Respiratory syncytial virus A in haematological patients with prolonged shedding: Premature stop codons and deletion of the genotype ON1 72-nucleotide-duplication in the attachment G gene.

BACKGROUND: Respiratory syncytial virus (RSV) can be associated with severe disease and prolonged shedding in immunocompromised patients. OBJECTIVE: To investigate the genetic variability of RSV in consecutive samples of haematological patients with prolonged RSV shedding. STUDY DESIGN: Haematological patients at the University Hospital Heidelberg are routinely screened for respiratory viruses during winter season. In patients with prolonged RSV shedding between 2011 and 2014, Sanger-sequencing of the second hypervariable region of the RSV G gene was performed in consecutive samples. Further, deep-sequencing was performed in representative samples. RESULTS: Patients with prolonged RSV-A shedding were analysed (n=16, mean shedding 90days, 81.2% male). Phylogenetic analysis identified RSV genotypes NA1 (2011/12) or ON1 (2012/13). In most patients (n=12/16), Sanger-sequencing of the G gene showed identical sequences over the course of the shedding period. However, in two patients with particularly long viral shedding (333 and 142days), Sanger-sequencing revealed the presence of mutations leading to premature stop codons (37 and 70 amino acids truncated) in the G gene. In one additional patient, deep-sequencing revealed variants with premature stop codons at different positions. All three patients received repeatedly intravenous immunoglobulins. Interestingly, deep-sequencing revealed also a loss of the characteristic 72-nucleotide-duplication in all analysed ON1 strains. CONCLUSIONS: Long shedding periods and lack of immune selective pressure in the immunocompromised host seems to allow the persistence of viruses stripping a part of the C-terminus of the G glycoprotein. The loss of the characteristic 72-nucleotide-duplication in RSV-A ON1 variant strains is here described for the first time.

Intralesional infliximab in noninfectious cutaneous granulomas: three cases of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica is a rare granulomatous noninfectious skin disease. Treatment of this chronic debilitating disease is of importance because ulceration of the plaques may induce important psychological and physical morbidity. OBJECTIVE: Infliximab, an anti-TNF-α chimeric monoclonal antibody used intravenously and intralesionally for other extradermatological granulomatous diseases including Crohn's disease and sarcoidosis, was administered by intradermal injection in necrobiosis lipoidica. The aim of this study was to evaluate the efficacy and safety profile of a locally delivered drug compared to its systemic use. PATIENTS AND METHODS: Weekly injections of intralesional infliximab for 3 weeks were followed by a 1-week treatment interruption. This treatment schedule was repeated thrice. RESULTS: Two patients who benefitted from complete treatment experienced almost complete remission for up to 18 months. The third patient, who had treatment interruptions, showed partial improvement. No serious side effects were noticed, although the injections caused pain. CONCLUSIONS: This is the first report about the efficacy and safety of a therapy consisting of intralesional injections of infliximab for a granulomatous skin disease. Although this approach was clearly effective for necrobiosis lipoidica, the disease recurred several months after treatment interruption, raising the question of the need for maintenance therapy. Further controlled long-term trials are thus necessary.

Omalizumab reduces oral corticosteroid use in patients with severe allergic asthma: real-life data.

BACKGROUND: Long-term oral corticosteroid (OCS) therapy is associated with significant burden on patients and healthcare resources; treatments that may help reduce their use are important to improve asthma management. METHODS: French and German clinicians prescribing omalizumab for >16 weeks to patients with severe persistent allergic asthma collected OCS use data. OCS use was recorded at baseline and at a non-specific time point beyond 16 weeks from initiation of omalizumab. The number of asthma exacerbations (FEV(1) < 60% of personal best, requiring OCS burst and unscheduled doctor/emergency visit or hospitalization) and asthma-related hospitalizations during the 12-months prior to omalizumab treatment and during the observation period were also recorded. RESULTS: Overall, 346 patients were treated with omalizumab for >16 weeks. Of these, 166 (48.0%) were receiving maintenance OCS (France, n = 64; Germany, n = 102). Following omalizumab therapy, 84 (50.6%) patients on OCS at baseline reduced/stopped OCS dose at the time of data collection; 34 (20.5%) stopped and 50 (30.1%) reduced OCS. In all patients receiving maintenance OCS at baseline, mean reduction from baseline in daily OCS dose was 29.6% (7.1 mg prednisolone). In patients who reduced/stopped maintenance OCS, mean reduction from baseline in daily OCS dose was 74.3% (15.4 mg prednisolone). Reductions in exacerbations and hospitalizations were observed from the 12-months prior to baseline in patients at the time of data collection, irrespective of change in OCS dose. CONCLUSION: European real-life experience demonstrates the OCS-sparing potential of omalizumab in some patients with severe allergic (IgE-mediated) asthma.

Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test.

BACKGROUND: Antitumour necrosis factor (anti-TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon-gamma release assays (IGRA) have been shown to be more sensitive and specific than TST. OBJECTIVE: To compare the TST and the T-SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti-TNF treatment. METHODS: A retrospective study was carried out over a 4-year period on patients with psoriasis requiring anti-TNF treatment. All were subjected to the TST, T-SPOT.TB and chest X-ray. Risk factors for LTBI and history of bacillus Calmette-Guérin (BCG) vaccination were recorded. The association of T-SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti-TNF therapy when indicated. RESULTS: Fifty patients were included; 90% had prior BCG vaccination. A positive T-SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7.43; 95% confidence interval 1.38-39.9), which was not the case for the TST. Agreement between the T-SPOT.TB and TST was poor, kappa = 0.33 (SD 0.13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T-SPOT.TB. All patients received an anti-TNF agent for a median of 56 weeks (range 20-188); among patients with a positive TST/negative T-SPOT.TB, no tuberculosis was detected with a median follow-up of 64 weeks (44-188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin. CONCLUSION: This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti-TNF therapy, even if LTBI is correctly diagnosed and treated.

Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany.

Omalizumab is a humanized monoclonal anti-immunoglobulin E (IgE) antibody indicated in Europe for the treatment of uncontrolled severe persistent allergic (IgE-mediated) asthma despite optimal therapy with inhaled corticosteroids and long-acting beta(2) agonists. Between 2005 and 2007 280 patients (58% female, mean age 44+/-16 yrs., 46% on oral corticosteroids, median serum IgE level 235IU/ml) who met the EU criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab by 134 physicians as part of a post-marketing surveillance trial and were followed-up for 6 months. The median follow-up time was 195 days, the patients were treated with a median dose of 450mg omalizumab every 4 weeks. After 6 months there was a marked effect of omalizumab treatment on daily (-76%) and nocturnal symptoms (-84%), exacerbations (-82%), unscheduled health care contacts (-81%), hospitalizations (-78%) and quality of life (Mini-AQLQ: score increase from 2.9 to 4.5). Overall, efficacy of omalizumab was rated as excellent or good by the majority of physicians (82%) and patients (86%). In 19 patients (7%) omalizumab-related adverse events were recorded. This post-marketing surveillance trial confirms the marked and clinically relevant effect of omalizumab on asthma symptoms and level of asthma control in the majority of patients with severe persistent allergic (IgE-mediated) asthma in a real-life situation.

Refractory chronic cutaneous sarcoidosis responsive to dose escalation of TNF-alpha antagonists.

Cutaneous sarcoidosis may be a chronic disease with important morbidity requiring aggressive therapy. The efficacy of different anti-tumor necrosis factor alpha(anti-TNF-alpha) treatments in refractory cutaneous and systemic sarcoidosis has been reported previously. We report the first patient with chronic cutaneous sarcoidosis who responded to dose escalation of anti-TNF-alpha agents that have been ineffective at the standard dosage, illustrating that the optimal dosing regimen has still to be defined for this indication before considering difficult-to-treat patients as nonresponders. Our case report also illustrates that the fusion protein etanercept, even used at a high dosage, may be less effective for the treatment of cutaneous sarcoidosis than the monoclonal antibodies infliximab and adalimumab.

[The biological treatments for moderate to severe plaque psoriasis]. / Les traitements biologiques du psoriasis en plaques modéré à sévère.

Psoriasis is a chronic inflammatory skin disorder that can cause substantial disability. The recognition of psoriasis as an immunologically mediated disease led to the development of agents that specifically target key steps in the pathological process. In this review, we focus on the mechanism of action, the efficacy and the safety data of the new biological treatments: alefacept, efalizumab, etanercept, infliximab and adalimumab.

Long-term control with etanercept (Enbrel) of a severe acrodermatitis continua of Hallopeau refractory to infliximab (Remicade).

Hallopeau's acrodermatitis is characterized by the presence of aseptic pustules on an inflammatory basis of the periungual or subungual region. The cyclic recurrences induce important physical and psychological morbidity. By analogy to the efficacy of TNF-alpha antagonists in the treatment of generalized pustular psoriasis, our patient illustrates the long-term efficacy and safety of etanercept (Enbrel) in the treatment of Hallopeau's acrodermatitis refractory to infliximab (Remicade). This treatment alternative should in consequence be considered in patients with a recalcitrant form of a potentially debilitating disease.

Chronic hemicorporal prurigo related to a posttraumatic Brown-Séquard syndrome.

Focal pruritus may have a neurological cause. According to the underlying mechanism, two categories of central itch have been distinguished, neuropathic and neurogenic pruritus. We here describe a patient with Brown-Séquard syndrome related to unilateral damage of the spinal cord. The patient progressively developed neuropathic pruritus with chronic prurigo lesions showing strictly hemicorporal distribution. The patient was given pregabalin, an analogue of the neurotransmitter gamma-aminobutyric acid,with significant improvement. Our observation of chronic prurigo with hemicorporal involvement is unique. It underscores the importance of a detailed neurological examination in case of persistent localized itch and further supports the idea that chronic prurigo reflects a neurological problem in a subset of affected patients. Antiepileptic drugs should be considered not only for neuropathic pain, but also for neuropathic itch.

Infliximab then efalizumab, the 'hit and run' approach does not work.

BACKGROUND: In a previous paper we described 2 patients treated with a sequential biologic therapy for chronic plaque psoriasis. We used infliximab as an induction treatment followed by efalizumab. We extended this approach to 3 other patients. OBJECTIVE: The purpose was to show the feasibility of a sequential approach with biologicals. METHODS: Five patients received three infusions of infliximab followed by weekly injections of efalizumab from week 10 on. RESULTS: The most important findings, summarized in a table, show that none of the patients continued the treatment for more than a year either because of non-responsiveness or because of spontaneous stopping. Moreover, 4 out of 5 patients did not respond or had serious adverse events on reintroduction of infliximab. CONCLUSION: Overall, we cannot recommend sequential therapy using infliximab and efalizumab.

Genotypic coreceptor analysis.

HIV infects target cells by binding of its envelope gp120 protein to CD4 and a coreceptor on the cell surface. In vivo, the different HIV-strains use either CCR5 or CXCR4 as coreceptor. CCR5-using strains are named R5 viruses, while CXCR4-using strains are named X4. X4 viruses usually occur in the later stages. Coreceptor usage is a marker for disease progression. Additionally interest on coreceptors continually raises as a consequence of the development of a new class of antiretroviral drugs, namely the coreceptor antagonists or blockers. These specific drugs block the CCR5 or the CXCR4 coreceptors. So far, the CXCR4 blockers are not allowed to be used in the clinical practice due to their severe side effects. On the other hand, CCR5 blockers are currently in clinical practice, although they can only be administered after a baseline determination of the coreceptor usage of the predominant viral strain. Most of the coreceptor analyses in clinical cohorts have been performed with commercially available phenotypic assays. As for resistance testing of NRTIs, NNRTIs and PIs, efforts have also been made to predict the coreceptor usage from the genotype of the viruses. Different rules have been published based on the amino acid sequence of the Env-V3 region of HIV-gp120, which is known to be the major determinant of coreceptor usage. Among these, the most widely used is the 11/25 rule. Recently, bioinformatics driven prediction systems have been developed. Three of the interpretation systems are freely available via internet: WetCat, WebPSSM, geno2pheno[coreceptor]. All three systems focus on the Env-V3 region and take the amino acid sequence only into account. They learn from phenotypic and corresponding genotypic data. So far, two cohorts have been analyzed with such a genotypic approach and provided frequencies of R5 virus strains that are within the range of those reported with phenotypic assays. For one of the systems, geno2pheno[coreceptor], additional clinical data (e.g. CD4+T-cell counts) or structural information can be used to improve the prediction. Such genotypic systems provide the possibility for rapid screening of patients who may be administered with CCR5 blockers like the recently licensed Maraviroc.

Multiple cutaneous osteomas of the face associated with chronic inflammatory acne.

Multiple miliary osteoma cutis of the face represents a rare and frequently unrecognized complication of chronic inflammatory acne. Their differentiation from microcomedones and macrocomedones may be challenging. The case of a 46-year-old Asian woman who suffered from chronic inflammatory acne is described. She had multiple papular lesions of the cheeks that did not respond to various topical and systemic therapies including oral isotretinoin. Light microscopy studies as well as ultrasound and computed tomography (CT) scan investigations demonstrated the presence of multiple osteoma cutis. Needle microincisions followed by mechanical extirpation of the bony formation resulted in a considerable cosmetic improvement of her skin disease. Knowledge of this rare complication of acne is mandatory, as its treatment is different from that of retentional and inflammatory acne and frequently relies on surgical modalities. Our novel technique consisting of needle microincisions with curettage of the lesions is simple and safe, leading to good cosmetic results.

Cutaneous adverse events of biological therapy for psoriasis: review of the literature.

The use of biological agents is expanding worldwide as a new treatment alternative for chronic inflammatory diseases including more recently skin diseases, especially psoriasis. Although frequently observed, the knowledge about acute and chronic dermatological adverse events is limited, and potential pathogenic mechanisms still have to be identified. Exact diagnosis is required considering that dermatological adverse events raise a decisional challenge about potential treatment discontinuation. The object of this publication is to present an overview of the dermatological adverse events of these new treatment alternatives.

[Dermatology]. / Dermatotogie.

This year, we are going over therapeutic acquisitions in a club-journal format with a special focus on biologicals for psoriasis. Other sections include relevant publications in different fields: mecanism of action, therapeutic perspectives in a near future, and side effects.

Affinity chromatography with the immobilized agonist N-0434 yields an active and highly purified preparation of the dopamine D-2 receptor from bovine striatum.

Partial purification of the dopamine D-2 receptor from bovine striatum, solubilized in the presence of 1% digitonin, was obtained by chromatography on wheat germ lectin agarose. The preparation was purified approximately 10-fold. The stability of the receptor preparation was considerably improved and non-specific protein absorption on the affinity gel used later was decreased. Further purification was achieved on a column containing a D-2-selective agonist, N-0434. Approximately 90% of the receptor activity was bound to the gel and 20-40% of the activity could be eluted by pH shock. The total purification factor after one affinity chromatography step was estimated to be at least 1500. An active preparation of at least 20% purity was obtained after a second cycle of affinity chromatography. This corresponds to an enrichment of more than 5000 times compared to the solubilized receptor preparation.