Search

Background Over the last 5 years, there has been a rapid growth in the number of clinical trials used to support a US Food and Drug Administration (FDA) approval for systemic therapies with labeled indications for plaque psoriasis. Objective We aim to evaluate the fragility of clinical trial data used to support FDA approval of therapies for psoriasis. Methods We reviewed the primary endpoints of the pivotal trials of all systemic medications with a labeled indication for plaque psoriasis available from Drugs@FDA. Results Sixty-nine clinical trial primary endpoints met inclusion criteria and were assessed for robustness, yielding a median fragility index of 72 and a median fragility quotient of 0.19. Limitations Efficacy and statistical analysis data for several approved medications were not available on the product label or on Drugs@FDA. Conclusions When compared with randomized controlled trials for FDA approval across various diseases, pivotal trials in psoriasis appear quite robust to changes in outcomes.

Background Mucous membrane pemphigoid (MMP) is characterized by subepithelial blistering due to IgG autoantibodies targeting various components of the dermal–epidermal basement membrane zone. Immunodiagnostics play an important role in making a precise diagnosis. Measures of test sensitivity and specificity, however, typically come from studies in diseases such as bullous pemphigoid, where the exact antigenic site may not be the same. Additionally, the association of clinical phenotype and autoantibody profiles has been an area of debate. Objective We evaluated the sensitivity and specificity of ELISA in MMP for the known target antigens BP180 and laminin-332, as well as characterized the frequency of IgG antibodies against each laminin-332 subdomain. Lastly, we analysed whether IgG auto-antibody profiles were associated with clinical phenotype. Methods We performed a systematic review of Medline/PubMed to compile MMP patient demographics, clinical manifestations and immunodiagnostic results. ELISA sensitivities and specificities for autoantigens were calculated in patients with positive immunoblot or immunoprecipitationstudies. IgG reactivity for each laminin-332 subunit was recorded. Associations between positive immunological tests and clinical presentation were evaluated using chi-squared test tests or Fisher's exact test when appropriate. Results For patients with a positive immunoblot or immunoprecipitation to NC16a, ELISA using both the NC16a and C-terminal portion of BP180 demonstrated a sensitivity and specificity of 73% and 93%. However, for individuals with IgG against the C-terminal domain of BP180, the sensitivity and specificity was 43% and 56%, respectively. LN-332 ELISA demonstrated 75% sensitivity, but only for patients with IgG reactivity against the α3 subunit. In patients with laminin-332 MMP, 86.4% demonstrated IgG against the α3 subunit. IgG autoantibodies against laminin-332 are significantly associated with pharyngo-laryngeal (P < 0.0001) and oro-pharyngo-laryngeal (P = 0.006) involvement. Conclusions Immunodiagnostics play a major role in diagnosing MMP, though limited sensitivity may necessitate several forms of testing for confirmation.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a rare disorder that manifests with severe mucocutaneous blistering and erosions accompanied by underlying malignancy. Constrictive bronchiolitis (CB) can occur in a subset of patients. We sought to characterize the particular group of PAMS patients with CB by comparing the underlying tumor in these patients versus all reported PAMS patients. We performed a systematic review of the Medline/Pubmed and compared the incidence of the most frequent tumor type in the CB cohort with the previously reported incidences of tumors in all documented PAMS patients. There is an increased occurrence of Castleman’s tumor in patients with mucocutaneous and pulmonary complications of PAMS OR 3.86, 95 % CI [2.2–6.7]. As PAMS is a syndrome with a heterogeneous presentation and autoantibody profile, the particular pathogenic pathway seen in Castleman’s tumor may provide additional insight into the antigenic sites involved in PAMS-related CB.

The US and Queensland populations both demonstrate an increased risk of secondary malignancies following the diagnosis of Merkel cell carcinoma (MCC). A recent Queensland study failed to demonstrate a significantly increased risk of developing non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukaemia (CLL) in these patients. In contrast, using the US Surveillance, Epidemiology, and End Results database, we demonstrate there is an increased risk in CLL and NHL following the diagnosis of MCC in the USA. We hypothesise that this difference may be a result of a differing pathogenesis.

Importance Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures Identification of somatic mutations associated with cherry angiomas. Results In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

Cutaneous T-cell lymphoma (CTCL) is a diverse group of extranodal non-Hodgkin lymphomas with malignant T lymphocytes localizing in the skin. CTCL can mainly be classified as mycosis fungoides, Sezary syndrome, or primary cutaneous CD30+ lymphoma. Patients with CTCL have an increased risk of developing second primary malignancies. Our objective was to analyze the overall incidence of second primary malignancies in patients with CTCL by age, sex, stage, and the primary cutaneous CD30+ lymphoproliferative subtype of CTCL, as this group has usually been excluded from previous analyses. We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate CTCL cases diagnosed between 1992 and 2011. We calculated the multiple primary standardized incidence ratio, comparing the observed incidence of second primary malignant neoplasms in the CTCL patient population versus the general population. CTCL is associated with an overall increased risk of cancers. This incidence is greatest within the first year of diagnosis. The risk of secondary Hodgkin disease is greatest in patients aged ≥60 years; the risk of secondary non-Hodgkin lymphoma is greatest in patients aged 20–39. Males demonstrated a significantly increased risk of developing Hodgkin lymphoma, while females showed a significantly increased risk of developing bronchopulmonary malignancy. Overall, secondary malignancy incidence was significantly elevated for stage I and IV CTCL. Patients with CD30+ CTCL had a significantly higher incidence of Hodgkin lymphoma, non-Hodgkin lymphoma, and urinary cancers than the general population. Occult secondary malignancies, particularly lymphomas, should be considered in adult CTCL patients, including those with the CD30+ subtype.

Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF-α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF-α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF-α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF-α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF-α in granuloma formation, the therapeutic role of TNF-α inhibition and immunologic abnormalities following treatment with these TNF-α inhibitors including drug-specific alterations involving interferon-γ, lymphotoxin-α, TNF receptor 2 (TNFR2) and T-regulatory cells.

The US and Queensland populations both demonstrate an increased risk of secondary malignancies following the diagnosis of Merkel cell carcinoma (MCC). A recent Queensland study failed to demonstrate a significantly increased risk of developing non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukaemia (CLL) in these patients. In contrast, using the US Surveillance, Epidemiology, and End Results database, we demonstrate there is an increased risk in CLL and NHL following the diagnosis of MCC in the USA. We hypothesise that this difference may be a result of a differing pathogenesis.

Background Systemic biologic and nonbiologic agents used to treat psoriasis may or may not contribute to serious infection (SI) risk. Safety data, particularly for biologic agents, and associated risk for SI, are scarce. The study's aim was to explore the risk for SI in psoriasis patients exposed to systemic biologic or nonbiologic agents. Methods A large, single-center electronic medical record repository was searched between January 2010 and December 2014. Records for patients prescribed a systemic agent for psoriasis (SAP) with psoriasis or psoriatic arthritis diagnoses were included (ICD-9 codes 696.1 and 696.0, respectively). SIs were those who required hospitalization, and/or injectable antibacterial, antiviral or antifungal therapy. SIs occurring within 120 days after exposure to a SAP, were included for study. Results A total of 1,346 patients were exposed to a SAP between January 2010 and December 2014; 27 (2%) had a SI. Comparing biologic and nonbiologic agent exposure, no statistically significant difference for risk of SI was detectable (p = .83). Conclusion In this population, the SI rate for biologic and nonbiologic systemic agents was clinically indistinguishable, thereby supporting consideration of the entire spectrum of available systemic therapeutic agents, both biologic and nonbiologic agents, for management of moderate to severe psoriasis.

Nail involvement is present in over half of patients with psoriasis and consequently has a prominently negative impact on society. The clinical gamut of nail involvement is diverse and includes changes to the nail matrix, the nail bed, or both. The main nail matrix dystrophy is nail pitting while onycholysis, subungual hyperkeratosis, splinter hemorrhages, and oil-drop discoloration are the major nail bed findings. Lesions of the nail plate are due to the location of disease in the nail matrix as well as the duration of the disease. This chapter will describe the broad array of clinical features of nail psoriasis in order to help clinicians identify the condition, which will enable dermatologists to treat the symptoms and hopefully improve patients’ lives.