Leg ulcers and hydroxyurea: forty-one cases.

BACKGROUND: Hydroxyurea is an antitumor agent used to treat chronic myeloproliferative disorders. Leg ulcerations have been reported in patients undergoing long-term hydroxyurea therapy for myeloproliferative diseases. To better define this dermatological adverse effect of hydroxyurea therapy and to try to understand the pathophysiological process of this disease, we collected medical information for such patients in a multicenter retrospective study. OBSERVATIONS: Forty-one patients (mean age, 67 years) developed leg ulcerations while undergoing hydroxyurea therapy (mean therapy duration, 5 years). The sex ratio was 1, and there was no underlying vascular disease. Hematologic abnormalities were identified. Complete recovery from the ulcerations occurred quickly after withdrawal of treatment in 33 (80%) of the cases. CONCLUSIONS: This longest-reported series of patients confirms the role of hydroxyurea therapy in the onset of leg ulcerations. Healing or improvement requires cessation of treatment. Cutaneous atrophy and impaired wound healing may explain the relationship between hydroxyurea and leg ulcers. In addition, the megaloblastic erythrocytes resulting from the presence of hydroxyurea may circulate poorly through the capillary network. A prospective study in hematologic centers would be valuable.     

Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease

BACKGROUND: Treatment with hydroxyurea may alleviate the symptoms of sickle cell disease (SCD). Because treatment with hydroxyurea may be responsible for several cutaneous side effects and is often lifelong in patients with SCD, we conducted this study to evaluate the risk of cutaneous adverse reactions in SCD patients treated with hydroxyurea. OBSERVATIONS: Seventeen adult patients with SCD treated with hydroxyurea at one institution were examined by a dermatologist. Hydroxyurea was given for a mean of 3.04 years (range, 0.42-6.5 years). None of the patients had skin cancer, but 5 (29%) had disabling hydroxyurea-induced leg ulcers. Four of these 5 patients had a previous history of SCD ulcer, compared with none of the 12 patients without hydroxyurea-induced leg ulcers (P<.05). The mean age of patients with induced ulcers was 35.8 years and for those without ulcers was 23.5 years (P<.01). CONCLUSIONS: Our rate of hydroxyurea-induced leg ulcers (29%) is higher than that reported for patients with myeloproliferative syndromes (9%). In addition, use of hydroxyurea has induced ulcers mainly in patients with previous SCD ulcers, suggesting that hydroxyurea could act in conjunction with other vascular abnormalities. Careful attention should be required when giving hydroxyurea to patients with SCD with previous ulcers as well as in older patients with SCD.     

Leg ulcer in a patient associated with hydroxyurea therapy

Hydroxyurea is a hydroxylated derivate of urea commonly used in the treatment of various hematologic disorders. Cutaneous side-effects such as alopecia, diffuse hyperpigmentation, scaling, poikiloderma, atrophy of the skin and subcutaneous tissues or nail changes can develop after long-term treatment with hydroxyurea. Painful leg ulcers in association with hydroxyurea have only rarely been reported. We present a report of a 52-year-old patient with essential thrombocythemia suffering from painful leg ulcers 3 years after starting therapy with hydroxyurea. We decided to treat the leg ulcers following a modern phase-adapted wound-healing strategy and continued hydroxyurea therapy until complete healing of the ulcers. In conclusion, cutaneous ulceration of the leg is one adverse effect in patients with essential thrombocythemia during hydroxyurea therapy. Healing does not necessarily require discontinuation of the drug. Therefore, therapists should first optimize a conservative and systematic wound-healing strategy. If these interventions fail, discontinuation of hydroxyurea therapy is advisable.     

Cutaneous ulcerations on hands and heels secondary to long-term hydroxyurea treatment

Hydroxyurea is a chemotherapeutic agent used to treat myeloproliferative disorders and other non-neoplastic conditions. Cutaneous side-effects have been described in long-term therapy with hydroxyurea and include xerosis, hyperpigmentation, skin atrophy, erythema, alopecia, skin tumours and ulceration of the skin, particularly of the legs. We present a 71-year old patient with chronic myelocytic leukemia (CML) who developed extremely painful ulcers on the hands and heels as well as skin tumours while on long-term therapy with hydroxyurea. The ulcers were resistant to therapy but healed three months after discontinuation of hydroxyurea therapy.     

Medikamente

In the last few decades it has been reported that the intake of some drugs may lead to the onset of a leg ulcer. In the etiology particularly allergic and toxic mechanisms have been postulated to induce pathological reactions which potentially lead to vasculitis or vasculopathies. The causal association of the intake of drugs and the occurrence of a leg ulcer is not always clearly proven. Most of the presented drugs in this overview are substances for which only a few case reports has been described for an association with leg ulcers. Diagnoses are often made by exclusion of other causes and because of a temporal relationship. One exception is drugs which contain the active ingredient hydroxyurea. More than 100 published patients have developed leg ulcers while on hydroxyurea. Moreover, these ulcerations have a typical clinical morphology. Numerous systemic medicaments can lead directly or indirectly to the onset of a leg ulcer. Therefore it is important to recognize this potentially relevant factor and adjust the medications as part of the therapeutic plan.     

Hydroxyurea-induced genital ulcers and erosions: Two case reports

Hydroxyurea is a chemotherapeutic agent used for myeloproliferative disorders and sickle cell anemia that is well known to cause painful mucocutaneous ulcers, typically involving the legs or mouth. However, genital ulcerations due to hydroxyurea therapy are a rare, and likely underrecognized, adverse effect with only a few cases reported in the literature to date. Ulcers of the lower legs caused by hydroxyurea are associated with a diagnostic delay, and this is likely exacerbated in cases of genital ulceration due to a lack of awareness. Herein we present two cases of painful genital ulceration in patients on hydroxyurea therapy. In the first Case, an 87 year-old male with polycythemia vera developed an ulcer on the scrotum, which was assessed initially through virtual visits during the COVID-19 pandemic, and was refractory to topical and oral antibiotic treatments. The second case was a 79 year-old male with essential thrombocythemia and a history of persistent leg ulcers who developed erosions of the glans penis. Both patients experienced complete resolution within weeks of discontinuing hydroxyurea therapy. In conclusion, genital ulcers and erosions induced by hydroxyrea may be underrecognized in clinical practice, but if identified, withdrawal of hydroxyurea leads to quick resolution of these lesions and the associated pain.     

The diagnosis and medical management of vascular ulcers

Of the many causes of non-traumatic, chronic skin ulceration in the lower extremities, vascular diseases are, by far, the most common etiologic factors. Consequently, there is a tendency to label patients as having peripheral vascular disease whenever recurrent leg ulcers are found, sometimes leading to inappropriate therapy. One cannot ascribe an etiologic diagnosis to a leg ulcer by its appearance alone, but must take into account the clinical context in which it occurs. The purposes of this chapter are to review the clinical features associated with various kinds of vascular ulcers and to discuss diagnostic methods and the appropriate medical therapy. Vascular ulcers are broadly divided into those associated with arterial insufficiency and those related to venous disorders.     

Aggressive, extensive, vasculitic leg ulceration associated with hydroxyurea therapy and a fatal outcome

The association of lower leg ulcer development and hydroxyurea therapy in patients with myeloproliferative disorders has been reported previously. In most of these cases the ulcers healed with cessation of the hydroxyurea together with meticulous attention to wound care. We report a patient who developed painful vasculitic ulcers secondary to hydroxyurea on both lower legs whilst on long-term hydroxyurea therapy for idiopathic thrombocytosis. The ulcers extended relentlessly despite stopping hydroxyurea, maximizing topical therapies and starting intensive systemic treatment. We discuss the association of hydroxyurea therapy with the development of painful ulceration.     

Leg ulcers: a new symptom of Blau syndrome?

Blau syndrome is a rare autosomal dominant condition, typically defined by granulomatous polyarthritis, uveitis and skin eruption. Biopsy specimens demonstrate non-caseating granulomas in all lesions. We present a case of Blau syndrome associated with large recalcitrant leg ulcers. Biopsies taken in the leg ulcers of our patient systematically showed granulomas. Although leg ulcers have not previously been described as a part of Blau syndrome, we assume that the ulcerations in this case form part of Blau syndrome.     

A Hydroxyurea-induced Leg Ulcer

Hydroxyurea is a cytostatic agent that has recently become the drug of choice in the treatment of various myeloproliferative diseases. The cutaneous side effects of hydroxyurea include xerosis, hyperpigmentation, nail discoloration, and scaling. Leg ulcers have only rarely been reported in association with hydroxyurea treatment. A 75-year-old woman presented with leg ulcers, nail discoloration, and xerosis. The leg ulcers were refractory to conventional treatment. She had been taking oral hydroxyurea since being diagnosed with essential thrombocytosis in 2002. Hence, we suspected hydroxyurea-induced leg ulcers and discontinued her hydroxyurea treatment; the ulcers gradually healed thereafter. We present a rare case of hydroxyurea-induced leg ulcers in Korea.     

Connective tissue ulcers

Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren's syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers.     

Hydroxyurea-induced leg ulcers: is macroerythrocytosis a pathogenic factor?

Hydroxyurea is a common cancer chemotherapy agent that inhibits ribonucleotide reductase, an enzyme essential to DNA synthesis. It is considered the drug of choice in the treatment of chronic myelogenous leukemia and essential thrombocythemia. The occurrence of leg ulcers have been described in 8.5% of patients receiving continuous treatment with hydroxyurea, but the cause of this complication is unknown. We report two additional patients and suggest that macroerythrocytosis, which occurs in almost all the patients taking hydroxyurea, may be a pathogenic factor. Macroerythrocytosis can be considered as an 'acquired' blood dyscrasia, and similar leg ulcers have long been known to occur with certain hereditary blood dyscrasias, such as sickle cell anemia, thalasemia, and spherocytosis.     

Concurrent infection due to Shewanella putrefaciens and Mycobacterium marinum acquired at the beach

Infection with marine bacteria is uncommon. A patient with systemic lupus erthematosus who developed concurrent infection with shewanella putrefaciens and Mycobacterium marinum (M. marinum) is described. After bathing leg ulcers in sea water, severe cellulites of the left leg with necrotic areas and extensive bullae developed. Infection due to S. putrefaciens was confirmed and a long course of hospitalization, oral ciprofloxacin and skin grafting was required. During hospitalization, oral ciprofloxacin and skin grafting was required. During hospitalization subcutaneous nodules developed on the other leg. Biopsy revealed acid-fast bacilli and culture grew M. marinum . These lesions responded to rifampicin and cotrimoxazole. Patients with leg ulcers, peripheral vascular disease, diabetes, or receiving immunosuppressive drugs may acquire unusual infections after salt water exposure.     

Autoimmune ulceration of the leg

Autoimmune diseases are those disorders characterized by circulating autoantibodies or specific immune effector cells targeted towards a variety of self antigens. These disorders have traditionally included the so-called collagen vascular diseases, such as lupus erythematosus or scleroderma, certain vascultides, and a variety of immunologically mediated bullous diseases. The collagen vascular diseases and vasculitides, in particular, are occasionally associated with chronic, relapsing lower extremity ulcerations that may be refractory to traditional management schemes. Table 1 offers a classification of such disorders and provides a basis for the discussion which follows.

The frequency of these diseases among leg ulcer patients in general is difficult to gauge and depends in large part on the demographics of one's patient population as well as on efforts made to solicit such patients. For the last 18 months at the University of Pittsburgh, we have seen 303 new patients with leg ulcerations as part of a multidisciplinary wound healing and limb preservation clinic. Of this number, 20 patients (6.6%) have had leg ulcerations that were felt to be directly attributable to a variety of collagen vascular diseases or vasculitides. An understanding of these disorders and their potential to form ulcerations of different types is important in the differential diagnosis of patients with leg ulcerations in general, and management of these patients in particular.

The following is a discussion of the most important autoimmune disorders associated with leg ulcerations, with emphasis on practical aspects of diagnosis and management.     

Surrounding skin management in venous leg ulcers: A systematic review

ObjectivesChronic venous insufficiency may lead to the development of venous leg ulcers, the most common form of chronic wounds in the lower extremity. Key to venous leg ulcer care is the maintenance of healthy skin surrounding the ulcer, as failure to maintain skin integrity may influence the healing outcome. We thus reviewed the scientific literature looking for assessment and management instruments regarding this common but often neglected issue.MethodThe search included all studies published between 2000 and May 2019. Keywords used were: “peri-wound skin care”, “surrounding skin venous ulcers”, “surrounding skin management leg ulcers”, and “peri-lesional skin management”.ResultsManagement of moisture-balance with the selection of appropriate dressings is the most important target in surrounding-wound skin care. Moreover, contact dermatitis related to products and the dressings themselves is a neglected problem in patients with chronic leg ulcers which clinicians increasingly have to manage. The literature search revealed that there is an increasing interest in the use of noninvasive assessment tools in the field of wound care, and focusing on the surrounding-wound skin plays a role in assessing the potential of wound healing. Transepidermal water loss measurement (TEWL) and ultrasonography are two of the measurement techniques available.ConclusionThe integrity of the surrounding skin is necessary for wound healing, and appropriate management is needed to address this aspect which is part of an overall approach to treating wounds.     

Kutane Nebenwirkungen einer Hydroxyurea-Therapie bei Polycythaemia vera

A 68-year-old women with polycythemia vera was treated with hydroxyurea for 8 years and developed painful ulcers on her lower legs, multiple hypertrophic actinic keratoses and a squamous cell carcinoma. After discontinuing hydroxyurea therapy the leg ulcers resolved within 8 weeks. The hypertrophic actinic keratoses and squamous cell carcinoma were treated with cryotherapy and excision, respectively. Hydroxyurea induces a variety of cutaneous side effects such as painful leg ulcers and squamous cell carcinomas. Given the wide variety of adverse cutaneous side effects associated with long-term hydroxyurea therapy, the first step in management is to insure that physicians and patients are aware of the specific risks of this treatment. Patients under hydroxyurea therapy should be monitored closely by dermatologists to early detect and treat the cutaneous side effects.     

Cutaneous manifestations of hydroxyurea therapy in childhood: case report and review

Hydroxyurea is commonly used in the treatment of various myeloproliferative disorders. In conventional pediatric clinical practice, its use is limited to benign hematologic conditions such as sickle cell disease and thalassemia. Long-term hydroxyurea use is associated with various adverse mucocutaneous effects including hyperpigmentation, alopecia, leg ulcers, and lichenoid eruptions. We report a 10-year-old boy with chronic myelogenous leukemia who presented with hyperpigmentation of the skin and nails 3 months after the start of hydroxyurea therapy. Melanonychia of all 20 nails with involvement of all three mucocutaneous areas (skin, nails, and mucosa) at presentation was a unique feature in our patient. With the recently increasing pediatric use of hydroxyurea in a variety of disorders, its benign and not so uncommon cutaneous adverse effects are emphasized here.     

Unusual case of calciphylaxis associated with metastatic breast carcinoma

Calciphylaxis is a relatively rare disorder associated with calcification of small- and medium-sized blood vessels, progressive ischemic skin necrosis, and ulcerations. It is usually seen in patients with end-stage renal disease with secondary hyperparathyroidism and is occasionally seen in primary hyperparathyroidism, hypercalcemia of malignancy, and end-stage liver disease. We report an unusual case of calciphylaxis seen in association with metastatic breast carcinoma in the absence of end-stage renal or parathyroid disease. A 73-year-old woman presented with painful leg ulcers. Serum calcium levels and parathormone levels were within normal limits. Skin biopsies from the ulcers revealed small- to medium-sized subcutaneous arteries with calcification of the media. Some of the arteries were narrowed by fibrointimal hyperplasia and fibrin thrombi. Calcification of the subcutaneous fat, fat necrosis, and suppuration were also seen. Calciphylaxis associated with metastatic osteolytic breast carcinoma is rare. Although end stage renal disease with secondary hyperparathyroidism is the most common cause of calciphylaxis, this case demonstrates that less common conditions with normal serum calcium and parathormone levels may also cause it.     

The iliac compression syndrome. A cause of recurrent leg ulcers]

The iliac compression syndrome is a congenital vascular anomaly which is presumed to predispose to deep thrombophlebitis. In untreated cases, severe changes with edema of the lower limbs and leg ulcers which is resistent to treatment frequently develop. The diagnosis is established by pelvic phlebography and measurement of venous pressure during weight-bearing. A case is described in which vascular surgery resulted in healing of the ulcerations and considerable improvement of the remaining symptoms.     

Ambulatory skin grafting in leg ulcers: a feasibility study of 34 patients

OBJECTIVES: Despite the advent of modern dressings, management of leg ulcers remains a long costly process, particularly if no etiological treatment is possible. Autologous skin grafting is more and more widely used in this indication. The aim of this open single center noncomparative study was to analyze the feasibility of ambulatory procedures for skin grafting and the incidence of ambulatory care in a medical nursing clinic as an alternative to traditional hospitalization on total cost in this pathological condition. PATIENTS AND METHODS: Thirty-nine grafts were performed in 34 consecutive patients. No selection was made for etiology or duration of the leg ulcers. Three grafting techniques were used after debridement-cleansing: flap grafts for medium sized ulcers (29 cases), mesh grafts for large ulcers (6 cases) and patch grafts for small ulcers or ulcers with irregular contours (4 cases). The dressing was opened on day 5, nursing care was provided every 2 days and daily in case of infection. Percentage of healing was evaluated clinically on days 5, 15 and 30 then at months 3, 6 and 12. Photographs were taken. RESULTS: Four patients were lost to follow-up and one died. Among the 34 grafts assessed at 6 months, we obtained total healing in 56 p. 100, 75 p. 100 healing in 6 p. 100, 50 p. 100 healing in 9 p. 100 and failure in 29 p. 100. Healing rates were those expected for arterial ulcers and necrotic angiodermas. For venous leg ulcers, the rate of total healing was only 30 p. 100 at 6 months and 43 p. 100 at 1 year. Outcome depended on duration of the lesion and not on the type of skin graft or patient age. DISCUSSION: This prospective study reports outcome of ambulatory skin grafting in a large representative sample of patients with leg ulcers of various etiologies. The less favorable outcome for venous ulcers can be explained by the duration of the ulcerations and infection in these often neglected lesions. The risk of graft displacement, contact eczema, and infection must be recognized for early treatment. There were no cases with general complications. This ambulatory technique has the enormous advantage of limiting the risk of hospital-related problems in this elderly population and of reducing overall cost of care for leg ulcers, and finally of limiting the risk of recurrence by regular post-graft follow-up in a specialized center and by treatment of the causal disease.