Enes Hajdarbegovic

Human IgE+ B cells are derived from T cell–dependent and T cell–independent pathways

BACKGROUND The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. OBJECTIVE We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. METHODS We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand-deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed. RESULTS Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE(+) plasma cells and CD27(+)IgE(+) memory B cells fitted with a germinal center (GC)-dependent pathway, often through an IgG intermediate, as evidenced from Sγ remnants in Sμ-Sε switch regions. CD27(-)IgE(+) cells showed limited proliferation and SHM and were present in CD40 ligand-deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE(+) plasma cells and CD27(+)IgE(+) memory B cells but increased numbers of CD27(-)IgE(+) memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis. CONCLUSIONS We delineated GC-dependent and GC-independent IgE(+) B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE(+) B cells in patients with severe disease undergoing anti-IgE treatment.

Neoplasms of the Facial Skin

Neoplasms of the skin are found most often on the face. Malignant tumors of the facial skin pose a challenge in treatment, prohibiting compromises between oncologically responsible surgery and functional plus cosmetic outcome. The incidence of melanoma and nonmelanoma skin cancers is rising. Not all malignancies of the skin need to be treated by surgery. For in situ variants there are other options, such as photodynamic therapy and medical treatment. Knowledge of the clinical manifestation, behavior, and prognosis and histopathologic analysis lead to correct diagnosis and choice of suitable treatment. This article presents a synopsis of nonmelanoma, melanoma, and other cancers of the skin.

Atopic dermatitis is not associated with actinic keratosis: cross-sectional results from the Rotterdam study

Epidermal barrier impairment and an altered immune system in atopic dermatitis (AD) may predispose to ultraviolet‐induced DNA damage.

Lower lifetime prevalence of atopy in rheumatoid arthritis.

There is evidence that the prevalence of atopic disorders may be lower in patients with autoimmune conditions [1]. In the past, five studies have looked into the associations between atopy and rheumatoid arthritis (RA). All have found evidence of a lower prevalence of atopy in RA patients. However, they were either only questionnaire based, without serological confirmation of atopy [2–4], or they did not account for all manifestations of atopy [4–6]. We have set out to assess the lifetime prevalence of clinical and serological manifestations of atopy in RA patients in a case control study. The subjects were recruited between July 2010 and July 2011, from outpatient clinic for rheumatology at the Maxima Medical Center, Eindhoven, and the controls were patients with varicosities from our phlebology outpatient clinic. All subjects provided informed consent, and the study protocol was reviewed by the local Medical Ethical Committee. The diagnosis of RA was made according to the criteria of the American Rheumatism Association. The disease activity and course severity in RA patients were assessed with disease activity score 28 (DAS) and Health Assessment Questionnaire Disability Index, respectively (HAQDI) [7, 8]. Manifestations of atopy were assessed using a questionnaire based on the European Community Respiratory Health Survey [9]. Blood samples were taken from all subjects and levels of total serum IgE, and IgE directed against common aeroallergens were measured using Phadiatop; Phadia AB, Uppsala Sweden, according to the manufacturers protocol. One hundred and thirty-three RA patients and 124 controls were included. Eighty-nine (66 %) of the RA patients were anti-CCP positive and 90 (67 %) were currently treated with methotrexate. The average age at onset of RA was 50 years, standard deviation 13. The average age was higher in RA patients than in controls (62 vs. 54 years, p \ 0.001). There were 48 (36 %) and 53 (42 %) males in RA and control group, respectively (p = 0.278). RA patients reported previous symptoms of dermatitis, itching and flexural rash less often (20 vs. 33 %, p = 0.020) and (9 vs. 19 %, p = 0.037) (Table 1). However, dry skin during last year, a measure of current symptomatology of atopic dermatitis, was reported equally in both groups (44 vs. 44 %, p = 0.896). RA patients also reported having had hay fever less often (11 vs. 20 %, p = 0.032). The percentage of patients diagnosed with asthma was lower in the RA group although the difference did not reach statistical significance (8 vs. 14 %, p = 0.086). Current asthma symptomatology expressed as asthma attacks in the last year and inhalator use were equally distributed across both groups (Table 1). Finally, serological evidence of atopy was less often found in RA patients. Twelve per cent of the RA group had a serum IgE level of more than 100 kU/L, and in controls, this was 21 %, p = 0.053. A smaller percentage of the RA group were sensitized to common aeroallergens than controls (22 vs. 33 %, p = 0.043). Having any atopic feature lowered the odds of having RA by roughly 60 % with OR 0.43; 95 % CI [0.25–0.75]. Adjusted for age and sex this was OR 0.51; 95 % CI [0.28–0.92]. The median HAQDI in sensitized RA patients did not differ from the median in non-sensitized patients (1.0; IQR [0.3–1.6] vs. 1.0; IQR [0.4–1.5], p = 0.375). The DAS28 score was equally distributed in sensitized and non-sensitized RA patients as well (2.6; IQR [2.1–3.9] vs. 3.2; IQR [2.2–4.0], p = 0.343). In conclusion, RA patients had a lower prevalence of clinical and serological atopic features. Atopy had no effect E. Hajdarbegovic (&) B. Thio T. Nijsten Rotterdam, The Netherlands e-mail: e.hajdarbegovic@erasmusmc.nl

Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: A cross-sectional study

BackgroundGlatiramer acetate (GA) and interferon-beta (IFN-β) are disease-modifying therapies (DMTs) for multiple sclerosis that are administered through subcutaneous (SC) or intramuscular (IM) injections. Skin reactions associated with DMTs are common and may influence patient’s health-related quality of life (QoL). We aimed to determine the prevalence of cutaneous adverse events associated with long-term DMT use, and to assess the impact of cutaneous adverse events on QoL.MethodsA cross-sectional study among patients with multiple sclerosis who had been treated with their first DMT for at least 2 years. Cutaneous events were assessed from photographs of injection-sites by dermatologists blinded for DMT. Generic and dermatology-specific health-related QoL were assessed using validated patient-reported questionnaires.ResultsA total of 229 patients were enrolled, of whom 156 (68%) had at least one skin reaction. The prevalence of cutaneous adverse events was higher for SC DMTs (75-82%) compared to IM DMT (41%) (P < 0.001). Erythema and lipoatrophy were the most common skin reactions, observed in 156 (68%) and 45 (20%) patients, respectively. Dermatology-specific, but not generic, QoL was significantly lower among patients with skin reactions compared to those without.ConclusionsThe prevalence of cutaneous adverse events was high in long-term DMT-treatment. Patients with cutaneous adverse events had a lower perceived dermatology-specific QoL.

Cidofovir Gel as Treatment of Follicular Spicules in Multiple Myeloma

IMPORTANCE The cause of follicular spicules in multiple myeloma (MM) is not known. OBSERVATIONS We present a case of follicular spicules in a patient with MM, which is very reminiscent of trichodysplasia spinulosa caused by a polyomavirus. No trichodysplasia spinulosa-associated polyomavirus could be isolated from the skin lesions; however, the spicules were positive for Merkel cell carcinoma virus, which is also a polyomavirus. CONCLUSIONS AND RELEVANCE Follicular spicules in MM are probably not caused by the trichodysplasia spinulosa-associated virus. Merkel cell polyomavirus could contribute to the origin of this dermatosis.

Drug-induced psoriasis: clinical perspectives

Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxy)chloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of “classical” nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments.

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.

Non-melanoma skin cancer: The hygiene hypothesis

Protection against ultra violet radiation-induced DNA-damage in the skin is not only provided by the pigmentary system. The epidermal barrier consisting of stratum corneum keratinocytes, filaggrin and other proteins is an additional component of the UV-shield. Disruption of the epidermal barrier through frequent body cleansing with soaps and cosmetics may increase the risk of non-melanoma skin cancer.

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.