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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 1  |  Page : 103-106

Chronotherapy in the treatment of oral pemphigus vulgaris: A case report

Department of Oral Medicine and Radiology, D.Y. Patil University School of Dentistry, Navi Mumbai, Maharashtra, India

Date of Submission22-Sep-2020
Date of Decision31-Jan-2021
Date of Acceptance01-Feb-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Dr. Mandavi Waghmare
Y Patil University, School of Dentistry, Sector 7, Highway Road, Dr. D.Y Patil Vidyanagar, Nerul, Navi Mumbai, Maharashtra - 400 706
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiaomr.jiaomr_192_20

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Oral vesiculobullous lesions are highly dynamic in their presentation making the current treatment strategies fall short of expected complete remission. With continuing research on the various treatment modalities of these lesions it is suggested that treating a disorder by following the biological and physiological behavior of the various bodily enzymes and hormones and their circadian rhythm helps in alleviating the symptoms faster with lesser or no side effects. This concept is termed “Chronotherapy.” It works by timing the treatment with the intrinsic timing of illness.

Keywords: Chronotherapy, pemphigus, steroid, vesiculobullous lesion

How to cite this article:
Waghmare M, Puthenveetil SS. Chronotherapy in the treatment of oral pemphigus vulgaris: A case report. J Indian Acad Oral Med Radiol 2021;33:103-6

How to cite this URL:
Waghmare M, Puthenveetil SS. Chronotherapy in the treatment of oral pemphigus vulgaris: A case report. J Indian Acad Oral Med Radiol [serial online] 2021 [cited 2022 May 21];33:103-6. Available from: https://www.jiaomr.in/text.asp?2021/33/1/103/312201

   Introduction Top

Pemphigus diseases are a group of life threatening rare autoimmune bullous diseases that affects the skin and mucous membranes. Their estimated incidence in India is 0.09 to 1.8%.[1] It commonly involves the buccal mucosa followed by the palate, lingual, and labial mucosa.[2] Since it occurs as common blisters it may pose a diagnostic challenge hence making it imperative for a dental specialist for early identification supplemented by suitable treatment.

The probable challenges faced in the management of chronic ulcerative lesions are achieving rapid remission, preventing relapse, and reducing the morbidity associated with the treatment agents. Steroids have been widely used in treating vesiculobullous lesions; however, their long-term use is associated with osteoporosis, myopathy, skin atrophy, and edema. Recent research has improved the approach to prescribe glucocorticoids by delivering low-dose corticosteroids using the chronotherapeutic strategy.[3]

“Chronotherapeutics” refers to a treatment method in which drug availability is timed to match the rhythms of disease in order to optimize therapeutic outcomes and minimize side effects.[4] “Chrono” refers to observations that every metabolic event undergoes rhythmic changes in time. In certain diseases, the optimal clinical outcome cannot be achieved if drug plasma concentration is constantly maintained by prescribing the drug at an evenly spaced time interval. Some medications may work better if their administration is co-ordinated with day–night patterns and biological rhythms.[5]

Here, we report a case of pemphigus vulgaris (PV) treated with chronotherapy. To the best of our knowledge, this is the first case of PV to be treated by chronotherapy.

Patient information

A 55-year-old male patient reported to our OPD with the chief complaint of ulcers in the oral cavity for 4 days accompanied by fever, swelling on the right side of the face, and difficulty in swallowing food. His medical history revealed that he was suffering from hypertension for the last 5 years and was on amlodipine 2.5 mg once daily. Family history and social history were noncontributory.

History of chief complaint revealed recurrent oral ulcers for the last 2 years for which he was being treated by a private dental practitioner and was prescribed local application of kenacort 0.1% oral paste.

Clinical findings

Extraoral examination showed facial asymmetry due to a diffuse swelling on the right body of the mandible. No surface changes were noted on the swelling. The swelling was soft and tender on palpation with a local increase in temperature. Bilateral submandibular lymph nodes were tender on palpation.

Intraorally, extensive ulcers were present involving the right and left buccal mucosae extending from the retromolar pad region to the commissure and the lower and upper lip bilaterally. The ulcers were irregular in shape and covered with pseudomembrane and surrounded by erythema [Figure 1]a, [Figure 1]b. On the manipulation of the tissues, bleeding was present and profuse salivation noted. Poor oral hygiene with generalized deposits of plaque and materia alba was present on the teeth. The gingiva was inflamed and bled on probing. Nikolsky's sign was negative.
Figure 1: (a and b) Extensive irregular severe ulceration involving right and left buccal mucosa extending up to the commissures, labial, and lingual mucosa and involving the lower lip

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Diagnostic assessment

A provisional diagnosis of the vesiculobullous lesion with a differential diagnosis of pemphigus vulgaris, erythema multiforme, and mucous membrane pemphigoid was made. Erythema multiforme lesions are drug induced which begin as mild erythema and which show characteristic bull's eye or target lesion on the skin. Oral ulcers appear as irregular deep ulcers with bloody crustations. Mucous membrane pemphigoid commonly occurs in the oral cavity with infrequent skin lesions. Bullae are larger compared to those in pemphigus. Immunofluorescence helps differentiate from pemphigus where the basement membrane zone shows deposition of immunoglobulins and complement, whereas intracellular antibodies are noted in pemphigus.

The patients' routine hematological investigations and blood sugar evaluation were within normal limits. An incisional biopsy was performed. Histopathological examination revealed intraepithelial separation above the basal layer of epithelium. Acantholysis was seen with Tzanck cells spread evenly. Chronic inflammatory cell infiltrate was evident [Figure 2]a, [Figure 2]b. This led to a diagnosis of PV.
Figure 2a: (a) (10x H&E) Photomicrograph shows suprabasillar blister formation with extensive acantholysis of keratinocytes. (b) (40x H7E) photomicrograph shows tombstone appearance of basal cell layer with acantholytic cells in cleft

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Therapeutic intervention

Treatment for the patient was started at the first visit. The patient was prescribed amoxicillin 500 mg with clavulanic acid 125 mg twice daily for 5 days, metronidazole 400 mg thrice daily for 5 days, aceclofenac 100 mg twice daily for 3 days, pantoprazole 40 mg twice daily for 5 days, and betamethasone 0.5 mg to be crushed and mixed with honey and applied on the ulcerative lesions. In addition, the patient was advised betadine gargles twice a day for 5 days. The patient reported after 5 days with mild resolution of the lesion on the left buccal mucosa but no improvement in the rest of the areas. The drug regimen was modified. The patient was further advised oral prednisolone 40 mg and pantoprazole 40 mg BD for 15 days. On the second follow-up patient showed a reduction in 50% of the lesions and was advised to continue the regime (twice daily) for a month. One month follow-up showed no complete remission [Figure 3]. The drug regimen was further modified with the oral prednisolone dose increased to 60 mg (once daily) OD to be taken early morning (6 am) on an empty stomach. The antacid was discontinued. The patient was also advised local application of clobetasol (0.05%). Patient reported after 10 days with complete resolution [Figure 4]a, [Figure 4]b. The steroid was tapered and stopped over a 3-month period.
Figure 3: Mild erythema over the right and left buccal mucosa, labial mucosa and lingual mucosa with pseudomembrane

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Figure 4: (a and b) No new lesions were noted during the 3 month follow-up

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Follow-up and outcomes

There was no evidence of any lesions after 3 months. The patient did not report any adverse effects of steroid therapy during the treatment phase. One year follow-up found the patient free of any oral ulceration.

   Discussion Top

Chronotherapy is a method of prescribing drugs depending on the time of the biological and physiological process of bodily enzymes, hormones, and immune cell production. By choosing an optimal dosing time, better clinical outcomes and reduced side effects can be achieved.[5] Thus, prescribing the drug at a specific time is more significant than giving it at a spaced time interval.

Chronotherapy was conceptualized by Thomas Sydenham (1624–1689) who used opium in patients in the late evening rather than the morning to obtain its optimum narcotic effect.[3] According to Smolensky et al. clinical use of glucocorticoid in the morning on an alternate day basis was widely practiced in the 1960s thus applying chronotherapy into practice. Here, the administration of glucocorticoid was focused primarily on the chronotoxicological aspect (i.e. rhythm dependent differences in manifestation and severity of adverse effects) rather than chronoeffectiveness (i.e. rhythm dependent differences in the magnitude of the desired therapeutic effect).[3] Since then a series of studies have been done indicating the use of a single early morning low dose of corticosteroid which leads to little or no adrenocortical suppression. An evening dose was however found to increase the risk of suppressing the Hypothalamus – Pituitary - Axis HPA axis.[3],[6]

Glass-Marmor et al. found that treating patients with multiple sclerosis with methylprednisolone at night time showed higher clinical recovery.[7] Krishnaswami et al. prescribed steroid inhalation in asthmatic patients at around 3-4 am in the morning and achieved a maximum 24 h cumulative cortisol suppression in plasma. This reduced the aggravation of early morning symptoms in patients with asthma.[8] These studies prove that clinical outcomes and side effects can be influenced by the time of administration of the drug. The normal bodily cortisol levels rise around 2 am and reach their peak by 8 am in the morning. When the therapeutic dose range of prednisolone is prescribed at 6 am in the morning it shows minimum cumulative cortisol suppression and maximum effects on the action of lymphocytes. This is achieved along with negligible side effects.[9] In the present case, remission was not achieved when the patient was treated conventionally; however, changing the dosage and timing of the drug delivery helped in faster and complete healing of the lesion without any side effects of the drug. Chronotherapy presently has been tried on patients with rheumatoid arthritis, systemic sclerosis, diabetes, hypertension, coronary heart disease, and cancer. A thorough PubMed and Scopus search was done and there was no literature available showing the application of chronotherapy in oral lesions. Due to the limited material available more longitudinal studies are required to substantiate the use of chronotherapy in PV.

Patient perspective

The patient had been suffering with oral ulcers for the last 2 years and was on medications for the same. But when the ulcers became severe the present treatment given was more effective and the lesions healed completely. There was no discomfort with any medication that was prescribed. The patient has not been taking any medications for the last 1 and a half year and has not suffered from any lesions since then.

   Conclusion Top

An effective treatment plan is necessary for accelerated remission of lesions to enhance patients' quality of life. Corticosteroids can be safely prescribed in patients to treat autoimmune disorders if it's normal rhythmic secretion in the body is followed, thus avoiding its potential side effects.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


The Authors would like to thank Dr. Freny Karjodkar, Professor and Head of Department of Oral Medicine and Radiology, Nair Hospital and Dental College, Mumbai and Dr. Anish Gupta, Professor and Head of Department of Oral Pathology and Microbiology, Peoples Dental Academy, Bhopal.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Mascarenhas MF, Hede RV, Shukla P, Nadkarni NS, Rege VL. Pemphigus in Goa. J Indian Med Assoc 1994;92:342-3.  Back to cited text no. 1
Scully C, Paes De Almeida O, Porter SR, Gilkes JJ. Pemphigus vulgaris: The manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol 1999;140:84-9.  Back to cited text no. 2
Spies CM, Cutolo M, Straub RH, Burmester GR, Buttgereit F. Prednisone chronotherapy. Clin Exp Rheumatol 2011;29 (5 Suppl 68):S42-5.  Back to cited text no. 3
Traynor K, Newton DW, Hrushesky WJ, Reiter RJ. A pharmacist's primer on chronotherapeutics. American pharmacy. 1992 Mar 1;32 (3):77-85.  Back to cited text no. 4
Sajan J, Cinu TA, Chako AJ, Litty J, Jaseed T. Chronotherapeutics and chronotherapeutic drug delivery systems. Tropic J Pharma Res 2009;8:467-75.  Back to cited text no. 5
DI Raimondo VC, Forsham PH. Some clinical implications of the spontaneous diurnal variations in adrenal cortical scretory activity. Am J Med 1956;21:321-3.  Back to cited text no. 6
Glass-Marmor L, Paperna T, Ben-Yosef Y, Miller A. Chronotherapy using corticosteroids for multiple sclerosis relapses. J Neurol Neurosurg Psychiatry 2007;78:886-8.  Back to cited text no. 7
Krishnaswami S, Hochhaus G, Derendorf H. An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy. AAPS Pharm Sci 2000;2:E22.  Back to cited text no. 8
Xu J, Winkler J, Sabarinath SN, Derendorf H. Assessment of the impact of dosing time on the pharmacokinetics/pharmacodynamics of prednisolone. AAPS J. 2008;10:331-41.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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