Discriminating minor and major forms of drug reaction with eosinophilia and systemic symptoms: Facial edema aligns to the severe phenotype.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a cutaneous and systemic drug allergy disorder. Patients exist on a severity spectrum, with some experiencing a mild form of the disorder that fails to meet the Registry of Severe Cutaneous Adverse Reactions (SCAR) to Drugs diagnostic criteria for DRESS. OBJECTIVE: We sought to determine whether there were any cutaneous or dermatopathologic features that discriminate between the mild form of DRESS (DRESS minor) and the severe phenotype (DRESS major). METHODS: Hospitalized patients from a single center with a diagnosis of DRESS were prospectively recruited over a 7-year period. Clinical and dermatopathologic features were analyzed to discriminate between DRESS minor and DRESS major. RESULTS: Forty-five patients were included, of whom 19 had a Registry of Severe Cutaneous Adverse Reactions (SCAR) to Drugs score of ≤3 (DRESS minor) and 26 had a score of ≥4 (DRESS major). The mean latency period (P = .001), fever >38.5 °C (P = .001), and a reaction lasting >15 days (P = .010) discriminated DRESS major from DRESS minor. Facial edema was the sole discerning cutaneous feature (P = .025). Discriminating histopathologic features included basal squamatization (P = .005), dermal red blood cell extravasation (P = .009), and interface inflammation (P = .005). CONCLUSION: We propose a new classification system-DRESS minor-to distinguish the milder illness from the severe form, DRESS major. Facial edema and certain histopathologic features can help discriminate between major and minor versions.

Sneddon's syndrome: it is all in the ectoderm.

A 51-year-old man gave a 2-year history of worsening mobility, cognitive decline and headaches. He had a history of thromboembolic stroke, recurrent transient ischaemic attacks and a spontaneous intraventricular haemorrhage. On examination, he had livedo reticularis and perniosis and a systolic murmur. Catheter cerebral angiography showed peripheral small-vessel and medium-vessel vasculopathy resulting in pruning of the distal cortical vessels and tortuous irregular distal collaterals. Skin biopsy showed subtle vasculopathy with ectasia of capillaries and postcapillary venules but no frank vasculitis or arterial thrombosis. Repeated serum antiphospholipid antibody titres were negative. The clinical features, skin biopsy and angiogram findings strongly supported a diagnosis of Sneddon's syndrome. Clinicians should consider Sneddon's syndrome in patients with livedo reticularis and stroke. There are treatment dilemmas in this situation when ischaemic and haemorrhagic cerebral events coexist.

Annular elastolytic giant cell granuloma associated with autoimmune hepatitis: Response to ciclosporin.

A 47 year old Caucasian female with a background of type 2 diabetes mellitus, hypothyroidism, and autoimmune hepatitis presented with a painful, pruritic, papular eruption in a photosensitive distribution across the upper chest, neck, face, dorsal hands and forearms. On examination, lesions coalesced into annular plaques each with an active, raised margin and an atrophic, yellow centre. Histopathology demonstrated an absence of mucin and elastophagocytosis with giant cells engulfing dermal elastin fibres. These histopathological features favoured a diagnosis of annular elastolytic giant cell granuloma (AEGCG). The patient was managed ciclosporin monotherapy 125 mg twice daily (3 mg/kg/day). At 8 week review, there was a marked improvement in the physical appearance of the dermatosis as well as diminishing of symptoms such as itch and cutaneous pain. AEGCG is a rare inflammatory dermatosis typically affecting sun-exposed sites. It has been proposed that AEGCG is triggered by a solar induced elastolysis however other theories suggest it is a primary granulomatous disorder and not a photodermatosis. AEGCG appears to be aligned to an autoimmune diathesis, indicated by its frequent association with autoimmune conditions such as Hashimoto's thyroiditis, vitiligo, giant cell arteritis and, as in our patient, auto-immune hepatitis. Diabetes mellitus occurring concurrently with AEGCG has also been observed, again like our patient. Histopathological features which distinguish AEGCG from granuloma annulare include absent mucin, absent necrobiosis, giant cells with more nuclei, non-palisading granulomata and marked loss of elastic tissue. AEGCG is often unresponsive to standard therapies. The literature indicates varying responses to photo-protection, topical/systemic/intralesional corticosteroids, and oral medications such as methotrexate, hydroxychloroquine, and dapsone. Few case reports have also documented improvement with ciclosporin. In aggressive forms of AEGCG, as in our patient, treatment with ciclosporin may be an effective intervention and should be initiated early in the disease.

The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status.

RATIONALE: Health status is impaired in patients with sarcoidosis. There is a paucity of tools that assess health status in sarcoidosis. The objective of this study was to develop and validate the King's Sarcoidosis Questionnaire (KSQ), a new modular health status measure. METHODS: Patients with sarcoidosis were recruited from outpatient clinics. The development of the questionnaire consisted of three phases: item generation; item reduction, Rasch analysis to create unidimensional scales and validation; repeatability testing. RESULTS: 207 patients with sarcoidosis (organ involvement: 184 lung, 54 skin, 45 eye disease) completed a 65-item preliminary questionnaire. 36 items were removed due to redundancy or poor fit to the Rasch model. The final version of the KSQ consisted of five modules (General health status, Lung, Skin, Eye, Medications). Internal consistency assessed with Cronbach's α coefficient was 0.70-0.93 for KSQ modules. Concurrent validity of the Lung module was high compared with St George's Respiratory Questionnaire (r=-0.83) and moderate when compared to forced vital capacity (r=0.49). Concurrent validity with skin-specific and eye-specific measures ranged from r=-0.4 to 0.8. The KSQ was repeatable over 2 weeks (n=39), intraclass correlation coefficients for modules were 0.90-0.96. CONCLUSIONS: The KSQ is a brief, valid, self-completed health status measure for sarcoidosis. It can be used in the clinic to assess sarcoidosis from the patients' perspective.

Dr Agnes Savill: Pioneer, polymath and dermatology's renaissance woman.

Dr Agnes Savill was the UK's first female consultant dermatologist with a career journey which was, by any standards, extraordinary. She was awarded her MA in 1893 making her the first female graduate from St Andrews University. She then trained as a doctor in Glasgow in the earliest cohort of women granted the opportunity to study medicine. Following qualification, and during her early professional years, she maintained an involvement in the women's suffrage movement by publicly indicting the government for its brutal treatment of women suffrage prisoners in the 'Votes for Women' campaign. During World War 1 Dr Agnes Savill was one of a handful of women doctors who served at the Scottish Women's Hospital, a combat hospital in France. Dr Savill worked as the radiologist for the unit and developed expertise in the radiographic appearances of gas gangrene. After the war she returned to her dermatology practice, becoming the UK's leading expert in disorders of the hair and scalp and publishing widely on the subject. However, Agnes Savill had interests which extended into the humanities, particularly music. She was advocate for the use of music as treatment for psychological and physical disorders and wrote a book on this subject which helped promote music therapy as a para-clinical discipline. In her latter years she became fascinated by the history of classical antiquity and, at the age of 79, published a biography of Alexander the Great, an account praised for being both lucid and authoritative. Agnes Savill was a remarkable pioneering doctor: she was a ground-breaking dermatologist, she fought for women's rights and served in France as a combat doctor. Her work in music therapy and her writings on ancient history brought acclaim beyond the realm of medicine. Dr Agnes Savill is Dermatology's Renaissance Woman.

Ten cases of drug reaction with eosinophilia and systemic symptoms (DRESS) treated with pulsed intravenous methylprednisolone.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, life-threatening, drug-induced illness characterised by a widespread polymorphic eruption, fever and multivisceral involvement. There is little published on the management of DRESS. Prompt recognition and withdrawal of the causative drug is essential, along with supportive treatment. However, the condition commonly progresses despite these measures. Oral corticosteroids are usually given but the response can be suboptimal and result in a prolonged exposure to systemic glucocorticoid. We conducted a prospective single-centre study to determine the efficacy of pulsed intravenous methylprednisolone followed by a short reducing course of oral prednisolone in ten patients with confirmed DRESS. Rash and fever responded rapidly to methylprednisolone in all patients. Compared to pre-treatment assessments, there was a significant reduction in eosinophil count at day 14 and AST level at day 90 post-treatment. One patient developed acute hepatic failure, necessitating a liver transplant, and died 4 months later. In the immediate post-treatment phase, 1 patient developed type 1 diabetes and 1 patient developed a corticosteroid-induced psychosis. Long-term follow-up on 8/10 revealed all patients to be well, although one patient had persistent pruritus. An aggressive corticosteroid regimen in the management of DRESS is associated with good clinical outcome and acceptable tolerance.

A method of purifying alpha-synuclein in E. coli without chromatography.

Research has implicated alpha-synuclein (aSyn) in pathological protein aggregation observed in almost all patients with Parkinson's disease and more than 50% of patients with Alzheimer's disease. An easy and inexpensive method of purifying aSyn and developing an in vitro model system of Lewy body formation would enhance basic biomedical research. We report aSyn purification technique that leverages the amyloidogenic property of aSyn suitable for purifying monomeric aSyn without chromatography and denaturing agents. We expressed full-length and untagged aSyn in Rosetta(DE3) pLysS and purified ~60 µg of aSyn from 500 mL culture within 24 h. After IPTG-induced expression of aSyn in E. coli, we disrupted the cells with a sonicator. We centrifuged the cell lysate in a 15 mL tube, which leads to aSyn-induced aggregation of native E. coli proteins. After removing aggregates, centrifugation in a 30 kDa cut-off filter followed by a 10 kDa cut-off filter led to purified water-soluble aSyn. The identity of aSyn was confirmed by Western blot using anti-aSyn antibody and Edman sequencing. Its mass was determined to be 14.6 kDa using a MALDI TOF-MS mass spectrometer. The majority of aSyn led to water-suspended (as opposed to precipitated) aggregation of E. coli proteins with visible fibrous structures. The broad-spectrum binding and amyloidogenic property of aSyn is thus not only useful for inexpensive aSyn production for diverse applications, but it also expands studying its possible roles in human physiology. The aggregate of E. coli proteins induced by aSyn during the purification process may serve as a Lewy body model.

Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy.

BACKGROUND: Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed. OBSERVATIONS: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen-UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia. CONCLUSIONS: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity.

Systemic hypersensitivity reaction to Omnipaque radiocontrast medium: a case of mini-DRESS.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a delayed drug reaction defined by physical signs and laboratory parameters. Mini-DRESS is a new entity, in cases that display some but not all features of DRESS. Cases of mini-DRESS have a less protracted course, and respond well to systemic corticosteroid treatment.

Mediation of systemic vascular hyperpermeability in severe psoriasis by circulating vascular endothelial growth factor.

BACKGROUND: Severe forms of psoriasis can be complicated by systemic microvascular hyperpermeability. Vascular endothelial growth factor (VEGF) possesses potent vascular permeability activity. We suggest that VEGF enters the systemic circulation and acts on microvessels to mediate hyperpermeability. OBJECTIVES: To quantify renal microvascular permeability and circulating VEGF concentration in severe psoriasis, and to investigate the relationship between plasma VEGF concentration and skin and joint involvement. DESIGN: Inception cohort studies of patients with generalized pustular psoriasis and plaque psoriasis. SETTING: St John's Institute of Dermatology, London, England. PATIENTS: Twenty-two patients (15 men and 7 women) with moderate and severe psoriasis were recruited (age range, 29-77 years; mean age, 47 years); 5 had generalized pustular psoriasis, 2 had erythrodermic psoriasis, and 15 had moderate-severe plaque psoriasis. An age- and sex-matched control group of 17 individuals (10 men and 7 women) was recruited (age range, 29-69 years; mean age, 42 years). RESULTS: There was pathological proteinuria in patients with relapsing generalized pustular psoriasis, (4-fold increase in urinary protein excretion rate in relapse compared with remission). In patients with moderate and severe psoriasis, mean plasma VEGF concentration during relapse was approximately 2.5 times greater than during remission (mean VEGF(relapse) = 257 pg/mL; mean VEGF(remission) = 103 pg/mL; P<.01). There was a correlation between extent of skin involvement and plasma VEGF level (mean VEGF(severe psoriasis) = 365 pg/mL; mean VEGF(moderate psoriasis) = 149 pg/mL; P =.03). There was a correlation between presence of psoriatic arthritis and plasma VEGF level (mean relapse VEGF(arthritis) = 277 pg/mL; mean relapse VEGF(nonarthritis) = 103.5 pg/mL; P =.03). CONCLUSIONS: Generalized pustular psoriasis is accompanied by pathological proteinuria and elevated plasma VEGF levels. Plasma VEGF concentration is significantly elevated in patients with extensive skin and joint involvement and may act on renal microvasculature to induce hyperpermeability.

Perceived stress, stress attributions and psychological distress in psoriasis.

OBJECTIVE: The objective of this study was to measure causal beliefs in individuals with psoriasis and to explore their relationship with perceived stress, quality of life, psychological well-being and psoriasis severity. METHODS: This study was cross-sectional in design, and patients were required to complete validated questionnaires assessing perceptions of illness, quality of life, psoriasis severity, perceived stress and psychological mood. A total of 141 individuals were recruited from two settings: an outpatient skin clinic at King's College Hospital and the Psoriasis Association. RESULTS: A strong belief in stress/psychological attributes as a causal factor was found in 61% of the sample. This belief was significantly associated with higher levels of anxiety, depression and perceived stress (r > or = .38; P < or = .0001). Perceived stress in this sample was significantly associated with a poorer level of quality of life, higher levels of anxiety and depression (r > or = .27; P < or = .002) but not with psoriasis severity. CONCLUSIONS: The belief that stress is causal was associated with lower levels of psychological well-being. However, there was no association between perceived stress and more objective measures of psoriasis severity.

Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris.

Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10(-11), odds ratio (OR) = 1.20), 5q11.2 (rs38055, P(combined) = 4.58 × 10(-9), OR = 1.17) and 1q41 (rs1159268, P(combined) = 4.08 × 10(-8), OR = 1.17). All three loci contain genes linked to the TGFß cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFß-mediated signalling in susceptibility to acne.

Stevens-Johnson syndrome/toxic epidermal necrolysis: are drug dictionaries correctly informing physicians regarding the risk?

BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe drug reactions associated with high mortality and multiple incapacitating sequelae. In the past 20 years, two large multinational case control studies, published in 1995 and 2008, had identified different degrees of drug association with SJS/TEN: 'strongly associated', 'associated', 'suspected' and 'not suspected' medications. OBJECTIVE: The aim of this study was to check the adequacy of mention of risk of SJS/TEN in the drug dictionaries most widely used by physicians in five European countries. STUDY DESIGN: In each country one expert investigator looked at the most widely used drug dictionary (2009 edition) for mentions of risk of SJS/TEN. This was done for a predefined list of medications with a different degree of risk. The presence and clarity or absence of warning was compared with available evidence provided by published results from case-control studies. SETTING: The five countries participating in the RegiSCAR group: Austria, France, Germany, The Netherlands and the UK. RESULTS: A total of 3,268 drug descriptions of medications for systemic use were analysed, including all brands of 14 'strongly associated' drugs, 5 'associated' drugs and 12 widely used drugs with no established association. Discrepancies were found by country, and between descriptions for different brands of the same generic. Among 522 descriptions of 14 'strongly associated' drugs, only 5 did not mention the risk. For the 1,013 descriptions of 'associated' drugs, 3 % did not mention the risk. One-third of 'not suspected' drugs contained a specific or less specific warning (e.g. bullous cutaneous eruption). Warnings for 'strongly associated' medications were often as imprecise as those for 'not suspected' drugs. CONCLUSION: Information on the risk of SJS/TEN in drug dictionaries needs improvement to enhance the quality of advice given by general physicians and to raise the understanding of risk by patients.