A Comparative Study to Assess Efficacy of Intralesional MMR Vaccine and Intralesional Vitamin D3 in Treatment of Warts (MMR)

A Comparative Study to Assess Efficacy of Intralesional MMR Vaccine and Intralesional Vitamin D3 in Treatment of Warts

A Comparative Study to Assess Efficacy of Intralesional MMR (Measles, Mumps, Rubella) Vaccine and Intralesional Vitamin D3 in Treatment of Warts

Common warts are papulonodular epidermal lesions caused by human papillomavirus (HPV) usually by the strains 1, 2, 4, 27 or 57. Cutaneous warts occur in 7% to 10% of the general population, with a maximum incidence between 12 and 16 years. There are multiple destructive treatment modalities of wart but they have many adverse effects. Hence immunotherapy is becoming popular in treatment of warts. It is believed that the injection to the HPV-infected tissue induces a strong nonspecific pro-inflammatory signal and attracts the antigen-presenting cells. Which then promotes a Th1 cytokine response and leads to delayed-type hypersensitivity reaction leading to the eradication of the HPV-infected cells. We are undertaking a study to evaluate and compare the safety and efficacy of 2 such immunotherapeutic agents namely, IL measles, mumps and rubella (MMR) vaccine versus IL vitamin D3 for the treatment of warts. RESEARCH HYPOTHESIS Null Hypotheses: IL MMR vaccine is not better than IL Vitamin D in the treatment of wart Alternative hypothesis: IL MMR vaccine is better than IL Vitamin D in the treatment of wart Method: A total of 60 patients will be included in the study, 30 in each group. Group A and Group B patients will be injected with 0.5 ml of IL MMR and 0.5 ml of IL vitamin D3 respectively into a single or a maximum of 5 warts at a time in case of multiple warts. The IL injection will be given every 3 weeks for a maximum of 5 doses. Clinical assessment will be done by taking photographs and measurements at baseline, before each treatment session, and 3 months after the completion of treatment. The response will be evaluated by a decrease in the size and number of the wart(s) and photographic comparison. The response will be considered complete if there is a complete clearance of the wart(s), good if the wart(s) will regress in size by 75-99%, moderate if they regress by 50-74% and no or mild if there will be a 0-49% decrease in wart(s). Immediate and late side effects of MMR and Vitamin D will be evaluated after each session. Follow up will be made monthly for 3 months to detect any recurrence. Quality of life (QoL) will be measured in wart patients, using the Nepali version of the dermatology life quality index (DLQI) questionnaire before initiation of treatment and at the end of follow up. Statistical analysis will be done using Statistical Package for the Social Sciences 10.5 version.

INTRODUCTION Warts are common skin conditions resulting from infection of keratinocytes by human papillomavirus (HPV). After infection of the basal layer, there is clonal proliferation leading to epidermal thickening and hyperkeratinization and eventually results in a visible wart. HPVs are ubiquitous, epitheliotropic non-enveloped small double-stranded DNA viruses. Over 150 types of HPVs have been identified. Among them verruca vulgaris are usually caused by HPV types 1, 2, 4, 27 or 57, and plane warts by HPV types 3 or 10. Cutaneous warts occur in 7% to 10% of the general population, with a maximum incidence between the ages of 12 and 16 years. In children, clearance can occur after only a few months, with 50% at 1 year and about 65%-78% by 2 years. The rate of clearance is influenced by factors like virus strain, host immune status, extent and duration of warts. The transmission of warts occurs from direct contact or indirectly via fomites. There are multiple destructive, antiproliferative and antiviral agents in treatment of warts. Other modalities include hypnotherapy, acupuncture, local hyperthermia, therapeutic vaccination and combinations of the previous agents. Destructive therapies usually come with many adverse effects hence immunotherapy is becoming more popular, especially in the treatment of refractory cutaneous and genital warts. These include various topical, intralesional (IL) and systemic agents. IL Measles, Mumps, rubella (MMR) and IL vitamin D3 are examples of immunotherapeutic agents. Immunotherapy is defined as a type of biological therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Immunotherapy can affect the immune system in general or can be cell-specific. Immunotherapy is believed to induce a strong nonspecific pro-inflammatory signal and attract the antigen-presenting cells. This is associated with the release of cytokines such as IL-2, IL-8, IL-12, IL-I8, tumor necrosis factor-α, and interferon-γ. This then promotes a Th1 cytokine response which leads to the activation of delayed-type hypersensitivity reaction leading to the eradication of the HPV-infected cells. Furthermore, the trauma of the injection may also cause a resolution in previously sensitized individuals. Vitamin D3 is also claimed to regulate epidermal cell differentiation and proliferation and may modulate cytokine production through its action upon vitamin D receptors (VDRs). Since IL antigen immunotherapy enhances recognition of the virus by the immune system it causes clearance of both treated and untreated lesions and helps to prevent future clinical infection through induction of long-term acquired immunity to HPV. MMR vaccine is included in immunization schedule of Nepal so pre-sensitization skin test is not needed as all patients are expected to be immune. The presence of 3 different antigens in MMR increases the sensitivity to the injected antigen and decreases the likelihood of anergy. Side effects of MMR include pain during injection, flu-like symptoms, pruritus and burning sensation. IL vitamin D is a novel addition to therapies in warts as it is a simple, effective, well-tolerable, and inexpensive method with negligible local and systemic side effects. Side effects of Vitamin D3 include transient mild to moderate pain, edema at the site of injection and mild erythema. Additionally, it would be safer to monitor serum vitamin D and calcium levels before and after intralesional vitamin D treatment to prevent possible hypervitaminosis D. RATIONALE Intralesional Immunotherapy is an emerging method of treatment of wart in which injection in a single wart causes the resolution of distant warts as well. Compared to other destructive modalities, it is more effective and comfortable for the patient as it obviates the need for individual treatment of each wart. In addition it has a lower rate of recurrence, avoids adverse effects such as scarring, is more cost-effective in multiple warts and decreases the time a physician has to spend on each patient. Further both injection MMR and Vitamin D3 are readily available as compared to other immunotherapeutic agents like purified protein derivative and candida antigen. IL MMR vaccine has been used for a longer time than IL vitamin D and there are more comparative studies showing efficacy of MMR vaccine with rates of clearance ranging from 70.4% to 82.4%. The clearance rates for IL vitamin D ranges from 40% to 90%. The advantages of vitamin D over MMR vaccine are cost-effectiveness, non-requirement of maintenance of cold chain, easy availability, and feasibility of use in immunosuppressed patients. As per Institute of Medicine (IOM), the tolerable upper intake of vitamin D is 4000 IU/day for anyone older than 9 years such that annual maximum dose will be 1,460,000 IU. The total amount of vitamin D that we will be administering will be 1,500,000 IU. Furthermore, since we are giving it intralesionally systemic absorption is likely to be low although data on exact amount of IL vitamin D that gets absorbed systemically is not available. In other studies, patients have been evaluated clinically for signs and symptoms of hypervitaminosis D however, no signs of toxicity were observed. As per our literature search, No previous studies on immunotherapy in wart have been conducted in our country No comparative studies have been done to compare IL MMR and IL vitamin D3 in treatment of wart hence we aim to establish efficacy of each and compare the two. OBJECTIVES Primary Objectives: To determine the efficacy of IL MMR vaccine in the treatment of Wart To determine the efficacy of IL vitamin D in the treatment of wart To compare the efficacy of IL MMR vaccine and IL Vitamin D Secondary Objective: To determine the clinical and demographic profile of patients with different types of warts visiting Dermatology outpatient department(OPD) of BP Koirala Institute of Health Sciences (BPKIHS) To determine the side effects of IL MMR vaccine and IL Vitamin D in treatment of wart To determine Dermatology life quality index (DLQI) in wart patients. Operational definition Wart - clinical diagnosis made by a dermatologist Complete response (100%)- Complete disappearance of warts including distant ones and skin texture at the site is restored to normal Excellent response (75-99%)-Reduction in size and number including distant ones and few residual warts still visible Good response (50-74%)-Some reduction in size only including that of distant ones but no decrease in number of warts Poor or no response (0-49%)-No significant change in size and number of warts Recurrence- Recurrence during the study period MATERIALS AND METHODOLOGY Materials: Study population will be all patients clinically diagnosed with warts visiting the Dermatology OPD of BPKIHS, Dharan. Study design: Prospective comparative longitudinal study Study Period: Probable duration of the study will be 1 year after approval from the Institutional Review Committee (IRC) and Nepal Health Research Council (NHRC) Ethical Clearance: Taken from IRC, BPKIHS and NHRC Conflict of interest: None Sampling Technique: Census method with all consecutive patients meeting inclusion criteria for initial 6 months Sample size The study considers a 95% confidence interval, 80% power to estimate sample size. According to the literature review, it was found that there was 84.6% and 40% improvement in MMR and Vitamin D respectively. Now using the sample size estimation formula for 2 proportion {(Zα√2p(1-p)+ Z1-β√((p1(1-p1) p2(1-p2)}2))/(p1-p2)2 Where n= sample size for each group p1 = 0.846 p2 = 0.40 p= (p1 +p2)/2 Zα=1.96 Z1-β = 1.28 Using above formula, n= 12.3 The formula for actual sample size is n/4{1+√(1+4/n|p1-p2|)}2 na = 16.48 Adding 10% in calculated value to reduce bias sampling technique, the minimum sample size in each group is 18.13 =19 Considering loss of follow up, sample size in each group= 30 Total sample size= 60 Methodology Based on the computer generated random number table, patients satisfying inclusion criteria will be assigned to either Group A or Group B once they come to OPD. Informed consent will be taken and detailed information including personal data, past history, medical history, drug history, clinical data like site, size, number and distribution of lesions will be recorded in preset pro forma. Photographs of the lesions will be taken before the first treatment session, in every treatment session and 3 months after last session. Group A Freeze-dried MMR vaccine single-use vials stored at 2°C-8°C will be reconstituted with 0.5 mL of distilled water immediately before IL use. If reconstituted vaccine is not used within 8 hours it must be discarded. All Group A patients will receive IL injection of upto 0.5 mL of reconstituted MMR vaccine into a single or a maximum of 5 warts at a time in case of multiple warts with 31 G insulin syringe with beveled edge facing upward. Amount of injection on each wart will depend on the size of each wart. The injection will be given every three weeks for a maximum of 5 doses. Group B All Group B patients will receive a maximum of 0.5 mL Inj. Vitamin D3 (600,000 IU; 15mg/ml) in each session after injection of IL lignocaine with 31 G insulin syringe. In cases of multiple warts, a maximum of 5 warts will be injected at a time. Amount of injection on each wart will depend on the size of each wart. The session will be done at 3 weekly intervals for a maximum of 5 sessions or until complete resolution of warts, whichever is earlier. In patients of group B serum vitamin D level will be measured after 20 days of 3rd dose and 1 month after the last dose to ensure safe monitoring. Patient and physician global assessment using 'Visual Analog Scale score' and photographic comparison will be used to assess the response to treatment as mentioned in operational definition. Immediate and late adverse effects in both groups will be evaluated after each treatment session. Necessary investigations and intervention will be done if needed. Follow up will be made monthly for 3 months to detect any recurrence. Quality of Life(QoL) QoL will be measured in wart patients, using the Nepali version of the dermatology life quality index (DLQI) questionnaire before initiation of treatment and at the end of follow up. DLQI contains 10 questions that involves 6 sections: symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. Questions 1 and 2 assess symptoms and feelings; 3 and 4, daily activities; 5 and 6, leisure; 7, work and school; 8 and 9, personal relationships and 10, treatment. The clinically meaningful change or reduction in the DLQI score is measured as the change in score from one band to the other. Statistical analysis Data handling: Data will be entered in Microsoft Excel 2010 and statistical analysis will be done using Statistical Package for the Social Sciences 10.5 version Coding: Alpha numerical code will be used Monitoring: Data will be entered after every day of work and supervised by guide. Statistical Analysis: Chi square test to compare the categorical data between the groups. Paired t test for comparing normally distributed continuous variables at different time point within the group Independent 't' test for comparing normally distributed continuous variables at different time point between the groups Wilcoxon signed rank test to compare the not normally distributed variables, ordinal data Mann- Whitney U test to compare the not normally distributed variables, ordinal data. Kaplan-Meier curves to compare the response rate on each follow up visit between the groups. Test of significance will be considered when value of p ≤ 0.05.

Group A patients will receive intralesional injection of upto 0.5 mL of reconstituted MMR vaccine into a single or a maximum of 5 warts at a time in case of multiple warts. Intralesional injection will be given every three weeks for a maximum of 5 doses or until complete resolution, whichever is earlier.

Group B patients will receive a maximum of 0.5 mL Inj. Vitamin D3 (600,000 IU; 15mg/ml) in each session after injection of IL lignocaine with 31 G insulin syringe. In cases of multiple warts, a maximum of 5 warts will be injected at a time. The session will be done at 3 weekly intervals for a maximum of 5 sessions or until complete resolution of warts, whichever is earlier

Percentage of patients showing complete response to IL MMR and IL Vitamin D3 Complete response -Complete disappearance of warts including distant ones and skin texture at the site is restored to normal (100%) Excellent response- Reduction in size and number including distant ones and few residual warts still visible (75-99%) Good response- Some reduction in size only including that of distant ones but no decrease in number of warts (50-74%) Poor or no response- No significant change in size and number of warts (0-49%)

Distribution of wart patients into different education level like professional degree, graduate, intermediate, high school, middle school, primary school or illiterate

Number of participants with different occupations like professional, semiprofessional, clerical/shop/farm, skilled worker, semiskilled worker, unskilled worker, unemployed

Quality of life (QoL) will be measured in wart patients, using the Nepali version of the dermatology life quality index (DLQI) questionnaire before initiation of treatment and at the end of follow up. DLQI contains 10 questions that involves 6 sections: symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. Questions 1 and 2 assess symptoms and feelings; 3 and 4, daily activities; 5 and 6, leisure; 7, work and school; 8 and 9, personal relationships and 10, treatment. The DLQI consists of 10 questions. Each question is given 4 options from not at all effect (score 0) to very much effect (score 3). The minimum and maximum possible score, thus, is 0 and 30 respectively. Meaning of DLQI Scores 0-1 = no effect at all on patient's life 2-5 = small effect on patient's life 6-10 = moderate effect on patient's life 11-20 = very large effect on patient's life 21-30 = extremely large effect on patient's life .

Number of participants with different progressions of warts like Gradual or rapid or stable or regressing lesions

Inclusion Criteria: 1. Clinically diagnosed patients who have more than three warts or single wart in difficult to treat sites (periungual, palms and soles) Exclusion Criteria: Patients not under any systemic or topical treatment of warts for the last four weeks Patients with a past history of an allergic response to MMR or any other vaccine or Vitamin D Patients with current acute febrile illness or any bacterial infection Immunosuppressed patients Pregnant or lactating women Patients having a past history of asthma, allergic skin disorders or convulsions Patients with keloidal tendency Patient refusal for consent Treating physician's decision to give other treatment modality Patients with hypervitaminosis D, muscle weakness, bone pain, altered sensorium

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