Nina Booken

Helicobacter pylori infection and dermatologic diseases

Recent evidence suggests that Helicobacter pylori infections play a role in the pathogenesis of a variety of skin diseases. The best evidence for such a link is found for two diseases: chronic urticaria and immune thrombocytopenic purpura. Other diseases that have a purported, but not yet proven link to H. pylori are: cutaneous pruritus, Behçets disease, nodular prurigo and lichen planus. Based on the current evidence for a relationship between H. pylori and chronic idiopathic thrombocytopenic purpura the European Helicobacter Study Group consensus 2007 recommended the eradication of Helicobacter pylori infection in affected patients. Lastly, single or few case reports have documented associations between Helicobacter pylori infection and rosacea, aphthous stomatitis, atopic dermatitis, alopecia areata, Schoenlein-Henoch purpura and Sjögren syndrome, but these are only descriptive in nature. Systematic studies examining the relationship between dermatologic entities and infection with H. pylori and documentation of the effect of H. pylori eradication are needed to further our understanding on this topic.

The diagnosis of Sézary syndrome on peripheral blood by flow cytometry requires the use of multiple markers

Background  Diagnosis of Sézary syndrome (SS)‐defining blood involvement is hampered by the lack of Sézary cell‐specific markers and nonspecific morphology of the tumour cells.

Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T‐cell lymphoma

MADAM, Primary cutaneous lymphomas represent the second most common extranodal non-Hodgkin lymphomas. According to the WHO-EORTC classification of primary cutaneous lymphomas, mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous T-cell lymphoma (CTCL). In patients with CTCL, pruritus is often severe and has a significant impact on quality of life. Especially in advanced stages (e.g. erythrodermic MF or SS), patients commonly report an ill-defined, severe, and diffuse pruritus that prevents them from sleeping and functioning. Due to a lack of major antipruritic capacity of emollients, topical steroids or oral antihistamines in CTCL, other treatment options have been discussed, such as gabapentin and mirtazapine, as well as naltrexone and amitriptyline. Substance P is an important mediator of pruritus. An increase in the expression of its receptor, neurokinin-1, has been reported on keratinocytes in pruritic skin diseases. Aprepitant, an oral neurokinin-1 receptor antagonist, has recently been described as a potential antipruritic treatment in different skin diseases, including erlotinib-induced pruritus in patients with tumours as well as in patients with CTCL. This prospective, open-label study includes five patients with erythrodermic CTCL (three with SS and two with erythrodermic MF) in whom pruritus was the main symptom and could not be controlled with conventional antipruritic treatments. The patients comprised three men and two women, mean age 61 (range 51–68) years. The diagnosis was established according to the WHO-EORTC classification of cutaneous lymphomas and the criteria of the International Society of Cutaneous Lymphomas. The study was conducted according to the ethical guidelines at our institution and the Helsinki declaration. Patients were treated with aprepitant 125 mg on day 1 and 80 mg on days 2 and 3 in 2-week repetitions for a median time of 15 weeks (range 6–24) and a median number of 7 therapy cycles (range 3–12). The median time between the diagnosis of CTCL and initiation of aprepitant was 25 months (range 10–67). Previous antipruritic therapies included a combination of antihistamines, gabapentin, mirtazapine, naltrexone or amitriptyline, without effect. During aprepitant treatment, all patients were instructed to continue with their previous antipruritic therapy, and their regular CTCL treatment was not modified (for details see Table 1). The severity of pruritus was assessed using a visual analogue scale (VAS), in which a score of 0 indicates no pruritus and a score of 10 indicates the worst pruritus imaginable. The quality of life was measured by the Dermatology Life Quality Index (DLQI) questionnaire (range 0–30, higher scores indicate worse outcome). A response was defined as > 50% reduction, no response < 25% and a partial remission between 25% and 50% reduction of the VAS compared with baseline. The overall response rate to the aprepitant therapy was 80%, with four of five patients demonstrating a good response and only one of five patients no response. The mean ± SD VAS score at the beginning of the study was 9Æ8 ± 0Æ4 and after intervention 4Æ3 ± 3Æ4 (P = 0Æ125; Fig. 1). The mean ± SD DLQI score at the beginning of the study was 20Æ4 ± 5Æ2 and decreased after intervention to 12Æ4 ± 8Æ1 (P = 0Æ0625; Fig. 1). In the responder group a first reduction of the VAS and DLQI was seen after one cycle of aprepitant therapy, with further decrease at follow up. Oral aprepitant was well tolerated and no side-effects were observed. However, no effects were seen on erythroderma or on reduction of the Sézary cell count. In summary, our clinical case series demonstrates that aprepitant is a safe, well-tolerated and effective drug for the therapy of severe pruritus in patients with erythrodermic CTCL who had not responded to previous therapies. Therefore, we suggest including an escalation scheme for the treatment of pruritus in the treatment guidelines for patients with CTCL. Aprepitant was developed and approved in 2003 as an antiemetic agent in chemotherapy-induced nausea and vomiting. The administration is usually for 3 days only, but also long-term application for up to 8 weeks was reported without major side-effects. We decided to use the more cost-effective standard dosage of aprepitant for 3 days only with repetition every 2 weeks. Interestingly, an improvement of pruritus was already observed after the first cycle of therapy and was stable over 2 weeks, suggesting no loss of efficiency using the standard dosage every 2 weeks. It was recently reported by another group that used aprepitant against pruritus in patients with solid tumours that pruritus relapsed after 3 days without treatment. However, the pathogenesis of pruritus in patients with erythrodermic CTCL and solid tumours might be different. It would be important to confirm the optimal dosage of aprepitant in the treatment regimen of pruritus of different BJD British Journal of Dermatology

A PP4 Holoenzyme Balances Physiological and Oncogenic Nuclear Factor-Kappa B Signaling in T Lymphocytes

Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas.

Successful treatment of mucous membrane pemphigoid with the anti-CD-20 antibody rituximab.

Mucous membrane pemphigoid (MMP) is an often diffi-cult-to-treat autoimmune bullous disease characterized by circulating auto-antibodies targeting the dermo-epidermal junctional zone (1–3). Due to limited disease control and/or severe adverse reactions to glucocorticoids and conventional immunosuppressants, alternative treatment options are frequently needed. We describe here the first successful therapy of refractory MMP with rituximab, a humanized anti-CD20 monoclonal antibody depleting B-lymphocytes (4, 5), that resulted in a complete and persisting remission.CASE REPORT

Combination therapy with extracorporeal photopheresis, interferon‐α, PUVA and topical corticosteroids in the management of Sézary syndrome

Background: Extracorporeal photopheresis (ECP) is recommended for the treatment of Sézary syndrome (SS), the leukemic variant of cutaneous T‐cell lymphoma (CTCL). Several combination therapies are used to increase response rates to ECP.

The value of molecular diagnostics in primary cutaneous B-cell lymphomas in the context of clinical findings, histology, and immunohistochemistry

BACKGROUND Primary cutaneous B-cell lymphoma (PCBCL) is classified into 3 major subtypes: primary cutaneous follicle center lymphoma (PCFCL); primary cutaneous marginal zone B-cell lymphoma (PCMZL); and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). Diagnosis of PCBCL is mainly based on clinical and (immuno)-histochemical grounds. OBJECTIVE We investigated the diagnostic value of the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol in PCBCL. METHODS We analyzed with the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol skin specimens from patients with well-defined clinical and (immuno)-histologic PCBCL (n = 18) in comparison with benign lymphocytic infiltrates (n = 9). For molecular staging we also investigated 13 extracutaneous samples from 6 patients with PCLBCL, LT. Each sample was investigated at least twice. RESULTS Monoclonality was detected in all of 5 PCFCL; 5 of 6 PCMZL; all of 6 PCLBCL, LT; and 2 of 9 benign lymphocytic infiltrates. In 5 of 6 patients with PCLBCL, LT, a clone corresponding to the clone detected in the skin was detected in 3 of 5 bone-marrow, 4 of 5 blood, and 1 of 3 lymph node specimens. DNA amplification using tubes A and B of IgH was not possible in PCFCL/PCMZL, benign lymphocytic infiltrates, and extracutaneous specimens of PCLBCL, LT, even after repeated analysis up to 11 times. Pseudomonoclonality was identified by repeated analyses in one case of PCMZL and in one case of benign lymphocytic infiltrate. LIMITATIONS A multicentric, randomized, blinded study is necessary to confirm our results. CONCLUSION Molecular diagnosis supports the clinical and (immuno)-histologic diagnosis in PCBCL. In PCLBCL, LT, molecular staging may be useful. Tubes C through E of IgH and Igκ analyses seem to be superior to tubes A and B of IgH. Each sample should be analyzed at least twice to assess the possibility of pseudomonoclonality.

Subacute cutaneous lupus erythematosus induced by terbinafine: case report and review of literature

Systemic lupus erythematosus and subacute cutaneous lupus erythematosus (SCLE) occasionally evolve as adverse reactions to a large variety of chemically different drugs. We here report on a 76‐year‐old woman who developed SCLE within 10 days after initiation of oral terbinafine. Analysis of the 27 cases of terbinafine‐induced SCLE in the literature revealed that this disorder has been reported 6 times more often in females than in males. Skin lesions evolved on average around 7 weeks after starting the drug. In 79% of the cases ANA could be detected while antibodies against Ro/SS‐A and La/SS‐B were found in 86% and 39%, respectively. Remarkably, anti‐histone antibodies were present in only 29%. In all cases terbinafine‐induced SCLE resolved after discontinuation of the triggering agent. Systemic treatment with anti‐malarials and/or corticosteroids does not appear to be mandatory.

Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases

Patients with erythrodermic disease are a diagnostic challenge regarding the clinical and histological differential diagnosis.

Cutaneous tumor cell load correlates with survival in patients with Sézary syndrome

Background: Sézary syndrome (SS) is defined by the triad of erythroderma, generalized lymphadenopathy and more than 1 000 circulating Sézary cells/μl in the peripheral blood.