Impaired SARS-CoV-2 specific T-cell response in patients with severe COVID-19.

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis.

Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force.

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.

Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study.

BACKGROUND: Mixtures of fumaric acid esters (FAE) are used as an oral systemic treatment for moderate to severe psoriasis. Large clinical studies with dimethylfumarate (DMF) monotherapy are scarce. OBJECTIVES: The objective of this study is to assess the effectiveness and long-term safety of high-dose DMF monotherapy in moderate to severe psoriasis. METHODS: A prospective single-blinded follow-up study was performed in a cohort of patients treated with DMF. Patients were followed-up at fixed intervals. Assessment of consecutive photographs was performed by two observers. Primary outcome was a change in static physician global assessment (PGA) score. Safety outcome was defined as incidences of (serious) adverse events. RESULTS: A total of 176 patients with moderate to severe psoriasis were treated with DMF for a median duration of 28 months. The median daily maintenance dosage of 480 mg was reached after a median of 8 months. Psoriasis activity decreased significantly by 1.7 out of five points. A total of 152 patients reported one or more adverse events, such as gastrointestinal complaints and flushing. CONCLUSIONS: High-dose DMF monotherapy is an effective and safe treatment option in moderate to severe psoriasis. It can be suggested that 50% of all patients may benefit from high-dose DMF monotherapy.

The Association between Atopic Disorders and Keloids: A Case-control Study.

BACKGROUND: Keloids and atopic disorders share common inducing and maintaining inflammatory pathways that are characterized by T-helper cell 2 cytokines. AIMS AND OBJECTIVES: The objective of this study was to test for associations between keloids and atopic eczema, asthma and hay fever. MATERIALS AND METHODS: This was a case-control study with 131 patients diagnosed with keloids at our dermatology outpatient clinic between 2000 and 2012. Controls were 258 partners of keloid or sarcoidosis patients. Patient who reported life time prevalences of atopic eczema, asthma and hay fever were assessed using a questionnaire based on The European Community Respiratory Health Survey (ECRHS) and The International Study of Asthma and Allergies in Children (ISAAC). RESULTS: The prevalence of asthma was lower in keloid patients (19/131 vs. 20/258, P = 0.035), as was being diagnosed with asthma by a physician (18/131 vs. 19/258, P = 0.039) and using inhalators for asthma (13/131 vs. 7/258, P = 0.02). After adjusting for age and non-European descent the odds ratio for having a keloid was (adjusted OR = 4.44; 95% CI 1.59-12.40) in asthmatics using inhalators. There were no clear and consistent associations found for keloids with atopic eczema or with hay fever. CONCLUSION: In conclusion, our study shows that keloids may be strongly associated with atopic asthma. Atopic eczema and hay fever do not seem to be correlated with keloid. Further studies are warranted to assess the validity of atopic asthma as a risk factor for the development of keloid scars.

Prevalence of atopic diseases in patients with sarcoidosis.

It remains unclear whether atopy is associated with the occurrence of sarcoidosis or affects its severity. The purpose of this study was to compare the lifetime prevalence of atopic eczema, asthma, and hay fever in sarcoidosis patients with controls and to assess whether atopy influences the severity of sarcoidosis. The prevalence of atopic disorders assessed with a validated postal questionnaire in sarcoidosis patients with pulmonary, uveitis, and cutaneous sarcoidosis was compared with that of their domestic partners in a case-control study. The serological parameters, the pulmonary function tests, and the high-resolution computed tomography (HRCT) scans of atopic and nonatopic sarcoidosis patients were compared in a nested cohort. Multivariate logistic regression models were used to calculate the odds ratios (ORs) and the 95% confidence intervals (CIs). Two hundred twenty-five sarcoidosis patients and 177 controls were included. The prevalences of atopic eczema, asthma, and hay fever were comparable between patients and controls (12.4% versus 12.4%, 5.3% versus 5.6%, and 16.9% versus 15.8%, respectively). After adjusting for gender and ethnicity, those with sarcoidosis and a history of atopic eczema were significantly less likely to have uveitis (OR, 0.30; 95% CI, 0.13-0.71). Within the sarcoidosis cohort, the distributions of serological markers, the lung function tests, and the HRCT scans were similar between atopic and nonatopic patients. Atopy is not associated with the occurrence of sarcoidosis, but atopic eczema may decrease the likelihood of eye involvement.

Atopic dermatitis is not a protective factor for melanoma but asthma may be.

BACKGROUND: There is evidence from cohort studies for an inverse association between atopic dermatitis and asthma and cutaneous melanoma. However, these studies have been too heterogeneous and did not show statistically significant results. Also, this association has not been compared to traditional melanoma risk factors. OBJECTIVES: To test for associations between history of atopic disorders and melanoma life-time prevalence, and for associations between atopic disorders and melanoma prognosis. METHODS: Validated questionnaires from the European Community Respiratory Health Survey and International Study of Asthma and Allergies in Children protocol on life-time prevalence of atopic disorders were sent to 280 patients with histopathologically confirmed melanoma. The control group consisted of their spouses. The skin phototype was also assessed using a validated questionnaire. RESULTS: One hundred and eighty-four melanoma patients and 169 controls responded to the questionnaire. The life-time prevalence of atopic dermatitis and hayfever was not different in melanoma patients (8.7 % vs. 8.2, p = 0.890 and 15.2 vs. 18.3 %, p = 0.432, respectively). Asthma was non-significantly lower in melanoma patients (3.8 vs. 8.2 %, p = 0.075). Atopic melanoma patients did not differ from non-atopic patients in terms of Breslow thickness, metastases and second melanomas. CONCLUSION: Atopic dermatitis is not a protective factor in cutaneous melanoma but a history of asthma may be.

Enteric-coated mycophenolate sodium in psoriasis vulgaris: an open pilot study.

BACKGROUND: Mycophenolate mofetil is a well-known immunosuppressive agent in transplantation medicine. The efficacy of enteric-coated mycophenolate sodium (EC-MPS) was confirmed in other inflammatory skin diseases, including atopic dermatitis and SCLE. OBJECTIVE: To investigate the efficacy and the tolerability/short-term safety of EC-MPS in patients with moderate to severe chronic plaque psoriasis. PATIENTS AND METHODS: An open-label pilot study in which 20 patients with a PASI >10 received EC-MPS 720 mg twice daily for 6 weeks followed by 360 mg twice daily for another 6 weeks. Patients who completed 12 weeks of treatment were followed-up for an additional 12 weeks. Treatment outcomes were assessed with PASI50% and PASI75%. RESULTS: Eighteen men and two women (mean age 46 years) entered the study. Sixty-five percent (13/20) finished the treatment period. By week 6, no patient achieved PASI 75% and 8/20 patients achieved a PASI 50%. Compared to week 6, 4/13 showed a deterioration of their psoriasis at week 12. Twenty-five percent (2/8) achieved a PASI 75% in week 24. The most-reported adverse events were itching (30%), diarrhea (10%), and a reversible elevation of the triglycerides level. CONCLUSION: EC-MPS does not seem effective as monotherapy for moderate to severe psoriasis, but might be used at a dosage of 1440 mg daily in well-selected patients with treatment-resistant psoriasis.

Decreased prevalence of atopic features in patients with psoriatic arthritis, but not in psoriasis vulgaris.

BACKGROUND: The prevalence of atopic disorders is reduced in patients with various autoinflammatory diseases but, to our knowledge, this association has not been studied in psoriasis vulgaris or psoriatic arthritis (PSA). OBJECTIVE: Prevalence of hay fever, asthma, and sensitization to common aeroallergens was compared in patients with psoriasis vulgaris to patients with PSA and control subjects; we also investigated whether atopy influences the arthritis activity and severity scores in patients with PSA. METHODS: In a cross-sectional cohort study design, the differences in patient-reported lifetime prevalence of atopic disorders and serum IgE directed against common aeroallergens were compared. The effect of atopy on arthritis severity was assessed using the 28-joint Disease Activity Score and Health Assessment Questionnaire. Logistic regression models were used to calculate crude and adjusted odds ratios with 95% confidence intervals (CI) for presence of atopy. RESULTS: A total of 168 patients with PSA, 133 patients with psoriasis vulgaris, and 147 control subjects were included. The lifetime prevalence of hay fever did not differ across groups. Patients with PSA were less likely to have had asthma than control subjects (adjusted odds ratio 0.20; 95% CI 0.04-0.92) and they were less likely to be sensitized (adjusted odds ratio 0.50; 95% CI 0.25-0.99). Health Assessment Questionnaire-visual analog scales for pain and for patient global score were significantly reduced by sensitization to common aeroallergens (beta-coefficients -0.54 [95% CI -0.84 to -0.25] and -18.4 [95% CI -28.5 to -8.25], respectively.) LIMITATIONS: This was a cross-sectional, small-numbered study. CONCLUSION: Atopy may protect against development of PSA and diminish its severity.

Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals.

Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.

Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses.

Psoriasis vulgaris, a type-1 cytokine-mediated chronic skin disease, can be treated successfully with fumaric acid esters (FAE). Beneficial effects of this medication coincided with decreased production of IFN-gamma. Since dendritic cells (DC) regulate the differentiation of T helper (Th) cells, this study focussed on effects of monomethylfumarate (MMF, bioactive metabolite of FAE) on polarization of monocyte-derived DC. MMF-incubated, lipo-polysaccharide-stimulated DC (MMF-DC) produced dramatically (p<0.05) reduced levels of IL-12p70 and IL-10 (8+/-4% and 20+/-4%, respectively) compared to control DC. MMF-DC were mature. MMF affected polarization of DC irrespective of polarization factor(s) and ligands for the various Toll-like receptors used. Coculture of MMF-DC with naive and primed allogenous Th cells resulted in lymphocytes producing less IFN-gamma, i.e. 59% and 54% of that by the respective Th cells cocultured with control DC. IL-4 production by primed, but not naive Th cells cocultured with MMF-DC was decreased as compared to cocultures with control DC. IL-10 production by naive and primed Th cells cocultured with MMF-DC and control DC did not differ. In addition, MMF inhibited LPS-induced NF-kappaB activation in DC. Together, beneficial effects of FAE in psoriasis involve modulation of DC polarization by MMF such that these cells down-regulate IFN-gamma production by Th cells.