Leprosy is a chronic bacterial infection caused by Mycobacterium leprae. According to the Ridley-Jopling classification, it is divided into five subtypes based on the patient’s immune status and the bacterial load: tuberculoid, borderline tuberculoid, mid-borderline, borderline lepromatous, and lepromatous leprosy. The bacterial load increases and patient’s immune system wanes across the spectrum from the tuberculoid variant to the lepromatous variant. There is also a rare form of leprosy called pure neuritic leprosy, which involves only the nerves and lacks the typical skin manifestations of the other types of leprosy.
Chronic trophic ulcers (CTUs) seen in patients with leprosy are situated over the foot in well-defined areas overlying bony prominences.1 Sensory loss over the plantar region, unprotected walking, muscular paralysis, autonomic nerve damage, vascular insufficiency, poor quality of scar formation after previous ulceration, and persistent infection are some of the main factors in the chronicity of these ulcers.2 Despite relentless effort, CTU management continues to vex practitioners and patients and has a significant impact on rates of disability and monetary issues, especially in resource-poor countries such as India. The many treatment modalities for CTU include wound debridement followed by oral and topical antibiotics, phenytoin sodium and zinc paste, hydrocolloid dressings, plaster boots, bioengineered tissue growth factors, and surgical measures, although none are infallible.1
The topical use of human regular insulin has been studied intensively in the management of CTUs, especially in patients with diabetes, burns, and pressure injuries.3–8 Ample evidence for the efficacy of topical insulin in ulcer healing prompted researchers to evaluate its efficacy in healing CTUs found in patients with leprosy in this pilot study. As a secondary objective, investigators deployed multiple linear regression to determine the various factors influencing the wound healing process in these patients’ CTUs according to their leprosy subtype.
A randomized patient-blinded placebo-controlled interventional study was conducted to evaluate the safety and efficacy of topical insulin in the treatment of plantar CTU among patients with leprosy. In this study, 49 patients with leprosy were initially recruited based on the following inclusion criteria: those who had completed a multidrug treatment for leprosy, bacterial index (BI) ≤1, no lepra reactions, ankle-brachial pressure index ≥0.8, and wounds less than 10 cm2 with a negative surface swab. Patients older than 70 years; smokers; and those with hypertension, osteomyelitis, immunodeficiency, vascular insufficiency, uncontrolled diabetes, and/or any signs or symptoms of secondary bacterial ulcer infection were excluded, as were pregnant patients. Complete blood cell count, platelet count, blood sugar levels (before and 1 hour after the application of topical insulin), urinalysis, renal and liver function tests, HIV testing, and X-ray of the involved foot were performed in all the patients at first visit. A week before the study began, any patient with hyperkeratotic ulcer borders who met the inclusion criteria underwent removal of the hyperkeratotic border and had a wound dressing applied.
Patients were randomized using two-block randomization and assigned to one of two groups. In the test group, ulcers were irrigated with 10 units (0.1 mL) of human soluble regular insulin (Actrapid; Novo Nordisk Pharmaceuticals Ltd, Bagsværd, Denmark) in 1 mL of normal saline (0.9%) twice daily. In the placebo group, ulcers were “treated” with a twice-daily application of normal saline. Bottles containing either insulin or saline of similar size and shape were used. In both groups, the wound was covered with sterile cotton gauze 15 minutes after treatment.
Ulcer area (greatest length × greatest width), depth, and healing were recorded weekly using clinical examination, transparency tracing, photography, and Dermatology Life Quality Index (DLQI) scoring. Physician Global Assessment Of Efficacy (PGA) questionnaires were undertaken by trial participants at baseline and at the conclusion of the study. The primary end point was the proportion of patients with complete wound closure by 12 weeks. Secondary end points included time to healing, wound area reduction after 12 weeks, and adverse effects. Evaluations were done by a board-certified dermatologist.
The institutional board at the authors’ facility approved the study protocol, and informed consent was obtained from participants in compliance with the Declaration of Helsinki (ethical clearance no. MC/217/2016/Pt1/16).
Efficacy evaluation was conducted using the percentage of wound area healing computed according to the Walker formula.9
To assess the magnitude of the effect of a given risk factor, single-variable (unadjusted) and multiple-variable (fully adjusted) logistic regression models to estimate odds ratios (ORs) were reported with 95% confidence intervals (CIs). Statistical analyses were carried out using SPSS 21 software (IBM, Armonk, New York). P ≤ .05 was considered significant.
The study comprised 49 recruits. Seven patients were either nonadherent to study protocols or lost to follow-up. The remaining 42 patients were taken as the final quanta (test group, n = 23; placebo group, n = 19). Of those, 27 were male and 15 were female (mean age, 43 years for males and 38.6 years for females). More than two-thirds of the patients (70%) had multibacillary-type leprosy. The majority of CTUs (80%) were present over the forefoot; the metatarsal head of the hallux (86%) was the most common site. In terms of depth, 31 extended to the dermis, 9 to the subcutis, and 2 to the tendon (Figure 1).
Demographics and ulcer characteristics are summarized in Table 1. The mean ulcer size on day 1 was 8.86 ± 2.57 cm2 in the test group and 7.11 ± 2.98 cm2 in the control group (P > .05). In the test group, the rate of healing was faster (0.61 ± 0.31 vs 0.14 ± 0.42 cm2 per week; unpaired two-tailed t test = −4.24; P = .0001; z = 3.72), and the CTU was completely healed sooner (31.5 ± 17.6 vs 44.3 ± 16.2 days; unpaired two-tailed t test = 2.43, P = .0196; z = 2.06). The t test value for reduction in mean wound area was 4.96 (P < .0001), a highly significant reduction.
A high level of significance was found in the percentage area reduction between baseline and the 12-week end point (t = 5.23 [95% CI, 1.71-3.85], P < .0001) in the test group compared with the control group (Tables 1 and 2, Figure 2).
The PGA is scored from 0 (clear/normal) to 7 (very severe). At baseline, the mean PGA score ± SD for the test group was 6.59 ± 0.92 and 6.11 ± 0.89 for the control group. At 12 weeks postintervention, the scores declined to 3.14 ± 1.86 and 5.91 ± 2.37, respectively. The P of the paired two-tailed t test for the reduction in PGA in the two limbs was P < .0001 (95% CI, −4.32 to −2.58) for the insulin group (highly statistically significant) and P = .73 (95% CI, −1.38 to 0.98) for the placebo group.
The impact of chronic leg ulcers on quality of life was assessed using the DLQI, which consisted of 10 questions divided into 6 domains; answers are provided using a Likert-type scale. The total score ranged from 0 to 30. Higher values are correlated with greater impact on quality of life. In the test group, DLQI scores decreased markedly from 14.72 ± 6.29 at baseline to 5.37 ± 4.49 at 12 weeks postintervention (P < .0001; 95% CI, −12.60 to −6.10). However, in the placebo group, scores decreased from 14.49 ± 5.98 to 10.09 ± 6.53 (P = .037; 95% CI, −85,198 to −0.2802).
Researchers also created a risk regression model for ulcer healing in patients with leprosy. The initial size of the CTU (OR, 2.96; 95% CI, 2.45–3.57; P = .001), multibacillary leprosy with history of BI greater than 2 (OR, 2.31; 95% CI, 1.5–3.6; P = .004), and wound duration (OR, 4.1; 95% CI, 2.50–7.10; P = .001) were all significantly and negatively correlated with epithelialization (Table 2).
The only observed adverse effect in the test group was white granular deposits in the wound bed; these are most likely attributable to the precipitation of zinc salt from the insulin preparation (n = 10). However, these deposits did not interfere with treatment. None of the patients in the test group developed signs and/or symptoms of hypoglycemia (Figures 3–5).
Plantar ulcers occur in 10% to 20% of patients with leprosy.1,2 Delays in diagnosis, lack of proper foot care and treatment, and recurrent leprosy reactions leading to nerve damage are the major culprits in CTU formation in patients with leprosy. Because of limited treatment options and its resistance to conventional treatment measures, CTU management can be frustrating for providers.
The therapeutic efficacy of topical insulin has been studied in patients with CTU with and without diabetes, as well as those with pressure injuries, deep burn wounds,3–8 corneal epithelial defects,9,10 and ruptured tympanic membranes.10,11 To date, its efficacy has not been explored in CTU in leprosy.
These results showed that the topical application of insulin significantly improves wound healing in CTUs for patients with leprosy, despite varying ulcer sizes. Investigators also observed complete healing in 20 patients who were treated with topical insulin (87% of the test group) at week 12, compared with a significantly lower percentage (21.05%) of patients from the control group (P < .0001). Study authors observed that patients with large CTUs of prolonged duration (>6 months), those with lepromatous and pure neuritic forms of leprosy, and those with a history of BI greater than 2 were slow to respond to the therapy (Table 2). Patients suffering from borderline forms of leprosy (ie, borderline tuberculoid and mid-borderline) experienced fast CTU healing. This finding supports current understanding that bacillemia may hinder CTU healing. Study authors also observed that ulcers on the forefoot took a longer time to heal (average, 10.4 weeks) than those over the lateral arch (average, 4 weeks), confirming that CTUs on the forefoot have a poor prognosis compared with those on other areas of the foot.
Topical insulin in ulcer treatment is thought to stimulate the development of keratinocytes, endothelial cells, and fibroblasts and alleviate inflammation.12 Insulin activates protein kinase B pathways, which in turn increase vascular endothelial growth factor and induces phosphorylation and endothelial nitric oxide activation in bone marrow and the mobilization of endothelial progenitor cells in circulation.13,14 Insulin (via insulinlike growth factor) stimulates endothelial nitric oxide and vascular endothelial cell migration, causing increased synthesis and maturation of collagen fibers with a basket weave-like organization (normal skin) rather than parallel alignment and cross-linking (scar tissue) in the wound.2–5 Essentially, topical insulin treatment results in a “healthier” wound bed with faster resolution of inflammation.11,12
Commercial topical insulin, such as the type used in this study, also contains zinc chloride (to crystallize insulin). Zinc has been shown to be beneficial in wound healing.15 However, it is still unclear whether the zinc in topical insulin influences wound healing.15
As a pilot study, this study has certain limitations. First, researchers were unsure about the optimal duration of the treatment; 12 weeks was arbitrarily selected as the end point of treatment. Other limitations include a small sample size, short study duration and the nonblinding of evaluators. Although the baseline wounds in the control group were smaller than those in the intervention group, this difference was not significant and therefore not thought to influence the results.
Topical insulin is a potentially safe, widely available, and cost-effective therapeutic approach for recalcitrant CTU in patients with leprosy. Future findings that could improve this treatment include the development of an improved delivery vehicle for insulin (eg, as a patch), so that it could be applied every 2 to 3 days, further improving the practicality, cost-benefit, and applicability of this treatment in day-to-day practice. Further large double-blind randomized controlled trials are needed to substantiate the efficacy of topical insulin in the treatment of CTU.
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