Panniculitis With Arthralgia in Patients With Melanoma Treated With Selective BRAF Inhibitors and Its Management

Zimmer, Lisa; Livingstone, Elisabeth; Hillen, Uwe; Dömkes, Stephanie; Becker, Arne; Schadendorf, Dirk

doi:10.1001/archdermatol.2011.2842

Cited by 92 publications

(67 citation statements)

References 15 publications

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“…Isolated noncaseating granulomas as reported by us were found in one of two cases of panniculitis described by Zimmer et al 3 for patients receiving BRAF inhibitor therapy. As for the diagnosis of granulomatous dermatitis, only two cases 4,5 have been described to date, referring to three patients treated with BRAF inhibitors.…”

supporting

confidence: 68%

Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor

Leal

Agut-Busquet

Romaní

et al. 2016

The Journal of Dermatology

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Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor Dear Editor, Metastatic malignant melanoma is associated with poor outcomes. The fact that up to 80% of cases of primary melanoma 1 harbor mutations in the BRAF gene has led to the development and recent approval of novel BRAF inhibitor drugs that, in comparison with dacarbazine, significantly improve progression-free survival. 2 Because of limited experience with these drugs, a number of unusual side-effects have not yet been described.A 41-year-old Caucasian woman was included in a clinical trial of dabrafenib therapy (150 mg twice daily) because she had a stage IV melanoma, harboring a BRAF V600E mutation, that failed to respond to radiotherapy and ipilimumab (CTLA-4 inhibitor). Eight months after inclusion, she presented with high fever, arthralgia, joint swelling and tender, painful, erythematous subcutaneous nodules located mainly in the upper and lower limbs (Fig. 1a). A punch biopsy revealed a lobular pattern of panniculitis with a predominantly lymphohistiocytic infiltrate forming non-necrotizing granulomas, a scarcity of neutrophils and no evidence of vasculitis (Fig. 1b). The lesions resolved completely in response to a tapered regime of corticosteroids. Five months later, the patient presented with multiple 1-1.5-mm non-painful erythematous and violaceous papules and nodules, scattered bilaterally and symmetrically over the antecubital skinfolds and dorsal aspect of the hands (Fig. 1c). The patient had no systemic symptoms. Anatomopathological findings for a second punch biopsy revealed a full-thickness dermal infiltrate of numerous epithelioid histiocytes and giant multinucleated cells forming non-necrotizing granulomas. A surrounding crown of lymphocytes was present in all the granulomas, prominent in approximately half and less noticeable otherwise (Fig. 1d). No Melan-A-positive cells were found in relation to the inflammatory infiltrate in either of the biopsies, indicating an absence of cancer cells. The rash responded well to treatment with a topical steroid ointment. The main causes of non-necrotizing granulomas, namely, sarcoidosis and infections, were excluded and both the 8-and 13-month reactions were attributed to treatment with dabrafenib. After 18 months, pulmonary progression of malignant melanoma was detected and dabrafenib therapy was suspended. The remaining granulomatous papules resolved completely within 2 weeks of dabrafenib suspension.Although the pathogenic mechanisms of granuloma formation have not yet been unraveled, our case reflects a previously unreported association between two infrequent granulomatous toxicities in the same patient, mild in nature and requiring no treatment discontinuation. Isolated noncaseating granulomas as reported by us were found in one of two cases of panniculitis described by Zimmer et al. 3 for patients receiving BRAF inhibitor therapy. As for the diagnosis of granulomatous dermatitis, only two cases ...

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confidence: 68%

Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor

Leal

Agut-Busquet

Romaní

et al. 2016

The Journal of Dermatology

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“…4 A recent report described 2 cases of panniculitis in patients on vemurafenib. 5 The underlying pathogenesis of these particular side effects is unclear, and the risk factors for vemurafenib-induced panniculitis and vasculitis are still unknown. Further investigation of the mechanisms linking BRAF inhibition with these cutaneous side effects is warranted.…”

Section: Vasculitis and Panniculitis Associated With Vemurafenibmentioning

confidence: 99%

Vasculitis and panniculitis associated with vemurafenib

Novoa

Honda

Koon

et al. 2012

Journal of the American Academy of Dermatology

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“…This is remarkable in patients with cutaneous and ocular melanomas, where concentration of major inflammatory factors is elevated both at tumor sites (Yurkovetsky et al, 2010) and peripheral blood (Ly et al, 2010), and can further increase within the tumor microenvironment during tumor progression (Moretti et al, 1999;Richmond et al, 2009) and administration of therapeutic agents such as dendritic cell vaccination (Nakai et al, 2010) and selective V-raf murine sarcoma viral oncogene homolog B1 inhibitors (Zimmer et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

IL-18 Regulates Melanoma VLA-4 Integrin Activation through a Hierarchized Sequence of Inflammatory Factors

Valcárcel

Carrascal

Crende

et al. 2014

Journal of Investigative Dermatology

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Very late antigen-4 (VLA-4) is frequently overexpressed on melanoma cells contributing to inflammation-dependent metastasis. Melanoma cell adhesion to endothelium via VLA-4-vascular cell adhesion molecule-1 (VCAM-1) interaction was used to study VLA-4 activation during melanoma cell response to inflammation. Cooperation among major inflammatory mediators was analyzed in melanoma cells exposed to single inflammatory factors in the presence of inhibitors for other assayed mediators. A stepwise cascade of hierarchized molecules heterogeneously made and used during melanoma response to IL-18, induced hydrogen peroxide (H2O2), in turn activating VLA-4 and melanoma cell adhesion to endothelium. The cascade involved prostaglandin E2 (PGE2) production from melanoma induced by IL-18-dependent tumor necrosis factor-α (TNFα); next, PGE2-induced IL-1β via vascular endothelial growth factor (VEGF) secretion, which in turn induced VLA-4 activation via cyclooxygenase 2-dependent H2O2. This sequence operated in IL-18R/VLA-4/VEGF-expressing murine (B16) and human (A375 and 883) melanomas, but not in those without this phenotype. Separation of active VLA-4-expressing B16 melanoma cells through immobilized VCAM-1 verified their higher IL-18R/TNFR1/VEGFR2 expression and metastatic growth than inactive VLA-4-expressing cells. However, cooperation among melanoma cell sub-populations with heterogeneous cytokine receptor levels may occur through VLA-4-stimulating factors, leading to intratumoral amplification of metastatic potential. Therefore, expression of the VLA-4-stimulating factor sequence may help to predict melanoma prometastatic risk, and offers therapeutic targets for metastatic melanoma deactivation through VLA-4 activation blockade.

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Panniculitis With Arthralgia in Patients With Melanoma Treated With Selective BRAF Inhibitors and Its Management

Cited by 92 publications

References 15 publications

Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor

Cutaneous granulomatous panniculitis and sarcoidal granulomatous papular eruption in a patient with metastatic melanoma treated with a BRAF inhibitor

Vasculitis and panniculitis associated with vemurafenib

IL-18 Regulates Melanoma VLA-4 Integrin Activation through a Hierarchized Sequence of Inflammatory Factors

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