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.