Leprosy (Hansen’s disease) is a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign 1.
Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes. Contrary to folklore, leprosy does not cause body parts to fall off, but they can become numb or diseased as a result of infection; infection results in tissue loss, and so fingers and toes become shortened and deformed as the cartilage is disintegrated 2.
Neuropathic ulcers are one of the most common sequelae of leprosy but little is known about their clinical and epidemiological aspects. Neural impairment results in a set of sensory, motor, and autonomic disturbances. About 30% of patients develop nerve damage that leads to loss of normal sensation, skin damage, cracking, infection, and ulcers originating primarily on the hands and feet. They are highly disabling to the patient and can result in deformity and/or amputation of the affected limb. Different methods of treatment have been used in ulcer management, but the outcomes are frequently dissatisfactory, and many patients must have to live with chronic wounds that result in high economic and social costs 3.
Tumor necrosis factor α (TNF-α) is a cytokine with a wide spectrum of activity that is predominantly produced by mononuclear cells. There is increasing evidence that TNF-α is involved in the pathogenesis of a wide variety of acute and chronic inflammatory diseases such as psoriasis, graft-versus-host disease, contact dermatitis, and leprosy reactions 4.
Several studies have shown that pentoxifylline (PTX) is an active inhibitor of TNF-α; therefore, it could be considered a therapeutic option in TNF-α-mediated skin diseases 5.
PTX increases fibroblast collagenases and decreases collagen, fibronectin, and glycosaminoglycan production. Although these effects could be because of the anti-TNF-α property of PTX, studies have shown that its effects on fibroblasts are mediated by a separate mechanism 6.
The primary hemorheologic effects of PTX are caused by increased red blood cell deformability and decreased blood viscosity by increasing erythrocyte ATP and other cyclic nucleotide levels 5. It inhibits other proinflammatory cytokines for example, interleukin-1, interleukin-6, and interleukin-8 7. Many studies have investigated the effect of PTX on wound healing; however, no study has investigated the influence of PTX on lepromatous ulcers. Thus, the present study has been designed to investigate the effects of intralesional PTX on lepromatous ulcers.
Patients and methods
This randomized-controlled clinical study was carried out on 40 patients with neuropathic lepromatous ulcers; they were selected from among patients attending the Dermatology, Andrology, and Leprosy Clinic, Benha Leprosy Center. They were divided into two groups and followed in exactly the same way: trial group (20 patients were injected with PTX) and control group (20 patients were treated by topical placebo). This study was carried out from March 2013 to September 2013 and all patients completed the study. There were no restrictions on sex, race, age group, or the duration of ulcers.
- Patients willing to attend weekly at the dressing service of the hospital.
- Patients who completed specific multi-drug therapy for Mycobacterium leprae.
- Clinically detectable infection in the ulcer.
- Use of drugs such as corticosteroids that could interfere with the wound-healing process.
- Use of special dressings such as hydrocolloid and calcium alginate.
- Pregnancy or lactation.
Patients signed an informed consent that was approved by the Ethics Committee Human Research of Benha University and were counseled as to the benefits and possible adverse events of the treatment before the first session. All patients were subjected to the following: assessment of history (name, age, sex, residence, occupation, duration of the ulcer, and previous treatment if any) and local examination including assessment of the number, site, size, and depth of the ulcer, which was measured using a sterile pincer introduced into the bottom of the deepest region of the ulcer and measured by a disposable ruler from the tip of the pincer to the surface of the skin.
All stages of the methodology were performed by the same researcher; patients were numbered consecutively from 1 to 40 and randomized to receive active or placebo treatment according to a computer-generated sequence after inclusion criteria had been evaluated. The patients received a code related to the order in which they were evaluated.
PTX ampoule (15 ml) (300 mg) (Trental; Sanofiaventis, Guillford, UK) was injected using an insulin syringe of 100 U (built-in needle) and isopropyl alcohol was used as a disinfectant to the ulcer and adjacent skin. Before starting the session, each patient was prepared by cleansing the ulcer with 0.9 saline solutions, removal of excess skin by debridement, and disinfecting the ulcer and the skin around it by isopropyl alcohol. The ulcer was injected intralesionally into the edge of the ulcer all around using a built-in insulin syringe containing 1 or 2 ml PTX weekly for 8 weeks (eight sessions). The amount of the drug depended mainly on the size of the ulcer. The distance between each injection site and the other was nearly 0.5 cm outside the edge.
In the control group, daily simple dressing with sterile gauze and topical placebo (creams contained only the aqueous cream base) was performed.
All patients were photographed at each visit using digital Panasonic LUMIX S5 16 mega pixels (Panasonic, Japan). Estimation of the ulcer depth was performed by the investigators in each session. The patients were asked about any possible side effects such as pain, skin rash, discoloration, or discomfort. Evaluation of clinical response was performed in terms of complete or incomplete closure.
The statistical analysis of data was carried out using Excel program (Excel Microsoft Way; Redmond, Washington, USA) for figures and SPSS version 16 (SPSS Inc., Chicago, Illinois, USA) program. Quantitative data were described as mean±SD and qualitative data were described as frequency and proportion. The analysis of the data was carried out to test statistically significant differences between groups. For quantitative data, the Student t-test was used to compare between two groups. The paired-sample t-test was used to compare one group at different times. The χ2-test was used for qualitative data. Odds ratio (OR) and 95% confidence interval were used as a measure of association between an exposure and an outcome. P value was considered significant if less than or equal to 0.05 at 95% confidence interval.
This study was carried out on 40 patients; all patients completed the study. In the trial group, there were 12 men (60%) and eight women (40%). Their age ranged from 32 to 64 years, mean age 50.65±9.03 years. The duration of ulcer ranged from 2 to 180 weeks, mean 51.9±40.0 weeks. Six of 20 patients had diabetes mellitus (DM). The control group included 11 men (55%) and nine women (45%). Their age ranged from 40 to 65 years, mean age 50.85±8.1 years. The duration of ulcers ranged from 3 weeks to 4 years, mean 47.9±30.3 weeks. Three of the 20 patients in the control group had DM.
In terms of the clinical response in the trial group, 10 of 20 (50%) patients showed complete closure of the ulcers, which were of a long duration (≥6 months), and 10 patients (50%) showed incomplete closure of the ulcers, whereas in the control group, 10% of the patients showed complete closure of the ulcers, which were of short duration (≤2 weeks), and in 90%, there was no change. OR showed that intralesional PTX was nine times better than placebo (Table 1) and differences were statistically significant (P=0.006), which means that the cure rate in patients injected with PTX was better than those who were administered placebo (Figs. 1 and 2).
In the trial group, the basal depth of the ulcer was 0.8±0.4 cm at week 0 and it became 0.23±0.16 cm after 8 weeks, with 71.5% improvement. In the control group, the basal depth of the ulcer was 0.5±0.41 cm at week 0 and it became 0.45±0.39 after 8 weeks, with 13.09% improvement. Although the depth of the ulcer was significantly more in the patients in the trial group than in those in the control group at week 0, the improvement was greater in the trial group at week 8 (P=0.04) (Table 2).
In the trial group, the duration of ulcers before the study that showed complete closure was 25.8±18.9 weeks and those with incomplete closure was 78±69 weeks. In the control group, the duration for complete closure was 0.5±0.000 weeks and that for incomplete closure was 53.16±83.2 weeks. These differences in each group were statistically significant (P<0.05), which means that the clinical response (ulcer healing) was affected by the duration of the ulcer. In the present study, there were no side effects after the use of intralesional PTX, except tolerable pain during the injection, which resolved at the end of the session.
In the trial group, six of 20 patients (30%) had DM. Two of these patients (33.3%) achieved complete closure and four patients (66.7%) showed incomplete closure. In the control group, three of 20 patients (15%) had DM. All of them (100%) showed no change, with no improvement. OR showed that diabetic patients are susceptible to incomplete closure 2.6 times more than nondiabetic patients in the trial group (P=0.32) and 1.2 times in the control group (P=0.53) (Table 3).
Delayed diagnosis, lack of appropriate treatment, and failure to control leprosy reactions contribute toward the occurrence of nerve damage and neuropathic ulcers in these patients. Different methods of treatment have been used in ulcer management, but the outcomes are frequently unsatisfactory, and many patients must live with chronic wounds that result in economic and social costs 3.
PTX is a methylxanthine derivative with a variety of anti-inflammatory effects; it has been approved by the Food and Drug Administration for the treatment of intermittent claudications, but studies 8 have shown that it exerts a variety of physiological effects at the cellular level that may be important in the treatment of a diverse group of diseases.
In the present study, 50% of the patients in the trial group showed complete closure of the ulcer, in 35%, there was no change, and 15% showed worsening. However, in the control group, 10% the patients showed complete closure of the ulcer and in 90%, there was no change. At 8 weeks, the percentage of improvement in the trial group was 71.5% compared with 13.09% in the control group, which is significant despite the significant greater depths of the ulcer in the trial group compared with that in the control group at baseline (week 0).
In the current study, the intralesional PTX was nine times better than simple dressing with placebo. These results can be explained by the fact that PTX affects almost all factors responsible for blood viscosity and is indeed the first known hemorheologically active drug 9. Thus, it increases the blood flow to the tissues and enhances the healing process.
The studies carried out by Pascarella et al.8 and Jull et al. 10 showed that the inflammatory reactions lead to fibrosclerotic remodeling of the skin and then to ulceration. The activation of leukocytes is accompanied by the expression of integrins and by the synthesis and release of many inflammatory molecules including proteolytic enzymes, leukotrienes, prostaglandins, bradykinin, free oxygen radicals, cytokines, and possibly other classes of inflammatory mediators. As leukocytes become activated, they become rigid and immobile, which leads to further occlusion of small vessels and trophic changes in the overlying skin. Considering all the aforementioned data together, the attention of many investigators has been drawn to the use of PTX as an adjunctive therapy in venous leg ulcers. In the previously mentioned studies, the most frequent adverse event of oral PTX was mild gastrointestinal disturbance (43%). Other adverse events included headache, sleep disturbance, hot flushes, itching, and hypotension. Of the reported withdrawals, only 25% were because of adverse events 10,11. In the present study, intralesional PTX led to no side effects in the patients, except tolerable pain at the time of injection.
OR showed that nondiabetic patients are likely to show complete closure than diabetics. This can be attributed to many factors that can interfere with healing of ulcers in diabetic patients, such as reduced sensation, deep pressure, temperature, and peripheral vascular disease 11.
It was found that intralesional PTX has good efficacy and a high success rate because it prevented disability in 50% of patients. To our knowledge, this is the first study to use intralesional PTX in the treatment of lepromatous ulcers. Further studies are needed to evaluate the safety of PTX and to determine the specific mechanism of its effect on the skin by histological and immunohistochemical studies.
Conflicts of interest
There are no conflicts of interest.