Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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On Sep 2018




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Prof. Somashekhar Nimbalkar
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Chairman, Research Group, Charutar Arogya Mandal, Karamsad
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Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



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Professor and Head
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Saraswati Dental College
Lucknow
On Sep 2018




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MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




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Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Case Series
Year : 2022 | Month : March | Volume : 16 | Issue : 3 | Page : WR01 - WR05 Full Version

A Case Series of Recalcitrant Pemphigus


Published: March 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/53400.16084
Rajkumar Kannan, Samuel Jayaraj Daniel, Poornima, Ramesh Aravamuthan

1. Associate Professor, Department of Dermatology, Madras Medical College, Chennai, Tamil Nadu, India. 2. Associate Professor, Department of Dermatology, Madras Medical College, Chennai, Tamil Nadu, India. 3. Resident, Department of Dermatology, Madras Medical College, Chennai, Tamil Nadu, India. 4. Professor, Department of Dermatology, Madras Medical College, Chennai, Tamil Nadu, India.

Correspondence Address :
Dr. Rajkumar Kannan,
Flat-C, New No. 3, Athipoo Flats, Thiruvalluvar Street, Methanagar,
Chennai-600029, Tamil Nadu, India.
E-mail: rajderm0002@gmail.com

Abstract

Pemphigus consists of a group of life threatening autoimmune bullous disorders characterised by flaccid blisters and erosions of the skin and mucosal membranes of oral, laryngeal, conjunctival, pharyngeal, anal, vaginal etc. Pemphigus vulgaris involves mucosa in 50-70% of the patients. Pemphigus is associated with other autoimmune disorders like myasthenia gravis and thymoma. Primary subsets of pemphigus include pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. Pemphigus vulgaris constitutes nearly 70% of cases of pemphigus, with its antigens desmoglein 1 and 3, which are calcium dependent calmodulins, being the crucial targets for IgG1 and IgG4 classes of antibodies. If left untreated at an early stage, pemphigus vulgaris is associated with significant morbidity and mortality. The authors present a case series of five patients (34-year-old male, 68-year-old male, 52-year-old male, 74-year-old female and 65-year-old female) presenting recalcitrant pemphigus with focus on the various factors that affect the disease outcomes, morbidity and mortality.

Keywords

Deep vein thrombosis, Pemphigus vegetans, Resistant pemphigus, Septicaemia

Pemphigus vulgaris is an autoimmune genetically predisposed intraepithelial blistering disease that affects the skin and mucous membrane. Pemphigus is noted for its chronicity, characterised by IgG class autoantibodies to the Intercellular Adhesion Molecules (ICAM) viz., desmoglein 3 and desmoglein 1 resulting in loss of cell adhesion and formation of intraepidermal cleft (1).

The prevalence of pemphigus vulgaris in India is 0.09-1.8%. As far as Indian patients of pemphigus vulgaris are concerned, they are said to be relatively younger than their western counterparts (2).

Primary lesion of pemphigus is a flaccid blister that arises on healthy skin or over an erythematous base. Blisters are fragile and filled with clear fluid. Acantholysis, apoptosis, and apoptolysis (3) are the molecular mechanisms that give rise to “row of tombstone” appearance in the routine haematoxylin and eosin (H&E) sections of biopsy and “fishnet pattern” in direct immunofluorescence.

Mucosal involvement occurs in 50-70% of cases. Deaths are common within the first five years of life since the diagnosis of pemphigus vulgaris is made, and if the patient could survive this crucial period, prognosis is really good.

Pemphigus vulgaris is associated with a three times higher mortality rate compared to the general population. It is a potentially life-threatening disease with a mortality rate of 5-15% (4). Morbidity and mortality are related to age of onset of the disease, extent of body surface area involved, co-morbidities of the patient and the daily dose of systemic steroids or other equivalent immunosuppressives needed.

Although the Dermatologist’s armamentarium is equipped with a wide array of therapeutic options ranging from simplest systemic steroids to biologicals (5), biosimilars (6), and biobetters (7), there are still sizeable number of patients who pose a great challenge to the treating Dermatologists by frequent episodes of relapses. The present case series focuses on such refractory patients of pemphigus vulgaris with an insight to find out various factors that affect the disease outcomes, morbidity and mortality.

Case Report

Patients with immunobullous disorder of pemphigus vulgaris attending bulla clinic in a tertiary care centre after confirmation of diagnosis by biopsy and other relevant investigations, were considered for the case series, in whom duration of single episode of pemphigus vulgaris lasted for >3 months, in spite of treatment with steroids and other steroid sparing immunosuppressive agents. The Helsinki guidelines were followed duly. After applying the inclusion and exclusion criteria, the following five patients (three males and two females) were chosen for the present case series (Table/Fig 1). The study was conducted between May 2021 and October 2021 and the patients are being followed-up till date. The study was approved by the Institutional Ethics Committee (IEC NO.25042021).

Inclusion and Exclusion criteria: Patients of biopsy proven pemphigus vulgaris aged >18 years, both genders, who needed more than 10 mg/day of tab. prednisolone or 2 mg/kg/day of tab. azathioprine for control of disease activity and who were willing to follow-up were included in the study. Patients with active Human Immunodeficiency Virus (HIV), Tuberculosis (TB), Hepatitis B/C virus infections and those not willing to participate/come for follow-up were excluded from the study.

Recalcitrant or resistant pemphigus is defined as recurrent blister formation in spite of immunosuppressive therapy with corticosteroids >10 mg/day of tab. prednisolone or tab. azathioprine 2 mg/kg/day or equivalent immunosuppression (8). The details of patients of recalcitrant pemphigus has been discussed below and tabulated (9) (Table/Fig 1).

Case 1

A 34-year-old male who is a known case of pemphigus vulgaris since two years, on conventional treatment with steroids and other immunosuppressants like tab. azathioprine, with no known co-morbidities, came with extensive erosions all over the body. Patient gave history of new vesicles and erosions all over the body after which he applied neem paste and siddha medications, that complicated the pre-existing insult. Patient was started on Inj. methylprednisolone 1 g for three days as pulse therapy and drastic clinical improvement was seen after first cycle. Now the patient is on remission with tab. azathioprine 50 mg OD (Table/Fig 2)a-c.

Case 2

A 68-year-old male, a case of recalcitrant pemphigus, came with extensive erosions of three weeks duration. The patient developed extensive erosions involving >80% body surface area mimicking Toxic Epidermal Necrolysis (TEN). Few erosions were also affected with myiasis due to neglected care. Patient finally landed up in sepsis and multi-organ failure which resulted in death of the patient, inspite of treating him with inj. methylprednisolone 1 gm for three days as pulse therapy (Table/Fig 3)a,b.

Case 3

A 52-year-old male, known case of systemic hypertension and recalcitrant pemphigus came with extensive erosions especially over the back and scalp of two weeks duration. The patient had assumed hunchback posture due to extensive erosions, that interfered with normal routine activities of life and maintaining erect posture. Patient had remission with six cycles of Dexamethasone Cyclophosphamide pulse therapy. The patient is now on tab. cyclophosphamide 50 mg OD with no new lesions (Table/Fig 4)a-c.

Case 4

A 74-year-old female, known case of pemphigus vulgaris since two years and known case of diabetes mellitus on oral hypoglycaemic agents, came with multiple erosions over back, chest, anterior neck of one week duration. This patient had preceding history of laryngeal ulcer two years ago, biopsy of which showed non specific laryngeal mucosal ulceration. Six months later patient developed multiple flaccid blisters and erosions involving back, chest, anterior neck.

Patient developed Deep Vein Thrombosis (DVT) during hospital stay and was started on treatment for the same as per vascular surgeon’s opinion with regular monitoring of prothrombin time/ partial thromboplastin time/international normalised ratio. The patient was discharged after resolution of skin lesions, but unfortunately developed pulmonary thromboembolism, two weeks after discharge since she lost to follow-up with vascular surgeon (Table/Fig 5)a-c.

Case 5

A 65-year-old female, known case of pemphigus vulgaris and type 2 diabetes mellitus/hypertension came to us with non healing erosions over bilateral axilla. The patient gave history of long standing papillomatous lesions in axilla that were subjected to biopsy outside, which later led to non healing erosions. This patient received three cycles of Dexamethasone Cyclophosphamide Pulse (DCP) pulse and is now on remission with tab. prednisolone 10 mg OD and tab. azathioprine 50 mg OD (Table/Fig 6)a,b.

Discussion

Pemphigus vulgaris has the preference for certain anatomical areas namely scalp, face, neck, upper chest and back. The disease is characterised by great variations in the duration of each episode of illness and also duration of illness as a whole. Factors influencing the chronicity of the illness which also predispose to recalcitrant pemphigus are the following namely (10),(11),(12).

1. Anatomic loci involved
2. Severity of the initial disease
3. Oral involvement
4. Presence of both desmoglein 1 and desmoglein 3
5. Early age of onset

Certain races like the Ashkenazi jews and Asian ancestry can predispose to recalcitrant pemphigus.

Common sites of involvement (cutaneous and mucosal) seen in the present cases that can predispose to recalcitrant pemphigus are :

1. Extensive lesions involving malar area of cheek (Table/Fig 2).
2. Periocular
3. Perinasal
4. Perioral (Table/Fig 3)a,b
5. Scalp- extensive areas of involvement causing loss of hair, secondary scaling and fissuring that heals with post inflammatory hypopigmentation. Scalp is a unique site for pemphigus due to the abundance of desmogleins located in hair follicles (Table/Fig 4)a (13).
6. Jawline- involving skin over ramus of mandible, extending into anterior and lateral aspect of neck (Table/Fig 3).
7. Oral mucosa- pain resulting out of mucosal involvement causes odynophagia/dysphagia interfering with normal feeding habits/fluid intake precipitating malnutrition. Superadded candidiasis adds to the pain and soreness during swallowing.
8. Anal and perianal mucosa- makes patients prone for painful bleeding fissures and perianal fistulae.
9. Laryngeal mucosa- causes hoarseness of voice and incoherent speech.
10. Presternal area: Takes longer time to heal and interferes with chest expansion. Corresponding involvement of extensive areas of the back may lead on to hunch back posture (pseudo kyphosis), that prevents patients from even assuming a proper erect posture (Table/Fig 4)b,c.
11. Involvement of Neck: anterior and lateral aspects, interfering with normal flexion and extension of neck (Table/Fig 5)a-b.
12. Groin involvement, wherein the intertriginous lesions, of thigh on maceration and friction leads to vegetans lesion.
13. Pressure or weight bearing areas, like gluteus maximus muscle, if involved, can give rise to bed sores that are very resistant to heal (Table/Fig 2)b, (Table/Fig 5)c.

Involvement of flexural areas or so called intertriginous areas predisposes the patient to the variant of pemphigus vulgaris called pemphigus vegetans (Table/Fig 6)a (14). The constant maceration of skin because of opposing nature of intertriginous areas, inadequate removal of debris, crusting resulting out of seropurulent discharge in the intertriginous areas favour the formation of papillomatous lesions (Table/Fig 6)b (15).

The Neumann type almost starting as a blister followed by erosions like that of classical pemphigus vulgaris also has a protracted course like that of pemphigus vulgaris.

The Hallopeau type which starts as pustule has a more benign course heals faster unlike Neumann type (14). The biopsy of papillomatous lesions in the intertriginous areas leads to long standing non healing erosions, post biopsy, like in our patient-case 5. These fleshy lesions in intertriginous areas are extremely resistant to topical treatment like saline soaks/potassium permanganate soaks (Table/Fig 5).

In our clinical practice, we commonly encounter patients presenting with cutaneous and mucosal lesions at the same time wherein diagnosis of pemphigus vulgaris will be of no challenge. But few patients, as in case 4, can present with exclusive mucosal erosions involving larynx without any cutaneous lesions which on biopsy shows non specific mucosal ulceration delaying patient from taking an expert opinion from Dermatologists. A high degree of suspicion is needed in this stage to diagnose mucosal pemphigus.

It is observed that a patient can have exclusive mucosal lesions of pemphigus for a period of six good months before development of classical cutaneous lesions (16).

Possible factors affecting disease activity and hence, predicting proneness for recalcitrant pemphigus :

1. Body Surface Area involved (ABSIS Score) and average dose of steroid needed to control disease activity-
Any patient with > 20% body surface area, with involvement of two or more anatomic loci that could predispose to recalcitrant pemphigus is of crucial importance, as it warrants longer duration of treatment with immunosuppressives. ABSIS score serves as a tool, and the dose of steroid if >10 mg/day is a cause of concern.
2. Direct Nikolsky’s sign- following initiation of treatment , out of marginal Nikolsky and direct, it is marginal Nikolsky that takes longer time to become negative. Also, presence of pemphigus paronychia is an indicator of activity of the disease.
3. Age of the individual- earlier the age of onset, the disease has a protracted course.
4. Co-morbidities- like obesity, diabetes mellitus, systolic and diastolic hypertension, dyslipidemia, association with other autoimmune disorders like thymoma and hashimoto’s thyroiditis will naturally prolong the duration of the ailment.
5. Duration of the disease- greater time interval between the onset of first lesion of pemphigus vulgaris and patient’s arrival at the OPD is of huge significance as more the delay, more will be the titre of circulating autoantibodies.

In all the above five patients, the control of disease activity (defined as the time at which occurrence of new lesions ceases and already existing lesions begin to heal) and end of consolidation phase (defined as the time at which no new lesions have developed for a minimum of two weeks, and approximately 80% of lesions have healed) (17) were not attained within the order of few weeks, which is the normal expected course of the disease activity from the day therapy is started by the physician, thereby enabling us to justify the terminology of recalcitrant pemphigus.

6. Prior to arrival at the Dermatology Outpatient Department, application of indigenous medications like: neem/turmeric paste, as in case 1, due to assumption of pemphigus lesions as chickenpox complicates the situation where the added insult of irritant contact dermatitis paves the way for sepsis.

Causes of Death
1) Disease related:
• Extensive involvement of skin and mucosal surfaces makes way for superadded infections,cutaneous myiasis due to loss of barrier functions of skin.This leads to septicaemia and therefore, multiorgan failure.
Mucosal involvement causing dysphagia, odynophagia and bleeding from gastrointestinal tract, compromise in the lumen of hollow viscera can add on to the already existing insult.
• Bronchiolitis obliterans can many a times be an important lethal terminal event in long standing patients of pemphigus vulgaris, which unfortunately goes undetected.
• Extensive denuded areas will lead to seropurulent/serosanguinous discharge which will induce resistance to topical agents used in treatment (Table/Fig 6)b. Also, pre- existing sero-sanguinous discharge will lead to heaping up of epithelial debris that over a period of time goes in for firm adherent concreting debris (Table/Fig 6)a, acting as space occupying lesion preventing new viable epithelial cells coming up to bridge up the erosions or favours papillomatous three dimensional projections in intertriginous areas leading to the recalcitrant variant of pemphigus vegetans.
Hence, its mandatory to have adequate saline or potassium permanganate soaks to remove debris periodically. Because of extensive involvement of skin and mucosa, there will be prevention of normal mobility, especially in elderly individuals, to accomplish day to day tasks of life. Such prolonged immobilisation in elderly individuals especially with co-morbidities makes them prone for DVT due to sluggish flow of blood. The worst sequelae of DVT is throwing of an embolus into the crucial areas of circulation like pulmonary or central nervous system. It becomes mandatory for the treating Dermatologist to add an appropriate antiplatelet or anticoagulant, wherever it is warranted, with its accompanying compulsion of monitoring Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International Normalised Ratio (INR).
In the present study, the authors have lost a patient, who was successfully brought out of recalcitrant pemphigus, but was highly unfortunate to lose the same patient to pulmonary embolism that was thrown out of a DVT (Case 4).
It is important to mention that aspirin given as an antiplatelet agent can precipitate pemphigus vulgaris, as it contains phenol group (18). Hence, safer alternatives like clopidogrel or rivoroxaban can be tried. Drugs like Warfarin, if prescribed, may warrant the necessity to monitor INR.
2) Treatment related:
• Opportunistic viral infections like herpes zoster and disseminated herpes due to long term use of systemic immunosuppressants.
• The preservatives used in ophthalmic antibiotic drops used for ocular involvement can cause Stevens-Johnson Syndrome (SJS) which can further worsen the lesions.
• Any of the co-prescription that the patient has taken can induce SJS/TEN (Table/Fig 3), which will further deteriorate the general condition of the patient. Because of massive areas of skin necrosis pseudo NIkolsky becomes positive and massive epidermal peeling will add on fuel to fire of the pre-existing pemphigus erosions.
• Prolonged immunosuppression, that too in patients with co-morbidities like diabetes, treated pulmonary/extrapulmonary Koch can precipitate a full blown septicaemia where the patient finally lands up with multiorgan failure, being the terminal event in the trail of an agonising course of the disease.

Treatment Considerations

The presence of overt or occult sepsis can decrease the therapeutic efficacy of steroids. This invites one more immunosuppressant drug, hence, increasing the quantum of immunosuppression.

Mode of administration of immunosuppressant also matters a lot. Pulse dosing of immunosuppressant is found to be of better therapeutic efficacy than daily dosing. Cyclophosphamide when given as pulse dosing (500 mg i.v. once in four weeks) has a cutting edge over daily administration of cyclophosphamide (50 mg tablets once daily) as it impairs immune surveillance for relatively short periods when given as pulse therapy once in 3-4 weeks than when given as daily dosing of 50 mg. Moreover, it doesn’t cause myelosuppression to cause immunosuppression.

As far as United States Food and Drug Administration (US FDA) approved dermatological indication of cyclophosphamide is concerned, it is only mycosis fungoides, but when it is used in the treatment of bullous disorders along with dexamethasone in form of dexamethasone cyclophosphamide pulse, it is very instrumental in limiting disease activity and, at the same time ensuring minimal adverse effects of corticosteroids like immunosuppression (19).

Also, it is seen that patients not responding to conventional corticosteroids/immunosuppressants are treated satisfactorily with injection methylprednisolone pulse. The commonest adverse effects noted were nausea, gastritis, vomiting, sudden shooting of blood pressure. Hence, monitoring for these symptoms is mandatory.

Conclusion

Majority of the patients of pemphigus vulgaris experience relapse and remission during the first five years of disease activity. Any patient who can successfully tide over the first five years of the disease activity is said to have a reasonably good longevity of life and the disease is said to have less mortality rate. Early diagnosis, either when the patient is still in the mucosal phase alone wherein they can stay in this phase for six months or when the lesions are confined to less than 10% of BSA in the case of mucocutaneous variant, and prompt treatment with Immunosuppressants, adequate follow-up, keen interest on factors predisposing to recalcitrant variant, co-morbidities of the patient after maths of the prolonged disease activity like DVT and PTE, has a very huge impact on the prognosis of the patient and successful restoration of near normal DLQI. Particularly in this era of Coronovirus Disease 2019 (COVID-2019) pandemic, to keep a patient on immunosuppressants for a longer time poses one more threat to the treating Dermatologists, wherein contracting COVID-19 infection is always there on the high rise in patients maintained on immunosuppressants for a long time.

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DOI and Others

DOI: 10.7860/JCDR/2022/53400.16084

Date of Submission: Nov 22, 2021
Date of Peer Review: Dec 15, 2021
Date of Acceptance: Jan 14, 2022
Date of Publishing: Mar 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Nov 24, 2021
• Manual Googling: Dec 09, 2021
• iThenticate Software: Feb 24, 2022 (2%)

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