Francisco Vanaclocha

p16INK4a Gene Alterations Are Frequent in Lesions of Mycosis Fungoides

Mycosis fungoides is usually an indolent disease that, after a variable period of time in a stable phase, evolves into a tumoral form with aggressive behavior. The molecular events that mark this progression remain essentially unknown to date, and this prompted us to investigate the hypothetical role of p16(INK4a) silencing in mycosis fungoides progression. We analyzed the three most frequent mechanisms of inactivation of the p16(INK4a) gene (deletion, promoter hypermethylation, and mutation) in nine cases with patch/plaque and tumoral lesions of mycosis fungoides. The existence of alterations was investigated by microsatellite analysis, methylation-specific polymerase chain reaction, and direct sequencing. Alterations of the p16(INK4a) gene were found in four of nine of the plaque lesions (hypermethylation in three samples and allelic loss in one sample) and seven of nine in the tumor lesions (hypermethylation in five samples and allelic loss in three samples). No case presented point mutations. Although a higher incidence of p16(INK4a) hypermethylation was observed in the cases that failed to achieve a complete remission, the limited size of our series prompted us to evaluate this finding cautiously. The results of this study therefore showed a common genetic alteration that is found more frequently in tumoral lesions than it is in plaque lesions of mycosis fungoides. It also offers data that could suggest a relationship between p16(INK4a) hypermethylation and unfavorable clinical outcome. Broader studies are needed to confirm both relationships.

Risk of Serious Adverse Events Associated With Biologic and Nonbiologic Psoriasis Systemic Therapy: Patients Ineligible vs Eligible for Randomized Controlled Trials

OBJECTIVE To describe the use of systemic therapy for psoriasis (biologic and nonbiologic [classic] drugs) in patients not adequately represented in randomized controlled trials (RCTs) and the risk of serious adverse events (SAEs) in these patients. DESIGN A registry inception cohort was used. SETTING Thirteen dermatology departments in Spain participated. PATIENTS A consecutive sample of patients treated with biologics and a systematic sample of patients treated with classic systemic therapy were evaluated. A total of 1042 patients (2179 person-years) were included. EXPOSURE Inadequate representation in trials was defined as the presence of any of the following factors: elderly age (>70 years); type of psoriasis other than chronic plaque psoriasis; history of infection caused by hepatitis B, hepatitis C, or human immunodeficiency virus; history of cancer (excluding nonmelanoma skin cancer); and chronic renal or hepatic disease. MAIN OUTCOME MEASURES Serious adverse events as defined by the International Conference on Harmonization were evaluated. RESULTS In all, 29.8% of patients receiving systemic therapy for psoriasis would not have been eligible for RCTs. These individuals had an increased risk of SAEs (incidence rate ratio, 2.7; 95% CI, 1.5-4.7). Patients exposed to biologics had an adjusted increased risk of SAEs (incidence rate ratio, 2.3; 95% CI, 1.1-4.8) that was similar in patients eligible and ineligible for RCTs. CONCLUSIONS Patients ineligible for RCTs are an important proportion (30%) of those receiving systemic therapy for psoriasis. These patients have a higher risk of SAEs and should be closely monitored. Patients exposed to biologics (whether these patients are eligible for RCTs or ineligible) are susceptible to the same increase in risk of SAEs, but biologics add to a higher baseline risk in patients who are ineligible for RCTs. The risk-benefit ratio in ineligible patients receiving biologics might be different from the ratio in eligible patients.

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study

Background: Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate‐to‐severe plaque psoriasis. Objective: To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods: Analysis of 52‐week data from CLEAR, a randomized, double‐blind, phase 3b study. Results: Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigators Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis‐related pain, itching, and scaling, and greater improvement across all quality‐of‐life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5‐Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire‐Psoriasis, and Health Assessment Questionnaire‐Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab (P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations: There was no placebo arm. Conclusion: In this head‐to‐head, double‐blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.

Consensus Document on the Evaluation and Treatment of Moderate to Severe Psoriasis. Spanish Psoriasis Group of the Spanish Academy of Dermatology and Venereology

The treatment of psoriasis has been revolutionized by the introduction of biologic agents; these agents achieve skin clearance and long-term improvement without the risk of toxicity that has limited use of the classic systemic treatments. The role of systemic treatment in the management of psoriasis is being reviewed on the basis of a large volume of scientific evidence on the efficacy and safety of biologic agents, and new therapeutic goals and strategies are being devised for patients with moderate-to-severe psoriasis. This has led to the need to establish severity criteria that will provide the rationale for the indication of the different systemic agents currently available for the treatment of moderate-to-severe psoriasis, as well as therapeutic goals, efficacy measures, therapeutic strategies, screening protocols, and choice of treatment based on the risk-benefit ratio of the different agents. These criteria must be established through consensus by experienced dermatologists and based on available scientific evidence. The present document reflects the consensus of the Spanish Psoriasis Group on these different issues in the management of moderate-to-severe psoriasis.

p16 INK4a Is Selectively Silenced in the Tumoral Progression of Mycosis Fungoides

Knowledge about the molecular mechanisms involved in the pathogenesis of tumoral progression in mycosis fungoides (MF) is still scarce. Because the 9p21 locus seems to be a good target for a detailed study in MF, this prompted us to compare the mechanisms of inactivation of the p16INK4a, p15INK4b, and p14ARF genes in aggressive and stable forms of MF, performing microsatellite analysis, methylation-specific polymerase chain reaction, direct sequencing, and p16INK4a protein expression by immunohistochemistry. Additionally, the p53 gene was also sequenced in tumoral lesions. Thirty-nine patients with stable MF were studied. Alterations in p16INK4a and p15INK4b genes were detected in 18% and 5% of the cases, respectively. None of the cases analyzed showed alterations of the p14ARF gene. In contrast with these findings, in the 11 patients with aggressive MF, alterations of the p16INK4a, p15INK4b, or p14ARF genes were found in 8 (73%), 3 (27%), and 2 (18%) cases, respectively. A significant proportion (4/11) of these alterations were already present in the p16INK4a gene in the initial plaque lesions in these aggressive forms of MF. Alterations in the p16INK4a gene, either methylation or loss of heterozygosity, were clearly more frequent than those in the p15INK4b and p14ARF genes. These p16INK4A alterations were confirmed using immunohistochemistry. None of the nine tumoral lesions analyzed showed mutations in exons 1-2 of the p16INK4a gene or in exons 5-8 of the p53 gene. These results seem to suggest that 9p21 alterations, and selectively p16INK4a silencing, could be a characteristic phenomenon in MF progression.

Febrile ulceronecrotic Mucha-Habermann disease

Febrile ulceronecrotic Mucha-Habermann disease in an 18-year-old man is reported. This disease is a severe form of pityriasis lichenoides et varioliformis acuta (PLEVA) and is characterized by the sudden onset of diffuse coalescent ulcerations associated with high fever and systemic symptoms. In the present case the disease was preceded by typical PLEVA. Histologically, a leukocytoclastic vasculitis was seen in addition to the usual features of PLEVA. Findings of laboratory studies revealed an elevated erythrocyte sedimentation rate, a high white blood cell count, and a mild increase in liver enzymes. No systemic involvement was detected. Findings of T cell receptor gene analysis in skin and peripheral blood showed no abnormality. The patient was treated with PUVA and methotrexate with a good response. We review the eight previously reported cases of febrile ulceronecrotic Mucha-Habermann disease.

Oral involvement in mycosis fungoides : Report of two cases and a literature review

Oral involvement is uncommon in cutaneous T-cell lymphomas and usually associated with poor prognosis. The clinicopathological and immunohistochemical findings of 2 new cases are described along with a literature review. The first patient had a 10-year history of mycosis fungoides when she developed lesions in the oral tissues. She died 6 months later despite treatment. The immunophenotype was CD3+, CD4+, CD8-, CD30-. The second patient had a mycosis fungoides for 5 years when she developed lesions in the uvula and oropharynx. She was treated with polychemotherapy and she is alive 5 years after oral involvement. The immunophenotype was CD3+, CD4-, CD8+, CD30-. There are conflicting reports about the prognosis in the CD8+ phenotype. The present cases and the literature review seem to indicate that in oral involvement the CD8- phenotype is not associated with a worse prognosis than the CD4+ subtype. However, it is necessary to study new cases to confirm this statement.

Aggressive granulomatous mycosis fungoides with clinical pulmonary and thyroid involvement

We report a patient with granulomatous mycosis fungoides (MF) that progressed to a tumoral pattern and finally developed clinical pulmonary and thyroid involvement, despite multiple and intensive treatments. We emphasize the visceral involvement in this case, which was manifest as dyspnoea simulating pneumonia and by palpable thyroid nodules. These features are very unusual even in classic MF, and this is the first case in our knowledge of thyroid involvement in granulomatous MF.

Survival of classic and biological systemic drugs in psoriasis: results of the BIOBADADERM registry and critical analysis.

Few reported studies compare drug survival in moderate‐to‐severe psoriasis vulgaris.

Cutaneous plasmacytosis: Report of a case in a white man

We describe a 40-year-old white man with a peculiar skin eruption in association with polyclonal hypergammaglobulinemia. No underlying disease was detected. A skin biopsy specimen showed a proliferation of mature plasma cells intermingled with some lymphocytes and histiocytes, an appearance consistent with cutaneous plasmacytosis. This disease had been previously described only in Japanese patients. In our patient the disease progressed slowly. Lymph node infiltration by mature plasma cells was later noted.