Proton pump inhibitor induced subacute cutaneous lupus erythematosus: Clinical characteristics and outcomes.

BACKGROUND: There is a growing literature reporting the association between proton pump inhibitor (PPI) use and subacute cutaneous lupus erythematosus (SCLE). AIMS: To compare the clinical characteristics of a cohort of patients with PPI-induced SCLE, their clinical course and treatment with a control group of primary SCLE patients not exposed to PPI. METHODS: We conducted a matched case-control study in a tertiary referral setting at the Louise Coote Lupus Unit. There were 64 SCLE patients: 36 with PPI-induced SCLE and 28 patients with primary SCLE. RESULTS: Twenty-six patients (72%) had pre-existing SLE in the PPI-induced SCLE group. Lower limb skin lesions were significantly more prevalent in the PPI group (p < 0.0001). The prevalence of anti-Ro and anti-Ro-52 antibodies was numerically higher in the PPI group (64% and 60%), respectively, compared with 46% and 42% in the primary SCLE group. Peripheral blood eosinophils were normal in all patients in the PPI group. Thirteen patients underwent skin biopsy in the PPI group and 12 had histology in keeping with SCLE. The median time to presentation was 8 months with a median resolution period of 6 weeks. PPIs were stopped in 34 patients, while 2 patients continued treatment for other clinical indications. Twelve patients received concurrent oral corticosteroids. Two patients had severe SCLE in the form of Toxic Epidermal Necrolysis requiring critical care admission and were managed with corticosteroids, IV immunoglobulin and/or belimumab. CONCLUSION: Lower limb involvement is a pointer to PPI-induced SCLE which is likely a class effect with all PPI.

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is defined by extreme sensitivity to sunlight, resulting in sunburn, pigment changes in the skin and a greatly elevated incidence of skin cancers. It is a rare autosomal recessive disorder and has been found in all continents and racial groups. Estimated incidences vary from 1 in 20, 000 in Japan to 1 in 250, 000 in the USA, and approximately 2.3 per million live births in Western Europe.The first features are either extreme sensitivity to sunlight, triggering severe sunburn, or, in patients who do not show this sun-sensitivity, abnormal lentiginosis (freckle-like pigmentation due to increased numbers of melanocytes) on sun-exposed areas. This is followed by areas of increased or decreased pigmentation, skin aging and multiple skin cancers, if the individuals are not protected from sunlight. A minority of patients show progressive neurological abnormalities. There are eight XP complementation groups, corresponding to eight genes, which, if defective, can result in XP. The products of these genes are involved in the repair of ultraviolet (UV)-induced damage in DNA. Seven of the gene products (XPA through G) are required to remove UV damage from the DNA. The eighth (XPV or DNA polymerase η) is required to replicate DNA containing unrepaired damage. There is wide variability in clinical features both between and within XP groups. Diagnosis is made clinically by the presence, from birth, of an acute and prolonged sunburn response at all exposed sites, unusually early lentiginosis in sun-exposed areas or onset of skin cancers at a young age. The clinical diagnosis is confirmed by cellular tests for defective DNA repair. These features distinguish XP from other photodermatoses such as solar urticaria and polymorphic light eruption, Cockayne Syndrome (no pigmentation changes, different repair defect) and other lentiginoses such as Peutz-Jeghers syndrome, Leopard syndrome and Carney complex (pigmentation not sun-associated), which are inherited in an autosomal dominant fashion. Antenatal diagnosis can be performed by measuring DNA repair or by mutation analysis in CVS cells or in amniocytes. Although there is no cure for XP, the skin effects can be minimised by rigorous protection from sunlight and early removal of pre-cancerous lesions. In the absence of neurological problems and with lifetime protection against sunlight, the prognosis is good. In patients with neurological problems, these are progressive, leading to disabilities and a shortened lifespan.

Retinal vein occlusion, homocysteine, and methylene tetrahydrofolate reductase genotype.

PURPOSE: The aim of this case-control study was to investigate the relationship between homocysteine (tHcy), 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T genotype, folate and vitamin B12 status, and retinal vein occlusion (RVO). METHODS: Subjects with RVO (n = 106) were recruited from outpatient and inpatient sources. Controls (n = 98) were selected to achieve a similar age and sex distribution. Full ocular examination was performed and medical history was taken for each study participant. Plasma and serum samples were analyzed for tHcy level and folate and vitamin B12 status, and extracted DNA was assessed for the MTHFR C677T genotype. RESULTS: There was no significant difference in plasma tHcy level or thermolabile MTHFR allele frequency between subjects and controls. Similarly, there was no significant difference in folate or vitamin B12 status between subjects and controls. MTHFR genotype did not affect folate or vitamin B12 concentrations in subjects or controls. However, tHcy was significantly higher in thermolabile homozygotes than in nonthermolabile homozygotes (ratio of geometric means, 1.35; 95% confidence interval [CI], 1.04-1.74; P = 0.024). CONCLUSIONS: Hyperhomocysteinemia, the MTHFR C677T mutation, and folate and vitamin B12 status are not important risk factors for RVO in this population.

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p.

OBJECTIVE: To replicate, in a Northern Irish population, the previously reported association between a locus on chromosome 6 and hip osteoarthritis (OA). METHODS: Patients with hip OA were identified from a registry of patients who had undergone total hip replacement surgery over an 8-year period at a single large orthopedic unit in Northern Ireland. Patients identified as index cases were contacted by mail and asked to reply only if another family member also had undergone total hip replacement surgery. Using this approach, we identified 288 sibling pairs concordant for primary hip OA. DNA was extracted from peripheral blood, and microsatellite markers were amplified by polymerase chain reaction and subsequently genotyped. RESULTS: No evidence of linkage to this region was demonstrated by either 2-point analysis or multipoint analysis of 17 microsatellites. CONCLUSION: The reported association between a locus on chromosome 6 and hip OA could not be confirmed in this population. Different methods of ascertainment and phenotyping of OA may contribute to the current inability to replicate genetic associations for hip OA.