Freja Lærke Sand

TNF-Alpha Inhibitors for Chronic Urticaria: Experience in 20 Patients

Patients with severe chronic urticaria may not respond to antihistamines, and other systemic treatment options may either be ineffective or associated with unacceptable side effects. We present data on efficacy and safety of adalimumab and etanercept in 20 adult patients with chronic urticaria. Twelve (60%) patients obtained complete or almost complete resolution of urticaria after onset of therapy with either adalimumab or etanercept. Further three patients (15%) experienced partial response. Duration of treatment ranged between 2 and 39 months. Those responding completely or almost completely had a durable response with a mean of 11 months. Six patients (30%) experienced side effects and five patients had mild recurrent upper respiratory infections, whereas one patient experienced severe CNS toxicity that could be related to treatment with TNF-alpha inhibitor. Adalimumab and etanercept may be effective and relatively safe treatment options in a significant proportion of patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom standard immunosuppressive drugs are ineffective or associated with unacceptable side effects.

Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients.

Tumor necrosis factor‐alpha (TNF)‐alpha inhibitors are licensed for patients with severe refractory psoriasis and psoriatic arthritis. However, TNF‐alpha inhibitors have also been used off‐label for various recalcitrant mucocutaneous diseases. This study aimed to evaluate the efficacy and safety of TNF‐alpha inhibitors used for off‐label dermatological indications. We retrospectively evaluated patient records of 118 patients treated off‐label with TNF‐alpha inhibitors in a dermatological university department. Patients presented with severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), dissecting cellulitis of the scalp (two), orofacial granulomatosis (four), sarcoidosis (four), granuloma annulare (two), granulomatous rosacea (one), granuloma faciale (one), subcorneal pustulosis (one), pyoderma gangrenosum (four), Sweets syndrome (four), Wells syndrome (one), benign familial pemphigus (one), lichen planus (one), and folliculitis decalvans (one). A significant number of these patients went into remission during therapy with TNF‐alpha inhibitors. A total of 11 patients (9%) experienced severe adverse effects during therapy. Off‐label therapy with TNF‐alpha inhibitors may be considered for selected patients with severe recalcitrant mucocutaneous diseases. The risk of severe adverse effects signals that a thorough benefit–risk assessment should be performed before initiating off‐label treatment with TNF‐alpha inhibitors for these conditions.

Efficacy and safety of TNF-α inhibitors in refractory primary complex aphthosis: a patient series and overview of the literature.

Background: Otherwise healthy patients with severe recurrent mucocutaneous aphthous ulcerations (complex aphthosis) may require systemic immunomodulatory therapy. However, a subset of patients remain resistant or intolerant to recommended therapeutic agents. Recently, case reports have described that tumor necrosis factor-α (TNF-α) inhibitors may induce remission in these patients. Methods: Data on efficacy and safety of various TNF-α inhibitors used as monotherapy in a case series of 18 patients with refractory primary complex aphthosis are presented. Results: A total of 16 patients (89%) obtained complete or almost clearance of orogenital aphthous ulcerations rapidly after onset of therapy either with etanercept, adalimumab, infliximab or golimumab. Duration of treatment ranged between 3 and 77 months. Nine patients (50%) received more than one TNF-α inhibitor during the course of treatment. Five (28%) patients experienced side effects that could be related to treatment with TNF-α inhibitors. Conclusion: TNF-α inhibitors are an effective and safe treatment option for patients with severe complex aphthosis who do not respond sufficiently to standard therapy as recommended by existing guidelines. However, the final position of TNF-α inhibitors in the therapeutic armamentarium awaits randomized controlled trials.

Adalimumab for the Treatment of Refractory Acne Conglobata

Tumor necrosis factor (TNF) inhibitors have become important components of the treatment of multiple chronic inflammatory disorders such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn disease, and ulcerative colitis. Furthermore, off-label use of TNF inhibitors has been reported for a variety of other diseases. We report a case of refractory acne conglobata treated with the TNF inhibitor adalimumab.

Dermatological Diseases Associated with Pregnancy: Pemphigoid Gestationis, Polymorphic Eruption of Pregnancy, Intrahepatic Cholestasis of Pregnancy, and Atopic Eruption of Pregnancy

Dermatoses unique to pregnancy are important to recognize for the clinician as they carry considerable morbidity for pregnant mothers and in some instances constitute a risk to the fetus. These diseases include pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. This review discusses the pathogenesis, clinical importance, and management of the dermatoses of pregnancy.

Adherence to TNF-alpha inhibitors in patients with hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory, painful skin disease characterized by abscesses, nodules, fistulas and scarring in the axillary, groin and infra-mammary areas (1). Severe HS remains a therapeutic challenge and in many patients treatment with topical or systemic antibiotics or retinoids is ineffective or not well tolerated. The discovery of tumor necrosis factor alpha (TNF-a) in the pathophysiology of HS holds promise that treatment with TNF-a inhibitors provides symptomatic relief in these patients (2). We read with interest the systematic review by van Rappard et al. concerning off-label treatment of HS with TNF-a inhibitors (3). Based on 65 studies, mainly case reports and case series, involving 459 patients, and including four randomized controlled trials (RCTs) it was concluded that infliximab and adalimumab – but not etanercept – can be a useful supplement to the treatment of recurrent severe HS (evidence 1B). Treatment recommendations based mainly on case reports (or case series) tend to appreciate the intervention more than if the recommendation was built on a higher level of evidence, for example, cohort studies or RCTs. In contrast, RCTs often include selected patient groups and therefore do not reflect the broad spectrum of patients represented in daily clinical practice. Consequently, data on adherence and sustainability of treatment of HS with TNF-a inhibitors are lacking, and importantly, longterm follow-up data from real-life studies are needed to establish further the position of TNF-a inhibitors in the therapeutic hierarchy of HS. Since June 2007, we have treated 27 HS-patients at a tertiary referral center (Bispebjerg Hospital, Copenhagen, Denmark) with TNF-a inhibitors. These patients did not respond sufficiently to other recommended systemic agents such as antibiotics (tetracycline, clindamycin, rifampicin and dapsone) or retinoids (isotretinoin, acitretin, etc.). All patients had frequent, recurrent and severe HS of the axillary, groin and/or infra-mammary areas. Prior to therapy all patients screened negative for tuberculosis and hepatitis. The mean age of the population was 40.9 years (range 21–64); 17 (63%) were women (mean age 37.9 years) and 10 (37%) were men (mean age 46.0 years). One patient was HIV-positive. A total of 19 patients (70%) initially received adalimumab 40 mg twice monthly; five patients (19%) received etanercept 50 mg once weekly; two patients received certulizumab twice monthly; and one patient received infliximab 500 mg once every second month. The choice of primary drug was not based on a pre-specified belief of superiority of one drug over another. The median adherence time summed over all drugs was 269 d for men and 182 d form women (log-rank p value for difference between men and women1⁄4 0.311). Age was a positive predictor for adherence, lowering the risk of adherence failure with 3% per year increase in age, however, not statistically significantly, HR (per year)1⁄4 0.97 (0.91–1.03), p1⁄4 0.269. After 6 months, 60% of the patients were still treated with the initial drug, whereas after 12 months around 30% of the patients were still adherent to treatment. There was no statistically significant difference in adherence rate between the various drugs, however, the sample was too small to explore this fully. Comparing adalimumab with the other drugs combined showed a trend towards a longer adherence in the adalimumab group (median: 269 versus 214 d), p1⁄4 0.922. Due to insufficient response to the primary TNF-a inhibitor, or unacceptable side effects, a total of 10 (37%) patients were subsequently treated with one or more different TNF-a inhibitors or with the IL-12/23 inhibitor ustekinumab, once every third month, before obtaining sustained reduction in disease activity or discontinued treatment due to insufficient response or side effects. The median adherence rate in the second round of treatment was only 91 d; 33 d for ustekinumab; 39 d for etanercept; 71 d for infliximab; and 354 d for adalimumab (p1⁄4 0.414 for difference between drugs). After 6 months, 40% of the patients were still treated with the second drug, whereas after 12 months all patients had failed treatment with the second drug due to insufficient effect or unacceptable side effects. TNF-a inhibitors are a promising group of agents for various off-label indications including HS. However, we show that adherence to, and consequently sustainability and long-term efficacy of these drugs in a real-life setting is less convincing compared to results from previously published reports (1). In particular, our data do not support a second round of treatment with another TNF-a inhibitor, or ustekinumab, when having failed treatment with an initial TNF-a inhibitor. There are several possible explanations for the relatively low adherence rate observed in our patient sample. First, it has been shown that patients with severe HS (Hurley grade 3), in contrast to patients with milder disease, lack up-regulation of b-defensin-3 in lesional HS skin, providing a reason for suboptimal treatment effect in these patients (4). Second, several recommended therapies were not tried in our sample, which could have Correspondence: Simon Francis Thomsen, MD, PhD, Department of Dermatology, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. Tel: +45 2613 9838. Fax: +45 3531 3113. E-mail: sft@city.dk J D er m at ol og T re at D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y G az i U ni v. o n 05 /0 4/ 15

Pemphigoid gestationis: current perspectives

Many skin diseases can occur in pregnant women. However, a few pruritic dermatological conditions are unique to pregnancy, including pemphigoid gestationis (PG). As PG is associated with severe morbidity for pregnant women and carries fetal risks, it is important for the clinician to quickly recognize this disease and refer it for dermatological evaluation and treatment. Herein, we review the pathogenesis, clinical characteristics, and management of PG.

The Use and Safety of TNF Inhibitors during Pregnancy in Women with Psoriasis: A Review

Psoriasis is a chronic immune-mediated inflammatory disease affecting women of childbearing potential. Biologic agents, notably Tumor Necrosis Factor inhibitors (TNFi), are the only current non-contraindicated systemic treatment option during pregnancy. TNFi comprised of complete immunoglobulin G (IgG) antibodies antibodies (adalimumab, golimumab, and infliximab) actively cross the placenta from the second trimester and are detectable in the child up to one year postpartum. Data on safety of TNFi are conflicting; however a trend towards drug-specific harm has been reported, with increased risk of congenital malformations and preterm birth. TNFi exposure may alter the immune system of the infant towards hypersensitivity and reduced response to intracellular infections. Confounding by indication should be considered, as chronic inflammatory disease itself may pose a risk of adverse pregnancy outcomes. The quality of the current evidence is very low and no studies specifically address TNFi safety in women with psoriasis. Nonetheless, risks associated with TNFi treatment must be balanced against the as-yet uncertain risk of adverse outcomes in infants born to women with severe psoriasis. We searched PubMed using Medical Subject Headings (MeSH) terms and identified relevant studies and guidelines. Herein, we present the current knowledge of the use and safety of TNFi during pregnancy in women with psoriasis.

Clinician’s Update on the Benign, Premalignant, and Malignant Skin Tumours of the Vulva: The Dermatologist’s View

Correct and rapid diagnosis of skin tumours often requires biopsy and histopathological examination to differentiate benign lesions such as seborrhoeic keratoses or melanocytic naevi from premalignant and malignant lesions such as malignant melanoma. Particularly, to the untrained eye, any benign skin tumour—pigmented or nonpigmented—is easily mistaken for a malignant lesion. Qualified clinical evaluation is paramount in order to reduce the frequency of unwarranted skin biopsies. Herein, the most common benign, premalignant, and malignant vulvar skin tumours are reviewed.

A case of refractory chronic neutrophilic pustular folliculitis treated with adalimumab

Neutrophilic folliculitis is an often overlooked chronic condition characterized by a monomorphic eruption of “sterile” papulopustules. Neutrophilic folliculitis is often refractory to conventional treatment with topical and systemic antibiotics or isotretinoin. We report a case of severe pustular neutrophilic folliculitis successfully treated with the tumor necrosis factor‐alpha inhibitor adalimumab.