Cutaneous side effects in a cohort of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: General description and further characterization, correlation with photoexposition and study of hypopigmentation as treatment's prognostic factor.

Cutaneous adverse effects (AE) related to tyrosine-kinase inhibitor (TKI) drugs have been mainly described as case reports. We have characterized their appearance and correlation with patient's photoexposition habits and, further, with treatment response, in 61 patients with chronic myelogenous leukemia (CML) treated with TKI drugs. We have found hypopigmentation in 49.2% of the cases and a statistically significant association with interferon (IFN) intake. Eyelid edema's frequency was 45.4%. Mean photo-exposure was 1.95 h/day and only 8.3% of the patients used sunscreen daily. 44.3% of the patients reported a lighter skin color with the treatment and a statistically significant relationship with conjunctival hemorrhage was also found. Concordance between patients and dermatologist was moderate (kappa index 0.41). We found xerosis (21.3%), eczematous eruptions (21.3%), melasma (4.9%) and other isolated skin problems (ie, granulomatous panniculitis) in up to 16.4% of cases. Appearance of hypopigmented macules is associated to vascular conjunctival fragility and these patients need a slightly longer time to reach a complete molecular response, but without additional changes in survival or relapse frequency. We have stablished a specific dermatologic diagnosis in all the cases and we have not found the previously published as maculopapular rashes. Hypopigmentation, the more frequent AE, was not perceived as a relevant side effect. Photosensitivity, in our cases, was not reported, although imatinib-treated patients avoided sun-exposure. In addition, we identified some nonpreviously described dermatologic conditions in patients taking TKI drugs, like granulomatous panniculitis tufted folliculitis or oral spindle cell lipoma.

Specific skin infiltration as first sign of localized stage Hodgkin's lymphoma involving an epitrochlear node.

Cutaneous manifestation as the first sign of Hodgkin lymphoma (HL) is very rare and diagnostically challenging; especially, because the clinical presentation of specific skin involvement by HL is polymorphous. We present a 44-year-old man with erythematous indurate papules and plaques in the right forearm and arm where skin biopsy showed an HL. He also has an enlarged epitrochlear node, and later histopathologic study confirmed the diagnosis of HL subtype-mixed cellularity. Immunohistochemical stains in both biopsies showed that the atypical cells were positive for CD30 and CD15, and negative for CD20 and CD3. PAX5 stained the nuclei of the atypical large lymphoid cells weakly and Oct-2 staining was negative in the atypical cells. EBER and LMP1 protein were negative in both biopsies. Epitrochlear involvement in HL, like in our case, is a rare event (<1%). We reviewed data about prognosis, clinical appearance, and treatment of all the cases of HL specific skin involvement published after Sioutos et al, emphasizing the cases where HL specific skin involvement was the first sign of the disease as in our patient.

Hypopigmented macules secondary to imatinib for the treatment of chronic myeloid leukemia: a histopathologic and immunohistochemical study.

BACKGROUND: A few series addressing the cutaneous side effects related to imatinib in the skin have been published, but only one described scarce histopathologic information in seven patients. OBJECTIVE: To characterize these lesions and compare the number of melanocytes between hypopigmented lesions and normal appearing skin. METHODS: We retrieved clinical data of the patients and performed 24 skin biopsies (13 from hypopigmented skin and 11 from normal-appearing skin) within a cohort of 41 patients with chronic myeloid leukemia treated with imatinib. We classified the biopsies into three patterns. RESULTS: About 45% of patients presented with periocular hypopigmentation. Perifollicular fibrosis was observed in hypopigmented skin biopsies (76.9%) and in normal-appearing skin (45.5%). Epidermal melanin, as determined with Masson-Fontana staining, and melanocyte number, as evaluated with MiTF, Melan A and c-kit immunostains, were lower in hypopigmented skin. CONCLUSIONS: Histopathologic study of hypopigmented macules demonstrates the presence of melanin with a statistically significant decrease in the number of melanocytes. Therefore, these findings differ from vitiligo, as melanocytes are present. Three histopathological patterns may be found, namely (a) perifollicular fibrosis, (b) lichen planopilaris-like and (c) apparently normal skin. One of the most striking histopathologic finding consisted of the presence of perifollicular fibrosis in both hypopigmented lesions and apparently normal skin.

Perforating folliculitis in a patient treated with nilotinib: a further evidence of C-kit involvement.

We present a case of perforating folliculitis in a patient treated with nilotinib, a kinase inhibitor. A 48-year-old man presented with a severely pruritic follicular rash for several months that started after reaching a complete molecular response of his myeloid chronic while treated with nilotinib. Clinical examination showed predominantly follicular pinpoint papules on trunk and proximal extremities and a biopsy showed a slightly dilated hair follicle with a focal disruption of the infundibular follicular epithelium. Other diseases related with perforating folliculitis were ruled out. The temporary relationship between the treatment and the appearance of the lesions suggests some pathogenic role of nilotinib. Relationship with nilotinib is also supported by previous similar cases related with sorafenib therapy. Both drugs inhibit c-kit and PDGF-R. PDGF-R has been previously involved in murine and human in vitro models of hair follicle cycle. So, our case supports in vivo the previous evidence of the importance of PDGF-R, a kinase, in the normal hair follicle development.

Association between psoriasis and polymorphisms in the TNF, IL12B, and IL23R genes in Spanish patients.

BACKGROUND & OBJECTIVES: Susceptibility to psoriasis has been associated with the HLA-C*0602 allele, although it may be affected by other polymorphisms. MATERIALS & METHODS: We genotyped 142 patients and 160 healthy volunteers to evaluate the possible relationship between susceptibility to psoriasis and the HLA-C*0602 allele and polymorphisms in the TNF, IL12B, and IL23R genes. RESULTS: The frequency of the wild-type TNF-238, TNF-308, and TNF-1031 genotypes was greater in patients with psoriasis than in healthy volunteers, although that of the mutant TNF-857 genotype was higher. The only difference between psoriasis and psoriatic arthritis was TNF-857. The frequency of the HLAC*0602 allele was higher in psoriatic patients than in healthy volunteers. No differences were observed for IL12B and IL23R. Multivariate logistic regression analysis only confirmed these associations for TNF-238, TNF-857, and HLA-C*0602. CONCLUSION: Our results support an association between susceptibility to psoriasis and TNF polymorphisms in the Spanish population.

Acute bacterial septic vasculopathy.

OBJECTIVES: The frequency and clinicopathologic characteristics of cutaneous lesions in sepsis are not well known. This study aimed to analyze cutaneous lesions in bacterial septic vasculopathy. METHODS: The study population comprised 32 patients with bacterial sepsis, cutaneous lesions, and skin biopsy-proven septic vasculopathy. The clinical and histologic characteristics of the lesions were analyzed. Findings in non-immunosuppressed patients (NISPs) and immunosuppressed patients (ISPs) were compared. RESULTS: Nine of 32 patients were immunosuppressed. The foci of sepsis were variable; in 17 patients, the focus was not identified. Although Neisseria meningitidis was the most common causal agent, several microorganisms were identified. Cutaneous manifestations were an early event in 90.6% of patients. The most common skin signs were purpuric lesions and petechiae. Overall mortality was 28.1%; 65.5% of patients survived without sequelae. Skin biopsies showed thrombi in 100% of cases. Other common findings were inflammatory infiltrate, blood extravasation, and epidermal involvement. Bacteria within the vascular wall were seen in 21.9% of cases and fibrinoid necrosis in 25%. A comparison of ISPs with NISPs disclosed that meningococcemia was more common in the latter group, and the presence of pustules was more common in the former. Histopathology testing revealed that fibrinoid necrosis and bacterial invasion of the vessel wall were more common in ISPs than in NISPs. Conclusions Several microorganisms can cause septic vasculopathy. Clinical presentation is variable and does not depend on the microorganism or the pathogenic mechanism. Histopathologically, septic vasculopathy is a thrombo-occlusive vasculopathy with variable morphology. Cutaneous lesions are an early event and allow for rapid diagnosis.

Sweet's syndrome with subcutaneous involvement associated with pegfilgrastim treatment: first reported case.

Neutrophilic panniculitis is an infrequent entity, considered by most authors as part of the 'neutrophilic dermatosis' spectrum. Few cases have been reported to be related with granulocyte colony-stimulating factor (G-CSF); we report a case of neutrophilic panniculitis and Sweet's syndrome lesions related with pegfilgrastim, a long-acting G-CSF. A 77-year-old woman with M2 acute myeloid leukemia was treated with chemotherapy as well as broad-spectrum antibiotics and antifungal drugs because of febrile neutropenia. Ten days after a single dose of pegfilgrastim, she developed a limited number of purple plaques on the neck, left leg, both arms and several indurated and slightly mobile nodules on her forearms. Skin biopsy of a plaque showed a diffused dermal neutrophilic infiltrate with dermal edema. Biopsy of a nodule showed a lobular neutrophilic panniculitis without vasculitis. No foreign material was found in those biopsies. No organisms were detected in blood, urine or tissue cultures. She was started with prednisolone 40 mg once a day, with dramatic improvement within the next 2 days. This case is noteworthy for the simultaneous appearance of Sweet's syndrome and neutrophilic panniculitis and it is the first case of neutrophilic panniculitis associated with this drug, pegfilgrastim.

Eccrine squamous syringometaplasia secondary to cutaneous extravasation of docetaxel: report of three cases.

Eccrine squamous syringometaplasia is characterized by the metaplasia of cuboidal epithelial cells of the eccrine sweat ducts into squamous epithelial cells. It has been associated with several conditions including chemotherapy-related bilateral dermatitis, an entity that can take place in body areas rich in eccrine glands, as well as in acral erythema related to chemotherapy. Only a few cases because of cutaneous extravasation of chemotherapy have been previously reported. We report three cases of eccrine squamous syringometaplasia secondary to extravasation of docetaxel.

Phototolerance induced by narrow-band UVB phototherapy in severe erythropoietic protoporphyria.

Erythropoietic protoporphyria arises from an inherited disorder of porphyrin metabolism which leads to an accumulation of protoporphyrin IX in the erythropoietic system and other tissues. It is characterized by cutaneous photosensitivity, usually difficult to keep under control. Among the scant therapeutic options proposed to reduce photosensitivity in erythropoietic protoporphyria, narrow-band UVB phototherapy has occasionally been used to induce sunlight tolerance. We report an adult case of erythropoietic protoporphyria with a severe photosensitivity treated with narrow-band UVB that developed an appropriate sunlight phototolerance, without adverse events during phototherapy.

Psoriasis in humans is associated with down-regulation of galectins in dendritic cells.

We have investigated the expression and role of galectin-1 and other galectins in psoriasis and in the Th1/Th17 effector and dendritic cell responses associated with this chronic inflammatory skin condition. To determine differences between psoriasis patients and healthy donors, expression of galectins was analysed by RT-PCR in skin samples and on epidermal and peripheral blood dendritic cells by immunofluorescence and flow cytometry. In the skin of healthy donors, galectin-1, -3 and -9 were expressed in a high proportion of Langerhans cells. Also, galectins were differentially expressed in peripheral blood dendritic cell subsets; galectin-1 and galectin-9 were highly expressed in peripheral myeloid dendritic cells compared with plasmacytoid dendritic cells. We found that non-lesional as well as lesional skin samples from psoriasis patients had low levels of galectin-1 at the mRNA and protein levels, in parallel with low levels of IL-10 mRNA compared with skin from healthy patients. However, only lesional skin samples expressed high levels of Th1/Th17 cytokines. The analysis of galectin-1 expression showed that this protein was down-regulated in Langerhans cells and dermal dendritic cells as well as in peripheral blood CD11c(+) DCs from psoriasis patients. Expression of galectin-1 correlated with IL-17 and IL-10 expression and with the psoriasis area and index activity. Addition of galectin-1 to co-cultures of human monocyte-derived dendritic cells with autologous T lymphocytes from psoriasis patients attenuated the Th1 response. Conversely, blockade of galectin binding increased IFNγ production and inhibited IL-10 secretion in co-cultures of monocyte-derived dendritic cells with CD4(+) T cells. Our results suggest a model in which galectin-1 down-regulation contributes to the exacerbation of the Th1/Th17 effector response in psoriasis patients.

Solar urticaria unresponsive to intravenous immunoglobulins.

The treatment of solar urticaria (SU) can be difficult. Only a few cases of SU have been treated with intravenous immunoglobulins (IVIg) (as monotherapy or combined with phototherapy), with reported fast and durable increase of solar exposure tolerance. A 61-year-old female with severe UVB- and UVA-induced SU and a 62-year-old female with severe UVA and visible light-induced SU were both treated with a single course of IVIg (total dose of 2 g/kg), infused over 3 days. Phototest, performed 3 months after the treatment, showed only a slight minimal urticating dose improvement, and both patients reported just a moderate and 'transient' subjective improvement. Our patient's poorer response, compared with previous reports, may be due to differences in IVIg's treatment schedules, which are reviewed.

Therapeutic drug monitoring of mycophenolic acid in patients with psoriasis.

Mycophenolate mofetil (MMF) has been shown to be effective in the treatment of psoriasis. MMF is the morpholinoethyl ester of mycophenolic acid (MPA), the active compound. Our objective was to characterize the pharmacokinetic profile of MPA in patients with psoriasis treated with MMF and to examine its correlation with effectiveness and toxicity. Eleven patients with moderate-to-severe chronic plaque psoriasis were treated with oral MMF 30 mg kg-1 daily over a period of 16 weeks. Patients were reviewed at 3, 8 and 16 weeks, checking the Psoriasis Area and Severity Index (PASI) and possible adverse events, and performing MPA C0 (trough) and C1 (1-hour post-dose) plasma levels. The reduction in PASI was statistically significant in all our patients. The drug was well tolerated. There was no significant correlation between C0 and C1 MPA levels and the reduction of PASI, improvement rates of PASI from baseline, weight of the patients and total dosage of MMF. Nevertheless, the highest detected mean levels of MPA C1 were observed in two of the patients with the highest improvement rate of PASI at the end of the study. Although C1 levels do not seem to strongly correlate with the effectiveness of the drug, the finding that the highest detected mean levels of MPA C1 were observed in two of the patients with the highest improvement rate of PASI suggests that the monitoring of C1 could be useful in some individual cases.