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The use of oral corticosteroids in inflammatory bowel diseases in Italy: An IG-IBD survey
Digestive and Liver Disease, Available online 22 July 2017
Corticosteroids have been used for the treatment of IBD for more than sixty years, having represented the first major therapeutic breakthrough for these conditions. Indeed, early controlled trials have demonstrated the clear superiority of oral corticosteroids over both placebo and sulphasalazine in inducing clinical remission in both UC and CD 1 2 3 4 , and optimization of intravenous corticosteroids administration has resulted in a dramatic drop in mortality due to severe UC attacks  . As a consequence, corticosteroids have been a mainstay in the treatment of these diseases for decades. In spite of this, very few further controlled trials have been subsequently conducted 6 7 8 9 10 11 12 13 14 15 16 and even less studies (either controlled or observational) have explored the best way of using these drugs in terms of dosage, duration and tapering modalities 17 18 19 20 21 . Therefore, available practice guidelines are generally elusive on these issues and the use of corticosteroids in clinical practice is still quite empirical 22 23 24 25 26 27 28 . Paradoxically, the use of newer preparations of oral low-bioavailability steroids (LBS) such as budesonide and beclomethasone dipropionate has been better delineated by clinical trials, case series and systematic reviews 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 and better codified in guidelines [22 28 44] .
We therefore designed a simple questionnaire aimed at exploring the habits and preferences of Italian IBD physicians in the use of oral steroids in their real-life clinical practice. The fields that were explored included preferences between CCS and LBS oral steroids for mild to severe IBD relapses, therapeutic strategies in case of failure of low-availability steroids, starting dose, length of treatment and tapering modalities for systemic steroids, mode of patients’ follow-up during steroid treatment.
2 Materials and methods
A 35-item web-based questionnaire was sent to all the 448 members of the Italian Group for Inflammatory Bowel Disease (IG-IBD). Three out of 35 questions were aimed at exploring the demographic characteristics of the participants, 12/35 the habits of Italian gastroenterologists in treating mild to severe relapses of CD and UC, 12/35 explored practical details such as starting dose, length of treatment, tapering modalities, 2/35 the behavior in case of steroid-dependency or resistance and the remaining on the modalities of treatment monitoring.
GraphPad Instat package software (GraphPad Software Inc., San Diego, CA, USA) was used to analyze data by means of Student’s t test, Mann–Whitney test, Fisher’s exact test and Chi-square test for independence, as appropriate. All the statistical tests were two-tailed and the statistical significance was set at p = 0.05.
One hundred and thirty one gastroenterologists (29.2%) completed the survey. The demographic characteristics of respondents are summarized in Table 1 .
|<30 years||7 (5%)|
|30–39 years||47 (36%)|
|40–49 years||41 (31%)|
|50–59 years||29 (22%)|
|>60 years||7 (6%)|
|Public, non academic||59 (45%)|
|Public, academic||50 (39%)|
|Private, non academic||12 (8%)|
|Private, academic||10 (6%)|
|Number of IBD patients followed|
3.1 Preferences between low-bioavailability and conventional steroids for IBD relapses (see also Figs. 1 and 2 )
For mild to moderate CD relapses, 37% of physicians use LBS as first line treatment, whereas 42% do so in patients with mesalazine-refractory mild to moderate UC; the remaining either prefer CCS or decide case by case. These figures were significantly higher among clinicians younger than 40, both in CD (50% vs 22%, p = 0,021) and UC (52% vs 35%, p = 0,043).
For moderate to severe flares, 85% and 92% start CCS as first line treatment in CD and UC respectively; however, 15% and 8% respectively consider starting with LBS. In case of LBS failure, 72% switch to CCS in both CD and UC patients, whereas 23% and 29% move to another drug class in CD and UC patients, respectively. In patients with UC, 3 percent increase LBS dosage.
3.2 Dosage and duration, tapering modalities, length of treatment, patients monitoring during treatment with CCS ( Figs. 3 and 4 )
When using CCS, 22% of gastroenterologists always determine the starting dose according to patients’ weight while 50% used a fixed, predetermined, starting dose (50–60 mg daily in most cases, see figure). Fifty-nine percent recommend taking the entire dose in the morning while 38% recommend dividing the dose between morning and early afternoon. A significantly higher percentage of academic clinicians recommend taking the entire dose in the morning (71% vs 53% p = 0,037). As for as duration of full-dose treatment, 40.5% always follow a standard regime (7–10 days 41%, 2 weeks 32%, 3 weeks 7%, 4 weeks 17%); the remaining tailor the length of full-dose treatment either always or sometimes. Before tapering the dose of steroids, 60% of gastroenterologists regularly re-evaluate patients, 35% re-evaluate patients occasionally and 5% never. Among those who re-evaluate patients before tapering the dose of CCS, 7% did it by means of a phone conversation, 40% by a face to face visit, 47% perform also blood tests and 6% endoscopic or ultrasonographic investigations.
Regarding tapering modalities, 60% of respondents stated they use a standard scheme (65% of them reduced the dose by 5 mg every week), the remaining personalizing according to patients’ characteristics either always or sometimes.
Among clinicians stating to personalize (always or sometimes) treatment modalities, factors taken into account include patients’ age, BMI, severity of the relapse and comorbidities.
3.3 Behaviour in case of steroid resistance or dependency ( Fig. 5 )
In case of unsatisfactory response to a course of full-dosage treatment with CCS, 35% of gastroenterologists switch to a different class of medications, 47% switch to parenteral administration, and 6% increased dosage. The percentage of in case of symptoms recurrence during the tapering phase, 57% increase the dosage of oral steroids while introducing a second line of treatment (either immunosuppressants or biologics), 25% switch directly to immunosuppressants or biologics, 14% increase the dose of CCS and try a second tapering.
3.4 Patients monitoring and prevention of complications
Before starting corticosteroids, 72% of respondents do not routinely perform any clinical or laboratory evaluation. A minority routinely request one or more among ohptalmologic evaluation (4%), chest X-ray 13%, DEXA (9%), tuberculin skin test (14%).
During a CCS course, 60% of respondents said they regularly monitor blood pressure, 60% serum glucose levels, 32% serum electrolytes while 14% do no perform any specific monitoring.
As for ostheoporosis prophylaxis, 38% of respondents prescribe calcium and vitamin D supplements every time, 55% do so only in patients with known risk factors and/or preexisting bone loss, while the remaining never prescribe supplementation. The percentage of clinicians routinely prescribing calcium and vitamin D supplements is significantly higher among those younger than 40 (49% vs 31% in older than 40, p = 0,037).
In case of presence of comorbidities ad/or relative contraindications to CCS (diabetes, hypertension, glaucoma, chataract, psychiatric disorders) 22% of respondents said they avoid prescribing corticosteroids whereas 78% proceed with caution monitoring patients strictly and/or consulting the appropriate specialists.
Finally, 44% stated to regularly co-prescribe a proton pump inhibitor along with steroids.
To the best of our knowledge, this is the first study exploring the practical use of corticosteroids by gastroenterologists in patients with IBD. The rate of response to the questionnaire was far from optimal, but similar to that achieved in several previous surveys on different topics 45 46 47 . However, demographic characteristics of responding clinicians suggest that the responding group is fairly representative of Italian gastroenterologists dealing with IBD patients. Several remarks can be made on our results.
Choice of drugs according to disease features. Only 37% of responders prescribed LBS as first line therapy in mild-to moderate CD relapse, although most recent guidelines strongly recommend them as the preferred fist-line treatment in mildly active CD flares and as an alternative for CCS in moderate flares [22 28] . On the other hand, it is remarkable that 42% of clinicians used LBS as first-line treatment in mild-to moderate mesalazine refractory UC relapses, and a further 43% decided case by case, thus considering using LBS first in some categories of patients. Although CCS are generally recommended as the preferred treatment of mesalazine-refractory UC flares 22 23 24 25 26 , LBS have recently emerged as a possible alternative [40 48] and some recent guidelines indeed mention this possibility [28 44] . It is also interesting to notice that in case of LBS failure, roughly one clinician out of 4 step-up directly to other drugs classes instead of switching to CCS, both in CD and UC patients. This is not currently recommended by any guidelines, but may result convenient in some categories of patients, in order to limit steroid-induced side-effects. Differently, it is quite disappointing that 10–15% of specialists considered LBS in moderate-severe IBD flares – a choice that is universally strongly discouraged 22 23 24 25 26 27 28 44] – and even more that 3% of them tried to increase LBS dosage in case of failure. Another finding that emerged from our study is that younger clinicians tend to prescribe LBS more frequently than their older colleagues.
Treatment dosage and duration. Very limited evidence-based data are available on this topic. In UC, two older controlled trials had shown that both 40 and 60 mg/die of prednisone are respectively equally effective and significantly more effective than 20 mg/die, and that a single daily dose is as efficacious as divided doses, respectively [17 18] . Conversely, the two pivotal European and American collaborative studies have demonstrated that both metilprednisolone ¼ to ¾ mg/kg/die (according to disease severity) and 48 mg/die are superior than sulphasalazine and placebo in inducing remission in active CD [4 5] , whereas lower doses have been shown to be even detrimental in older case series  . More recently, higher rates of remission were reported in case series in which up to 1 mg/kg/die of prednisone was administered [19 21] . Finally, no difference was found between a tapering schedule of 4 weeks duration and another of 12 weeks duration in a small controlled trial  . Generally, a starting daily dosage of 40–60 mg of prednisone is recommended in patients with UC [24 26 44] , and of either 40–60 mg or 0,75–1 mg/kg in patients with CD 26 27 28 . As for full-dose treatment duration, it is usually recommended to start tapering after 1–3 weeks 26 27 28 and to complete it within 8–12 weeks 25 26 27 28 . Looking at data of our survey, we can notice that starting dose and treatment duration used by interviewed specialists are in the vast majority of cases in line with such recommendations, only 15% starting treatment at dosages either lower of higher than recommended and 17% commencing tapering after more than 3 weeks. The preferred tapering schedule was 5 mg per week, identical to what suggested by the IBD Ahead Education Program  , and not much different from the schedule recommended by the AGA  . Our data show also that more Italian clinicians prefer a fixed starting dose over a weight-based one, and that 60% recommend taking steroids in a single morning dose, the remaining recommending two divided doses.
Management of steroid-dependent and steroid-refractory patients. There is nowadays a full consensus that patients not responding to full dosage of corticosteroids and those experiencing symptoms recurrence during CCS tapering must be timely switched to other drug classes [22 28 44] . In this respect, it is somewhat surprising that, in case of resistance to CCS, 47% of responders used to switch to parenteral administration and 6% to increase the dose over that recommended, two conducts that are not supported by any guidelines or expert opinion. On the other hand, the majority stated to timely switch steroid-dependent patients to biologics or immunosuppressants, only 14% increasing steroid dose again and then starting a new tapering.
Patients monitoring before and during treatment. At present, no specific screening is deemed mandatory before initiating a CCS course, although screening for tuberculosis and/or Clostridium Difficile infection has been sometimes recommended [50 51] . On the other hand, it is generally believed that during CCS treatment some monitoring for complications (mainly ocular disease, diabetes, hypertension and bone loss) is advisable, although very evasive recommendations are reported in published guidelines 25 26 27 . Our data show that only a minority of Italian gastroenterologists (28%) perform any sort of pre-treatment screening, whereas the vast majority (85%) monitored at least blood pressure and/or serum glucose during treatment. Very few respondents said to perform regular ophthalmologic examination, a practice that has sometime been recommended  . It is also noteworthy that about 15% of respondents performed TB screening (by means of either X-ray or skin test) before initiating corticosteroids.
Prevention of complications. It is generally recommended that patients on corticosteroids should receive calcium and vitamin D supplementation and undergo regular DEXA examination  , although the real effectiveness of these measures in preventing bone loss has not been clearly demonstrated. In our survey, 38% of specialists stated they routinely prescribe calcium and vitamin D supplementation along with corticosteroids, and a further 55% prescribed them only if risk factors and/or pre-existing bone damage were present. This figures appear to be somewhat higher than those reported in a previous Italian survey  ; noticeably, prescription of supplementation resulted more frequent among younger clinicians. Finally, it is surprising that 44% said to regularly prescribe proton-pump inhibitors along with steroids, since it has been known for a long time that corticosteroids are not per-se a risk factor for peptic disease and co-prescription of anti-secretive dugs has never been recommended in IBD patients on corticosteroids, unless also on NSAIDs  .
In conclusion, our survey has uncovered some heterogeneities among Italian gastroenterologist regarding the way to prescribe and monitor corticosteroid therapy in IBD patients, as well as some significative deviances from current recommendations. No major differences were found according to age of respondents, the type of institution and the number of followed-up patients, except for a higher rate of LBS prescription and calcium/vitamin D supplementation among younger clinicians. Therefore, some educational intervention appears desirable.
The work described in the present paper has not been published previously (except in the form of an abstract) and is not under consideration for publication elsewhere. The publication of the present article was approved by all authors and if accepted, it will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of the copyright-holder.
Conflict of interest
Gianmichele Meucci has received consultancy fees and educational grants from: Chiesi , MS&D , Mundipharma , Takeda , Zambon .
Claudio Papi has received consultancy fees and educational grants from Takeda, Abbvie , MSD , Chiesi , Sofar .
Simone Saibeni has received feed for board participations by Abbvie.
Appendix A Supplementary data
The following is Supplementary data to this article: Attached file
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