VIMS Journal: July 2017

Review Article

Role of Deflazacort in Treatment of Sino-Nasal Polyposis: A Review Study

Sri Abhishek Gupta, Dr. B. K. Roychaudhuri, Dr. Amitabha Roychoudhury, Dr. Soumitra Ghosh

Background :
A polyp presents in the nasal cavity with a grapelike appearance, having a 'body' and a 'stalk'. The surface is smooth and the colour is more yellow than the pink mucous membrane. Nasal polyps originate in the upper part of the nose around the openings to the ethmoidal sinuses. The polyps protrude into the nasal cavity from the middle and superior meatus, resulting in nasal blockage and abolishing airflow to the olfactory region. Nasal polyposis, consisting of multiple, bilateral polyps, is part of an inflammatory reaction involving the mucous membrane of the nose, the paranasal sinuses and often the lower airways.[1,2] The relationship between nasal polyposis and chronic rhino sinusitis (CRS) is much debated but in its broadest sense nasal polyposis should probably be regarded as one form of chronic inflammation in the nose and sinuses, i.e. part of the spectrum of CRS.[3]
Histologically, sino-nasal polyposis show infiltration of inflammatory cells like eosinophils and neutrophils. The diagnosis of nasal polyps is based on the finding of pale-gray, semi translucent, round or bag-shaped mucosal protrusions from the sinuses into the nasal cavity, filled with gelatinous or watery masses.
Etiology and pathophysiology are only partly understood. There is no valid classification of polyp subgroups to allow prediction of outcome after medical or surgical therapy, and recurrences are frequent regardless of treatment, mandating repeated surgical interventions. Furthermore, surgical interventions may lead to unsatisfactory healing and may cause complications due to scar formation, because mucosal wound healing may also be impaired as a result of poorly defined factors in the inflamed mucosa.
Several hypotheses have been put forward regarding the underlying mechanisms including chronic infection, aspirin intolerance, alteration in aerodynamics with trapping of pollutants, epithelial disruptions, epithelial cell defects/gene deletions (Cystic fibrosis transmembrane conductance regulator gene), and inhalant or food allergens.

Nasal Endoscopy :
With the introduction of rigid endoscopes, nasal polyps are now discovered in earlier stages than they were 30 years ago. Although anterior rhinoscopy may detect large polyps, it is not considered sufficient to exclude polyps. Especially for the differential diagnosis, an endoscopy of the nose after topical decongestion is necessary.

CT Scan :
To investigate the extent of disease within the sinuses, a computer tomography (CT) scans, with special reference to mucosal structures and the delicate anatomy of the sinuses. A CT scan is mandatory before sinus surgery, and the films must be available during surgery to guide the surgeon about anatomic variations.

MRI :
In addition, magnetic resonance imaging (MRI) may be helpful for the diagnosis of expansion of polyps beyond sinuses. Sino-nasal polyposis may represent part of systemic diseases like asthma and other lung diseases, aspirin sensitivity, Churg-Strauss syndrome, inhalant allergies etc.

Treatment :
The mainstay of therapy consists of both medical and surgical modalities. No single surgical technique including Functional Endoscopic Sinus Surgery (FESS) has proved to be entirely curative and patients often require revision surgery despite receiving long-term medical therapy. Recurrence is common in around 5%-10% of patients.[4] The objectives of medical management of nasal polyposis are
1) eliminate nasal polyps and rhinitis symptoms,
2) re-establish nasal breathing and olfaction, and
3) control recurrence.
Although antibiotics are used for infective nasal polyposis, only glucocorticosteroids have a proven effect on the nasal polyps, due to its antiinflammatory actions.
Topically applied steroids like fluticasone, mometasone etc, are the therapeutic modality that has been best studied in controlled trials. It reduces rhinitis symptoms, improves nasal breathing, reduces the size of polyps and the recurrence rate, but it has a negligible effect on the sense of smell and on any sinus pathology. Topical steroids can, as long-term therapy, be used alone in mild cases, or combined with systemic steroids/surgery in severe cases. Systemic steroids have an effect on all types of symptoms and pathology, including the sense of smell. This type of treatment, which can serve as "Medical Polypectomy" is only used for short-term improvement.
Systemic corticosteroids with step-down dose reduction during a 14-day to 20-day oral course, are extremely effective in reducing polyp size and symptoms. The suppression of gene transcription for many cytokines is a prominent action of glucocorticosteroids, including IL-5 and eotaxin. Because of these effects, recruitment and localization of inflammatory cells into polyp tissue are inhibited. This has a prominent effect on numbers of nasal eosinophils, eosinophil products, and survival and may also affect plasma protein retention. However, polyps will recur rapidly in patients with severe disease, and little evidence thus far suggests that the natural course of the disease is influenced by long-term lowdose treatment regimes.
In a study, the authors demonstrated that a 2- week course of oral steroid therapy, in addition to exerting rapid effects on symptoms of CRS with nasal polyps, had a long-term effect extending beyond the time of treatment. In most patients with CRS with nasal polyps, a burst of 25 mg of oral prednisolone followed by intranasal steroids was generally more effective than topical therapy alone in decreasing polyp size and improving sense of smell over 20 weeks of observation. The author further stated that a short course of oral steroids turned out to be safe, as after transient suppression of adrenal function and an increase in bone resorption, these safety parameters returned to baseline at 10 weeks. In practical terms, the study demonstrated that a short course of oral corticosteroids could be recommended for most patients with moderate to severe CRS with nasal polyps as an initial therapy if subsequent chronic treatment with topical steroids is planned.[5]

Antibiotics are frequently used in chronic rhinosinusitis as well as in acute sinusitis but they are not effective in medical management of uncomplicated nasal polyps. Mucolytics can be used as adjuncts to antibiotics in acute sinusitis to reduce viscosity of sinus secretion but no clinical trials have tested their effects in nasal polyps. Antihistamines can have significant reduction in symptoms in simple nasal polyps. One study showed reduction in sneezing, rhinorrhoea, and obstruction compared with placebo, but there was no significant reduction in size of polyp even at 3 months.[6]
Other medical therapies have been used for treatment of nasal polyps. Leukotriene receptor antagonists have recently been shown to be effective. Topical capsaicin has also been shown to be effective, but side-effects including burning of the nasal mucosa limit its acceptability to patients. There is little evidence to advocate the usage of other treatments including frusemide and interferon-alpha2a and neither of these is available in routine medical practice.
Most commonly used oral corticosteroids for sino-nasal polyposis are prednisolone, triamcinolone and in recent years, deflazacort. Deflazacort is a synthetic glucocorticoid. Its chemical formula is C25H31NO6.

Chemical structure of Deflazacort molecule

Based on data obtained from various trials (including double-blind crossover studies, paired patient studies, and between-patient studies) the potency ratio of deflazacort vs. prednisolone was estimated to be 1.28. It has been suggested that 6 mg of deflazacort has approximately the same anti-inflammatory potency as 5 mg prednisolone. Deflazacort is well absorbed after oral administration and converted to an active metabolite (D 21-OH) by plasma esterases. Peak plasma concentrations are achieved in 1.5-2 h and elimination plasma half life is 1.1-1.9 h. It is 40% protein-bound and is mainly (70%) excreted via the kidneys. Fecal excretion contributes to 30% of drug elimination.[7]
The bioequivalence of deflazacort and prednisolone has been investigated in various studies. In normal subjects,[8] 15 mg deflazacort inhibits T cell reactivity to the same extent as 12.5 mg prednisolone, but for a longer period of time (based on phytohemagglutinin-induced T cell proliferation in vitro). In a study comparing deflazacort vs. methyl prednisolone using a 1.5:1 ratio (which is equivalent to a 1.2:1 deflazacort/prednisolone ratio). Elli et al.[9] concluded that there was a more potent immunosuppressive activity of deflazacort with a lower ratio of CD4+/CD8+ lymphocytes. It has been suggested that deflazacort depresses the osteoblast less than prednisolone, leading to a smaller decrease in serum osteocalcin levels with this drug.[10] A bone-sparing effect of deflazacort at the level of lumbar spine has been described in various clinical situations.
Researchers have claimed that some of the bonesparing effect of deflazacort compared to that of prednisolone could be explained by a less impaired intestinal calcium absorption by the former.[11] In general, deflazacort appears to have less effect than prednisolone associated with the development of corticosteroid-induced osteoporosis. Further, the drug appears to have less negative impact on growth rate in children with diseases requiring corticosteroid therapy. Thus, deflazacort may be associated with less serious metabolic sequelae than prednisone. Histomorphometry and densitometry techniques have shown that when used at doses with approximately equivalent anti-inflammatory efficacy, it appears to have fewer detrimental effects on bone mass than prednisone.[12]
In children, deflazacort should be considered as an initial option in those requiring corticosteroid therapies since the adverse effects are comparatively less. Gastrointestinal symptoms are the most frequently reported adverse events in deflazacort recipients; other adverse events associated with the drug include metabolic and nutritional disorders, central and peripheral nervous system disturbances and psychiatric disorders. Past reports have indicated that deflazacort is less diabetogenic than prednisolone in healthy subjects.[13] However, in a recent study, it has also been reported to be having similar effect on glucose tolerance.[14] Different studies also show that a long-term treatment with deflazacort has a smaller effect on glucose metabolism than other drugs of this class.[15]
Another study reinforces the finding by obtaining a result that indicates that betamethasone-induced greater glucose intolerance and insulin resistance than deflazacort.[16] These results indicate that deflazacort when employed in an antiinflammatory dose equivalent to prednisone should prove advantageous in insulin-treated diabetics who require steroid treatment. The overall incidence of adverse events in deflazacort recipients (16.5%) is lower than that recorded in patients treated with prednisone (20.5%) or methylprednisolone (32.7%).[17]

Conclusion :
Sino-nasal polyposis is a chronic inflammatory condition, presenting as soft, painless, nonneoplastic swelling due to hypertrophy and oedema of mucosa and submucosal tissue in the nasal cavity and paranasal sinuses.
The goal of treatment of sino-nasal polyposis is symptomatic relief with elimination of polyps from the nose and paranasal sinuses along with minimizing recurrence.
Surgery often alone fails to achieve the desired goals in sino-nasal polyposis. Oral and topical corticosteroids are quiet effective in this regard, when used alone or as an adjuvant to surgical treatment.
Deflazacort, a relatively new molecule of corticosteroid has superior immunosuppressive and anti-inflammatory action. It is bone sparing with less metabolic sequelae and also with less negative impact on children. It therefore, appears to be a more useful, safer and potent option among other systemic corticosteroids in patients with sino-nasal polyposis.

References
  1. Settipane GA, Lund VJ, Bernstein JM, Tos M (eds). Nasal polyps: Epidemiology, pathogenesis and treatment. The New England and Regional Allergy Proceedings, Providence, Rhode Island, 1997.

  2. Mygind N, Lildholdt T (eds). Nasal polyposis: An inflammatory disease and its treatment. Copenhagen: Munksgaard, 1997.

  3. European Academy of Allergology and Clinical Immunology. European position paper on rhinosinusitis and nasal polyps. EAACI Task Force. Rhinology Supplement. 2005; 18: 1-87.

  4. Fokkens W, Lund V, Mullol J, European Position Paper on Rhinosinusitis and Nasal Polyps Group. Rhinology. 2007 Jun; 45(2):97-101.

  5. Kowalski ML. Oral and Nasal Steroids for Nasal Polyps. Current Allergy and Asthma Reports. 2011;11(3):187- 188. doi:10.1007/s11882-011-0192-9.

  6. Baudoin T, Kalogjera L, Hat JI. Capsaicin significantly reduces sinonasal polyps. Acta Otolaryngol. 2000; 120:307-11.

  7. Avioli LV. Potency ratio: A brief synopsis. Br J Rheumatol 1993;32:24-6.

  8. Scudeletti M, Pende D, Barabino A, Imbimbo B, Grifoni V, Indiveri F. Effect of single oral doses of prednisone and deflazacort on human lymphocyte distribution and functions: Analysis with monoclonal antibodies. Adv Exp Med Biol. 1984;171:335-44.

  9. Elli A, Rivolta R, Di Palo FQ, Parenti M, Vergallo G, Palazzi P, et al. A randomized trial of deflazacort vs. 6-methylprednisolone in renal transplantationimmunosuppressive activity and side effects. Transplantation. 1993;55:209-12.

  10. Montecucco C, Baldi F, Fortina A, Tomassini G, Caporali R, Cherie-Ligniere EL, et al. Serum osteocalcin (bone Gla protein) following corticosteroid therapy in postmenopausal women with rheumatoid arthritis. Comparison of the effect of prednisone and deflazacort. Clin Rheumatol. 1988;7:366-71.

  11. Gennari C. Differential effect of glucocorticoids on calcium absorption and bone mass. Br J Rheumatol. 1993;32:11-4.

  12. Nayak S, Acharjya B. Deflazacort versus other glucocorticoids: A comparison. Indian Journal of Dermatology. 2008;53(4):167-170. doi:10.4103/0019- 5154.44786.

  13. Scudeletti M, Puppo F, Lanza L, Mantovani L, Bosco O, Iudice A, et al. Comparison between two glucocorticoid preparations (Deflazacort and prednisone) in the treatment of immune-mediated diseases. Eur J Clin Pharmacol. 1993;45:S29-34.

  14. Bruno A, Pagano G, Benzi L, Di Ciani G, Spallone V, Calabrese G, et al. Change in glucose metabolism after long-term treatment with Deflazacort and betamethasone. Eur J Clin Pharmacol. 1992;43:47-50.

  15. Pagano A, Bruno A, Cavallo-Perin P, Cesco L, Imbimbo B. Glucose intolerance after short-term administration of corticosteroids in healthy subjects: Prednisone, Deflazacort and betamethasone. Arch Intern Med. 1989;149:1098-101.

  16. Lippuner K, Casez JP, Horber FF, Jaeger P. Effects of Deflazacort versus prednisone on bone mass, body composition, and lipid profile: A randomized, double blind study in kidney transplant patients. J Clin Endocrinol Metab. 1998;83:3795-802.

  17. Bruno A, Cavallo-Perin P, Cassader M, Pagano G. Deflazacort vs prednisone: Effect on blood glucose control in insulin-treated diabetics. Arch Intern Med. 1987;147:679-80.

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