Cutaneous Ulcer Caused by Apixaban Treatment Is Resolved after Replacement with Dabigatran.

Nowadays, novel oral anticoagulants (NOACs) have shown improved safety profile and efficacy compared to vitamin K antagonists in the prevention of thromboembolic events occurring during different pathological conditions. However, there are concerns and safety issues, mostly related to adverse events following interactions with other drugs, in real-world practice. We report the case of an 83-year-old woman who developed a non-bleeding leg ulcer not caused by trauma or other evident pathological conditions after 10 days of treatment with apixaban 5 mg/q.d. She was switched from apixaban to dabigatran and the leg ulcer rapidly improved and completely cicatrized in 40 days. The resolution of the ulcer and the toleration of dabigatran therapy suggest an apixaban-specific reaction; however, the pathological mechanism of ulcer onset is currently unclear. Careful evaluation of hospital databases of Molise region (Southern Italy) hospitals identified two similar cases between 2019 and 2021. These cases underline the necessity of careful post-marketing surveillance, considering the rapidly increasing number of patients treated with NOACs and patient's risk factors such as old age, high polypharmacy rate, co-morbidities, and peculiar genetic background related to NOACs pharmacokinetic features.

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.

Chronic Myeloid Leukaemia with Sudden Bilateral Deafness and Leg Ulcer Associated with Hydroxyurea Therapy.

Deafness occurs rarely in patients with chronic myeloid leukaemia. Hydroxyurea-induced leg ulcer has been found in patients on long-term hydroxyurea therapy. We present a 53 year old man who developed spontaneous bilateral deafness shortly after he was diagnosed with chronic myeloid leukaemia and subsequently developed hydroxyurea induced leg ulcer in the course of treatment. A 53 year-old male presented to our clinic with six months history of left abdominal mass, associated with easy satiety, occasional fever, night sweats, loss of appetite, weight loss, easy fatiguability and bilateral leg swelling. Physical examination showed a middle-aged man in no obvious distress, afebrile, anicteric, pale, with no peripheral lympadenopathy but had bilateral pitting pedal edema to the lower third. There was no significant finding on the chest. Abdominal examination showed hepatosplenomagaly. Full blood count showed anaemia, hyperleucocytosis and thrombocytosis. Peripheral blood film and bone marrow aspiration examinations were in keeping with chronic myeloid leukaemia. The BCR/ABL-1 transcript was negative, thus he was started on hydroxyurea in addition to other supportive treatment. Before commencement of hydroxyurea therapy, he spontaneously developed bilateral sensorineural deafness. Subsequently, he also developed leg ulcers, having been on hydroxyurea therapy for seven years which healed within eight weeks on discontinuation of hydroxyurea. Spontaneous deafness can occur in patients with chronic myeloid leukaemia due to hyperleucocytosis and urgent cytoreduction may help to prevent this complication. In addition, leg ulcer due to long-term hydroxyurea therapy can occur and usually do not respond to the conventional treatment but discontinuation of hydroxyurea.

La surdité survient rarement chez les patients atteints de leucémie myéloïde chronique. Un ulcère de jambe induit par l'hydroxyurée a été trouvé chez des patients sous traitement à long terme par hydroxyurée. Nous présentons un homme de 53 ans qui a développé une surdité bilatérale spontanée peu de temps après avoir été diagnostiqué avec une leucémie myéloïde chronique et qui a ensuite développé un ulcère de jambe induit par l'hydroxyurée au cours du traitement. Un homme de 53 ans s'est présenté à notre clinique avec des antécédents de six mois de masse abdominale gauche, associée à une satiété facile, une fièvre occasionnelle, des sueurs nocturnes, une perte d'appétit, une perte de poids, une fatiguabilité facile et un gonflement bilatéral des jambes. L'examen physique a montré un homme d'âge moyen sans détresse évidente, apébrile, anictérique, pâle, sans lympadénopathie périphérique mais présentant un œdème bilatéral de la pédale par piqûres au tiers inférieur. Il n'y avait aucune découverte significative sur la poitrine. L'examen abdominal a montré une hépatosplénomagie. Une formule sanguine complète a montré une anémie, une hyperleucocytose et une thrombocytose. Les examens de frottis sanguin périphérique et d'aspiration de la moelle osseuse étaient conformes à la leucémie myéloïde chronique. Le transcrit BCR / ABL-1 était négatif, il a donc commencé à prendre de l'hydroxyurée en plus d'un autre traitement de soutien. Avant le début du traitement par hydroxyurée, il a développé spontanément une surdité neurosensorielle bilatérale. Par la suite, il a également développé des ulcères de jambe, après avoir été sous traitement à l'hydroxyurée pendant sept ans, qui ont guéri en huit semaines à l'arrêt de l'hydroxyurée. Une surdité spontanée peut survenir chez les patients atteints de leucémie myéloïde chronique due à une hyperleucocytose et une cytoréduction urgente peut aider à prévenir cette complication. De plus, un ulcère de jambe dû à un traitement à long terme par hydroxyurée peut survenir et ne répond généralement pas au traitement conventionnel mais l'arrêt de l'hydroxyurée.

Programmed cell death protein 1 inhibitor-induced recalcitrant mixed small and medium vessel vasculitis.

Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor, has been known to be associated with several adverse reactions, including immune related adverse events. In less than one percent of patients, PD1 inhibitors have been linked to the development of connective tissue disease. Patients with previously known connective tissue disease are hypothesized to be at increased risk of flares in as many as 40% of cases. A 70-year-old man with a past medical history significant for rheumatoid arthritis in remission and stage IV lung adenocarcinoma presented to the dermatology clinic after one cycle of nivolumab and eight cycles of pembrolizumab exhibiting worsening, painful bilateral lower extremity ulcers for approximately one month. On the lower legs, three large black retiform eschars and bullous purpuric plaques were observed. Vasculitis is a rare complication of PD1 inhibitor therapy, with the majority of cases reported in literature either medium vessel or large vessel vasculitis. Only glucocorticoids have proven effective for PD1-induced vasculitis and these patients generally require multi-specialty management.

Polycythemia vera and hydroxyurea resistance/intolerance: a monocentric retrospective analysis.

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed.

Leg ulcer induced by hydroxycarbamide in sickle cell disease: What is the therapeutic impact?

Major sickle cell disease syndrome (SCD) is a set of potentially serious and disabling constitutional haemoglobin pathologies characterised by chronic haemolysis and vaso-occlusion phenomena. If expression takes the form of acute vaso-occlusive crisis, SCD is currently considered to be a chronic systemic pathology, primarily associated with vasculopathy and ischaemia-reperfusion phenomena. The haemolytic aspect of the disease may be associated with endothelial dysfunctional complications, including leg ulcers, which are a classic spontaneous complication of major SCD. Their frequency, all aetiologies combined, varies considerably according to the series under consideration. Hydroxycarbamide has become the standard treatment for some SCD phenotypes, but has classically been described as one of the causes of leg ulcer. This causality is widely debated and is still difficult to establish because it is a specific complication of the disease. Comorbidity factors (eg, iron deficiency) are also often implicated as causal or aggravating factors so research into all the potential aetiologies of leg ulcers in a sickle cell patient must be exhaustive. We discuss the aetiologies of a leg ulcer in a patient treated by hydrocarbamide for major SCD. The imputation of the drug was established, followed by a marrow allograft in this patient.

[Necrotic leg ulcers after topical application of chlormethine]. / Ulcères de jambe nécrotiques après application locale de chlorméthine.

BACKGROUND: Topical chlormethine has been widely used in the early stages of mycosis fungoides for many years. Cutaneous reactions (skin irritation and itch) are the most frequent adverse effects. Herein we report a rare side effect: severe necrotic leg ulcers. PATIENTS AND METHODS: An 82-year-old woman with a history of high blood pressure developed hyperalgesic necrotic ulcers on the lower limbs following local trauma one month after initiation of topical chlormethine (Valchlor®) to treat mycosis fungoides. Aetiological examination showed moderate peripheral arterial disease which, while constituting an aggravating factor, did not account fully for these skin ulcers. Moreover, drug-induced ulcer was suspected on account of the chronology. Dermal corticoids and topical treatment were prescribed in place of chlormethine and led to a favourable outcome. CONCLUSION: Incrimination of chlormethine was based on the chronological and semiological criteria. This is the first published case of leg ulceration induced by Valchlor®.

Case Report of Calciphylaxis Secondary to Calcium and Vitamin D3 Supplementation.

BACKGROUND: Calciphylaxis is a rare disorder that is very unusual outside the setting of end-stage kidney disease. CASE SUMMARY: A 64-year-old woman with normal renal function presented with painful leg ulcers. She had previously received 300 000 IU of vitamin D3 followed by daily calcium and vitamin D3 supplementation. A skin biopsy was consistent with calciphylaxis, and she was treated with sodium thiosulphate infusions and wound debridement. CONCLUSION: Calcium and vitamin D3 supplements are widely prescribed. We report a case of calciphylaxis triggered by calcium and vitamin D3 supplementation in a patient with none of the typical risk factors. Our patient had an excellent response to treatment with sodium thiosulphate.

[Leg ulcers occurring under tyrosine kinase inhibitor therapy (sunitinib, nilotinib)]. / Ulcères des membres inférieurs développés sous inhibiteurs de tyrosine kinase (sunitinib, nilotinib).

BACKGROUND: Certain anticancer drugs are known to induce leg ulcers, mainly chemotherapy agents such as hydroxyurea. We report 2 cases of leg ulcers in cancer patients treated with the tyrosine kinase inhibitors, sunitinib and nilotinib, and we discuss the role of these treatments in the pathogenesis of leg ulcers. PATIENTS AND METHODS: Case 1. A 62-year-old patient on sunitinib for intrahepatic cholangiocarcinoma developed a lesion on her right foot. The vascular evaluation was negative. After progressive worsening, sunitinib was stopped and healing was observed within a few months. Case 2. A 83-year-old patient had been treated for chronic myeloid leukemia since 2005. Nilotinib was introduced in 2009. Peripheral arterial revascularization was required in May 2013. A few months later, worsening was noted with the onset of ulceration and necrosis of the third toe. Further revascularisation surgery was performed, and nilotinib was suspended and antiplatelets introduced. Healing occurred a few months later. DISCUSSION: Many skin reactions have been described in patients on nilotinib and sunitinib, but few publications report the development of de novo ulcers in patients without risk factors. The pathophysiology of the development of ulcers in patients receiving tyrosine kinase inhibitors is not clear, and probably involves several mechanisms of action. The increasing use of this type of treatment could lead to an upsurge in the incidence of vascular complications. CONCLUSION: We report two cases of leg ulcers developing in patients on tyrosine kinase inhibitors and raise the question of causal implication of these treatments in the pathogenesis of ulcers.

A multidisciplinary team approach to hydroxyurea-associated chronic wound with squamous cell carcinoma.

Hydroxyurea (HU) has been shown to induce a variety of cutaneous adverse reactions, including severe leg ulcers. This report shows a successful treatment of a HU-induced chronic wound associated with squamous cell carcinomas (SCC). A 62-year-old patient affected with polycythemia vera and treated with HU for 10 years, presented with a non healing ulcer on a left heel. The patient gave a history of suffering from the wound for over 2 years. Biopsy showed evidence of invasive SCC. The patient underwent Mohs surgery and a greater saphenous vein ablation for polycythemia vera-associated vascular complications. The wound consistently decreased in size following successive debridements and coverage with human skin equivalent. The wound healed completely after a 6-month period. A multidisciplinary team approach to the treatment proved to be effective resulting in healing of this multifactorial chronic ulcer.

Clinical follow-up of hydroxyurea-treated adults with sickle cell disease.

Hydroxyurea-derived clinical and biological benefits and safety were retrospectively studied for 123 adult patients from 2 sickle cell disease referral centers during a total follow-up of 654 patient-years and total hydroxyurea exposure of 549 patient-years. Fifty-six adverse events occurred (incidence: 12%/patient-year), with leg ulcers being the most frequent. Adverse events could arise at any time and were usually reversible. No malignancy was observed. Clinical and biological benefits of our cohort were similar to those previously reported. Based on this relatively long retrospective study, the risk/benefit ratio for moderate hydroxyurea doses was satisfactory.

Nicorandil-induced leg ulceration without mucosal involvement.

We report a case of leg ulceration occurring in a patient without mucosal ulcers, in whom nicorandil appeared to be the main aetiological factor. Having failed to heal on compression therapy, the ulcer rapidly improved and healed after the discontinuation of nicorandil. Most cases of nicorandil-induced ulcers reported in the literature develop on mucosal surfaces, including oral, vulval, perianal and peristomal ulcers. There are rare reports of cutaneous ulceration attributable to nicorandil, occurring concurrently with mucosal ulcers. To our knowledge, this is the first case of nicorandil-induced leg ulceration affecting the skin without mucosal involvement.

[Medications. A rare cause for leg ulcers]. / Medikamente. Eine seltene Ursache für ein Ulcus cruris.

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.

[Necrotic leg ulcers induced by vitamin K antagonists: five cases]. / Ulcères de jambe nécrotiques induits par les anti-vitamines K : à propos de cinq cas.

BACKGROUND: Vitamin K antagonists (VKAs) are widely used in thromboembolic diseases. We report five cases of necrotic leg ulcers having a particularly severe course and in which withdrawal of VKA treatment alone enabled healing. CASE REPORTS: Five patients presented with necrotic leg ulcers clinically evocative of necrotic angiodermatitis or vasculitis. Histological features were variable, including inconstantly inflammatory lesions (leukocytoclastic vasculitis) and microthrombosis. None of the patients had laboratory signs of autoimmune disease. Healing occurred in all patients only after withdrawal of VKA therapy (fluindione or acenocoumarol). Associated vascular diseases included superficial venous, distal arterial insufficiency and postphlebitic disease. In three cases, thrombotic factors were observed: hyperhomocysteinaemia or heterozygous Factor V Leiden mutation. DISCUSSION: Although the causative role of VKAs is based solely on chronological criteria, this potential side effect deserves publication because of its practical therapeutic consequences. The physiopathological mechanisms accounting for the role of VKAs, including immunoallergic phenomena and, above all, microcirculatory thrombotic processes, are hypothetical and not universally accepted.

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients.

Hydroxyurea (HU) is frequently given as treatment for myelofibrosis (MF), but data on its efficacy and tolerability are scarce. The results of HU therapy were evaluated in 40 patients with hyperproliferative manifestations of primary (n = 32), post-polycythemia vera (n = 6), or post-essential thrombocythemia (n = 2) myelofibrosis. Median interval between diagnosis and HU start was 6.2 months (range 0-141.7). Reasons for treatment were constitutional symptoms (55%), symptomatic splenomegaly (45%), thrombocytosis (40%), leukocytosis (28%), pruritus (10%), and bone pain (8%). The starting dose was 500 mg/day, subsequently adjusted to the individual efficacy and tolerability. Response was bone pain 100%, constitutional symptoms 82%, pruritus 50%, splenomegaly 40%, and anemia 12.5%. According to the International Working Group for Myelofibrosis Research and Treatment criteria, clinical improvement was achieved in 16 patients (40%). Median duration of response was 13.2 months (range 3-126.2). Worsening of the anemia or appearance of pancytopenia were observed in 18 patients, requiring administration of erythropoietin-stimulating agents (n = 17) and/or danazol (n = 9). Oral or leg ulcers appeared in five patients and one had gastrointestinal symptoms. HU is an effective and generally well-tolerated therapy for the hyperproliferative manifestations of MF. The accentuation of the anemia often induced by HU is usually manageable with concomitant treatment.