Successful treatment of a leg ulcer occurring in a rheumatoid arthritis patient under leflunomide therapy

Objective We report the case of a leg ulcer in a rheumatoid arthritis (RA) patient under treatment with leflunomide, discuss the influence of the drug on the aetiopathogenesis of the ulcer and describe its successful treatment. Case summary A 68‐year‐old woman with a 12‐year history of RA developed a leg ulcer after 4 months of leflunomide treatment. Other ulcerogenic factors were ruled out. There were some clinical hints for rheumatoid vasculitis. The ulcer was resistant to ambulant conservative phase adapted wound bed preparation and a split skin transplantation failed. After omission of leflunomide and washout procedure with cholestyramine a second split skin transplantation resulted in complete healing. Discussion Leflunomide inhibits the division of activated T cells and thus inhibits among others the production of proinflammatory cytokines and the adhesion of cells to the endothelium. These mechanisms may partly explain the possible influence of leflunomide on the perpetuation of the ulcer. Until now, occurrence of vasculitis and leg ulcers has been described in one case each for the novel immunomodulator leflunomide. No successful treatment of a leg ulcer under leflunomide has been described yet. Omission of leflunomide and a washout treatment in our case led to a complete healing. This may indicate a critical role of leflunomide in the maintenance of this slow healing ulcer. Conclusions An association between leflunomide intake, occurrence of leg ulcers in RA patients and delayed wound healing should be considered.     

Granulocyte adsorptive apheresis for leg ulcers complicated by rheumatoid arthritis: a report on three successfully treated cases

BACKGROUND: The treatment of inflammatory leg ulcers complicated by rheumatoid arthritis (RA), which are unresponsive to conventional care, can be frustrating. Furthermore, as granulocytes and monocytes (GM) are major sources of inflammatory cytokines, they have the potential to initiate and perpetuate inflammatory skin lesions. Accordingly, a recent study reported the remission of pyoderma gangrenosum following the reduction of activated peripheral blood GM by adsorptive apheresis (GMA). METHODS: In this clinical study, we applied GMA to three cases, each with one leg ulcer below the knee and RA. The ulcers had not responded to conventional therapy, including disinfection, dressing, and antimicrobials, and therefore were thought to represent inflammatory vasculitic lesions. GMA was performed using a column with a capacity of 335 mL, filled with cellulose acetate beads that selectively adsorb granulocytes and monocytes/macrophages (Adacolumn). Each patient received one GMA session/week for five consecutive weeks. The duration of one session was 60 min, with a flow rate of 30 mL/min. RESULTS: The ulcers began to recede after two GMA sessions and, by the end of the fifth session, the ulcers in all three patients had healed. No recurrence has been observed up to the time of this report. The treatment was well tolerated and no severe side-effects were observed. CONCLUSIONS: GMA, which depletes activated neutrophils and monocytes/macrophages, appears to be effective for inflammatory skin ulcers which do not respond to conventional medications.     

Sickle cell leg ulcers are associated with HLA-B35 and Cw4

We determined the HLA-A, B, C, and DR types in nine patients with sickle cell anemia (SS) who had leg ulcers or a history of leg ulcers, and in 29 control patients with SS without leg ulcers. Six (67%) of the nine patients with leg ulcers had HLA-B35 and each of these six patients also had HLA-Cw4. In contrast, only eight (28%) of the 29 control patients with SS had HLA-B35 and only three (10%) of these patients had both HLA-B35 and Cw4. The relative risk for development of leg ulcers in patients with SS who had both HLA-B35 and Cw4 was 17 times greater than that of patients without these antigens or who had only one antigen. The frequency of HLA-B35 was also significantly higher in patients with SS and leg ulcers than in a reference population (31%) consisting of 68 healthy black persons. These results suggest that genetic factors or an HLA-related altered immune response may contribute to the development of leg ulcers in sickle cell anemia.     

Resistance to activated protein C due to factor V Leiden mutation: high prevalence in patients with post-thrombotic leg ulcers

BACKGROUND: Activated protein C (APC) resistance is the most frequently diagnosed heritable thrombophilic defect predisposing to thrombosis. OBJECTIVES: To determine the prevalence of APC resistance due to factor V Leiden mutation in patients with leg ulcers. METHODS: Within a 2-year-period 100 consecutive patients with leg ulcers were examined for factor V Leiden mutation. RESULTS: APC resistance due to factor V Leiden mutation was detected in 19 of 53 patients (36%) with post-thrombotic leg ulcers and in three of 47 patients (6%) with ulcers caused by primary varicosis. In a healthy control group APC resistance due to factor V Leiden mutation was found in five of 96 (5%) volunteers. CONCLUSIONS: In view of this high prevalence of APC resistance of 36%, which has never previously been reported, patients with post-thrombotic leg ulcers should be investigated for APC resistance.     

Leg and foot ulcers. Nursing care in Malm?, Sweden.

Questionnaires concerning nursing care of leg and foot ulcer patients in three major care-giving sectors of the national health service, namely the Department of Dermatology, general hospital wards/clinics, and primary care, have been analysed. The overall response rate was 88% (primary care: 100%). Forms regarding 193 patients with leg ulcers and 64 patients with foot ulcers were analysed. Substantial differences in nursing care were noted between the three sectors. In 55% of the leg ulcers and 45% of the foot ulcers fibrin slough was present in the ulcer. Black, necrotic tissue was present in 8% of the leg ulcers and 22% of the foot ulcers. Profuse ulcer-exudation was most commonly reported for leg ulcer patients treated at the Department of Dermatology, while the majority of foot ulcers had only a mild exudation. Frequency of dressing changes varied between 1.4 times/week for leg ulcers at the Department of Dermatology and 9.2 times/week (foot ulcers 11.6) at general hospital clinics. Local wound dressings were exclusively chosen by physicians at the Department of Dermatology, mainly by physicians at general hospital clinics, and equally often by physicians and nurses in primary care. Time since last evaluation of the ulcer by a physician varied. At the general hospital clinics, 89% of the patients with leg ulcers had been seen by a physician within the last 2-month period. At the Department of Dermatology, 89% and in primary care 61% of the patients were examined within this period. 11% of the patients in primary care had never consulted a physician for their ulcers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Skin Manifestations Associated with Rheumatoid Arthritis

We examined cutaneous manifestations of rheumatoid arthritis (RA) of 142 Japanese patients who visited both the Departments of Dermatology and Rheumatology of our hospital. We classified cutaneous lesions into specific and/or characteristic or nonspecific ones. Nonspecific lesions predominated in our series. Among the specific skin manifestations, which comprised 10% of the total, rheumatoid nodules, rheumatoid papules, rheumatoid neutrophilic dermatitis, and severe vasculitic ulcers correlated with high titers of rheumatoid factors and progression of RA, while purpura and livedo did not. Nonspecific skin manifestations failed to correspond with the level of rheumatoid factors. Among the nonspecific lesions, asteatotic eczema, candida interdigitalis, and tinea unguium were commonly detected.     

Dermal oedema assessed by high frequency ultrasound in venous leg ulcers

Oedema is considered a key pathogenic factor in the development of venous leg ulcers. The purpose of this study was to determine the localization of oedema in legs with ulcers. Twelve patients with 13 venous leg ulcers (one bilateral), with a duration of 7–18 months, were examined by high-frequency B-mode ultrasound scanner. This was performed at three sites in the leg (low, middle and upper sites of the lower leg). In the same group of patients, the legs without ulcers were used as controls. The echogenicity and the thickness of the whole dermis were quantified by digital image analysis; the echogenicities of the upper (papillary) and lower portions of the dermis were measured. In the upper site no significant difference was found between the legs with ulcers and controls. In the middle and low sites of legs with ulcers, the dermal echogenicities were 34% and 64% ( P  < 0.01) less than those in controls, and the dermal thicknesses were 0.4 mm and 0.8 mm ( P  < 0.01) thicker than those in controls, respectively. This indicated intradermal oedema existing in the lower part (gaiter area) of the legs with ulcers. The ratios of low echogenic pixels in the upper and lower portions of the dermis, in the middle and low sites of legs with ulcers, were 0.5 and 0.9 ( P  < 0.05 and P  < 0.01), respectively, higher than those in controls, suggesting the papillary dermis as a preferential site of oedema formation. The present study demonstrates that in the low sites of legs with ulcers, a marked increase in oedema was seen in the papillary dermis. This may add to the understanding of the origin of leg ulcers in the gaiter area of the leg.     

A demographic survey of leg and foot ulcer patients in a defined population.

By means of a questionnaire sent to all medical units in Malm?, including primary care, homes for the elderly, and industrial health clinics, 275 patients with leg and foot ulcers were identified. With a population of 232,908 in Malm?, this corresponds to a prevalence of 0.12%, which is lower than reported by others. Since the response rate was high (88% total, Primary Care: 100%), the prevalence of 0.12% is, however, believed to be real and might be explained by the urban area investigated, with easy access to care and proximity to one somatic hospital. 50% of the patients with leg and foot ulcers were treated in Primary Care, and 30% of the leg ulcer patients were treated at the Department of Dermatology. 88% of leg and foot ulcer patients were over 75 years of age. Median age was 79.5 years, with 80 for women and 76.5 for men. In Primary Care the median age was 82. There was a predominance of women in the study population with an overall sex ratio of 3:1. A higher proportion of patients living alone was found in Primary Care. The etiology of the ulcers was considered to be "unknown" or "other" or else no statement was given in 36% of the leg ulcer- and 22% of the foot ulcer patients. This might reflect an overall uncertainty about the underlying etiological cause. Medially and laterally located leg ulcers were reported equally often, but there was also a great proportion of wholly or partially circumferential ulcers. 76% of the foot ulcers were located on the toes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Local treatment of chronic cutaneous leg ulcers with recombinant human granulocyte-macrophage colony-stimulating factor

AIM: To test the efficacy and safety of recombinant granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in the treatment of chronic cutaneous leg ulcers. METHODS: Five patients with chronic cutaneous leg ulcers were recruited for this 4-month study using only rHuGM-CSF to treat the ulcers. One patient had a neuropathic-diabetic ulcer, and four had long-standing vascular leg ulcers. RESULTS: The patient with the neuropathic diabetic ulcer showed complete healing after 1 month of treatment. The other four patients with vascular leg ulcers with a long history of ulceration had a poor prognosis for healing. The first, with three venous ulcerative lesions, presented complete resolution of one ulcer and stabilization of the other two; the second and third patients, with large vascular ulcers, improved with more then 50% reduction of the mean diameter of the ulcers; the fourth patient, with one large venous ulcer, did not show any improvement. CONCLUSIONS: Pathogenesis, size and duration of the ulcers seemed to be the most important parameters regarding wound repairing capability of rHuGM-CSF. None of the ulcers increased in size and none of the patients developed clinical side-effects or peripheral blood cell count abnormalities during the treatment. All the results described were stable after 6 months of follow up. The absence of peripheral leucocyte count variation and the size-dependent therapeutic effect indicate that the drug exercises local rather than systemic actions.     

Arterial hypertension causing leg ulcers

We report clinical and histological features of 16 consecutive patients with hypertensive leg ulcers. The lumen/wall ratio in arterioles at the edges of these hypertensive leg ulcers was compared with that in other types of chronic leg ulcers and was found to be significantly reduced (P < 0.001). Additional conditions such as venous hypertension or main vessel arterial disease contributed. Nineteen of 22 ulcers were completely healed after a mean of 4.9 months. Recognition of this condition enables correct treatment choice, which usually involves excision and grafting, and early healing. The classical hypertensive leg ulcer was initially described by Martorell in 1945¹ and subsequently by others.^2–8 As described, it is situated on the lateral aspect of the lower leg above the ankle, is painful, often severely so, and has necrotic edges. Patients have a history of arterial hypertension, although the blood pressure may be normal at presentation. There is usually no surrounding oedema or stasis pigmentation and peripheral vascular disease is absent. The ulcers are often resistant to conservative treatments and most reported cases eventually require excision and grafting or lumbar sympathectomy before healing occurs. Martorell¹ emphasized that usually there is no evidence of main vessel arterial disease or a disturbance in the venous circulation. Milder or atypical cases may be misdiagnosed. We studied patients with leg ulcers in which hypertension was considered the main aetiological factor to document features.     

Leg ulcers in peripheral arterial disease (arterial leg ulcers): impaired wound healing above the threshold of chronic critical limb ischemia

BACKGROUND: Peripheral arterial disease is the only identifiable etiology in approximately 10% of leg ulcers. Clinical data on the management of these chronic wounds are scarce. OBJECTIVE: We attempted to outline the threshold of systolic ankle pressure and ankle-brachial-index (ABI) below which arterial leg ulcers can occur and to outline the indication for revascularization in arterial leg ulcers. METHODS: Diagnostic and outcome analysis was performed for 26 consecutive patients with arterial leg ulcers. We calculated sensitivities, specificities, and receiver operating characteristic (ROC) curves for the identification of arterial leg ulcers among all 223 consecutive leg ulcer patients within a 3-year period, as well as the ROC curve for patients who required revascularization. RESULTS: The systolic ankle pressure was 88 (18-130) mm Hg (median; 95% confidence interval) and the ABI was 0.60 (0.15-0.86), respectively. Eighteen patients (69%) were subjected to revascularization. By the end of the study, 24 patients (92%) healed completely, 1 improved (90% wound closure), and 1 patient had to undergo below-knee amputation for chronic osteomyelitis. During this study, the ankle pressure and ABI were poor in distinguishing those patients who required revascularization from those who healed without revascularization. CONCLUSION: Most arterial leg ulcers do not meet the criteria of chronic critical limb ischemia, but they do not heal under conservative measures, either. A majority of these patients benefit from revascularization and should, therefore, be referred for arterial duplex ultrasound investigation or angiography. In our study, an ankle pressure below 110 mm Hg identified all patients (100%) who were subjected to revascularization procedures. However, controlled clinical studies are required to find the systolic ankle pressure and ABI below which revascularization can be recommended to speed up the healing time.     

Calf muscle pump impairment and delayed healing of venous leg ulcers: air plethysmographic findings

There is a need for a diagnostic tool to predict clinical outcome of venous leg ulcer patients, as the prognosis of healing based on clinical data alone has not appeared to be satisfactory. Air plethysmographic assessment of calf muscle pump was performed in the supine and upright position in 129 patients with active ulcers on their legs. All patients were managed in a specialized leg ulcer clinic. Results of air plethysmography were compared to clinical data and time of healing of ulcers. Muscle pump failure was found in 42.6% of extremities (supine position, 33.3%; upright, 22.5%; both, 12.4%). Patients with insufficient pump were older, and their ulcers were larger. Failure of pump was found more often in patients who began the treatment after long, unsuccessful, non-specialized care. Healing time of ulcers was prolonged in cases with insufficient pump. Regarding the subgroups with good clinical prognosis (patients with small ulcers or with a short history of ulceration), it was found that insufficiency of muscle pump correlated with delayed healing. It could be summarized that venous leg ulcers associated with calf muscle failure were larger, long-standing, and that their healing even after specialized treatment was delayed. Impaired muscle pump function revealed in plethysmographic examination can be a prognostic factor of delayed healing of leg ulcer. Ulcers with poor prognosis according to plethysmographic findings, and no quick recovery after standard management, should be considered for advanced therapies.     

Pathogenesis of therapy refractory ulcus cruris

BACKGROUND AND OBJECTIVE: The most common cause of leg ulcers ischronic venous insufficiency (CVI), found in 70-80% of cases. The aim of this study was to analyze the causes of chronic, non-healing leg ulcers in inpatients. PATIENTS AND METHODS: 101 patients with leg ulcers admitted to the Dermatology Clinic of the Ruhr University, Bochum, Germany, were examined. Standardized diagnostic procedures were used to search for CVI, arterial disease, vasculitis, polyneuropathy and diabetes mellitus. RESULTS: CVI was found in 95% of the patients. Only 17% had isolated venous disease. In most patients we found a combination of two or more possible etiologic agents; most commonly (92%) arterial plus venous disease. Arterial disease was confirmed in 74% of the patients. A combination of 3 etiologic factors was found in 27%. CONCLUSION: Non-healing leg ulcers are likely to have multiple etiologies. Thus extensive and complete diagnostic approaches are mandatory.     

Oxygen pressure fields in ulcers of the lower leg

Using a multi-wire surface electrode, oxygen pressure fields were determined in leg ulcers of 11 patients with chronic venous insufficiency (cvi). In three of them, cvi was combined with arterial occlusive disease. The histograms of all patients with very low PO2 values revealed microcirculatory disturbances of the ulcer tissue. The influence of leg position is reflected in the histograms. Patients with cvi showed higher PO2 values when the leg was raised in comparison with when it was in the hanging position. The patients with mixed ulcerations showed a significant increase in tissue PO2 when the leg was in the hanging position, which shows the importance of arterial perfusion pressure. After a compression bandage had been applied to the legs with cvi, the tissue oxygen pressure of the ulcers increased markedly, probably as a result of diminished blood stasis. These results can be explained either by a rarefaction of capillaries in the ulcer tissue or by fibrin diffusion barriers around the capillaries. The changes in the histograms after bandaging are thought to be caused by an improvement in venous circulation.     

Prostaglandin E1 treatment of leg ulcers caused by venous or arterial incompetence

An open and a double-blind study were undertaken on patients with leg ulcers caused mainly by venous (VI) or arterial incompetence (AI). They were treated with intravenous infusions or injections of prostaglandin E1 (PGE1). Eight of 10 patients in the open study experienced relief of pain and a complete or almost complete healing of their ulcers. In the double-blind study (20 patients) 4 out of 5 patients with a history of leg ulcers due to VI for more than 5 year responded to the PGE1 treatment, compared with one of 5 treated with saline. In the saline group 3 more patients with VI of shorter duration improved. In 3 of 5 patients of PGE1 with ulcers due to AI the original ulcer area was reduced by 78--65% after 70 days, while in the 2 remaining cases healing occurred later on. No effect was noted in the 2 patients with ulcers due to AI who received saline infusions. The results indicate the beneficial effect of PGE1 on pain and healing in leg ulcers caused by peripheral vascular disease.     

Lupus anticoagulant and venous leg ulceration

BACKGROUND: Most leg ulcers occur in patients with venous insufficiency. However, not all patients with venous insufficiency develop leg ulcers. Recent studies have found that factors causing clotting abnormalities, e.g. anticardiolipin antibody (ACA), are associated with leg ulcers. Although lupus anticoagulant, like ACA, belongs to the group of antiphospholipid antibodies, its presence in patients with venous leg ulceration has not been previously reported. OBJECTIVES: To determine the presence of lupus anticoagulant in patients with venous leg ulceration. METHODS: We investigated the presence of lupus anticoagulant in 27 patients with venous leg ulcers and compared these data with controls. Lupus anticoagulant was evaluated in all subjects by the Russell's viper venom test. RESULTS: Of 27 patients with venous leg ulceration, 16 (59%) were shown to have lupus anticoagulant, while only one of 32 controls (3%) was found to have lupus anticoagulant. Thus, lupus anticoagulant was significantly more frequent in patients with venous leg ulcers than in controls (P < 0.001). CONCLUSIONS: We suggest that lupus anticoagulant could be a hitherto unknown factor contributing to the development of venous leg ulcers.     

Etiology of chronic leg ulcers in 31,619 patients in Germany analyzed by an expert survey

Background: The etiology of chronic leg ulcers is heterogenous and they exhibit quite different healing rates depending on the underlying cause. Although the prevalence and incidence of chronic leg ulcers appear to be increasing, data on these patients in Germany are lacking. Patients and Methods: Altogether 100 German wound care professionals were asked to complete a questionnaire regarding the diagnosis and etiology of their patients with chronic leg ulcers. Results: We received the data on 31,619 patients. In these patients, venous insufficiency was the dominating causative factor in 47.6 % and arterial insufficiency in 14.5 %, 17.6 % of ulcers were due to combined arterial and venous insufficiency. Rarer causes included vasculitis (5.1 %), exogenous factors (3.8 %), pyoderma gangrenosum (3.0 %), infection (1.4 %), neoplasia (1.1 %), calciphylaxis (1.1 %) and drug‐induced (1.1 %). The used diagnostic methods used varied widely between the medical and surgical specialties. Conclusions: Even though the results of our study cannot claim to be a representative overview, they demonstrate clearly that next to known etiologies, e. g. chronic venous insufficiency or peripheral arterial insufficiency, which are relevant in 79.7 % of all patients a multitude of other causes exist, which are responsible in 20.3 % of all patients for the development of chronic leg ulcers.     

Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study

BACKGROUND: In the conservative therapy of venous leg ulcers modern types of dressings are used most frequently. In the past 20 years 'active wound dressings' - cultured epidermal keratinocytes as autografts and allografts - were also introduced in the management of leg ulcers. METHODS: The aim of our study was to compare the effect of cryopreserved and lyophilized cultured epidermal allografts in the treatment of venous leg ulcers. Evaluation of the therapy was documented as photodocumentation, planimetry, healing time and evaluation of pain relief over a 3-month period after application. Fifty patients with venous leg ulcers were selected. Twenty-five patients (group I) were treated with cryopreserved keratinocytes and 25 (group II) with lyophilized keratinocytes. RESULTS: The final evaluation 3 months after the application of allografts showed 84% of healed ulcers in group I and 80% in group II. The number of healed ulcers and the healing rate both showed no statistically significant differences. The size of the ulcer was reduced by half during the first week in both groups. The size differences during the first week are statistically significant in both groups and they are comparable (P < 0.001). The intensity of the pain was statistically significantly reduced during the first week after application in both groups (P < 0.001). CONCLUSIONS: The cryopreserved and lyophilized cultured allografts are comparable in healing rate, course of healing and relief of pain, and also in planimetric changes during the healing of venous leg ulcers. Lyophilized allografts are more convenient for routine use than cryopreserved allografts as they can be stored at room temperature. These results could give rise to the more frequent use of lyophilized allografts in slow-healing venous leg ulcers.     

Contact allergy in chronic leg ulcers: results of a multicentre study carried out in 423 patients and proposal for an updated series of patch tests

Background:  There is a lack of prospective studies investigating contact sensitization in patients with chronic leg ulcers.
Objectives:  To determine the frequency of contact sensitization in patients with chronic leg ulcers using a special series of patch tests and to determine whether the number of sensitizations was correlated with the duration of the chronic leg ulcers.
Patients/methods:  Multicentre study carried out in patients with chronic leg ulcers; patch tests with the European baseline series and with an additional 34 individual allergens or mixes and 3 commercial products.
Results:  Of the 423 patients (301 women, 122 men, mean age 68.5 years) with chronic leg ulcers, 308 (73%) had at least one positive patch test with 3.65 positive patch tests per patient. The main allergens were Myroxylon pereirae (41%), fragrance mix I (26.5%), antiseptics (20%), and corticosteroids (8%). The number of positive tests per patient was not correlated with the cause of ulcer but was increased with the duration of the ulcer with a statistical difference between the group of the <1 year compared with the group >10 years duration.
Conclusions:  From this large prospective multicentre study, polysensitization is frequent in patients with chronic leg ulcers, increasing with the duration of the ulcer. We propose avoidance of topical antiseptics and ointments containing perfumes in patients with chronic leg ulcers and an updated patch test series for investigating these patients.     

Healing effect of ketanserin on chronic leg ulcers in patients with diabetes

BACKGROUND: The treatment of chronic leg ulcers remains a stubborn problem in many patients. Topical 2% ketanserin ointment, a 5HT2-serotoninergic blocking agent, has been reported to improve healing of decubitus, venous, diabetic and ischaemic ulcers. METHOD: The present double-blind intra-individual comparative study was performed in 12 women with diabetes presenting with at least two similar leg ulcers. In each subject, the two lesions were randomly assigned to be treated for 8 weeks by 2% ketanserin ointment or its unmedicated vehicle. OBJECTIVE: assessments of the dynamics of wound healing were performed using computerized morphometry. Evaluations were performed at 2-week intervals for 8 weeks. RESULTS: A significant decrease in relative wound area was observed on the ketanserin-treated ulcers compared with the placebo group. CONCLUSION: Topical ketanserin is a valuable therapy for difficult-to-treat leg ulcers.