Efficacy and safety of iontophoresis combined sodium salicylate in acquired plantar keratoderma-a randomized controlled study

INTRODUCTION

Palmoplantar keratodermas (PPK) are a diverse entity of keratinization disorders characterized by abnormal thickening of the palms and soles.¹ They are traditionally divided into genetic² and acquired types.³ Various Acquired PPKs have varying epidermal involvement patterns: diffuse, focal, punctate and transgradient.³

As the terms hyperkeratosis and keratoderma have been used interchangeably throughout the literature, we define acquired keratoderma as a non-hereditary hyperkeratosis of the palms and/or soles that involves ≥30% of the surface of involved acral areas and that may or may not be associated with clinical inflammation.³

Acquired PPK can be due to common causes like, keratoderma climactericum (menopause), drug related, malnutrition associated, chemically induced, systemic disease related, malignancy associated, dermatoses related, infectious, and idiopathic.³

Treatment of keratoderma remains problematic and restricted to symptomatic therapy. Topical therapies like keratolytic (such as urea, salicylic acid, and lactic acid), topical retinoids, topical corticosteroids and topical psoralen and ultraviolet A phototherapy are showing variable results in the small database of keratoderma.⁴

Salicylic acid is widely and commonly used keratolytic compound. In addition to keratolytic action, it has anti pruritic ⁵, sun-protective, bacteriostatic as well bactericidal⁶ actions. It has been included in many over the counter dermatological agents and has been widely used for plaque psoriasis, acne, corn, wart, pigmented lesions, seborrheic dermatitis, ichthyosis etc.⁷ But in literature, case reports revealed mixed responses to topical salicylic acid in keratoderma.

Iontophoresis is a noninvasive, convenient and rapid method of delivering water soluble, ionized medication into skin. It allows higher concentration of drug to be delivered to a limited area with negligible side effects.⁸

Till now, there are only few studies evaluating clinical profile of palmoplantar dermatoses and only few case reports showing varied response to treatment. We could not find any study comparing efficacy of iontophoresis in keratoderma. In our study, we compared efficacy of iontophoresis combined aqueous solution of sodium salicylate with topical salicylic acid 12% ointment.

METHODS

After receiving approval from institutional review board and clinical trials registry India (CTRI) registration (CTRI/2019/09/021444) this randomized controlled study was undertaken during October 2018 to December 2019. Patients of either gender >18 years of age, clinically diagnosed as plantar keratoderma and had involvement of bilateral symmetrical plantar surfaces with >30% of area of each sole were included in the study. Sample size was calculated as 80 by using Openepi software with confidence interval 95% and power 80%. Then they were randomly allotted to group A (Iontophoresis) and group B (Topical) according to random number generator. We excluded patients with infective etiology of keratoderma, with pacemaker or bone plate, who had taken treatment within last 3 months, pregnant and lactating females.

A written informed consent was taken from all patients and a pre - set proforma was used to collect detailed history and demographic details. Certain Laboratory tests e.g., Complete blood count, renal and liver function tests, blood sugar level, thyroid function tests were ordered for every patient.

Group A (Iontophoresis)

Two square plastic trays are filled with this 12% aqueous solution of salicylate (by dissolving 12 gm of sodium salicylate powder in 100 ml tap water) and metal electrodes of iontophoresis were put in them. Patient was instructed to put both soles over electrodes in plastic tray. Then direct current was applied with gradually increasing intensity guided by mild tingling sensation felt by the patient. The maximum intensity was 10mA and the minimum was 5 mA. After 10 min, direction of current was reversed using switching arrangement and reversed current was applied with same intensity for 10 min. So, iontophoresis was applied within range of 5-10 mA for 20 min of duration. This procedure repeated twice a week for 8 weeks, covering total 16 sittings. Patient was counselled to apply emollient cream twice daily at home.

Group B (Topical)

The 12% salicylic acid ointment was applied twice daily, along with emollient cream at home. Patients were counselled to wash immediately if severe irritation occurs. Patients were followed up every 4 weeks for duration of 2 months. This regimen was continued till 8 weeks of duration. Patients from both groups were also given antihistamines for pruritus.

Outcome measures of study

Objective outcome measures

EASI (eczema area severity index) score, which is calculated at time of enrollment and then at 4^th and 8^th week.

The EASI score is the sum of severity grading of different parameters [1. Fissures 2. Hyperkeratosis 3. Erythema. 4.xerosis 5. Scaling] multiplied by Image J score. Image J software was used to measure area of involvement of plantar surfaces.

Parameter’s severity grading is as follows: None [0] - absent, mild [1]-just perceptible, moderate [2]-obvious and severe [3]-very prominent.

For image j score calculation, 1-10 cm² graded as 1, 11-20 cm² graded as 2 and so on. Severity of image J score was decided as: None: no area of involvement, Mild: 1-4.5 score, Moderate: 4.6-9.0 score, Severe: 9.1-13.5 score. Clinical photographs by using canon SLR camera

Subjective outcome measures

Physician’s global assessment score and patient’s self-assessment score.

Statistical analysis of study

Data collected were analyzed in Graphpad Instat 3.0 software (California USA). All the quantitative parameters were expressed in Mean ± standard deviation (SD) frequencies (number of cases) and relative frequencies (percentages) when appropriate whereas categorical data given as number and percentages. Nonparametric tests were applied as the collected data were in non- Gaussian distribution. Mann–Whitney test was used for the comparison between two groups. Friedman test with Dunn’s test was applied for comparing different parameters same group. Chi square test was used to compare observed frequencies between groups. P<0.05 considered statistically significant.

RESULTS

A total of 81 patients of plantar keratoderma were screened during study period, out of them 73 met inclusion criteria and among them, 70 patients had completed 8 weeks of treatment as shown in Figure 1.

As stated in table 1 age of patients in both groups ranged from 25-65 years (mean age was being 41.2). Most number of patients belonged to age group of 35-50 years (60%) and there were 39 females (55.7%) and 31 males (44.3%). Among associated conditions, maximum association was found with menopause (18.5%), followed by diabetes (10%), hypertension (8.5%), other dermatoses- psoriasis (7%) and hypothyroidism (3%).

A higher incidence of keratoderma was observed among laborers (54.2%) followed by housewives (27.1%). Also, greater number of patients showed exacerbation in winters (52.8%) as compared to summers (35.7%).

Out of 70 patients, there were 66 patients (94.2%) with diffuse keratoderma, whereas only 3 (4.2%) had focal keratoderma and 1 (1.4%) had trans-gradient pattern. 35 (50%) had duration of disease for 1-3 months, 17 (24.2%) had <1 month, 14 (21.4%) had 3-12 month and 5 (7.14%) had >12 month of duration. As depicted in table 2, statistically significant (p=0.004 and 0.001) higher mEASI (mean EASI) score among patients who had longer duration (>12 moths) of disease in both groups. Although, there was no significant (p>0.05) impact of disease duration on treatment response. Besides, as shown in Figure 2, greater the severity of keratoderma higher intensity of DC current required during treatment.

Amid of associated symptoms, most common was pruritus present in 59 patients (84.2%) followed by pain in 50 (68.5%) and burning in 22 (31.4%). At end of 8^th week, only 6 patients (12%) had pain, 3 had (13.6%) burning and 15 had (25.4%) pruritus. Here, pruritus was found to be relieved in significantly (p=0.003) higher number of patients in group A as compare to group B. Whereas, remission of pain and burning was comparable in both groups (p>0.05).

Evaluation parameters

As mentioned in methodology, we evaluated EASI score using 6 parameters: fissures, hyperkeratosis, xerosis, scaling, erythema and image J score. Among both groups, maximum improvement was found in hyperkeratosis. 64.2% of patients had nil hyperkeratosis, followed by fissures (52.8%), xerosis (47.1%) and scaling (20%) and image J score (7%).

As shown in Figure 3, significant number of patients shifted from higher grade (severe, moderate) to lower grade (mild, no disease) of severity at end of 8 weeks for all parameters in both groups.

But intergroup comparison of number of patients showing decrement of severity grading, was not statistically significant.

On comparing intra-group mean values of severity gradings of parameters in Table 3, extremely statistically significant reduction was there at 4^th and 8^th week in both groups (p<0.0001 using Friedman’s test f/b Dunn’s test) but inter-group comparison was not statistically significant for any parameter (p>0.05 using Mann Whitney’s test).

EASI score

As mentioned in table 4, intra-group reduction of mEASI was statistically significant at 4^th and 8^th weeks (p<0.0001 using Friedman’s test f/b Dunn’s test). Inter-group comparison also revealed significantly lower mEASI in group B as compared to group A at 8^th week (p=0.03 using Mann Whitney’s test). Besides, on comparing mean % of reduction of EASI score, significantly higher reduction was seen in group B as compare to A (p=0.03 using Mann Whitney’s test) [Figure 4].

Table 5 depicted about severity of keratoderma according to EASI score at baseline and 8^th week. At time of enrollment, a total number of 12 patients had mild keratoderma, 28 had moderate keratoderma, 23 had severe keratoderma and 7 had very severe keratoderma. Whereas, at end of 8 weeks, only subtle keratoderma was found in 66 patients, only 2 had moderate and 2 had very severe keratoderma.

Physician’s global assessment score [Figure 5] and patient’s self-assessment score [Figure 6] were also compared at end of treatment between both groups but no any significant difference was found (p>0.05).

Side effect profile

An excessive tingling sensation among 34.2% of patients in group A, none in group B. There was aggravation of itching during treatment in 0.2% and 28.5% among group A and B respectively. 25.7% of patients from group A found difficulty to adhere treatment plan, none in group B. Whereas, signs of salicylism were not found in any single patient. Also followed up patients for duration of 2 months post-treatment, but no any recurrence was noted.

P>0.05, not statistically significant.

**p value ≤0.001.

*- p≤0.05, ^# - p≤0.01, **- p≤0.001.

*- p≤0.05, **- p≤0.001.

P>0.05, not significant.

DISCUSSION

Palmoplantar keratoderma is a heterogenous group of keratinization disorder with hyperkeratotic thickening of palms and soles. Palmoplantar keratoderma poses minimum threat to patients in terms of mortality, but has capacity to affect individual’s quality of life. Routine day to day activities are hampered which can also lead to loss of wages.

The current study revealed mean age of 41.42 years for acquired keratoderma and greater prevalence in middle age group (35-50 years), in concordance with studies done by Nair et al and Kodali et al.^9,10 There was female preponderance (55.7%) in present study, whereas Mahajan et al and Kodali et al observed male predominance.^9,10 Female preponderance in our study is probably because of exposure to various detergents, soaps and chemicals while doing washing and cleansing activities. Females, also who are engaged in outdoor work i.e., laborer are exposed to repeated mechanical friction, trauma additionally.^9,12 Furthermore, greater incidence of plantar keratoderma among laborers and exacerbation of plantar keratoderma more in winter (52.8%) than summer (35.7%) was in concordance with other studies.^9,10,19

The present study reflected remarkable association with menopause (18.5%) due to female preponderance. Followed by, diabetes mellitus (10%), hypertension (8.5%) and hypothyroidism (4.2%). In literature, there were case reports potentiating the same.^13-17 Furthermore, 7% of patients had chronic plaque Psoriasis, as Palms and soles are usually involved in 3-5% cases of psoriasis.⁹ As 94% of patients had diffuse pattern of involvement, we can accept it as commonest pattern for acquired keratoderma.

In the treatment aspect, apart from empirical management comprising systemic retinoids and topical keratolytics like salicylic acid and urea, newer physical modalities like CO2 laser and iontophoresis had also been used for keratodermas.^18,19 Although there are no any RCTs comparing any of treatment modalities, available in literature.

Salicylic acid in concentrations 5% and above, exerts a potent, deep and rapid keratolytic effect. Additionally, it also comprises anti-inflammatory and antipruritic actions.²⁰ From the literature, various case reports depicting variable response to different topical agents in keratoderma were stated in Table 6.

Iontophoresis a recognized noninvasive therapeutic method for delivering water soluble ionized medication into the skin. It improves efficacy by continuous release and decreases the total dose and dosing frequency. Table 7 portrayed different case reports and pilot studies about efficacy of iontophoresis. As the different scoring system was used there, we could not compare our study variables with them.

In the present study, extremely significant number of patients showed reduction in severity grade of all parameters in both groups. But intergroup comparison was not statistically significant. In similar way, there was significant reduction in mean value of gradings of all parameters at 4^th week and at 8^th week in both groups. But intergroup comparison showed no statistically significant difference between groups. So, here it was found that both treatment modalities are highly effective in acquired keratoderma. Furthermore, we didn’t find any case of contact dermatitis or signs of salicylism in any of our patients, so topical and iontophoresis both have proven their safety also.

But on analyzing EASI score, mean EASI score was significantly lower in group B as compared to A. Additionally, mean % of reduction in EASI score was higher in group B at 8^th week. So, at the end, we can interpret that topical salicylic acid had higher efficacy as compared to iontophoresis and iontophoresis had not added any additional merits to patient.

Interestingly, present study showed better and earlier remission of pruritus in iontophoresis group as compared to topical. So, iontophoresis is more efficacious to remit pruritus as compared to topical. Besides, higher intensity of current (DC voltage) was required for more severe hyperkeratosis. So, intensity of current was directly proportional to thickness of soles. As these observations were not defined earlier in literature, more future studies require to potentiate the same.

Mukherjee et al had conducted study of 10 patients having hyperkeratosis and were treated with iontophoretic sodium salicylate in total of 6-8 sittings with excellent results. But in that case series, no any variables or scores were evaluated and there was no any comparison group also.¹⁹

The present study acts as its own control. The parameters in our study are useful for grading of severity of keratoderma and they can also be used to monitor effect of treatment. Our results are based on the best available scoring systems and are analyzed by appropriate statistics, which were interpreted strictly.

So, salicylic acid is surely an effective keratolytic when used in adequate concentration (i.e., 12%) or with effective modality (iontophoresis). But iontophoresis device has not added any significant impact on treatment outcome when compared to topical.

Limitations

In current study, patients were followed up for only 2 months post treatment to observe any recurrence. Also, we have evaluated response in only plantar keratoderma patients, so efficacy in palmar keratoderma is yet to be established.

CONCLUSION

The present study stated that iontophoresis, although it is efficacious, it doesn’t add any additional benefit over topical ointment in management part. The scores and parameters from the study may direct similar future studies. Our results will serve as an authentic reference for future studies.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the institutional ethics committee

REFERENCES

1. 1. Stypczyńska E, Placek W, Zegarska B, Czajkowski R. Keratinization Disorders and Genetic Aspects in Palmar and Plantar Keratodermas. Acta Dermato venerol Croat. 2016;24(2):116-23.
2. 2. Emmert S, Kuster W, Hennies HC. 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol. 2003;13:16-20.
3. 3. Patel S, Zirwas M, English JC 3^rd. Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8:1-11.
4. 4. Lienemann AO, Colucci VJ, Jones MS. Treatment of Palmoplantar Keratoderma With Continuous Infusion 5-Fluorouracil. Cutis. 2004;73:303-8.
5. 5. Dawn A, Yosipovitch G. Treating itch in psoriasis. Dermatol Nurs. 2006;18:227-33.
6. 6. Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol. 1999;38:16-24.
7. 7. Arif T. Salicylic acid as a peeling agent: a comprehensive review. Clinical, Cosmetic and Investigational Dermatol. 2015:8:455-61.
8. 8. Haseena K, George S, Riyaz N, Sasidharanpillai S, Puthussery PV. Methotrexate iontophoresis versus coal tar ointment in palmoplantar psoriasis: A pilot study. Indian J Dermatol Venereol Leprol. 2017;83:569-73.
9. 9. Nair PA, Diwan NG, Singhal R, Vora RV. A prospective study of clinical profile in patients of palmoplantar dermatoses. Indian Dermatol Online J. 2017;8:331-5.
10. 10. Kodali S. A Clinico-Histopathological Study of Acquired Palmoplantar Keratoderma in a Rural-Based Tertiary Hospital. J Evolution Med Dental Sci. 2014;3(30):8500-5.
11. 11. Mahajan PM, Gharpuray MB, Kulkarni V. Clinical and histopathological study of palmoplantar keratoderma. Indian J Dermatol Venereol Leprol. 1994;60:258-61.
12. 12. Chopra A, Maninder, Gill SS. Hyperkeratosis of palms and soles: clinical study. Indian J Dermatol Venereol Leprol. 1997;63:85-8.
13. 13. Lynch FW. Keratoderma climactericum (Haxthausen). Arch Derm. 1943;48:270-81.
14. 14. Wathcel TJ. Plantar and palmar hyperkeratosis in young castrated women. Int J Dermatol. 1981;20:270-1.
15. 15. Lestre S, Lozano E, Miereles C, Barata Feio A. Autoimmune thyroiditis presenting as palmoplantar keratoderma. Case Rep Med. 2010;2010:604890.
16. 16. Thomas A, Robert A, Kumar AS. Remarkable improvement of palmar hyperkeratosis to thyroxine replacement in a patient with severe undiagnosed severe hypothyroidism. J Diabetes Endocr Pract. 2018;1:12-4.
17. 17. Nakamura Y, Muto. Spiny keratoderma of the palms in an insulin treated diabetic patient. Int j Dermatol. 2013;67:439-41.
18. 18. O’Connor EA, Dzwierzynski WW. palmoplantar keratoderma treatment with CO2 laser case report and review of literature. Ann Plast Surg. 2011;67:439-41.
19. 19. Mukherjee S, Gupta AB, Haldar MB. Iontophoretic treatment of hyperkeratosis with sodium salicylate. Indian J Dermatol, Venereol, Leprol. 1989;55:22-4.
20. 20. Jacobi A, Mayer A, Augustin M. keratolytics and emollients and their role in therapy of psoriasis: a systemic review. Dermatol Ther (Heidelb). 2015;5(1):1-18.
21. 21. Gupta R, Mehta S, pandhi D, Singal A. hereditary punctate palmoplantar keratoderma. J Dermatol. 2004;31:398-402.
22. 22. Bukhari. Punctate Palmoplantar Keratoderma: A Case Report of Type 1 (Buschke Fischer-Brauer Disease) Case Rep Dermatol. 2019;11:292-6.
23. 23. Kiatsurayanon C, Rojanamatin J, Sudtikoonaseth P, Kamoirapap K, Wichaidit M, Niyonsaba F. unilateral linear punctate keratoderma: a case report. Case Rep Dermatol. 2017;9(1):86-9.
24. 24. Kong MA, Harford R, O’Neill JT. Keratosis punctate palmoplantaris controlled with topical retinoids: a case report and review of literature. Cutis: 2004;74(3):173-9.
25. 25. Gandhi N, Sanke S, Chander R. Familial acral peeling skin syndrome with palmoplantar keratoderma. Astrocyte. 2016;3:42-4.
26. 26. Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and soles. J Am Acad Dermatol. 1992;26(5 Pt 2):879-81.
27. 27. Errichetti E, Piccirillo A. Aquagenic keratodermatreated with tap water iontophoresis. Indian J Dermatol 2015;60:212.
28. 28. Zeinalzade A, Kalantari K, Kobarfard F. The Effect and Persistency of 1% AluminumChloride Hexahydrate Iontophoresis in the Treatment of Primary Palmar Hyperhidrosis. Iran J Pharmace Res. 2011;10(3):641-5.
29. 29. Kacar SD, Ozuguz P, Eroglu S, Serap Polat S, Karaca S. Treatment of primary hyperhidrosis with tap water iontophoresis in paediatric patients: a retrospective analysis. Cutan Ocul Toxicol. 2014;33(4):313-6.
30. 30. Tupker RA, Coenraads PJ, Zanen P, Schuttelaar ML. Randomized Controlled Observer-blinded Treatment of Chronic Foot Eczema with Iontophoresis and Bath-PUVA. Acta Derm Venereol. 2013;93:456-60.
31. 31. Sobhi RM, Sobhi AM. A single-blinded comparative study between the use of glycolic acid 70% peel and the use of topical nanosome vitamin C iontophoresis in the treatment of melasma. J Cosmetic Dermatol. 2002;11, 65-71.