Dermatologic Therapy, Vol. 26, 2013, 493–495 Printed in the United States · All rights reserved
© 2013 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Periungual and subungual pyogenic granuloma following anti-TNF-a therapy: is it the first case? Cataldo Patruno, Nicola Balato, Teresa Cirillo, Maddalena Napolitano & Fabio Ayala Department of Dermatology, University of Naples Federico II, Naples, Italy
ABSTRACT: Tumor necrosis factor-alpha (TNF-a) antagonists have advanced treatment of psoriasis and other chronic inflammatory diseases but are not free of adverse effects. Pyogenic granuloma is yet described in literature as a dermatological side effect of multiple drugs such as retinoids, antiretroviral, and antineoplastic drugs but, to the best of our knowledge, it has never been reported among the adverse skin reactions following anti-TNF-a therapy. We report on a 20-year-old Caucasian man with psoriatic arthritis who developed multiple eruptive periungual and subungual pyogenic granulomas following treatment with TNF-a antagonist etanercept. KEYWORDS: etanercept, psoriasis, pyogenic granuloma
The use of tumor necrosis factor-alpha (TNF-a) antagonists has deeply improved clinical management of psoriasis and other chronic inflammatory diseases, but acute and chronic adverse reactions are becoming increasingly recognized. We present a case of pyogenic granuloma (PG) occurring in a patient with psoriatic arthritis (PsA) following antiTNF-a treatment. A 20-year-old Caucasian man suffering from PsA developed multiple easily bleeding periungual and subungual granulomas during etanercept treatment (Enbrel®; Pfizer Italia Srl, Latina, Italy). The patient had a 3-year history of arthritis affecting Address correspondence and reprint requests to: Maddalena Napolitano, MD, Department of Dermatology – University of Naples Federico II, Via Pansini, 5, 80131 Napoli, Italy, or email: [email protected]. Conflict of interest: The authors report no conflicts of interest.
several joints; mild psoriasis was limited to the scalp and toenails. He had been treated by methotrexate, with poor results. Switching from methotrexate to etanercept (subcutaneous injection of 50 mg twice weekly, followed by 50 mg once weekly) led to improvement of both arthropathy and psoriasis. An area of granulation tissue appeared in the nail sulcus of both toes after 3 months of treatment. There was neither a specific episode of trauma to feet nor a past history of paronychia or PG. Clinical examination (FIG. 1) revealed fleshy, hemorrhagic papules, sized from 2 to 6 mm, some crusts and erosions arising bilaterally from the periungual and subungual region of the first toe. Fungal and bacterial cultures were negative. All routine laboratory tests (serum chemistry, hematology, urinalysis) and antinuclear antibody profile did not show abnormalities.
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Patruno et al.
A
B
FIG. 1. Pyogenic granuloma. (A) Clinical manifestation in both toes and (B) detail of the lesion involving the periungual and subungual region of the left first toe.
Histopathological features showed a lobulated proliferation of capillary vessels circumscribed in edematous stroma and a dense mixed perivascular cellular infiltrate, thus confirming the clinical diagnosis of PG. Our choice was to do not discontinue etanercept. Therapy with topical high-potency corticosteroid and mupirocin for 20 days was unsuccessful. Surgical curettage was performed, but 2 months later, PG recurred. In our patient, we supposed the underlying PsA or a cutaneous reaction to etanercept as the most likely triggers for PG onset. The lack of previous episodes of PG and its multiple appearances after 3 months of treatment with etanercept seem to favor the diagnosis of a cutaneous adverse drug reaction. To the best of our knowledge, PG has never been reported among the adverse reactions following anti-TNF-a treatment. On the other hand, PG is
494
described in literature as a dermatological side effect of other drugs. It is well known that systemic retinoids (isotretinoin, etretinate) may occasionally trigger PG. It may also appear on the application site of topical retinoids (tretinoin, tazarotene) (1). Antiretroviral therapy (indinavir, lamivudine) has been associated with the development of PG, mainly of the first toe (1). In addition, PG develops during erythropoietin treatment or antineoplastic drugs (1–5), namely, 5-fluorouracil, capecitabine, mitoxantrone, docetaxel, epidermal growth factor receptor inhibitors (EGFRIs: gefitinib, erlotinib), rituximab, and mammalian target of rapamycin (mTOR) inhibitors (mTORIs: everolimus, temsirolimus). The most consolidated theory attempting to explain the potential mechanism for drug-induced PG has been formulated for retinoids (1,2). These compounds decrease the attachments between keratinocytes (onychoclasis). The subsequent desquamation at the undersurface of the proximal nail fold may act as a foreign body in the lateral nail groove inciting an inflammatory response. Moreover, retinoids show angiogenic properties and are able to inhibit collagenases and gelatinases in vitro. The onset of PG during EGFRIs treatment could reflect a retinoid-like effect of EGFRIs including the development of desquamation of the nail fold with entrapping of squames between the nail plate and the surrounding epidermis, followed by a foreign body reaction (3). EGF cellular signaling pathway has also been shown to be regulated through mTOR and this could explain the appearance of PG following mTOR inhibitor treatment (5). In the same way, TNF-a-induced cytokine production is mediated by mTOR signaling in vitro (6). Clinical trials documented onychoclasis as an adverse event at least possibly related to anti-TNF-a drug adalimumab (7). We speculate that a similar phenomenon could be supposed for other anti-TNF-a, such as etanercept. The development of PG might also reflect the effects of angiogenic factors, such as vascular endothelial growth factor (VEGF), that are overexpressed in this lesion. The actions of retinoids on VEGF expression in vitro are known to depend on culture conditions displaying inhibition as well as stimulation (3). TNF-a is able to induce keratinocyte expression of EGF and EGFR family, that, in turn, up-regulate VEGF production (8,9). We report a case of PG likely due to an antiTNF-a drug. Notably, quality of life (QoL) may be compromised in patients with recurrent PG of the toes. This aspect is of the outmost importance in patients with preexisting high impairment of QoL,
Etanercept and pyogenic granuloma
like those affected with psoriasis or PsA because it might potentially lead to incompliance or termination of anti-TNF-a therapy.
References 1. Piraccini BM, Bellavista S, Misciali C, Tosti A, de Berker D, Richert B. Periungual and subungual pyogenic granuloma. Br J Dermatol 2010: 163: 941–953. 2. Gaudiello F, Scalvenzi M, Gallo L, Balato N. Excess granulation tissue and hair loss following acitretin. Dermatology Reports 2011: 3: e2. 3. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005: 16: 1425– 1433. 4. Wollina U. Multiple eruptive periungual pyogenic granulomas during anti-CD20 monoclonal antibody therapy for rheumatoid arthritis. J Dermatol Case Rep 2010: 4: 44–46.
5. Sibaud V, Dalenc F, Mourey L, Chevreau C. Paronychia and pyogenic granuloma induced by new anticancer mTOR inhibitors. Acta Derm Venereol 2011: 91: 584–585. 6. Young CN, Koepke JI, Terlecky LJ, Borkin MS, Boyd Savoy L, Terlecky SR. Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol 2008: 128: 2606–2614. 7. Adalimumab datasheet (Humira®; Abbott). 2011. 8. Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008: 128: 1365–1374. 9. Trompezinski S, Berthier-Vergnes O, Denis A, Schmitt D, Viac J. Comparative expression of vascular endothelial growth factor family members, VEGF-B, -C and -D, by normal human keratinocytes and fibroblasts. Exp Dermatol 2004: 13: 98–105.
495
© 2013 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Periungual and subungual pyogenic granuloma following anti-TNF-a therapy: is it the first case? Cataldo Patruno, Nicola Balato, Teresa Cirillo, Maddalena Napolitano & Fabio Ayala Department of Dermatology, University of Naples Federico II, Naples, Italy
ABSTRACT: Tumor necrosis factor-alpha (TNF-a) antagonists have advanced treatment of psoriasis and other chronic inflammatory diseases but are not free of adverse effects. Pyogenic granuloma is yet described in literature as a dermatological side effect of multiple drugs such as retinoids, antiretroviral, and antineoplastic drugs but, to the best of our knowledge, it has never been reported among the adverse skin reactions following anti-TNF-a therapy. We report on a 20-year-old Caucasian man with psoriatic arthritis who developed multiple eruptive periungual and subungual pyogenic granulomas following treatment with TNF-a antagonist etanercept. KEYWORDS: etanercept, psoriasis, pyogenic granuloma
The use of tumor necrosis factor-alpha (TNF-a) antagonists has deeply improved clinical management of psoriasis and other chronic inflammatory diseases, but acute and chronic adverse reactions are becoming increasingly recognized. We present a case of pyogenic granuloma (PG) occurring in a patient with psoriatic arthritis (PsA) following antiTNF-a treatment. A 20-year-old Caucasian man suffering from PsA developed multiple easily bleeding periungual and subungual granulomas during etanercept treatment (Enbrel®; Pfizer Italia Srl, Latina, Italy). The patient had a 3-year history of arthritis affecting Address correspondence and reprint requests to: Maddalena Napolitano, MD, Department of Dermatology – University of Naples Federico II, Via Pansini, 5, 80131 Napoli, Italy, or email: [email protected]. Conflict of interest: The authors report no conflicts of interest.
several joints; mild psoriasis was limited to the scalp and toenails. He had been treated by methotrexate, with poor results. Switching from methotrexate to etanercept (subcutaneous injection of 50 mg twice weekly, followed by 50 mg once weekly) led to improvement of both arthropathy and psoriasis. An area of granulation tissue appeared in the nail sulcus of both toes after 3 months of treatment. There was neither a specific episode of trauma to feet nor a past history of paronychia or PG. Clinical examination (FIG. 1) revealed fleshy, hemorrhagic papules, sized from 2 to 6 mm, some crusts and erosions arising bilaterally from the periungual and subungual region of the first toe. Fungal and bacterial cultures were negative. All routine laboratory tests (serum chemistry, hematology, urinalysis) and antinuclear antibody profile did not show abnormalities.
493
Patruno et al.
A
B
FIG. 1. Pyogenic granuloma. (A) Clinical manifestation in both toes and (B) detail of the lesion involving the periungual and subungual region of the left first toe.
Histopathological features showed a lobulated proliferation of capillary vessels circumscribed in edematous stroma and a dense mixed perivascular cellular infiltrate, thus confirming the clinical diagnosis of PG. Our choice was to do not discontinue etanercept. Therapy with topical high-potency corticosteroid and mupirocin for 20 days was unsuccessful. Surgical curettage was performed, but 2 months later, PG recurred. In our patient, we supposed the underlying PsA or a cutaneous reaction to etanercept as the most likely triggers for PG onset. The lack of previous episodes of PG and its multiple appearances after 3 months of treatment with etanercept seem to favor the diagnosis of a cutaneous adverse drug reaction. To the best of our knowledge, PG has never been reported among the adverse reactions following anti-TNF-a treatment. On the other hand, PG is
494
described in literature as a dermatological side effect of other drugs. It is well known that systemic retinoids (isotretinoin, etretinate) may occasionally trigger PG. It may also appear on the application site of topical retinoids (tretinoin, tazarotene) (1). Antiretroviral therapy (indinavir, lamivudine) has been associated with the development of PG, mainly of the first toe (1). In addition, PG develops during erythropoietin treatment or antineoplastic drugs (1–5), namely, 5-fluorouracil, capecitabine, mitoxantrone, docetaxel, epidermal growth factor receptor inhibitors (EGFRIs: gefitinib, erlotinib), rituximab, and mammalian target of rapamycin (mTOR) inhibitors (mTORIs: everolimus, temsirolimus). The most consolidated theory attempting to explain the potential mechanism for drug-induced PG has been formulated for retinoids (1,2). These compounds decrease the attachments between keratinocytes (onychoclasis). The subsequent desquamation at the undersurface of the proximal nail fold may act as a foreign body in the lateral nail groove inciting an inflammatory response. Moreover, retinoids show angiogenic properties and are able to inhibit collagenases and gelatinases in vitro. The onset of PG during EGFRIs treatment could reflect a retinoid-like effect of EGFRIs including the development of desquamation of the nail fold with entrapping of squames between the nail plate and the surrounding epidermis, followed by a foreign body reaction (3). EGF cellular signaling pathway has also been shown to be regulated through mTOR and this could explain the appearance of PG following mTOR inhibitor treatment (5). In the same way, TNF-a-induced cytokine production is mediated by mTOR signaling in vitro (6). Clinical trials documented onychoclasis as an adverse event at least possibly related to anti-TNF-a drug adalimumab (7). We speculate that a similar phenomenon could be supposed for other anti-TNF-a, such as etanercept. The development of PG might also reflect the effects of angiogenic factors, such as vascular endothelial growth factor (VEGF), that are overexpressed in this lesion. The actions of retinoids on VEGF expression in vitro are known to depend on culture conditions displaying inhibition as well as stimulation (3). TNF-a is able to induce keratinocyte expression of EGF and EGFR family, that, in turn, up-regulate VEGF production (8,9). We report a case of PG likely due to an antiTNF-a drug. Notably, quality of life (QoL) may be compromised in patients with recurrent PG of the toes. This aspect is of the outmost importance in patients with preexisting high impairment of QoL,
Etanercept and pyogenic granuloma
like those affected with psoriasis or PsA because it might potentially lead to incompliance or termination of anti-TNF-a therapy.
References 1. Piraccini BM, Bellavista S, Misciali C, Tosti A, de Berker D, Richert B. Periungual and subungual pyogenic granuloma. Br J Dermatol 2010: 163: 941–953. 2. Gaudiello F, Scalvenzi M, Gallo L, Balato N. Excess granulation tissue and hair loss following acitretin. Dermatology Reports 2011: 3: e2. 3. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005: 16: 1425– 1433. 4. Wollina U. Multiple eruptive periungual pyogenic granulomas during anti-CD20 monoclonal antibody therapy for rheumatoid arthritis. J Dermatol Case Rep 2010: 4: 44–46.
5. Sibaud V, Dalenc F, Mourey L, Chevreau C. Paronychia and pyogenic granuloma induced by new anticancer mTOR inhibitors. Acta Derm Venereol 2011: 91: 584–585. 6. Young CN, Koepke JI, Terlecky LJ, Borkin MS, Boyd Savoy L, Terlecky SR. Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol 2008: 128: 2606–2614. 7. Adalimumab datasheet (Humira®; Abbott). 2011. 8. Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008: 128: 1365–1374. 9. Trompezinski S, Berthier-Vergnes O, Denis A, Schmitt D, Viac J. Comparative expression of vascular endothelial growth factor family members, VEGF-B, -C and -D, by normal human keratinocytes and fibroblasts. Exp Dermatol 2004: 13: 98–105.
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