional DMARD could not control the
symptoms well, physicians may try ‘explorative use’ of bioDMARDs based
on their clinical experience. As to tocilizumab, an IL-6 antagonist,
physicians may have a tendency to prescribe for some rheumatic diseases
especially with an elevated of IL-6 level.
We found the titles of physicians couldn’t be an influence factor which
affect the number of off-label prescription significantly, according to
a logistic regression analysis result (R=0.039, P=0.755). Some possible
reasons of this result could be concluded as follow. First of all, it
could contribute to the unique system of making the rounds of wards in
our hospital. In our hospital, all of clinical departments follow the
“three-level ward around” system that represent various professional
title physicians making around the ward simultaneously. As such, during
the ward-around process, all the physicians have opportunities to
exchange their ideas and in turn they would evaluate all of advice and
patient situation comprehensively. Eventually, a normalized therapeutic
regimen is recorded and taken to cure similar disease. In general, the
junior physicians prefer to look through online resource as their
medical evidence while the senior physicians tend to rely on their
abundant clinical experience. however, it is noticeable that the
“three-level ward around” system is an unique feature of our hospital
that means other hospitals may have different influence factors. In
addition, another possible factor is the literature reviewing ability of
the junior physicians because this may affect their clinical judgement
directly.
For systematic review evaluation, the involved three researches with
relatively high AMSTAR score, which means the quality of the systematic
reviews referred in this study are relatively high. According to Oxford
Centre for Evidence-Based Medicine scheme, the quality rating of each
study was related to study type. The most studies involved have high
quality rating. For the evidence, category I to category III can be
considered as relatively high level evidence. As such, our results
showed that 12 out of 16 off label indications have high level evidence
support. Analysing possible causes, these indications are all rheumatoid
immune diseases and IL-6 plays a vital roll in terms of disease
pathology. Theoretically, IL-6 receptor antagonist
(tocilizumab) could decrease the
level of elevated IL-6. Therefore, physicians have more confidence and
motivation to prescribe tocilizumab with the purpose of treatment and
furthermore conduct clinical trials. Among these 12 indications, giant
cell arteritis and Castleman disease have been approved in foreign
countries. Its use in Takayasu Arteritis[5],
Behcet’s disease[11, 12], Polymyalgia
Rheumatica[17, 18] have been recommended by
authoritative guidelines. Its use in Adult-onset Still’s Disease,
Relapsing Polychondritis, Systemic Scleroderma, Neuromyelitis Optic
Spectrum Disease have been recommended by Up-to-date. Tocilizumab used
in treating Ankylosing Spondylitis has been supported by systematic
review. One RCT has confirmed the safety and effectiveness of
tocilizumab in managing Sjögren’s Syndrome While it used in
Systemic Lupus Erythematosus has
been supported by non-randomized controlled trial.
Apart from these 12 relative high level evidence supported off-label
use, the rest 4 indications have weak evidence or no evidence support.
These off-label prescriptions normally based on physicians’ clinical
experience, mostly they have no alternative choice. For cases like this,
physicians should acquire Informed consent of the patients before
prescribing off-label indications. Besides, clinical supervision should
be strengthened, and the effectiveness and adverse reactions after
medication should be closely observed. The treatment regimen should be
stopped if there is no obvious benefit after treatment or serious
adverse drug reaction was observed.
From the clinical practice perspective, the use of
tocilizumab is not only restricted
to the 18 indications that met in our research. In fact, it has been
widely used in managing other diseases as an innovative therapy such as
myocardial infarction[35] and
Covid-19[36]. We are looking forward to more
comprehensive research.