Biomedical subjects
T P Millard
Publications and source records attributed to T P Millard.
Changing patterns of contact allergy in chronic inflammatory ear disease.
Chronic inflammatory ear disease comprises a wide range of conditions. Although contact allergy to topical medicaments is common in such conditions, the causes of these reactions have not been examined in a large series for over a decade. Our aim was to investigate the major sensitizers recorded in 179 patients over the last 17 years. Medicament contact allergic dermatitis was diagnosed in 45 patients (25%), of whom 34 (76%) demonstrated a relevant allergy to neomycin, 28 (62%) to framycetin, 11 (31%) to gentamicin, 8 (18%) to quinoline mix and 5 (11%) to caine mix. Of all neomycin-allergic patients, 28 (76%) were also allergic to framycetin and 12 (43%) to gentamicin. Comparing the first 60 patients (1985-94) to the most recent 60 (1998-2002) identified a significant recent reduction in the number of patients allergic to neomycin (P = 0.002) and framycetin (P = 0.050), with a non-significant reduction in the total number diagnosed as medicament-allergic (P = 0.066). We have therefore demonstrated a high frequency of medicament contact allergy in chronic inflammatory ear disease, supporting the routine use of patch testing in these patients. We have also shown a significant recent reduction in the number of such patients with allergy to neomycin and framycetin.
Cutaneous hyperpigmentation during therapy with hydroxychloroquine.
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Aleukaemic leukaemia cutis presenting as a benign-appearing eruption.
A 68-year-old Caucasian male presented with a 5-week history of a widespread pruritic papular eruption. Histology from a papule on the left shoulder showed a dense dermal infiltrate of large mononuclear cells which were positive for leucocyte common antigen, KP1 and PGM1, with an MIB-1 proliferating fraction of 40%, diagnostic of acute monocytic (M5) leukaemia cutis. Full blood count revealed pancytopaenia but no blasts. Bone marrow aspirate showed reduced red cell precursors and 10% blasts, consistent with myelodysplastic syndrome (refractory anaemia with excess blasts). The patient was managed with a 3 unit transfusion of packed red cells, after which his skin eruption resolved within 6 weeks and his peripheral blood counts returned to normal. No chemotherapy was administered. In conclusion, leukaemia can present in the skin, the eruption may be nonspecific and it may precede systemic involvement by either myelodysplastic syndrome or acute leukaemia.
Erythrodermic cutaneous adverse drug reaction to oral pseudoephedrine confirmed on patch testing.
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Human Ro60 (SSA2) genomic organization and sequence alterations, examined in cutaneous lupus erythematosus.
BACKGROUND: The Ro 60 kDa protein (Ro60 or SSA2) is the major component of the Ro ribonucleoprotein (Ro RNP) complex, to which an immune response is a specific feature of several autoimmune diseases. The genomic organization and any sequence variation within the DNA encoding Ro60 are unknown. OBJECTIVES: To characterize the Ro60 gene structure and to assess whether any sequence alterations might be associated with serum anti-Ro antibody in subacute cutaneous lupus erythematosus (SCLE), thus potentially providing new insight into disease pathogenesis. METHODS: The cDNA sequence for Ro60 was obtained from the NCBI database and used for a BLAST search for a clone containing the entire genomic sequence. The intron-exon borders were confirmed by designing intronic primer pairs to flank each exon, which were then used to amplify genomic DNA for automated sequencing from 36 caucasian patients with SCLE (anti-Ro positive) and 49 with discoid LE (DLE, anti-Ro negative), in addition to 36 healthy caucasian controls. RESULTS: Heteroduplex analysis of polymerase chain reaction (PCR) products from patients and controls spanning all Ro60 exons (1-8) revealed a common bandshift in the PCR products spanning exon 7. Sequencing of the corresponding PCR products demonstrated an A > G substitution at nucleotide position 1318-7, within the consensus acceptor splice site of exon 7 (GenBank XM001901). The allele frequencies were major allele A (0.71) and minor allele G (0.29) in 72 control chromosomes, with no significant differences found between SCLE patients, DLE patients and controls. CONCLUSIONS: The genomic organization of the DNA encoding the Ro60 protein is described, including a common polymorphism within the consensus acceptor splice site of exon 7. Our delineation of a strategy for the genomic amplification of Ro60 forms a basis for further examination of the pathological functions of the Ro RNP in autoimmune disease.
Treatment of plaque psoriasis.
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Photodermatoses in the elderly.
Several photodermatoses specifically affect the elderly, and many others continue into old age. Photodermatoses present unique challenges in diagnosis and management when considered in the context of the multiple pathologies and problems of polypharmacy in this age group. This article examines the idiopathic photodermatoses, which include chronic actinic dermatitis, specifically a disease of the middle-aged and elderly. Endogenous (metabolic) and exogenous (drug and chemical) photodermatoses, as well as photo-exacerbated dermatoses, also are discussed.
Familial clustering of polymorphic light eruption in relatives of patients with lupus erythematosus: evidence of a shared pathogenesis.
BACKGROUND: Abnormal photosensitivity is a common feature of many forms of lupus erythematosus (LE). OBJECTIVES: To examine the role of polymorphic light eruption (PLE) as a possible predisposing factor for cutaneous forms of LE. METHODS: Eighty-five patients with well-characterized subacute cutaneous LE (SCLE) and discoid LE (DLE) were recruited from outpatient clinics, and the prevalence of PLE determined by detailed interview and clinical examination. RESULTS: Symptoms consistent with PLE were reported in 61% and 55% of SCLE and DLE patients, respectively; this was significantly higher than the overall population prevalence of 13.6% (P < 0.001), giving a relative risk (RR) for PLE in SCLE patients of 3.37 (95% confidence interval, CI 2.46--4.28) and DLE patients of 3.11 (95% CI 2.31--3.91). PLE developed before the onset of LE in 61% of cases (median interval 12 years, range 1--40), concomitantly in 24%, and subsequently in a further 15% (median interval 3.5 years, range 1--25). To delineate the relationship between PLE and LE further, the prevalence of PLE was determined in 103 otherwise unaffected first-degree relatives of SCLE and DLE probands; we had previously demonstrated clustering of PLE in families, reflecting a strong genetic component. We found a significantly higher PLE prevalence in relatives of the LE probands than in the general population (P < 0.001), giving an RR for PLE of 2.29 (95% CI 1.55--3.03) and 2.61 (95% CI 1.32--3.89) for female and male relatives, respectively. CONCLUSIONS: The high prevalence of PLE in LE patients, together with clustering of PLE among first-degree relatives of SCLE and DLE probands, suggests that there may be a shared pathogenetic basis for PLE and cutaneous LE. We propose that predisposition to PLE may contribute to the LE phenotype in otherwise susceptible individuals.
A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo.
BACKGROUND: Polymorphic light eruption (PLE) is a common inherited photosensitivity disorder, which may predispose to several related but distinct conditions, including subacute cutaneous lupus erythematosus (SCLE), discoid lupus erythematosus (DLE) and actinic prurigo (AP). OBJECTIVES: To examine specific candidate genes for shared susceptibility alleles between these related phenotypes. METHODS: Eighty-five caucasian patients with annular SCLE or DLE were recruited, in addition to 102 first-degree relatives. The prevalence of PLE in both the patient and relative groups was determined by detailed interview and clinical examination. Eighty-five patients with pure PLE and 59 patients with AP were also recruited. Candidate genes were analysed by typing of single nucleotide polymorphisms of IL10 (-1082 G/A and -819 C/T), FCGR2A (131 R/H), SELE (128 S/R), ICAM1 (241 G/R and 469 E/K), IL1A (+ 4845 G/T), IL1B (-511 C/T and + 3954 C/T), IL1RN (+ 2018 T/C) and TNF (-308 G/A) using polymerase chain reaction (PCR) with sequence-specific primers and 5'-nuclease PCR. RESULTS: A significant association was found between SCLE and the rare TNF -308 A allele when compared with patients with DLE (P = 0.043), PLE (P = 0.001), AP (P < 0.001) and healthy controls (P < 0.001). However, there was strong linkage disequilibrium between TNF -308 A and the HLA A*01, B*08, DRB1*0301 haplotype. A negative association was also found between SCLE and the IL1B + 3954 T allele (P = 0.039), but the significance was lost on correction for multiple testing. CONCLUSIONS: We have demonstrated the association of SCLE with the rare TNF -308 A allele, which may be pathogenic or, alternatively, a marker allele for the extended HLA A*01, B*08, DRB1*0301 haplotype that is associated with a number of autoimmune conditions. Although many of the other loci that we chose failed to demonstrate an association, a candidate gene approach remains the most logical one, and the most likely to yield positive results in the future.
Molecular genetics of cutaneous lupus erythematosus.
The cutaneous forms of lupus erythematosus (LE) are true complex traits, susceptibility to which is determined by multiple factors. Good evidence exists for both genetic and environmental components to this complexity. Several different experimental techniques have found the strongest genetic associations with cutaneous LE to include sequence polymorphisms of genes encoding HLA, TNF-alpha and complement molecules, particularly in anti-Ro-positive patients. Abnormal expression of multiple other cytokines, adhesion molecules and cellular proteins (such as Ro and La) points towards a range of candidate genes that are currently being examined in cutaneous LE. Combinations of specific polymorphisms of genes encoding these immunoregulatory molecules may determine individual susceptibility to LE.
Bone mineral density of patients with chronic plaque psoriasis.
Reduced bone mineral density (BMD), the major risk factor for osteoporotic fracture, has been linked to palmoplantar pustular psoriasis, but no significant studies have examined BMD in chronic plaque psoriasis (CPP). In this study, in-patients with severe CPP had their BMD measured at the nondominant hip and lumbar spine using dual energy X-ray absorbtiometry. Ten male and 10 female Caucasian patients were recruited, with a mean age of 47 years (range 20--71 years). There were no significant differences in BMD between patients and controls. However, patients with psoriatic arthropathy in addition to CPP had a significantly lower mean lumbar spine Z-score (- 1.16) than those without arthropathy (+1.38, P = 0.015). Neither previous nor current treatment with systemic steroids, retinoids or methotrexate significantly affected BMD. We found no evidence that patients with CPP, despite risk factors, have a significantly low BMD, although the subgroup with joint involvement appear be at significantly higher risk of osteoporosis and may therefore require preventative treatment.
Avoidance of adrenaline in peripheral local anaesthesia: a perpetuated medical myth?
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Ultraviolet therapy in lupus.
This review examines the use of ultraviolet (UV) therapy in lupus erythematosus (LE), a disorder usually associated with abnormally increased photosensitivity. In addition to the abnormal cutaneous response to ultraviolet radiation (UVR) exposure, photo-aggravation of systemic disease activity in systemic LE (SLE) may also occur. However, courses of UVR exposure may also be used in the treatment or prophylaxis of various photodermatoses, and LE now appears to be included in that group. Thus, several studies have reported apparent benefits of phototherapy in both cutaneous and systemic LE, although the underlying mechanisms remain obscure and final confirmation of such efficacy is still awaited in continuing studies.
Polymorphic light eruption and the HLA DRB1*0301 extended haplotype are independent risk factors for cutaneous lupus erythematosus.
Recent evidence suggests that polymorphic light eruption (PLE) is an inherited photosensitivity disorder which may predispose to cutaneous lupus erythematosus (LE). In this study we examine the relative risk (RR) attributable to the presence of PLE, together with the effect of the major histocompatibility complex (MHC) in the development of cutaneous LE. Eighty-five Caucasian patients with annular subacute cutaneous LE (SCLE) and discoid LE (DLE) were recruited, together with 102 first degree relatives and 200 healthy local Caucasian controls. Symptoms suggestive of PLE were elicited in patients and relatives, and human leukocyte antigen (HLA) typing determined by PCR-SSP. Standard association analysis and family transmission disequilibrium testing (TDT) were then used to compare the HLA frequencies between groups. We found a significant (P < 0.05) association of the HL4 A*01, B*08, DRB1*0301 extended haplotype with both SCLE and DLE and also significant association of DLE with the HLA A*03, B*07, DRB1*15 haplotype, with a possible protective effect in SCLE for HLA B*44 and DRB1*04 (P=0.002 and 0.001 respectively). Association was observed between PLE and cutaneous LE (P < 0.001), but not between PLE and any HLA allele. From these figures we estimate, for the general population, that the RR of developing SCLE given the presence of (a) PLE, (b) DRB1*0301 and (c) both PLE and DRB1*0301 is 3.37, 5.45 and 12.03, respectively. For DLE, equivalent RRs are 3.11, 2.15 and 6.94. In conclusion, these data imply the involvement of both PLE and HLA DRB1*0301 in the development of SCLE and DLE. They form a basis for examining the genetic architecture of photosensitivity, some aspects of which may be common to both cutaneous LE and PLE.
Atypical pigmented lesions following extensive PUVA therapy.
We report a 38-year-old woman with psoriasis who developed multiple atypical lentigines following psoralen photochemotherapy (PUVA). The lentigines first appeared 12 years ago, 3 years after she commenced intermittent PUVA treatment. New lesions continued to develop over the subsequent years with further photochemotherapy. Clinically, the lentigines were strikingly atypical, deeply pigmented, dark brown or black, large stellate macules. Histology of a representative lesion was consistent with a PUVA lentigo and no atypical melanocytes were seen. At present, a link between malignant melanoma and PUVA lentigines has not been established. Instead, limited evidence suggests that PUVA lentigines may be more closely linked with the risk of nonmelanoma skin cancer.
The heritability of polymorphic light eruption.
Polymorphic light eruption is classified as an acquired idiopathic photodermatosis, yet it appears to cluster in families, suggesting a possible genetic component. In this study, we assess the heritability of polymorphic light eruption using the classical twin model. Polymorphic light eruption was investigated by a nurse-administered questionnaire in a sample of 420 pairs of adult female twins from St Thomas' Hospital UK Adult Twin Registry, including 119 monozygotic and 301 dizygotic pairs. Probandwise concordance for the presence and absence of disease was calculated and the heritability of polymorphic light eruption assessed by a quantitative genetic model fitting approach using Mx software. The prevalence of polymorphic light eruption was 21% and 18% in monozygotic and dizygotic twins, respectively. A family history of polymorphic light eruption in first-degree relatives (not including the cotwin) was present in 12% of affected twin pairs (where at least one twin had polymorphic light eruption) compared with 4% of unaffected twin pairs, providing evidence of familial clustering (p < 0.0001). The probandwise concordance for polymorphic light eruption was higher in monozygotic (0.72) than in dizygotic twin pairs (0.30), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising additive genetic (A) and unique environmental (E) factors provided the most parsimonious fit, although a dominant gene effect could also explain our data. In the AE model, 84% (95% confidence interval 65-94%) of the variance in susceptibility to polymorphic light eruption is attributed to additive genetic factors with the remaining 16% (95% confidence interval 6-35%) to unique environmental effects. These data establish a clear genetic influence in the expression of polymorphic light eruption and provide a basis for examining candidate genes that may be pathogenic in this common condition.
Photosensitivity in lupus.
A wide variety of skin conditions may present in patients with lupus erythematosus (LE). These can be broadly divided into three main groups: cutaneous forms of LE ('LE-specific skin disease'), non-specific cutaneous manifestations of SLE ('LE non-specific skin disease') and cutaneous complications of drug treatments for LE. This review examines clinical photosensitivity in LE, a trait most commonly associated with cutaneous forms of LE but which may also manifest in SLE. All humans are photosensitive, developing reddening of the skin if exposed to sufficient ultraviolet radiation (UVR). Therefore we define photosensitivity in clinical practice as an abnormal cutaneous response to UVR. Abnormal photosensitivity in LE may manifest in a number of different forms. The lesions of LE-specific skin disease may be induced or exacerbated by UVR. Patients with LE who are prescribed photosensitizing medications such as thiazide diuretics, neuroleptics and tetracyclines may also develop phototoxic reactions which usually present as easy sunburn. Photosensitivity may also, rarely, manifest as fragile skin and blistering in patients with both LE and porphyria cutanea tarda. Several other photosensitive disorders have been reported in association with LE, including solar urticaria and erythropoetic protoporphyria (EPP), but these appear to be chance associations. Assessment of patients with LE and photosensitivity requires a careful history and examination. Phototesting and photoprovocation tests may be used to demonstrate photosensitivity in some cases, but these are rarely required for diagnosis. Photosensitive patients should be advised about sun avoidance, photoprotection and sunscreen use as a first line treatment.