Evidence based Dermatology - part 9 docx

32. Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol 1987; 16 :745–8. 33. Fiedler-Weiss VC, West DP, Buys CM, Rumsfield JA. Topical minoxidil dose-response effect in alopecia areata. Arch Dermatol 1986; 122 :180–2. 34. Price V. Double-blind, placebo-controlled evaluation of topical minoxidil in extensive alopecia areata. J Am Acad Dermatol 1987; 16 :730–6. 35. White SI, Friedmann PS. Topical minoxidil lacks efficacy in alopecia areata. Arch Dermatol 1985; 121 :591. 36. Vestey JP, Savin JA. A trial of 1% minoxidil used topically for severe alopecia areata. Acta Derm Venereol 1986; 66 :179–80. 37. Feidler VC. Alopecia areata: Current therapy. J Invest Dermatol 1991; 96 (Suppl.):69. 38. Lei Y, Nie Y-F, Zhang J-M, Liao D-Y, Li H-Y. Effect of superficial hypothermic cryotherapy with liquid nitrogen on alopecia areata. Arch Dermatol 1991; 127 :1851–2. 39. Hay I, Jamieson M, Ormerod A. Randomized trial of aromatherapy. Arch Dermatol 1998; 134 :1349–52. 40. Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the treatment of alopecia areata. Acta Derm Venereol 1983; 63 :49–52. 41. van der Steen PHM, van Baar HMJ, Perret CM, Happle R. Treatment of alopecia areata with diphenylcyclopropenone. J Am Acad Dermatol 1991; 24 : 253–7. 42. Winter RJ, Kern F, Blizzard RM. Prednisolone therapy for alopecia areata. Arch Dermatol 1976; 112 :1549–52. 43. Unger WP, Schemmer RJ. Corticosteroids in the treatment of alopecia totalis. Arch Dermatol 1978; 114 :1486–90. 44. Sharma VK. Pulsed administration of corticosteroids in the treatment of alopecia areata. Int J Dermatol 1996; 35 :133–6. 45. Gupta AK, Ellis CN, Cooper KD et al . Oral cyclosporin for the treatment of alopecia areata. J Am Acad Dermatol 1990; 22 :242–50. 46. Davies MG, Bowers PW. Alopecia areata arising in patients receiving cyclosporine immunosuppression. Br J Dermatol 1995; 132 :827–9. 47. Berth-Jones J, Hutchinson PE. Treatment of alopecia totalis with a combination of inosine pranobex and diphencyprone compared to each treatment alone. Clin Exp Dermatol 1991; 16 :172–5. 48. Galbraith GMP, Thiers BH, Jensen J, Hoehler F. A randomised double-blind study of inosiplex (Isoprinosine) therapy in patients with alopecia totalis. J Am Acad Dermatol 1987; 16 :977–83. 49. Pipoli M, D’Argento V, Coviello C, Dell’Osso A, Mastrolonardo M, Vena GA. Evaluation of topical immunotherapy with squaric acid dibutylester, systemic interferon alpha and the combination of both in the treatment of chronic severe alopecia areata. J Dermatol Treat 1995; 6 :95–8. 50. Schuttelaar M-LA, Hamstra JJ, Plinck EPB et al . Alopecia areata in children: treatment with diphencyprone. Br J Dermatol 1996; 135 :581–5. 51. Orecchia G, Malagoli P. Topical immunotherapy in children with alopecia areata. J Invest Dermatol 1995; 104 (Suppl.):35S–36S. 588 Evidence-based Dermatology Part 3: The evidence Section G: Leg ulceration Editor: Berthold Rzany Background Definition Venous ulcers are wounds that usually occur in a gaiter distribution of the lower leg (Figure 44.1). They are associated with increased pressure in the superficial venous system of the lower legs during ambulation, and are possibly related to failure of the calf muscle pump to return venous flow effectively. 1 Incidence/prevalence A recent study utilising the General Practice Research Database found the incidence of venous ulcers in people over 65 years of age in the UK to be 0·76 (95% confidence interval (CI) 0·71–0·83) per 100 person-years for men and 1·42 (1·35–1·48) for women. 1 Venous ulcers therefore represent a major public health problem. Aetiology Venous ulcers result from poor venous return. It is hypothesised that the calf muscle pump fails to return blood flow effectively. These wounds may also be associated with varicose veins and other venous disease. In addition, arterial disease and diabetes may also complicate the clinical picture of venous leg ulceration. 2 Prognosis Many venous ulcers heal within 24 weeks of care, but the proportion healed after 24 weeks varies widely between studies. There are multiple risk factors for venous ulcers failing to heal, including the age of the wound, the size of the wound, a history of vein surgery, and arterial insufficiency. 2 There is also a significant risk of recurrence in patients who have had a single venous ulcer in the past. 3 Aims of treatment The aims of treatment are to improve the rate of healing and to increase the likelihood that a patient will heal over a given period of time. Relevant outcomes Relevant outcomes include the proportion of wounds healed by the end of the study and the rate of healing. Methods of search Medline and the Cochrane Database of Systematic Reviews were searched for the terms 44 Venous ulcers Jonathan Kantor and David J Margolis 591 Figure 44.1 Venous ulcer of the lower extremity (case scenario 1) “venous ulcer” and “heal” or “treat”. Current issues of Clinical Evidence were reviewed for relevant additions, 3 and bibliographies of relevant articles and systematic reviews were also reviewed. QUESTIONS What therapies are effective for curing venous leg ulcers? Case scenario 1 A 56-year-old woman has a 25 × 6 cm ulcer on the medial side of the left ankle (Figure 44.1). The ulcer’s red base is covered with yellowish fibrinous debris. On the edges are some signs of re-epithelialisation. The left lower leg was oedematous before use of a limb compression stocking. The limb shows signs of chronic venous insufficiency – pigmentation, enlargement of the cutaneous veins and fibrosis. What therapies would be effective for curing a venous leg ulcer? Compression Benefits Compression of the lower extremities is one of the oldest and most widely used treatments for venous ulcers. Methods of compression vary and include stockings, multilayer bandages, high-pressure compression boots, and an Unna boot. A Cochrane collaborative review has evaluated the role of compression in the treatment of venous ulcers. 4 This review included 22 trials using a number of different compression methods. Six trials compared compression with no compression, and demonstrated a clear benefit of compression over no compression. Of these, three trials evaluated compression using an Unna boot versus no compression. Two of the three studies demonstrated a benefit of compression. 5,6 Three additional studies compared compression bandages with non-compressive bandages and demonstrated a benefit of compression bandages. Of note, the results of only four of these six trials were statistically significant, although the preponderance of evidence suggests that compression results in a greater chance of healing than no compression. Three trials compared elastic high-compression bandages with inelastic low-compression bandages. 7 Pooled results from these studies evaluated in the Cochrane review suggest that the relative risk of healing with elastic high- compression bandages over inelastic low- compression bandages was 1·54 (CI 1·19–2·00). Four trials compared multilayer high- compression bandages with single-layer (low) compression. 8 A pooled analysis of these studies demonstrated a relative risk of healing of 1·41 (CI 1·11–1·80) when using multilayer compression bandages rather than single-layer bandages. Four trials compared multilayer high-compression bandages with inelastic high-compression bandages (Unna boot and short-stretch bandages). No statistically significant differences were shown between these types of high-compression therapy. Similarly, studies comparing other types of high-compression therapy, including the four-layer Charing Cross bandage system, did not show statistically significant differences between the different types of high-compression therapies. Complications Complication rates are not usually noted in trials, partly because compression therapy is generally benign. Inexpertly applied high compression could lead to soft tissue damage, the development of additional wounds, and potentially amputation, although the chance of this occurring is remote. 592 Evidence-based Dermatology Comment Compression has been the mainstay of therapy for venous ulcers, and with good reason. Compression has been shown to have a clear benefit over no compression. Moreover, the evidence suggests that a high level of compression (>25 mmHg) lends a clear benefit over low-level compression. Therefore, treatment with minimally compressive bandages, while better than nothing, is less than ideal. Depending on location and the skill of the provider, different types of high-compression bandage (Unna boot, multilayer elastomeric compression) can be used effectively. The method used to apply these bandages is important, and there is some suggestion that the ability to apply compression bandages effectively varies widely among nurses. Compression therapy should not be used in patients with an impeded blood supply to the lower extremities, whether from diabetes or arterial disease. Infection, however, has not been shown to be a contraindication to compression. Implications for clinical practice Compression should represent the cornerstone of the clinical management of patients with venous ulcers. Most studies evaluating novel therapies for venous ulcers use compression as the standard care regimen. Those caring for patients with venous ulcers should be sure that they use sufficient compression, namely more than 25 mmHg of compression to the lower leg. This can be accomplished either with multilayer bandages or an Unna boot, depending on the preference and training of the provider. Pentoxifylline Benefits Pentoxifylline is a trisubstituted xanthine derivative that has been used to treat a variety of systemic disorders, most notably intermittent claudication. 9 Theoretically, its beneficial effects in vaso-occlusive disease could extend to therapy for venous ulcers, and so several studies have explored the potential benefits of pentoxifylline in treating patients with venous leg ulcers. A Cochrane collaborative review has addressed the efficacy of pentoxifylline for the treatment of venous ulcers. 10 Nine trials including 572 patients were included in the Cochrane review. Of note, only five of the trials included compression therapy in both the pentoxifylline and placebo groups. One of the included trials compared pentoxifylline with defibrotide rather than placebo, and was therefore excluded from the meta-analysis used to evaluate the potential benefit of pentoxifylline. Combining the data from the eight trials that compared pentoxifylline (in varying doses) with placebo, pentoxifylline demonstrated a beneficial effect. The relative risk of healing with pentoxifylline versus placebo was 1·41 (CI 1·19–1·66). A separate examination of just the trials that compared pentoxifylline plus compression with placebo plus compression also showed a benefit of pentoxifylline therapy with a relative risk of 1·30 (CI 1·10–1·54). Most of the studies used the probability of healing by 24 weeks as the endpoint. Complications Pentoxifylline therapy is associated with an increased risk of side-effects, mostly gastrointestinal in nature. This increase in adverse events was not, however, statistically significant (relative risk 1·25; CI 0·87–1·80). Comment Given the pooled results of these clinical trials, it appears that pentoxifylline is beneficial as an adjuvant treatment for venous ulcers. Of note, some of the studies included in the meta- analysis conducted by the Cochrane group did 593 Venous ulcers not individually show statistical significance. Moreover, the dose of pentoxifylline used in the studies varied, and there is a legitimate question regarding the optimal dosing for the treatment of patients with venous ulcers. For example, in the study by Falanga et al ., the dose of pentoxifylline used was greater than that used to treat intermittent claudication (800 mg versus 400 mg three times daily). 9 In some of the studies included in the Cochrane meta-analysis patients did not necessarily receive compression as standard care. Even including these studies, however, pentoxifylline therapy was shown to be more beneficial than placebo, resulting in a higher proportion of patients healed by the study endpoint. However, it is important to note that this was a relative benefit, and that the relative benefit of pentoxifylline over placebo persisted even for patients treated with compression. Since compression therapy has been shown to increase the baseline chance of healing, patients treated with pentoxifylline should always be treated with compression therapy as well. Implications for clinical practice Pentoxifylline has been shown to increase the relative risk of healing by 30% over compression therapy alone, although this benefit may be as low as 10% or as high as 54%. Clinicians must ultimately decide whether this potential benefit is worth both the practical and the financial cost of pentoxifylline. Skin grafting Benefits Most venous ulcers respond well to compression therapy. However, a minority of wounds fail to heal with compression therapy alone. One of the options available to the healthcare provider is to treat the wound with a skin graft. Grafts can include full-thickness, partial-thickness, allogeneic (cultured), and artificial skin grafts. The use of skin grafts for the treatment of venous ulcers is the subject of a Cochrane collaborative review. 11 Two trials evaluated split-thickness autografts, three trials evaluated cultured keratinocyte allografts, one compared artificial skin with a dressing, and one compared artificial skin with a split-thickness skin graft. The two small studies evaluating split-thickness autografts were pooled by the Cochrane group, but the results did not show a significant benefit of skin grafting. 11 Both studies were small, and used different placebo treatments. Graftskin (Apligraf) is a bilayered skin equivalent that includes both dermal and epidermal components. 12 It is manufactured by harvesting neonatal foreskins and extracting both keratinocytes and fibroblasts, which are then separately cultured to create the epidermal and dermal components, respectively. Graftskin has been studied for the treatment of venous leg ulcers. 13,14 In a study that enrolled 240 patients, the percentage of ulcers healed after 24 weeks was significantly higher in those treated with Graftskin plus standard care (compression) than in those treated with compression alone (57% versus 40%). 15 Notably, secondary analyses evaluating the relative efficacy of Graftskin in wounds of more than one year’s duration demonstrated that the benefit of Graftskin was most significant for patients with older wounds (47% versus 19%). Among patients with wounds of less than one year’s duration, there was no statistically significant difference in the percentage healed after 24 weeks between those treated with Graftskin and those treated with placebo (66% versus 73%). The Cochrane group analysed this trial data and concluded that the relative risk of healing with artificial skin versus standard dressings is 1·29 (CI 1·04–1·60). Three studies compared cultured keratinocyte allografts with standard dressings. A pooled 594 Evidence-based Dermatology analysis of these trials conducted by the Cochrane group did not demonstrate a significant benefit of allografts over control dressings, and the relative risk of healing with the keratinocyte allografts was 1·42 (CI 0·71–2·84). These were all small trials and may have been underpowered to demonstrate an effect. A single study compared tissue-engineered skin with a split-thickness allograft, but failed to show any significant benefit of either treatment. 16 Note, however, that this study was small and was conducted before the newest tissue-engineered skin became available. Complications Risk of infection, bleeding and other tissue damage is inherent in any autologous skin grafting procedure. Moreover, there is always an inherent risk that the donor site will prove difficult to heal as well. Using cultured autologous keratinocytes is likely to delay of treatment because it takes several weeks for the cells to be cultured. Moreover, patients need to undergo a skin biopsy in order to provide the laboratory with the necessary cells. 11 Artificial skin theoretically could be cultured from samples that are infected with viruses, including HIV. Given the aggressive screening associated with this harvesting, however, the chance of infection is remote, although it does remain a possibility that the allogeneic human cells were taken from an HIV-positive but seronegative donor. 17 Comment While autologous skin grafts are occasionally used in some centres to aid the closure of recalcitrant wounds, the difficulties associated with harvesting the donor graft, as well as the complexities associated with inducing closure of the grafted site (in addition to the donor site), mean that this procedure cannot be undertaken lightly. Similarly, use of autologous cultured keratinocytes is a time-consuming, expensive and complex process that demands multiple patient visits and a laboratory capable of culturing the autologous keratinocytes. Artificial skin for the treatment of venous ulcers is not in widespread use. This may because of the substantial cost involved. This concern has been addressed in an economics study. 18 Implications for clinical practice While most clinicians would not treat all venous ulcers with skin grafts, patients who have wounds recalcitrant to compression therapy could be considered for skin grafts as an adjunct to improve their likelihood of healing. Of the available skin grafting methods, the use of artificial skin appears to be the most promising, conferring a 29% increase in the likelihood of healing by 24 weeks and an increased rate of healing. These results are based on a randomised controlled trial in patients with recalcitrant venous ulcers. 17 However, the significant costs associated with this therapy, as well as the theoretical risk of viral infection and the existence of only a single trial supporting its use, means that clinicians need to think carefully before treating patients with artificial skin. Vitamins and minerals Benefits Few practitioners dispute the importance of adequate nutrition for promoting wound healing. However, despite the assumption that vitamin and mineral supplements may aid in healing these wounds, few studies have addressed the potential benefits of supplementation in a rigorous fashion. Vitamin C supplements are often prescribed for patients with chronic wounds. Presumably, the well-known effects of excessive ascorbic acid deprivation, as seen in 595 Venous ulcers scurvy, include a susceptibility to non-healing wounds. Some reports have evaluated the use of vitamin C as an adjunctive wound-healing agent, with mixed results, and failed to demonstrate a clear benefit of vitamin C supplements in patients with chronic wounds of all types. 19,20 Zinc has been used for more than a century as a topical adjunct for the care of chronic wounds. 21 Unna believed that the zinc paste in his boots had a beneficial effect on healing; however, it now appears more likely that the continued popularity of the Unna boot for patients with venous leg ulcers stems from its compressive effects on the lower leg in patients with venous ulcers. 22 Oral zinc for the treatment of venous ulcers has been addressed in a Cochrane collaborative review evaluating six trials of oral zinc therapy, most of which failed to show a beneficial effect of therapy. 23 Five of these studies included patients with venous ulcers. The doses of zinc varied across studies. A study by Greaves et al . failed to demonstrate a significant benefit of oral zinc therapy, with a relative risk of healing of 1·5 (CI 0·28–7·93). 24 The remaining studies also failed to show a benefit of zinc therapy. 23,25,26 Topical zinc has also been evaluated as a treatment for venous ulcers. One study suggested that topical zinc oxide improves healing in both arterial and venous ulcers. 21 However, a study in porcine skin suggested that the only beneficial action of zinc on the wound bed was that it inhibited bacterial growth. 27 Several studies have addressed the efficacy of rutinoids in decreasing the oedema associated with venous insufficiency. 28–33 Results appear to be promising, and these drugs may be useful in patients with venous ulcers, since these wounds generally cannot heal in the setting of persistent oedema. Moreover, reducing the oedema of venous insufficiency may reduce the likelihood of future wounds. Complications There are few side-effects associated with vitamin or mineral therapy for venous ulcers. Comment Despite a marked lack of supporting evidence, one of the tenets of good wound care, at least in the US, is supplementary vitamin C and zinc. This is largely a result of the relatively benign nature of these treatments, as well as their modest cost. No studies have effectively evaluated the role of daily multivitamins in patients with chronic wounds. Another unexplored therapy is iron supplementation. An adequate tissue iron level is needed for appropriate metabolic functioning, and indeed mildly decreased iron levels may be associated with hair loss. 34 Since granulation tissue represents an environment of rapid cell proliferation, it is possible that wound healing may be sensitive to mildly decreased levels of iron, although this has yet to be demonstrated. Implications for clinical practice Given the prevalence of malnourishment among adults with chronic wounds, the low cost of vitamin C and zinc, and the low incidence of side-effects associated with supplementary water-soluble vitamins and minerals, it would certainly be reasonable to provide vitamin C and zinc supplements to patients. However, little evidence exists to support this practice, and clinicians should not feel compelled to provide patients with vitamins and minerals, particularly those who appear to be nutritionally replete. Laser therapy Benefits Laser therapy, using a variety of different lasers, has been proposed as an adjunct therapy for venous leg ulcers. Low-level lasers have been shown to stimulate cellular function, leading to 596 Evidence-based Dermatology increased protein synthesis and fibroblast and macrophage proliferation. Laser therapy for venous ulcers is the subject of a Cochrane collaborative review which included four trials. 35 Two trials compared laser therapy with sham laser, and failed to detect a significant difference in healing between the groups. 36,37 The results of these studies were pooled in the Cochrane review and failed to demonstrate a significant benefit of laser therapy, with a relative risk of 1·21 (CI 0·73–2·03). One study compared three types of laser therapy and found that a combination of laser and infrared light resulted in significantly more wounds being healed than using non-coherent unpolarised red light alone, with a relative risk of healing of 2·4 (CI 1·12–5·13). The study endpoint was healing after 9 months. Another very small study comparing low-level laser therapy with ultraviolet light in six patients failed to show a significant difference between the groups. Harms Laser therapy, including low-level laser therapy, may be associated with adverse effects, including burns and retinal damage, although these complications occur very rarely when therapy is administered by well-trained and experienced staff. Comment The studies evaluating the potential effect of low- level laser therapy for the treatment of venous ulcers included a total of only 139 patients. Moreover, the types of laser, power and duration of follow up varied across the studies. Some of these studies used very short endpoints, and it is possible that potential benefits were missed because the studies failed to follow patients for long enough. Moreover, there is some suggestion that laser therapy may have an effect on endpoints other than chance of healing, for example pain at the wound site and the amount of granulation tissue, 38 although this remains an area in need of further investigation. Implications for clinical practice There is currently insufficient evidence to support the use of low-level laser therapy in treating venous ulcers. Only one study showed a benefit of laser therapy. Intermittent pneumatic compression Benefits Intermittent pneumatic compression has been used for a number of indications, and is currently employed in the US as an adjunctive for the prophylaxis of nosocomial deep vein thrombosis. Since the underlying cause of venous ulceration is postulated to involve deficient blood return in the calf muscle pump, it has been suggested that intermittent pneumatic compression could improve the healing rates of venous ulcers by improving venous return. Intermittent pneumatic compression for the treatment of venous ulcers has been the subject of a Cochrane collaborative review. 39 This review evaluated four randomised controlled trials of intermittent pneumatic compression for the treatment of venous ulcers. One trial of 45 patients compared intermittent pneumatic compression plus standard limb compression with standard limb compression alone, and found a significant benefit in the intermittent pneumatic compression plus standard compression group, with a relative risk of healing of 11·4 (CI 1·6–82). Two other small trials (including 75 people altogether) failed to find a significant benefit of intermittent pneumatic compression plus standard compression over standard compression alone. Notably, the duration of therapy with intermittent pneumatic compression in these trials varied considerably. Moreover, the study endpoints differed 597 Venous ulcers [...]... 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Vasa 198 9; 18 :235–8. 31. Nocker W, Diebschlag W. Dose-response study with O-(beta-hydroxyethyl)-rutoside. Acta Derm Venereol 198 6; 66 :1 79 80. 37. Feidler VC. Alopecia areata: Current therapy. J Invest Dermatol 199 1; 96 (Suppl.): 69. 38. Lei Y, Nie Y-F, Zhang J-M, Liao D-Y, Li H-Y. Effect of superficial. immunotherapy in children with alopecia areata. J Invest Dermatol 199 5; 104 (Suppl.):35S–36S. 588 Evidence- based Dermatology Part 3: The evidence Section G: Leg ulceration Editor: Berthold Rzany Background Definition Venous