Efficacy and safety of intralesional Candida albicans antigen versus intralesional mumps, measles, rubella vaccine in the treatment of multiple cutaneous warts: A double-blinded randomized controlled trial

INTRODUCTION

Cutaneous warts are a common benign presentation of human papillomavirus (HPV) infection of keratinocytes. Traditional destructive modes of treatment such as topical salicylic acid, topical 5 fluorouracil, curettage, cryotherapy, light amplification by stimulated emission of radiation (LASER), and electrosurgery have several side effects, including irritant and allergic contact dermatitis, dyspigmentation, pain, blistering, scarring, and underlying tissue damage. Immunotherapy is beneficial for patients with multiple, recurrent, recalcitrant warts and warts in difficult-to-treat areas such as periungual areas and palmoplantar surfaces. Furthermore, these are relatively easy to use, non-destructive, and have lesser side effects and recurrence rates.

Immunotherapy is a type of biological therapy that uses substances to stimulate or suppress the immune system to help the body combat cancer, infection, and other diseases.¹ The principle of this therapy for warts is to deliver an antigen, either intralesionally or systemically, to produce an immune response resulting in clearance of the wart. Immunotherapy acts by stimulating Th1 responses and inhibiting Th2 responses. Immunotherapy is also proposed to downregulate the gene transcription of HPV through stimulation of tumor necrosis factor-α and interleukin-1.² Many immunotherapeutic agents such as Candida albicans antigen, mumps, measles, rubella (MMR) vaccine, Mycobacterial antigens (purified protein derivative, bacille Calmette-Guérin, Mycobacterium w vaccine), Trichophyton antigen, vitamin D3, and IFNs have been used for intralesional therapy. The efficacy of these agents varied widely from 26.5% to 93%, with good clearance rates (23.3– 95.2%) even in pediatric population also.³ Older individuals (above 40 years) tend to respond less to immunotherapy, probably due to their weaker immune responses.⁴

Candida antigen was the first antigen to be studied for immunotherapy of warts in 1979 by Harada.⁵ It involved intralesional injection of a killed yeast protein.⁵ Immunotherapy with C. albicans antigen should be effective considering the high prevalence of Candida infection in the general population.⁶

MMR is a live-attenuated vaccine commonly used for intralesional immunotherapy of warts nowadays. Numerous studies on intralesional MMR conducted in India have reported good efficacy with the antigen. However, there are only a few studies on intralesional C. albicans for warts in India. Studies comparing intralesional C. albicans with MMR are few. Therefore, we chose to compare the efficacy and safety of intralesional MMR with intralesional C. albicans.

MATERIAL AND METHODS

RESULTS

The flow of study participants according to consolidated standards of reporting trials (CONSORT) is shown in Figure 1. Per-protocol analysis of the study included 53 patients, after excluding the patients who were lost to follow-up.

Close

Figure 1:

Flow of study participants according to consolidated standards of reporting trials. MMR: Mumps, measles, rubella

Export to PPT

The average age of patients included in the study was 29.6 years, with a male-to-female ratio of 3.82:1. The majority of the patients were students (32.08%). The mean duration of warts was 12.58 ± 13.74 months. Most of the patients (73.58%) had warts of <1-year duration. 67.92% of the patients (n = 36) had a previous history of receiving treatment for warts, among which topical salicylic acid was the most common (27.78%) treatment used by patients. Ayurvedic, homeopathic, and home remedies were also commonly used by patients. The mean number of warts per patient in this study was 12.75 ± 10.994. A comparison of the demographic data and wart characteristics showed no significant difference between the two groups [Table 1].

Complete clearance of warts was observed in 34.48% and 37.5% of patients belonging to MMR and Candida groups, respectively [Figures 2 and 3]. A comparison of the overall therapeutic response, response to treatment for injected warts, and distal clearance rates showed no significant difference between the two groups [Table 2]. Complete response was achieved in 30% of the Candida group and 33.3% of the MMR group according to the intention to treat analysis [Table 3].

Close

Figure 2:

A 50-year-old female with multiple warts over dorsum of left foot (a) before immunotherapy with Candida albicans, and (b) at week 8 after intralesional Candida albicans immunotherapy showing complete clearance of both injected and uninjected warts.

Export to PPT

Close

Figure 3:

A 27-year-old male with filiform warts over beard area (a) before immunotherapy with MMR, and (b) at week 8 showing complete clearance of both the injected and uninjected warts with intralesional. MMR. MMR: Mumps, measles, rubella.

Export to PPT

Among those who achieved complete clearance, the mean time to clearance of warts was 7.20 ± 1.687 weeks in the MMR group and 7.33 ± 2.000 weeks in the Candida group. There was no statistically significant difference with respect to response rates (P = 0.955) and time to complete clearance (P = 0.877) between the two groups. None of the patients who achieved complete clearance had a recurrence of their warts during the 1-month follow-up period. Injection site pain was complained of by all patients. Flu-like symptoms such as shivering or mild headache were observed in 6 patients receiving C. albicans injection (25% of patients in the Candida group). One patient who received a C. albicans injection reported transient erythema. New lesions appeared during treatment and follow-up in 7 patients in each of the MMR and Candida groups. The mean number of new lesions was 2.86 ± 1.952 in the MMR group and 4.14 ± 5.047 in the Candida group, with no significant difference between the two groups (P = 0.902). Therapeutic response was found to be relatively higher in children (12–18 years), in those presenting with warts <12 months, and in patients without multiple site involvement. Patients with only palmoplantar warts responded better with either of the two treatment modalities. Patients with filiform warts seemed to respond better with intralesional Candida.

DISCUSSION

The use of various intralesional immunotherapeutic agents for warts, including MMR vaccine and C. albicans antigen has been reported previously with varied success rates. Head-to-head randomized trials (one open labeled⁹ and two double-blinded^10,11) comparing intralesional Candida with MMR showed comparable efficacy of both antigens, similar to our study [Table 4]. However, response rates were higher than ours in these studies, which might be due to the different dosing protocols employed. One open-labeled randomized trial showed significantly better efficacy with Candida when compared to MMR.¹²

Pain, erythema, edema, and flu-like symptoms were reported in these studies in both the groups, except in the study by Rageh et al.,¹² where flu-like symptoms were not reported with MMR, like in our study. We noted that the flu-like symptoms started 1 h after injection and subsided on their own within 12 h or earlier with NSAIDs. We also observed that the intralesional injection was more painful when injected on plantar and periungual warts. None of the other side effects previously reported with intralesional MMR was observed in our study, thus confirming the safety of this antigen compared to Candida.

The time to achieve complete clearance was 8 weeks in most patients but one patient in the C. albicans group achieved complete clearance with a single injection in our study. A smaller number (n = 4) and shorter duration of wart (1 month) might be the reason for achieving faster clearance for that patient. Signore,⁸ also observed complete resolution with a single dose of intralesional Candida antigen in 16 out of 44 patients. Kaur et al.,¹³ noted that there is continuous improvement during the follow-up visits after the last dose of intralesional MMR (3^rd dose), with an increase in grade 4 response (more than 76% improvement) from 20% at week 6 (visit for the last dose) to 76.67% at the end of 20 or 24 weeks after the last dose. Similar findings were noted by Saini et al.,¹⁴ with an increase in grade 4 response from 4.6% at week 4 (visit of the last dose) to 49.43% at the end of 16 weeks without further injections. This could suggest that the response to immunotherapy is slow and patients can achieve clearance without further injections while maintaining them on follow-up. However, there are no guidelines as to how long the patient should be followed up before considering them as non-responders.

Shaheen et al.,¹⁵ noted in their study that the minimum number of sessions needed for complete clearance was two, which was similar to our study where two patients achieved complete clearance within two doses. Majid and Imran,¹⁶ observed that patients who failed to show any response with the first or second injection are less likely to show any response with further injections. Although this was true in the majority of patients, 3 patients from the Candida group and 5 patients from the MMR group started to show some response only after the third dose in our study.

Few studies^15-19 included only patients with positive immune response to the antigen following an intradermal test before performing intralesional immunotherapy with it. Most of these studies showed a relatively higher clearance rate compared to our study. Both the antigens were administered without presensitization in our study. This approach was practical in our study as carrying out a pre-sensitization test would have increased the number of visits by each patient, affecting compliance.

Placebo-controlled trials on MMR have noted complete response rates of up to 27.5%^20-22 in the placebo (saline) group. However, distal clearance rates in all these studies were 0%, suggesting that widespread HPV-targeted immune response cannot be achieved with localized trauma alone. Placebo-controlled trials on Candida have observed complete clearance in 0%,^18,23,24 8.6%,²⁵ and 21.2%²⁶ in the control group (saline). Even though we did not have a placebo-control group, our complete response rates and distal clearance rates were higher than those achieved by the placebo group in other studies. This would suggest that the resolution of warts observed in both the groups in our study was due to the effect of antigens and not due to spontaneous resolution or not just due to trauma of the injection eliciting an immune response against HPV.

5 out of the 14 patients who developed new lesions during the course of treatment in both groups achieved complete regression of warts and one patient from the Candida group had a partial clearance of warts within 8 weeks (i.e., the last follow-up visit). This could imply that the development of new lesions during treatment may not be a bad prognostic factor in determining treatment response.

In our study, response to intralesional therapy was better with younger age, shorter duration of warts, and lesser number of warts. Na et al.,²⁷ noted a significant negative correlation of wart clearance with age. Few studies have found a statistically significant negative correlation between the degree of response and duration of warts,^15,20,28,29 suggesting that warts having shorter duration are more likely to respond better with treatment. As warts can increase in size and number over time and become more treatment-resistant, early institution of therapy is necessary rather than waiting for spontaneous resolution.¹⁵ Furthermore, a longer duration of warts might denote a sort of virus-specific immunodeficiency.¹⁵

One of the two patients who had received intralesional MMR in the past and received intralesional Candida in our study had complete resolution of lesions. This might imply that Candida might be a better immunotherapeutic option in instances where intralesional MMR has failed.

There are no strict guidelines for dosing amount, the concentration of Candida antigen, dosing frequency, and duration of intralesional immunotherapy with either of the two antigens used in immunotherapy of warts. It is possible that efficacy would have been higher if the total number of sessions or dose per session or duration of follow-up had been more or if only sensitized subjects were included in the study. Our criteria for categorization of treatment response were more stringent. We had five patients (four in the MMR group and one in the Candida group) with <50% clearance rate who were included under “no response.” Among those patients who had some clearance of warts, we continued our treatment with further injections (up to a total of 5 doses) beyond the last follow-up mandated by the study and observed complete response in them. Furthermore, the difference in the study population selected for treatment, the number of patients, the type and duration of warts, and different brands of the antigen used could be the reasons for this variation in response. These could be the possible reasons for the low percentage of clearance in both treatment modalities.

A shorter follow-up period, the absence of intradermal skin tests with the antigens, and a higher number of patients lost to follow-up in the Candida group compared to the MMR group were the limitations of this study. Previous studies,^18,19,27 which reported recurrence with either of the two antigens used, had followed up their study subjects for a period of 6 months after completion of treatment. While there are no specific guidelines regarding the period of follow-up to detect recurrences, it is possible that we would have detected recurrences if we had followed up with our patients longer than 2 months, which we could not because of logistical reasons.

This was a double-blinded randomized trial comparing intralesional MMR with intralesional candida antigen for multiple warts, while the earlier ones were open-label or for periungual or plane warts. Intralesional immunotherapy with Candida and MMR are both effective in the treatment of multiple warts, with comparable overall and distal response rates. Intralesional immunotherapy with MMR was found to be relatively safer than C. albicans antigen.

CONCLUSION

Intralesional MMR can be considered as a first-line therapy in the treatment of multiple warts, and intralesional C. albicans can be considered in patients where intralesional MMR has failed to elicit a favorable response.