Treatment of granuloma annulare and related granulomatous diseases with sulphasalazine: a series of 16 cases.

BACKGROUND: Granuloma annulare (GA) and the related annular elastolytic giant cell granuloma (AEGCG) and interstitial granulomatous dermatitis (IGD) are idiopathic histiocytic inflammatory disorders, which are frequently recalcitrant to treatment. OBJECTIVES: Evaluate the efficacy of sulphasalazine in treating GA, AEGCG and IGD. METHODS: Sixteen patients were identified with granulomatous disease who were treated with sulphasalazine between September 2015 and September 2019. Outcomes were based on patients' and providers' subjective evaluations. RESULTS: Sixteen patients were included in the study (ages 56-89, four male and twelve female). Previous treatments were attempted in fifteen patients. Clinical improvement was seen in fourteen patients (87.5%). Initial improvement was noted within a mean (SD) of 66.4 (35.1) days after starting therapy, with increasing benefits over time. Ten patients (62.5%) reported complete or near-complete clearance, three patients (18.8%) reported significant improvement, and one (6.3%) reported partial improvement. Twelve patients elected to stop or reduce therapy, resulting in relapse or worsening in five patients. CONCLUSIONS: Sulphasalazine may be considered as treatment for GA and GA-related conditions.

Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-α inhibitor therapy.

Pityriasis amiantacea (PA; also known as tinea amiantacea) is a relatively rare but distinctive scalp condition characterized by thick scales that adhere to each other and to the hair shaft, resulting in agglomeration and matting of hair. Temporary alopecia is a common complication. Although a specific cause remains unclear, PA is associated with several inflammatory diseases such as psoriasis and seborrhoeic dermatitis. We present a case of PA as a complication of underlying psoriasis, which developed during tumour necrosis factor (TNF)-α inhibitor therapy for Crohn disease. This paradoxical cutaneous reaction to anti-TNF-α therapy has been recently described as an emerging and perplexing cause of psoriasis and psoriasiform eruptions.

Activating BRAF mutations in eruptive melanocytic naevi.

BACKGROUND: Eruptive melanocytic naevi (EMN) are melanocytic proliferations developing rapidly on previously unaffected skin in association with various clinical scenarios, most commonly systemic immunosuppression. However, the exact mechanism leading to development of EMN is not understood. In particular, it is not known whether EMN harbour the BRAF mutations which occur frequently in melanoma and most common naevi. OBJECTIVES: To evaluate whether activating BRAF mutations may play a role in genesis of EMN. METHODS: Genomic DNA was isolated from 20 EMN from a patient treated with 6-mercaptopurine (6-MP). Primary BRAF genotyping was performed by allelespecific polymerase chain reaction, followed by validation using direct sequencing. RESULTS: The BRAF V600E mutation was identified in 85% of EMN examined. CONCLUSIONS: Our results implicate mutational activation of the BRAF­MAPK pathway as a factor in development of EMN in the setting of 6-MP treatment. The mechanism leading to development of EMN in this, and potentially other patients, may relate to synergistic mutagenic effects of thioguanines and ultraviolet (UV) A. Together with the documented importance of BRAF mutations in melanoma development and maintenance, these findings highlight the importance of UVA protection, especially in patients treated with thiopurines such as 6-MP.

Metastatic malignant melanoma.

Metastatic malignant melanoma is an incurable malignancy with extremely poor prognosis. Patients bearing this diagnosis face a median survival time of approximately 9 months with a probability of surviving 5 years after initial presentation at less than 5%. This is contrasted by the curative nature of surgical resection of early melanoma detected in the skin. To date, no systemic therapy has consistently and predictably impacted the overall survival of patients with metastatic melanoma. However, in recent years, a resurgence of innovative diagnostic and therapeutic developments have broadened our understanding of the natural history of melanoma and identified rational therapeutic targets/strategies that seem poised to significantly change the clinical outcomes in these patients. Herein we review the state-of-the-art in metastatic melanoma diagnostics and therapeutics with particular emphasis on multi-disciplinary clinical management.

Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas.

Ahi-1 (Abelson helper integration site 1) is a novel gene frequently activated by provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in human leukemia cells, particularly in cutaneous T-cell lymphoma cell lines where increases in AHI-1 transcripts of 40-fold are seen. To test directly whether deregulated expression of AHI-1 contributes to their transformed properties, knockdown of AHI-1 expression in Hut78 cells, a cell line derived from a patient with Sezary syndrome (SS), was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited expression of AHI-1 and its isoforms in transduced cells by 80% and also reduced autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNFalpha) by up to 85%. It further significantly reduced their growth factor independence in vitro and the ability to produce tumors in immunodeficient mice. Interestingly, aberrant expression of AHI-1, particularly truncated isoforms, was present in CD4+CD7- Sezary cells from some patients with SS. Elevated expression of IL-2 and TNFalpha was also found in these cells. These findings provide strong evidence of the oncogenic activity of AHI-1 in human leukemogenesis and demonstrate that its deregulation may contribute to the development of SS.

Update on detection, morphology and fragility in pili annulati in three kindreds.

BACKGROUND: Pili annulati is an inherited hair shaft abnormality with a wide range of clinical expression. OBJECTIVE: We have examined closely three kindreds to reveal levels and character of expression of the phenotype and supplement current literature on the threshold for detection and aspects of hair shaft fragility. PATIENTS AND METHODS: Eleven cases of pili annulati from three families were included in a clinical and morphological study. All cases were assessed clinically and by light and scanning electron microscopy (SEM) of hair shafts. In addition, transmission electron microscopy (TEM) (four patients) and amino acid analysis (three patients) were undertaken on clinically overt cases. Results Examination by light microscopy with a fluid mountant was more sensitive than clinical examination, increasing the detection rate by 120%. Microscopic examination revealed that the characteristic periodic bands become less frequent distally in the hair shaft. Microscopic features of weathering were found in two cases, adding pili annulati to the list of structural hair shaft dystrophies that may weaken hair and dispose to weathering. Amino acid analysis of the hair of three patients with pili annulati showed elevated lysine and decreased cystine content compared to 12 normal controls, consistent with the reduced threshold for weathering. CONCLUSION: Careful light microscopy with fluid-mounted hair is needed to detect subjects mildly affected by pili annulati. Expression of the phenotype varies widely between individuals, between hairs and within hairs of the same individual, where ageing of the hair diminishes detectable features.

Cutaneous T-cell lymphoma and atopy: is there an association?

BACKGROUND: Case reports have suggested a relationship between atopic diatheses and Sézary syndrome, pre-Sézary syndrome or mycosis fungoides. However, Sézary and pre-Sézary syndromes are rare entities, and this association has never been analysed in greater detail for specific subtypes of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To evaluate the prevalence of atopy in subjects with Sézary syndrome, pre-Sézary syndrome or mycosis fungoides, and to compare the rates with the reported prevalence of atopy in the general population. METHODS: We retrospectively reviewed the records of 157 patients with the diagnosis of Sézary or pre-Sézary syndrome seen between 1965 and 2000, and 102 patients with the diagnosis of mycosis fungoides evaluated from 1994 to 2000 at Mayo Clinic. RESULTS: Of 157 subjects with Sézary or pre-Sézary syndrome and 102 subjects with mycosis fungoides, 18 and 12, respectively, were identified as having a history of atopic dermatitis, asthma or allergic rhinitis. The prevalence rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides were 11.5% (95% confidence interval 6.9-17.5%) and 11.8% (6.2-19.7%), respectively. CONCLUSIONS: No significant difference exists in the prevalence of atopy in Sézary or pre-Sézary syndrome compared with that in mycosis fungoides (chi2-test, P = 1.00). Furthermore, the rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides are not significantly different from the prevalence of atopy in the general population (17-40%). On the basis of these observations, no evidence currently implicates a causal association of CTCL with atopy.

Progressive extensive osteoma cutis associated with dysmorphic features: a new syndrome? Case report and review of the literature.

Osteoma cutis, also called cutaneous ossification, refers to the rare occurrence of bone in the skin. It may be primary, occurring in normal skin, or secondary, occurring in disrupted skin tissue. A 42-year-old white woman presented with long-standing progressive primary osteoma cutis involving her head and neck, trunk and extremities. She had craniofacial dysmorphism with mid-face hypoplasia, including saddle nose deformity, mild to moderate generalized joint hypermobility, extensive paravertebral ossification, and disc space calcification. The differential diagnosis for this entity is presented. This phenotype may be a previously undescribed syndrome.

IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes.

IEX-1, an immediate early gene, is widely expressed in epithelial and endothelial tissues, and is altered by a variety of growth regulatory factors. We have shown that expression of IEX-1 in keratinocytes increases the growth rate of these cells. The effects of IEX-1 on apoptosis, however, are unclear. To clarify the effects of IEX-1 on apoptosis, we investigated the effects of IEX-1 expression in keratinocytes (HaCaT cells) in the basal state and after the induction of cellular stress. Under normal, non-stressed conditions, both control (HaCaT) and IEX-1-transfected (IEX-HaCaT) cell lines showed no significant differences in the activity of a key apoptotic enzyme, caspase 3 despite significantly higher levels of IEX-1 expression. IEX-HaCaT cells grew faster than HaCaT cells. When both cell lines were irradiated with ultraviolet B radiation, caspase 3 activity increased to a greater extent in the IEX-HaCaT cells than in HaCaT cells. Camptothecin increased caspase 3 activity twice as much in the IEX-HaCaT cells when compared to HaCaT cells. When histone-complex DNA fragments were measured in IEX-HaCaT or HaCaT cells following UVB irradiation or treatment with camptothecin, significantly higher amounts of nucleosomes were seen in the IEX-HaCaT transfected cells. Likewise, serum deprivation induced higher degrees of apoptosis in IEX-HaCaT cells than in HaCaT cells. We conclude that overexpression of IEX-1 in HaCaT keratinocytes increases the growth rate of cells under basal conditions; in the basal state the rate of apoptosis is unchanged. However, the rate of apoptosis increases in IEX-1 overexpressing HaCaT keratinocytes after cells are subjected to stress.

Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation.

Human EGF receptor (HER), also designated HER1, is an activatable tyrosine kinase receptor. HER1 activation regulates cell growth and differentiation in epidermal keratinocytes. Expression of other HER family members was investigated in human keratinocytes cultured under autocrine conditions. HER2 and HER3 are expressed and upregulated by confluence, concurrent with induction of epidermal differentiation. HER4 is not expressed by keratinocytes. Maximum expression of the cognate ligand, heregulin, is observed in subconfluent keratinocytes, and the expression of both heregulin alpha and beta isoforms is downregulated with confluence. Recombinant heregulin isoforms have no effect on colony formation and keratinocyte proliferation, but heregulin beta activates tyrosine phosphorylation of HER2 and HER3, with no effect on HER1, in confluent differentiating keratinocyte cultures. Also, heregulin beta increases HER2/HER3 heterodimerization under those conditions. Treatment of confluent cultures by heregulin beta correlates with cell signaling and inhibition of epidermal differentiation. Together, HER2, HER3, and heregulin constitute a potential autocrine-paracrine system involved in epidermal homeostasis and repair, as well as in hyperproliferative pathologies.

H(2)O(2) mediates oxidative stress-induced epidermal growth factor receptor phosphorylation.

We used a well-established thiol-alkylating agent, N-ethylmaleimide (NEM), to oxidatively stress human keratinocytes. Time course studies revealed that NEM rapidly depleted keratinocytes of reduced glutathione (GSH), which was followed by rapidly increasing levels of intracellular reactive oxygen species (ROS) and subsequently by phosphorylation of epidermal growth factor receptor (EGFR). Pretreatment with antioxidants or enhanced catalase activity in keratinocytes inhibited ROS/H(2)O(2) accumulation and EGFR phosphorylation, demonstrating that H(2)O(2) production is a mediator required for EGFR phosphorylation. Collectively, these results suggest a sequence of events leading to EGFR phosphorylation which is likely shared by oxidative stress-inducing agents, namely: (1) GSH depletion; (2) H(2)O(2) accumulation; and (3) EGFR phosphorylation. We propose that depletion of GSH and accumulation of H(2)O(2) are upstream events and critical mediators required for ligand-independent phosphorylation of growth factor receptors in response to oxidative stress.

Expression of an immediate early gene, IEX-1, in human tissues.

IEX-1 is an immediate early gene that is induced by ionizing radiation, ultraviolet radiation, and a variety of growth factors. It plays an important role in the regulation of cellular growth. Earlier, we performed studies on the distribution of IEX-1 messenger RNA in different tissues and on the subcellular localization of IEX-1 protein. No reports, however, have appeared concerning the distribution of IEX-1 protein in a variety of human tissues. We raised a polyclonal antibody against a synthetic IEX-1 peptide (amino acids 51-75) and used the antibody to study the distribution of the protein in human tissues. We demonstrate that IEX-1 is strongly expressed in epithelia of the skin, trachea, gastrointestinal, and genitourinary systems, as well as in the pancreas and breast. Endothelial cells within the vasculature of most tissue/organs also strongly express IEX-1. Liver, lung, lymph nodes, and placenta stain weakly. No IEX-1 epitopes were detected in the thymus, testes, ovary, myocardium, skeletal muscle, or spleen. We conclude that IEX-1 is widely expressed in epithelial and endocrine tissues, as well as in vascular endothelium.

Human calmodulin-like protein is an epithelial-specific protein regulated during keratinocyte differentiation.

Human calmodulin-like protein (CLP) is a calcium-binding protein down-regulated in a cell culture model of mammary tumorigenesis as well as in a majority of breast cancers in vivo. CLP down-regulation may be a result of the poorly differentiated state of these cell lines and tumors, or CLP expression may be incompatible with the uncontrolled cell growth associated with tumorigenesis. To learn more about CLP expression and regulation, we determined the distribution of CLP in various human tissues by immunohistochemistry. CLP was expressed exclusively in the epithelium of the tissues surveyed and was most abundant in thyroid, breast, prostate, kidney, and skin. CLP expression appears to increase in stratified epithelium during differentiation, as illustrated in the skin where CLP staining intensified from the basal through the spinous to the granular layers. Using a normal human keratinocyte culture model, we examined CLP expression in response to various agents known to affect keratinocyte differentiation. Agents that inhibit (epidermal growth factor, EGF) or permit (keratinocyte growth factor) terminal differentiation correspondingly regulate CLP expression. Factors modulating the EGF receptor signaling pathway were particularly potent in regulating CLP expression. CLP expression correlated with an agent's ability to promote terminal differentiation regardless of the agent's effect on keratinocyte proliferation. These studies show that CLP expression is coordinately regulated by, and may be involved in, the program of terminal differentiation in human keratinocytes and, likely, other differentiating epithelial cell types.

Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes.

Trichothiodystrophy (TTD) refers to a heterogeneous group of autosomal recessive disorders that share the distinctive features of short, brittle hair and an abnormally low sulfur content. Within the spectrum of the TTD syndromes are numerous interrelated neuroectodermal disorders. The TTD syndromes show defective synthesis of high-sulfur matrix proteins. Abnormalities in excision repair of ultraviolet (UV)-damaged DNA are recognized in about half of the patients. Three distinct autosomal recessive syndromes are associated with nucleotide excision repair (NER) defects: the photosensitive form of TTD, xeroderma pigmentosum, and Cockayne syndrome. The unifying feature of these conditions is exaggerated sensitivity to sunlight and UV radiation. In contrast to patients with xeroderma pigmentosum, no increase of skin cancers in patients with TTD has been observed. Genetically, 3 complementation groups have been characterized among photosensitive patients with TTD. Most patients exhibit mutations on the two alleles of the XPD gene. Rarely, mutated XPB gene or an unidentified TTD-A gene may result in TTD. In UV-sensitive TTD, the TFIIH transcription factor containing XPB and XPD helicase activities necessary for both transcription initiation and DNA repair is damaged. Beyond deficiency in the NER pathway, it is hypothesized that basal transcription may be altered leading to decreased transcription of specific genes. Depressed RNA synthesis may account for some clinical features, such as growth retardation, neurologic abnormalities, and brittle hair and nails. Therefore the attenuated expression of some proteins in differentiated cells is most likely explained by a mechanism distinct from DNA repair deficiency. The first transgenic mouse models for NER deficiencies have been generated. The TTD mouse as well as related cell models will provide important tools to understand the complex relationships between defects in DNA repair, low-sulfur hair shaft disorders, and the genotype-phenotype correlates for this constellation of inherited disorders, including the lack of predisposition to cancer in patients with TTD.

Human papillomavirus in cutaneous squamous cell carcinoma and cervix of a patient with psoriasis and extensive ultraviolet radiation exposure.

"High-risk" human papillomaviruses (HPVs) are associated with intraepithelial neoplasia and cancer of the uterine cervix. HPV has also been found in nonmelanoma skin cancer (NMSC), especially in squamous cell carcinomas (SCCs) of immunosuppressed patients. Recently, lesions of psoriasis have been shown to harbor HPV, and patients with psoriasis often have a history of extensive therapy with ultraviolet radiation (UVR). UVR is the major known risk factor in the occurrence of NMSC, in which HPV may be a cofactor for SCC. We report an otherwise healthy, nonimmunosuppressed patient with psoriasis who had a history of extensive exposure to UVR and experienced multiple SCCs on UV-exposed body sites. By the polymerase chain reaction method, we detected HPV in 5 of 9 SCCs. Automated sequencing showed HPV types 12 and 17. Only 1 of 3 normal skin specimens was HPV positive (HPV type 17). This positive specimen was from UV-exposed skin; one of the two HPV-negative, normal skin specimens was located on a body site not exposed to sun. In addition, HPV type 62 was found in a brush specimen of the uterine cervix. This case report suggests an association between psoriasis, HPV infection, and UVR exposure, in onset of SCC.

Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus.

BACKGROUND: Recent studies suggest that paraneoplastic pemphigus (PNP) is a heterogeneous autoimmune syndrome involving several internal organs and that the pathophysiological mechanisms mediating cutaneous, mucosal, and internal lesions are not limited to autoantibodies targeting adhesion molecules. OBJECTIVE: To classify the diverse mucocutaneous and respiratory presentations of PNP and characterize the effectors of humoral and cellular autoimmunity mediating epithelial tissue damage. METHODS: We examined 3 patients manifesting the lichen planus pemphigoideslike subtype of PNP. A combination of standard immunohistochemical techniques, enzyme-linked immunosorbent assay with desmoglein (DSG) baculoproteins, and an immunoprecipitation assay were used to characterize effectors of humoral and cellular autoimmunity in patients with PNP and in neonatal wild-type and DSG3-knockout mice with PNP phenotype induced by passive transfer of patients' IgGs. RESULTS: In addition to the known "PNP antigenic complex," epithelial targets recognized by PNP antibodies included 240-, 150-, 130-, 95-, 80-, 70-, 66-, and 40/42-kd proteins but excluded DSG1 and DSG3. In addition to skin and the epithelium lining upper digestive and respiratory tract mucosa, deposits of autoantibodies were found in kidney, urinary bladder, and smooth as well as striated muscle. Autoreactive cellular cytotoxicity was mediated by CD8(+) cytotoxic T lymphocytes, CD56(+) natural killer cells, and CD68(+) monocytes/macrophages. Inducible nitric oxide synthase was visualized both in activated effectors of cellular cytotoxicity and their targets. Keratin 14-positive basal epithelial cells sloughed from the large airways and obstructed small airways. CONCLUSIONS: The paraneoplastic disease of epithelial adhesion known as PNP in fact represents only 1 manifestation of a heterogeneous autoimmune syndrome in which patients, in addition to small airway occlusion and deposition of autoantibodies in different organs, may display a spectrum of at least 5 different clinical and immunopathological mucocutaneous variants (ie, pemphiguslike, pemphigoidlike, erythema multiforme-like, graft-vs-host disease-like, and lichen planus-like). We suggest that the more encompassing term "paraneoplastic autoimmune multiorgan syndrome," or PAMS, be applied. The pathophysiological mechanisms of PAMS involve both humoral and cellular autoimmunity responses. Epithelial cell membrane antigens other than DSG1 or DSG3 are targeted by effectors of PAMS autoimmunity. Apoptosis of damaged basal cells mediates epithelial clefting, and respiratory failure results possibly from obstruction of small airways with sloughed epithelial cells.