10.1177/1534734605277465 ARTICLEWOLLINA ET ALLEG ULCERS ARE A DIAGNOSTIC AND THERAPEUTIC CHALLENGE4

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Leg Ulcers Are a Diagnostic andTherapeutic Challenge

Uwe Wollina, MD,* Mohamed Badawy Abdel Naser, MD,† Gesine Hansel, MD,*

Cathrine Helm, MD,* André Koch, MD,* Helga Konrad, MD,*

Jacqueline Schönlebe, MD,‡ Leonore Unger, MD,§ and Erich Köstler, MD*

*Department of Dermatology, ‡Institute of Pathology “Georg Schmorl,” and §Department of Internal MedicineI/Rheumatology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital of theTechnical University of Dresden, Friedrichstrasse 41, 01067 Dresden, Germany, and

†Department of Dermatology, Ain Shams University, Cairo, Egypt

Leg ulcers are common. They cause a substantial burden tothe patient and society. However, there is no need for thera-peutic nihilism. The target of leg ulcer therapy is the individ-ual patient. To be treated in a rational and successful way, ex-act diagnosis of the underlying cause(s) and associateddiseases is necessary. This can be done in the most effectiveway with an interdisciplinary approach. The collection ofcases demonstrates the need for careful clinical investigationsubstantiated and supported by vascular, histopathologic,

and microbiologic techniques wherever needed. It is difficultto heal every ulcer completely, but improvement of the medi-cal situation as well as the quality of life of the patient ispossible in most cases.

Key words: leg ulcers, metabolic disease, vascular disease,neuropathic ulcers, vasculitis, malignant ulcer

Leg ulcers are the most common conditions. Pa-tients often present with chronic and, in many

cases, disabling wounds. The spectrum of underlyingdisease causing leg ulcers is remarkably broad, al-though its most common cause in Europe and otherWestern countries is venous insufficiency. In Africa,Asia, and South America, infectious diseases count fora significant number of cases. In a global terms, the his-toric pattern of disease is becoming a mixed picture.1-4

Leg ulcers are by no means a diagnosis, just a symp-tom of an underlying chronic cause. In every case, asearch for the underlying cause is necessary to providethe appropriate treatment for the patient. Therefore,standardization of treatment is not the final target but a

merely tool to offer optimal treatment in individual pa-tients. In this short paper, we demonstrate the need foraccurate diagnostics illustrated by individual clinicalcases.

CASE REPORTS

Case 1

A 72-year-old woman in poor health in general wasreferred to our department with extremely painful bi-lateral ulcers of the lower legs. She had a medical his-tory of absolute arrhythmia and diabetes mellitus. Shewas on oral antidiabetic agents and anticoagulants forarrhythmia.

On examination, she presented sharply demarcated,slough-covered ulcers of both the proximal and distalparts of her lower legs that were reminiscent of livedovascularis. The contours of the ulcers were marked by atight zone of necrosis (Fig. 1a,b). The ulcer surround-ings were slightly edematous but otherwise lacked in-flammatory symptoms. We performed Doppler

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Correspondence should be sent to: Dr Uwe Wollina, MD, Departmentof Dermatology, Hospital Dresden-Friedrichstadt, Academic TeachingHospital of the Technical University of Dresden, Friedrichstrasse 41,01067 Dresden, Germany; e-mail: wollina-uw@khdf.de.

Conflict of interest: None declared.

DOI: 10.1177/1534734605277465© 2005 Sage Publications

sonography to exclude peripheral arterial occlusivedisease and measured an ankle-brachial systolicpressure index >1.

Laboratory investigations were consistent with ab-normal pathology for the following parameters: bloodsugar, 7.02 mmol/L (normal range, 3.35-5.55); HbA1c,8.5% (4.1-5.9); cystatin C, 1.42 mg/L (0.50-0.96); alka-line phosphatase, 3.12 µkat/L (≤ 1.70); parathormone,156 pg/mL (9.0-55.0); and calcium and phosphate in24-hour urine (calcium 1.0 mmol/d, normal range, 3.0-6.0; phosphate 21.9 mmol/d, normal range, 25.0-65.0).Routine laboratory, including blood count, urea,creatinine, serum minerals (sodium, potassium, cal-cium, phosphate), antinuclear antibodies, p- and c-ANCA, and phospholipid[*ANTIPHOSPHOLIPID?*]antibodies, was either normal or negative.

A deep skin biopsy was taken from the left lower leg,and hematoxylin/eosin and Kossa stains were done.

Histopathology examination revealed a lipophagic,partly fibroblastic, and granulating panniculitis of sub-cutaneous fat tissue. There were marked calcium de-posits within the intima and media of arterioles andsmall arteries of the septal tissue (Fig. 1c).

The diagnosis of calciphylaxis in the case of initialdiabetic nephropathy and secondary hyperpara-thyroidism was confirmed.

Treatment and Course

Because of the high risk of septic complications incalciphylaxis, intravenous sultamicillin (Unacid;Pfizer GmbH, Karlsruhe, Germany), 3 × 3 g/d, wasgiven for 2 weeks. Pain was treated with transdermalfantanyl (Durogesic Smat, 25 µg/h; Janssen-CilagGmbH, Neuss, Germany). Oral 1.25-(OH)2-cholecalciferol (Einsalpha, 0.25 µg/d; Leo PharmaGmbH, Neu-Isenburg, Germany) was added.

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Fig. 1 (a, b) Ulcerated calciphylaxis: Presentation with livedo-like painful leg ulcers. (c) Histology shows calcium deposits in cutaneous ar-terioles (Kossa stain) ([*PLS. INSERT MAGNIFICATION*]). (d) Successful mesh graft transplantation after shaving of the ulcers.

Anticoagulation was changed to heparin (Fraxiparin,7600 IE/d; GlaxoSmithKline, Munich, Germany). Afterwound bed preparation with repeated debridement ofthe ulcers, shave excision under general anesthesia fol-lowed by mesh graft transplantation was carried out.The transplants stabilized within 3 weeks, and the pa-tient was discharged free from pain and leg ulcers (Fig.1d).

Case 2

A 71-year-old woman was referred to our depart-ment with painful leg ulcers on the feet and lower legsthat developed after formation of large asymptomaticbullae. This patient had been referred to several univer-sity departments for treatment of the nonresponsive ul-cers over recent years and had received a variety oftreatments, including skin grafts, without success. Shehad been suffering from Parkinson’s disease for 15years and had been treated with dopamine antagonists,and she had chronic obstructive pulmonary disease,sick-sinus syndrome and a therefore pacemaker, a com-pensated renal insufficiency, and hypochromousmicrocytic anemia.

On examination, we found some large tense bullaeand slough-covered, painful, superficial ulcers on thefeet and lower legs. Bullae had developed onnonerythematous skin. The skin in the region wastight, with the appearance of scleroderma (Fig. 2a).

Laboratory investigations showed the following: re-duced hemoglobin, 5.3 mml[*CORRECT?*]/L (normalrange, 7.4-10.7); mean cellular volume, 77.0 fL; meancellular hemoglobin, 1.58 fmol/L; serum iron, 6.6µmol/L (14.0-27.0); and serum protein, 52.8 g/L (65-85). There was an increased percentage of eosinophilsin the peripheral blood on admission (5.2%, later on12.9%).

Indirect immunofluorescence showed variable re-sults with antibodies to the pemphigoid antigen (1:320)on one occasion and antibodies to the pemphigus anti-gen (1:80) on another occasion. Therefore, we per-formed immunoblotting that failed to demonstrate an-tibodies against desmoglein 1 and 3 and bullouspemphigoid antigen 180. Patch testing showed sensiti-zation against thiuram mix, zinc diethyldithio-carbamate, and oak moos.

Echocardiography revealed an ejection fraction of65% with mitral and atrial insufficiency grades I and II,but there were no signs of valvular fibrosis. Chest x-raydid not show any signs of pulmonary fibrosis. Bonedensity was markedly reduced, with signs of severeosteopenia. A skin biopsy from a fresh bulla revealedsubepidermal blistering with a dense inflammatory in-

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LEG ULCERS ARE A DIAGNOSTIC AND THERAPEUTIC CHALLENGE

Fig. 2 Large, chronic leg ulcer induced by dopamine agonists inParkinson’s disease. (a) Initial presentation. (b) Histopathology of abullous lesion (HE) ([*PLS. INSERT MAGNIFICATION*]). (c) Out-come after mesh graft transplantation.

filtrate composed mainly of eosinophils and a band-like dermal fibrosis (Fig. 2b). Direct immunofluo-rescence showed only a weak IgG-positivity along thebasement membrane in surrounding nonblisteringskin.

The diagnosis reached was dopamine-induced sub-cutaneous fibrosis with blistering and secondaryulcerations.

Treatment

We started an oral low-dose prednisolone therapywith 15 mg/d and added 100 mg/d azathioprine. Par-kinson’s treatment was changed from Parkotil toRequip (Ropinirol, 3 × 2 mg/d; GlaxoSmithKline, Mu-nich, Germany). Osteoporosis therapy with calcium 1g/d and Actone (Risedronic acid, 35 mg/week; Procter& Gamble Pharmaceuticals, Weiterstadt, Germany) wasstarted.

Ulcer treatment was performed according to theprinciples (TIME[*PLS. SPELL OUT*]) with regulardebridement and topical antimicrobials, octennidin-2HCl plus ohenoxyethanol (Octenisept solution;Schülke & Mayr, Norderstedt, Germany), andSulmycin ointment (Gentamycin-Salbe; Essex Pharma,Munich, Germany) twice daily. Because of the dermalfibrosis, surgery with shaving and mesh graft trans-plantation was planned. The patient got several trans-fusions of erythrocyte before and immediately aftersurgery that was performed with local anesthesia. Themesh graft transplantation was successful (Fig. 2c).

Case 3

A 78-year-old woman was referred to our depart-ment because of a history of 2 months of progressiveskin lesions on the trunk and limbs with secondary ul-ceration on her left lower leg. She had decompensatedchronic ischemic heart disease and was in poor condi-tion of general health. Several skin biopsies were takenthat revealed a typical mycosis fungoides-like cutane-ous T cell lymphoma (CTCL). After topical treatmentwith bethamethasone ointment and cream PUVA(PUVA; photochemotherapy with UVA and 8-methoxypsoralen) to which she was initially re-sponded, the patient developed a massive tumor infil-tration of the left lower leg. The patient was thereforetreated with a combined approach of methotrexate 20mg IV per week, 15 mg/d prednisolone orally, and frac-tionated radiotherapy for the leg with a cumulativedose of 20 Gy. After radiotherapy, she developed multi-ple deep painful ulcers heavily covered by slough (Fig.3a). Regular debridement was hardly possible even af-ter opiate premedication for pain relief. Control biop-

sies excluded local remnants of CTCL. Therefore, wedecided to perform ulcer surgery in general anesthesiawith shaving and mesh graft transplants (Fig. 3b).

After surgery, a complex rehabilitation programwith mobilization and bandaging was performed. Theleg remained tumor free, and she was pain free.

Case 4

A 31-year-old man developed leg ulcers 9 years ago.He was treated twice with skin transplants in other de-partments, first in 1997 and again in 2001. These trans-plants, however, were unstable and completely disap-peared, leaving him with open lesions. About 5 yearsago, he developed swellings of the ankles but did notreceive any specific treatment for this.

He was admitted to our department with large, mal-odorous, slightly painful leg ulcers of the lower leg andthe ankles. There was no sign of reepithelialization buta great amount of discharge from the wound areas. Onexamination, we observed swellings of the meta

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Fig. 3 Leg ulcers in a patient with mycosis fungoides (a) beforeulcer treatment and (b) after combined shaving and mesh grafttransplantation.

interphalangeal (MIP) joints II to IV of both hands andan ulnar deviation of the left fifth finger (Fig. 4a). Healso had disfigurements of the ankles.

A biopsy was taken from an ulcer to exclude tumorand vasculitis. The biopsy revealed a vascularfibroplastic corial chronic inflammation but no malig-nancies or leukocytoclastic vasculitis.

Laboratory investigations showed a massive in-creased blood sedimentation rate (105 mm/h; normalrange, 3-8), C reactive protein 106 mg/L (<5),antistreptolysin titer 913 U/mL (0-200), solubleinterleukin-2 receptor 2503 U/mL (200-1000), and γ-globulins 46.4% (11.2-19.9). Antinuclear antibodieswere 1:1280; ANCA and extractable nuclear antibodieswere negative. The Bence-Jones protein was positivefor κ and λ chains. Serum levels for zinc (7.7 µmol/L;11-24) and copper (27.5; 11-22) were changed.Treponema pallidum hemagglutinin assay and anti-bodies against citrullin were negative. Chromosomalanalysis did not show any anomalies.

Cull[*DEEP?*] x-ray was normal, and no osteolysescould be found. Cystic erosions were evident in theMIP joints of the hands and feet (Fig. 4b). The toes alsoshowed subluxations. Iliosacral joints were ankylotic,and Schmorl’s rheumatoid nodules were seen. Abdom-inal ultrasound showed a splenomegaly. Gastros-copy, colonoscopy, and bone marrow biopsy were allnormal.

Diagnosis

Based on clinical, x-ray, and laboratory findings, thediagnosis of an ulcerating aggressive rheumatoid ar-thritis was confirmed.

Treatment and Course

We started with an intravenous antibiosis usingsultamicillin (Unacid PD oral 2 × 750 mg/d; Pfizer,Karlsruhe, Germany) for 10 days, topical debridement,and disinfection. Because of the iron deficiency, oraliron supplementation (Ferro Sanol bid; Sanol,Monheim, Germany) was given. Erythrocyte transfu-sions were necessary to improve delayed healing. Westarted anti-inflammatory therapy with 60 mg/dprednisolone and added etanercept 25 mg twiceweekly subcutaneously (Enberel, Wyeth Pharma,Münster, Germany). At the end of the hospitalstay[*HOW LONG?*], the wound began to granulate,pain and discharge were remarkably reduced, and askin transplantation was planned (Fig. 4c).

Case 5

A 56-year-old was referred to the department with a5-year history of diminished sensation on hands andfeet and weakness of the left leg. About 1 year previous,the patient had developed an ulcer on the leg that wasresistant to conventional treatment.

On examination, a slough-covered leg ulcer wasseen (Fig. 5a). There was loss of touch, pain, and tem-perature sensation in a glove and stocking distribution,

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LEG ULCERS ARE A DIAGNOSTIC AND THERAPEUTIC CHALLENGE

Fig. 4 Rheumatoid arthritis with vasculitic leg ulcers. (a) Swell-ing of the meta interphalangeal (MIP) joints and ulnar deviation ofthe fifth finger. (b) MIP erosions in the x-ray investigation. (c) Large legulcers of the lower extremities with ankle deformity.

with weakness of leg muscles and secondary ichthyo-sis. Superficial nerves were thickened, and testes weresmall and atrophic. He also showed a loss of eyelashesand outer one third of eyebrows with loss of nasalseptum (Fig. 5b).

The lepromin test was negative. Skin lit[*CORRECTWORD?*] from ear pinna revealed acid fast bacilli.

A diagnosis of leg ulcer in lepromatous leprosy wasconfirmed.

The patient was set on multidrug therapy withrifampicin, clofazimine, and dapsone recommendedby the World Health Organization (WHO) and contin-ues to receive this treatment.

DISCUSSION

Leg ulcers are only a symptom and never a firm diag-nosis. In every patient, the cause of ulceration and theconcomitant diseases and risk factors have to be identi-fied. Thereafter, the proper treatment can be chosenthat adopts best to the individual situation of the pa-tient and patient’s needs.

Pain is a significant symptom of leg ulcers mostcommonly found in occlusive arterial disease; how-ever, it is not uncommon in venous leg ulcers.5 Thequality of pain can be different between patients. If thepain is extraordinarily “heavy” and palpation of the legis painful, both vasculitis and calciphylaxis have to beconsidered in arriving at a diagnosis.

Calciphylaxis is also known as calcific uremicarteriolopathy (CUA).6 Complex laboratory investiga-tion, sonography, and histopathology were capable toconfirm the final diagnosis. Histopathology can be ex-tremely helpful in the case of metabolic disease, but thepathologist needs enough information to choose thespecial stains needed. Calcium deposits in cutaneousand subcutaneous vessels may be overlooked in con-ventional hematoxylin-eosin (HE) stains. Kossa stain,however, provided the clue needed in case 1. This pa-tient did not show pathologic creatinine but had an in-creased cystatin C level that was indicative of an im-paired glomerular filtration rate and superior tocreatinine.7

Mortality in the untreated may be as high as 80%.8 Amultidisciplinary approach is necessary, involving thenephrologist, endocrinologist, vascular surgeon, anddermatologist/dermatosurgeon.9 The treatment forcalciphylaxis is by no means standardized, but leg ul-cer surgery with deep shaving has been a valuable toolin removing intravascular calcium deposits and mark-edly reducing pain and the risk of septic infections.This technique offers the possibility of limb salvage inmany cases.

Autoimmunity may be a cause of resistance to treat-ment in leg ulcers. But autoimmune phenomena needcautious interpretation. Case 2 was presented withtense bullae, suggesting bullous pemphigoid, and thepatient belonged to the typical age group that is af-

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Fig. 5 (a) Neuropathic leg ulcer in leprosy. (b) Loss of eyelashes,lateral eyebrows, and nasal septum in leprosy.

fected by this blistering disease. Even the presence ofeosinophils in the skin biopsy may be considered an ar-gument for pemphigoid. On the other hand, the limita-tion of the disease to the lower legs and feet, inconsis-tent laboratory findings, and negative immunoblottingraised concerns about the diagnosis. Recently, the in-duction of fibrosis in different organs by dopamine an-tagonists has been observed. Major targets are heart andlungs,10-12 but retroperitoneal fibrosis has also been de-scribed in patients with Parkinson’s disease treatedwith bromocriptine.12,13 The skin biopsy revealed a der-mal fibrosis. Carbidopa, a dopamine antagonist, isknown to induce scleroderma-like lesions. Eosino-philia in blood and skin can also be explained by drugreactions. Investigations had excluded a paraneo-plastic blistering disease. The diagnosis in this casewas a preliminary one. Further studies are necessary todepict the prevalence and risk of dermal fibrosis in-duced by dopamine antagonists. Considering all possi-bilities led to a cure of ulcers for the first time during aseveral yearlong medical history of ulcerations by achange in medications, mild immunosuppression, andshaving the fibrotic tissue before transplantation.

Mycosis fungoides has a variable clinical presenta-tion. It might be present as ischemic foot and leg ul-cers.14 Not only CTCL-like mycosis fungoides but alsothe much rarer B cell lymphomas of skin may show as aleg ulcer.15 A sufficiently large and deep skin biopsy ismandatory for diagnosis. In case 3, CTCL did showwith classic plaques and tumors. Ulcerated tumors arenot uncommon in progressive disease. The ulcers beara great risk of septic infections and are mostly painful.In the present case, CTCL ulcerations were primarilyfound, but the ulcers enlarged during successful radio-therapy. These ulcers caused a lot of pain and costs.There was no clinical sign of improvement with con-servative treatment. Therefore, active surgical treat-ment was performed under palliative purposes and toimprove the patient’s quality of life. In noncurable dis-eases such as CTCL, surgery is not contraindicated butmay substantially help the patient to carry on with analmost normal life.16

Case 4 was a young male with longstanding ulcers.In such cases, genetic diseases such as progeria orKlinefelter syndrome must be excluded. Vasculitis isanother rare cause of ulcers. Taking together the clini-cal findings of joint disease, highly inflammatory reac-tions in the lab profile, and resistant ulcers, the diagno-sis was confirmed. Vasculitic ulcers are a challenge fortreatment. Immunosuppressive therapy is a corner-stone that needs to be underpinned by topical treat-ment. Recently, leg ulcer healing in rheumatoid arthri-tis was observed during leflunomide therapy.17 On the

other hand, some immunosuppressive drugs used forconditions such as rheumatoid arthritis (eg,methotrexate) may also cause ulcers. In any case, acombined approach of pharmacologic treatment andwound management is recommended. The presence ofconcomitant vascular disease has to be seriously con-sidered.18 Surgical ulcer treatment with grafting oftenis necessary because of delayed healing in immuno-compromised rheumatoid arthritis patients.19

Painless ulcers may be found predominantly in pe-ripheral neuropathies. In Europe, the United States, orCanada, neuropathic ulcers are not uncommon and aremainly caused by diabetes mellitus.20,21

In other parts of the world, leprosy is a major diseaseassociated with neuropathic ulcers. Use of 100 mgmonofilaments to test for loss of touch sensation is asimple but practicable method to identify leprosy pa-tients at risk for plantar ulcers.22 Topical therapy aloneis not able to ensure an effective treatment of these ul-cers. A study on more than 2500 patients from Chinareported that (1) off-loading or appropriate foot sup-port, (2) avoidance of long-distance walking, (3) educa-tion on foot self-care, and (4) financial support were allmajor beneficial factors to achieve ulcer healing and toprevent the development of secondary ulcers after sur-gery.23 Those with longstanding, neglected, chronicneuropathic ulcers in leprosy are also at risk for devel-oping squamous cell carcinoma.24

The above collection of cases shows the broad spec-trum of causes of leg ulcerations and the demand for di-agnosis, including histology. In many cases, the treat-ment is based on an interdisciplinary approach withconventional and surgical measures.

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