We have investigated the Kodak Ektachem 400 Analyzer procedure for CO2 for interferences from benzyl alcohol, benzoic acid, and several compounds structurally similar to benzoic acid. Benzoic acid in plasma, at concentrations found in neonates intoxicated with benzyl alcohol, caused a large increase in the results for CO2, as did substantially above-normal concentrations of certain fatty acids and keto-acids, and toxic concentrations of aspirin. We observed a correlation between increasing benzoic acid concentrations (up to 17 mmol/L) and falsely increasing CO2 values (greater than 47 mmol/L) obtained with the Ektachem Analyzer for samples from a neonate in the intensive-care unit, who was receiving benzyl alcohol-preserved saline solutions. Although the Ektachem CO2 procedure is simple and rapid, and in most cases accurate, questionable results are occasionally encountered, as indicated by a low anion gap or a measured CO2 exceeding that calculated from blood gas measurements. Such results require the use of another method for verification.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a multipotent cytokine produced by many cutaneous cell types including keratinocytes. Langerhans cells (LC) represent the major antigen-presenting cells in skin, and in vitro studies demonstrate that GM-CSF is of pivotal importance in LC. Healthy volunteers (n = 3 non-atopic, n = 3 with atopy) received recombinant human GM-CSF (0. 05 microg/mL) by intradermal injection for 3 days to the same site. Diluent was injected in a similar manner as control. Biopsies were taken 24 h after the final injection and examined immunohistochemically for LC and inflammatory cell markers. Compared with control sites, intradermal GM-CSF resulted in shortening of dendritic cell processes and redistribution of LC in the epidermis; numbers of CD1a + cells in the epidermis were significantly decreased (P < 0.005), while those in the dermis were significantly increased (P < 0.05) following intradermal GM-CSF when compared with controls. Double labelling studies on epidermal CD1a + cells indicated de novo expression of intercellular adhesion molecule (ICAM)-1 and increased expression of HLA-DR following GM-CSF (P < 0. 005, P < 0.005, respectively). Additional findings included a marked mixed inflammatory cell infiltrate in the dermis and increased expression of the endothelial cell adhesion molecules E-selectin and ICAM-1. These data indicate that in normal human skin, GM-CSF induces changes in the phenotype and distribution of CD1a + cells consistent with LC functional maturation and exit from the epidermis to the dermis. As these events are central to the initiation of cutaneous inflammation, GM-CSF may potentially play a critical role in the pathogenesis of inflammatory dermatoses.

Summary We report a patient with diffuse plane xanthomatosis, acquired palmoplantar keratoderma, and myeloma. Although diffuse plane xanthomatosis is a recognized manifestation of paraproteinaemia, keratoderma is not. However, successful treatment of the myeloma in our patient coincided with a dramatic improvement in the keratoderma, suggesting a genuine association between the two disorders.

Background:Atopic dermatitis (AD) is a common skin condition with a prevalence of 2–10% in adults1. IL-4 and IL-13 play a key role in the pathogenesis. Dupilumab, a human IgG4 monoclonal antibody binding the alpha subunit of the IL-4 receptor, blocking IL-4 and IL-13 signaling, has important efficacy in this difficult to treat disease. We first reported a musculoskeletal (MSK) adverse effect of enthesis/arthritis developing in 3 patients in 20192.Objectives:To report the ongoing experience at our centre of this new clinical paradigm, incidence and patient progress including clinical presentation, imaging and management.Methods:Clinical and radiological data was collected from electronic case records of all cases presenting with features of enthesitis/arthritis between October 2018 and January 2021.Results:Since initiation of dupilumab at GSTT, approximately 400 adults with moderate-to-severe AD have received at least one dose. Of these, 23 patients (14 men, 9 women) had the clinical syndrome of inflammatory enthesitis/tenosynovitis/arthritis. Nine patients had both enthesitis and arthritis, 10 enthesitis, 3 enthesitis and tenosynovitis and 1 arthritis only. Four of these also reported new onset inflammatory back pain symptoms. None had a preceding history of arthritis or enthesitis. Median onset of symptoms following initiation of dupilumab was 4 months. However, onset of symptoms ranged between 2 weeks and 48 months. Imaging (US/MRI) was performed in 18 patients, 11 with Doppler US positive enthesitis confirming clinical findings. Most common sites were lateral epicondyles, achilles and patella tendons. Two patients with more disabling symptoms had MRI confirmed gluteus medius and hamstring enthesitis and arthritis. Spine and SI joint MRI in 4 patients was negative. Most patients had normal inflammatory markers except 2; CRP 117, ESR 96 and CRP 13, ESR 10. All patients had very good AD response to dupilumab, average EASI score before and after Dupilumab was 21 and 4.2 respectively. One patient developed skin manifestations of guttate psoriasis, with subsequent disabling arthritis/enthesitis. Due to the life-changing beneficial effect of dupilumab therapy most patients did not want to stop therapy. We used NSAID therapy, etoricoxib/celecoxib/naproxen for symptom relief which was usually partly effective allowing continuation of dupilumab treatment in most. Five patients with severe MSK symptoms stopped Dupilumab completely. Some patients temporarily paused therapy but re-started as their AD became worse, often changing from the usual 2 weekly to 4 weekly dosing. Most patients continuing dupilumab had persistent MSK symptoms. Four patients who stopped dupilumab were treated with baricitinib, which has potential efficacy for both MSK symptoms and AD. Two did not tolerate it and remained on NSAID therapy.Conclusion:These data further characterize a new syndrome of enthesitis and/or arthritis induced by Dupilumab. In those with mild MSK symptoms use of NSAIDs allows continuation of full-dose dupilumab, in moderate cases reducing dupilumab dose frequency plus NSAID therapy maintains function. Most patients had on-going MSK symptoms. In more severe cases JAKi therapy may be an effective strategy. Our initial hypothesis that inhibition of IL-4/13 by dupilumab triggers an IL-17/23/TNF-mediated inflammatory MSK syndrome in some patients is supported by a recent in vitro study3.References:[1]Beck L et al. Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis. July 10, 2014. N Engl J Med 2014; 371:130-139[2]Willsmore ZN et al. Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series. Br J Dermatol 2019; 0. doi:10.1111/bjd.18031.[3]Bridegwood C et al. Regulation of entheseal IL-23 expression by IL-4 and IL-13 as an explanation for arthropathy development under dupilumab therapy. Rheumatology (Oxford). 2020 Nov 30:keaa568. doi: 10.1093/rheumatology/keaa568Disclosure of Interests:Joseph Nathan: None declared., Catherine Hughes Speakers bureau: Presented for Abbvie, Samir Patel: None declared., Libin Mathew: None declared., Catherine Smith Grant/research support from: Grants/research support; Professor Smith is a PI/CoPI on a number of commercially supported studie (Abbvie, Janssen, Leo, Sanofi)., Andrew Pink Paid instructor for: Speaker or advisor to Lilly, Abbvie, Sanofi, Leo, Almirall, Novartis, Janssen, UCB, Galderma, BMS, La-Roche Posay, Richard Woolf: None declared., Bina Menon Speakers bureau: Presented for Abbvie, L Bruce Kirkham Grant/research support from: Professor Kirkham has received honoraria and/or research funding from AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer and UCB.