We report 2 cases of squamous dysplasia associated with long-term hydroxyurea therapy. The association between hydroxyurea and multiple aggressive squamous cell carcinomas, Bowen's disease, and multiple actinic keratoses in sun-exposed areas after a variable latency period has been increasingly reported. On reviewing the literature, 17 cases were identified and are reviewed, with emphasis on possible pathogenetic mechanisms of carcinogenicity. Squamous dysplasia, a precursor state to a more aggressive condition of multiple squamous cell carcinomas in photoexposed areas, should be added to the well-known cutaneous toxicities of hydroxyurea therapy.

https://www.jaad.org/article/S0190-9622(03)04570-5/pdf

Hydroxyurea-associated squamous dysplasia.

The 'old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NFkappaB and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-alpha and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not 'clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes.

Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea

Background The development of painful leg ulcers in the ankle area is a rare and only partially described complication in patients receiving high-dose, long-term hydroxyurea treatment for myeloproliferative diseases. Several reports have described treatments for chronic wound management with this type of lesion. Observations We describe 2 patients who were diagnosed as having hydroxyurea-induced leg ulcers that were successfully treated with a freeze-dried sponge containing oxidized regenerated cellulose and bovine purified collagen. This dressing is able to modulate the activity of proteases such as plasmin, neutrophil-derived elastase, and matrix metalloproteinase by physically entrapping them and thus inhibiting their activity. Conclusion This case demonstrates that topical application of a matrix metalloproteinase modulator can be a successful and safe treatment option for patients with hydroxyurea-induced recalcitrant leg ulcers.

https://jamanetwork.com/journals/jamadermatology/articlepdf/654400/dob70028_1310_1313.pdf

Hydroxyurea-Induced Leg Ulcers Treated With a Protease-Modulating Matrix

Zusammenfassung: Die „alten Favoriten”, die zur Therapie entzundlicher Erkrankungen verwendet wurden, und somit die ursprunglichen Immunmodulatoren sind, umfassen Glukokortikoide, Azathioprin, Methotrexat und Hydroxyharnstoff. Glukokortikoide zahlen noch immer zu den wirksamsten antiphlogistischen Medikamenten, da sie mehrere unterschiedliche intrazellulare Vorgange beeinflussen und somit viele Komponenten hemmen, die an Entzundungs- und Immunreaktionen beteiligt sind. Sie binden sich an intrazellulare Glukokortikoid-Rezeptoren, welche sie in den Kern transportieren. Hier kann sich der Rezeptor/Steroid-Komplex an viele Gene binden, die Glukokortikoid-Response-Elements in ihrer Promoter-Region enthalten. Der Komplex kann mit Transkriptionsfaktoren wie NFκB und AP-1 in Wechselwirkung treten und deren Aktivierung hemmen, wodurch die Aktivierung vieler Gene gehemmt wird, die Immun-Effektor- und proinflammatorische Zytokine kodieren. Proteinkinasen, die an der intrazellularen Signalgebung beteiligt sind, werden ebenfalls direkt aktiviert, was zur Phosphorylierung verschiedener Zielmolekule fuhrt. Unter ihnen ist Annexin (AXA)-1 von erheblicher Bedeutung zur Hemmung der Bildung von Prostaglandinen. Die Wirkung von Azathioprin verlauft vollig anders. Es hemmt die Biosynthese sowohl der Purine als auch der DNS. Dies fuhrt zu einer verringerten Proliferation von B- und T-Lymphozyten, verringerten Immun-Effektor-Mechanismen und verringerter Rekrutierung von mononuklearen Zellen wie Monozyten im Bereich entzundlicher Reaktionen. Methotrexat blockiert ebenfalls die DNS-Synthese und somit die Zellproliferation, induziert jedoch gleichzeitig die Freisetzung von Adenosin. Das hemmt die Chemotaxis polymorphkerniger Neutrophiler und die Freisetzung wesentlicher Zytokine wie TFN-α und Interleukine 6 und 8. Hydroxyharnstoff hemmt ebenfalls die DNS-Synthese und hat inhibitorische Wirkungen auf die Proliferation von Lymphozyten und moglicherweise Keratinozyten. Auch wenn viele neue Substanzen mit erheblich groserer Selektivitat zur klinischen Anwendung gelangen, hat diese Gruppe alter Medikamente noch immer eine absolut zentrale Stellung in der Gruppe der verwendeten Substanzen. Ihre Bedeutung liegt in der Tatsache, dass sie keine „clean drugs” mit engem Wirkungsbereich sind, sondern eine Reihe von Mechanismen hemmen, die an Immun- und Entzundungsvorgangen beteiligt sind.



Summary: The “old favourites” used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that contain glucocorticoid response elements in the promoter regions. The complex may interact with transcription factors including NFκB and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting generation of prostaglandines. Azathioprine works very differently, inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-α and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly keratinocytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not “clean” drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes.

Traditionelle Therapien: Glukokortikoide, Azathioprin, Methotrexat, Hydroxyharnstoff

This clinicopathologic study involved 42 cases of leukemia cutis: 3 of acute lymphocytic leukemia (ALL), 16 of chronic lymphocytic leukemia (CLL), 12 of acute granulocytic leukemia (AGL), 3 of chronic granulocytic leukemia (CGL), 5 of acute monocytic leukemia (AML), and 3 of acute myelomonocytic leukemia (AMML). The clinical appearance of leukemia cutis included papules, macules, plaques, nodules, ecchymoses, palpable purpura, and ulcerative lesions, and these were seen in all types of leukemias. Gingival hypertrophy was seen only in AML or AMML, and erythroderma and bullous lesions of leukemic infiltration were observed only in CLL. Cutaneous leukemic lesions may be concomitant with or preceding the diagnosis of systemic leukemia. Therefore, skin biopsy may be helpful in detecting the leukemia and may facilitate the work-up. Leukemia cutis probably is a dissemination of systemic leukemia to the skin, and the demonstration of leukemia in skin is associated with a very poor prognosis.

https://www.jaad.org/article/S0190-9622(84)70145-9/pdf

Clinicopathologic correlations in leukemia cutis.

The clinical course of a patient with chronic granulocytic leukemia cutis associated with myeloid metaplasia is described. Cutaneous manifestations of leukemia appeared only at the sites of bone marrow aspiration and vena puncture. Radiotherapy to both spleen and skin and chemotherapy with busulfan failed to control spreading cutaneous lesions. Treatment with hydroxyurea was followed by a marked reduction in spleen size, a decrease in white cell count and healing of the skin lesions.

Chronic granulocytic leukemia cutis treated with hydroxyurea. Report of a case.

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Chronic granulocytic leukemia cutis treated with hydroxyurea. Report of a case.