Search

Background: Heavy metal Resistance-Nodulation-Division (HME-RND) efflux systems help Gram-negative bacteria to keep the intracellular homeostasis under high metal concentrations. These proteins constitute the cytoplasmic membrane channel of the tripartite RND transport systems. Caulobacter crescentus NA1000 possess two HME-RND proteins, and the aim of this work was to determine their involvement in the response to cadmium, zinc, cobalt and nickel, and to analyze the phylogenetic distribution and characteristic signatures of orthologs of these two proteins., Results: Expression assays of the czrCBA operon showed significant induction in the presence of cadmium and zinc, and moderate induction by cobalt and nickel. The nczCBA operon is highly induced in the presence of nickel and cobalt, moderately induced by zinc and not induced by cadmium. Analysis of the resistance phenotype of mutant strains showed that the ΔczrA strain is highly sensitive to cadmium, zinc and cobalt, but resistant to nickel. The ΔnczA strain and the double mutant strain showed reduced growth in the presence of all metals tested. Phylogenetic analysis of the C. crescentus HME-RND proteins showed that CzrA-like proteins, in contrast to those similar to NczA, are almost exclusively found in the Alphaproteobacteria group, and the characteristic protein signatures of each group were highlighted., Conclusions: The czrCBA efflux system is involved mainly in response to cadmium and zinc with a secondary role in response to cobalt. The nczCBA efflux system is involved mainly in response to nickel and cobalt, with a secondary role in response to cadmium and zinc. CzrA belongs to the HME2 subfamily, which is almost exclusively found in the Alphaproteobacteria group, as shown by phylogenetic analysis. NczA belongs to the HME1 subfamily which is more widespread among diverse Proteobacteria groups. Each of these subfamilies present distinctive amino acid signatures.

CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative). We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.

The innate immune system can recognize pathogen-associated molecular patterns (PAMP) through toll-like receptors (TLRs). TLR stimulation by TLR-ligands (TLR-L) induces several genes that can regulate the immune response. In this study, we compared the ability of diverse TLR2-L to activate professional antigen presenting cells (pAPCs). We found that in comparison to whole non-replicating microorganism Mycobacterium butyricum, the smaller components; lipoteichoic acid and Pam3CSK4 significantly enhanced the expression of several pro-inflammatory mediators. These included IL-6, TNF-α and nitric oxide both at the mRNA and the protein levels. Moreover, the higher response was associated with a differential activation of nuclear transcription factor kappa-B (NF-κB) by the diverse TLR2-L. However, all three ligands enhanced antigen cross-presentation and T cell induction after virus infection to the same extent. In conclusion, the data highlight the potential for small components of TLR agonists to induce superior inflammatory immune responses than whole microbial preparation in the field of vaccine studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown., Methods: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks., Results: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab., Conclusions: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).

Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress., (© 2012 New York Academy of Sciences.)

Background & Aims: We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC)., Methods: Patients (6-17 years old) who had active UC (Mayo scores of 6-12; endoscopic subscores ≥ 2) and had not responded to or tolerated conventional treatment were given 5 mg/kg infliximab at weeks 0, 2, and 6. The primary end point was response at week 8 (decreases in Mayo scores ≥ 30% and ≥ 3 points and decreases in rectal bleeding subscores of ≥ 1 or an absolute subscore of ≤ 1). At week 8, only responders were randomly assigned to groups given infliximab every 8 or 12 weeks (q8w or q12w) and followed through week 54. Maintenance end points included pediatric UC activity index scores <10 points, defined as remission., Results: At week 8, infliximab induced a response in 73.3% of patients (44 of 60) (95% confidence interval, 62.1%-84.5%; a positive result was defined by 95% confidence interval lower limit >40%). Among responders, twice as many were in remission at week 54 after q8w (8 of 21, 38.1%) than q12w (4 of 22, 18.2%; P = .146) therapy. Assuming the q8w remission rate for responders, the overall remission rate at week 54 would be 28.6%. Serious adverse events and infusion reactions occurred in similar proportions in the q8w and q12w groups. No deaths, malignancies, opportunistic infections, tuberculosis, or delayed hypersensitivity reactions were reported., Conclusions: Infliximab was safe and effective, inducing a response at week 8 in 73.3% of pediatric patients with moderate to severely active UC who did not respond to conventional therapy. The overall remission rate at week 54 for all enrolled patients was 28.6%, assuming the more effective q8w remission rate., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

IL-27, which is produced by activated APCs, bridges innate and adaptive immunity by regulating the development of Th cells. Recent evidence supports a role for IL-27 in the activation of monocytic cells in terms of inflammatory responses. Indeed, proinflammatory and anti-inflammatory activities are attributed to IL-27, and IL-27 production itself is modulated by inflammatory agents such as LPS. IL-27 primes LPS responses in monocytes; however, the molecular mechanism behind this phenomenon is not understood. In this study, we demonstrate that IL-27 priming results in enhanced LPS-induced IL-6, TNF-α, MIP-1α, and MIP-1β expression in human primary monocytes. To elucidate the molecular mechanisms responsible for IL-27 priming, we measured levels of CD14 and TLR4 required for LPS binding. We determined that IL-27 upregulates TLR4 in a STAT3- and NF-κB-dependent manner. Immunofluorescence microscopy revealed enhanced membrane expression of TLR4 and more distinct colocalization of CD14 and TLR4 upon IL-27 priming. Furthermore, IL-27 priming enhanced LPS-induced activation of NF-κB family members. To our knowledge, this study is the first to show a role for IL-27 in regulating TLR4 expression and function. This work is significant as it reveals new mechanisms by which IL-27 can enhance proinflammatory responses that can occur during bacterial infections.

Objective: To characterize the effect of HIV infection on IL-27-induced gene expression., Design: During HIV infection, cytokine expression and function become deregulated. IL-27 is an important modulator of inflammatory responses. Interestingly, IL-27 can inhibit HIV replication in T cells and monocytes, implicating IL-27 as a potential adjunct to anti-viral treatment. Our previous work demonstrated that circulating HIV may suppress IL-27 expression, therefore, this study, in continuation of our previous work, aimed to understand how HIV affects expression levels of the IL-27 receptor and downstream functions of IL-27., Methods: Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of HIV negative and HIV positive (viremic) individuals to assess IL-27-induced gene expression by flow cytometry and ELISA. PBMC were also processed for monocyte enrichment to assess IL-27 receptor expression by flow cytometry and real-time PCR., Results: Expression of the IL-27 receptor subunit, gp130, was upregulated in response to IL-27 in HIV negative individuals, however, in HIV positive individuals, this IL-27 response was diminished. Furthermore, we observed downregulation of IL-27-induced IL-6, TNF-α, and IL-10 expression in HIV positive subjects., Conclusion: In HIV infection, IL-27-induced gene expression was impaired, indicating HIV-mediated dysregulation of IL-27 functions occurs during HIV infection. This study provides evidence for new viral pathogenic mechanisms contributing to the widespread impairment of immune responses observed in HIV pathogenesis.

IL-27 modulates inflammatory responses by influencing cytokine secretion and CD4 T cell differentiation. Recently, IL-27 was demonstrated to inhibit HIV replication by inducing type I interferon (IFN) expression and subsequent IFN-dependent expression of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-3 family members, a group of antiviral cytidine deaminases. To characterize other anti-viral genes modulated by IL-27, we examined another IFN-responsive gene: tetherin/bone marrow stromal cell antigen 2 (BST-2). Our study shows that IL-27 can directly induce BST-2 expression, independently of an intermediary type I IFN response. Quantitative RT-PCR analysis demonstrated IL-27-induced BST-2 mRNA expression as early as 2h after exposure of cells to IL-27. In the presence of the type I IFN-neutralizing protein, B18R, IL-27-induced BST-2 expression was maintained, demonstrating that IFN is not an intermediary in IL-27-induced BST-2. Taken together, our findings identify a novel function of IL-27 as a direct stimulator of BST-2 expression.

The signaling pathways of mammalian Toll-like receptors (TLRs) are well characterized, but the precise mechanism(s) by which TLRs are activated upon ligand binding remains poorly defined. Recently, we reported a novel membrane sialidase-controlling mechanism that depends on ligand binding to its TLR to induce mammalian neuraminidase-1 (Neu1) activity, to influence receptor desialylation, and subsequently to induce TLR receptor activation and the production of nitric oxide and proinflammatory cytokines in dendritic and macrophage cells. The α-2,3-sialyl residue of TLR was identified as the specific target for hydrolysis by Neu1. Here, we report a membrane signaling paradigm initiated by endotoxin lipopolysaccharide (LPS) binding to TLR4 to potentiate G protein-coupled receptor (GPCR) signaling via membrane Gα(i) subunit proteins and matrix metalloproteinase-9 (MMP9) activation to induce Neu1. Central to this process is that a Neu1-MMP9 complex is bound to TLR4 on the cell surface of naive macrophage cells. Specific inhibition of MMP9 and GPCR Gα(i)-signaling proteins blocks LPS-induced Neu1 activity and NFκB activation. Silencing MMP9 mRNA using lentivirus MMP9 shRNA transduction or siRNA transfection of macrophage cells and MMP9 knock-out primary macrophage cells significantly reduced Neu1 activity and NFκB activation associated with LPS-treated cells. These findings uncover a molecular organizational signaling platform of a novel Neu1 and MMP9 cross-talk in alliance with TLR4 on the cell surface that is essential for ligand activation of TLRs and subsequent cellular signaling.

Background: Ustekinumab has been evaluated in Caucasian patients with psoriasis, but no studies have been conducted in Asian patients., Objective: To assess the efficacy and safety of ustekinumab in Taiwanese and Korean patients with moderate-to-severe psoriasis., Methods: In this 36-week, multicenter, double-blind, placebo-controlled study, 121 patients with moderate-to-severe psoriasis were randomized (1:1) to receive subcutaneous injections of ustekinumab 45mg at weeks 0, 4, 16 or placebo at weeks 0, 4 and ustekinumab 45mg at weeks 12, 16. Efficacy endpoints at week 12 included the proportion of patients achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75; primary endpoint), proportion of patients with Physician's Global Assessment (PGA) of cleared or minimal, and change from baseline in Dermatology Life Quality Index (DLQI)., Results: At week 12, the proportion of patients achieving PASI 75 was 67.2% and 5.0% in the ustekinumab 45mg and placebo groups, respectively (p<0.001). PGA of cleared or minimal was achieved by 70.5% (ustekinumab) and 8.3% (placebo; p<0.001), and median DLQI changes were -11.0 and 0.0, respectively (p<0.001). Efficacy was maintained through week 28 in ustekinumab-treated patients. Adverse event (AE) profiles at week 12 were similar between the ustekinumab and placebo groups: 65.6% and 70.0%, respectively, had at least one reported AE. Through week 36, no disproportionate increase in AEs was observed, with the exception of abnormal hepatic function, which was related to concomitant isoniazid treatment for latent tuberculosis. Injection-site reactions were rare and mild. No deaths, malignancies, or cardiovascular events were reported., Conclusions: Treatment with subcutaneous ustekinumab 45mg offers a favorable benefit/risk profile for Taiwanese and Korean patients with moderate-to-severe psoriasis. The efficacy and safety profile is consistent with the global phase III studies of ustekinumab in psoriasis., (Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Interleukin (IL)-23 plays a critical role in the development of the T helper (Th) cell response and is responsible for the maintenance of the IL-17 producing subset of Th cells, Th17. IL-23 is a heterodimeric cytokine composed of IL-23p19 and IL-12p40 subunits, and the signaling pathway for IL-23 involves 2 receptor chains: IL-12Rβ1 and IL-23Rα. The IL-23 receptor complex is expressed on a number of cells, including natural killer cells, monocytes, macrophages, dendritic cells, and CD4 T cells. Currently, the molecular mechanisms governing expression of the IL-23 receptor chains, IL-23Rα and IL-12Rβ1, are not well understood. Our results show that IL-23 induces upregulation of IL-23Rα and IL-12Rβ1 expression in human CD4 T cells. Further, we demonstrate that inhibition of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway by SD-1029, a JAK2 inhibitor, 5'-deoxy-5'-(methylthio) adenosine, a STAT1 inhibitor, and STAT3 VII, a STAT3 inhibitor, were able to block IL-23-induced expression of IL-23 receptor subunits in the human SUPT-1 T cell line and in primary CD4 human T cells. Taken together, our results suggest a positive feedback regulation of the IL-23 receptor via IL-23-mediated activation of the JAK/STAT pathway.

The development of ustekinumab as a first-in-class anti-interleukin (IL) 12/23p40 therapeutic agent for psoriasis represents an important example of modern and rational drug design and development. Psoriasis is a chronic, systemic, immune-mediated skin disorder with considerable clinical, psychosocial, and economic burden. Ustekinumab is a human monoclonal antibody (mAb) that binds the p40 subunit common to IL-12 and IL-23, key cytokines in psoriasis pathogenesis. The therapeutic mAb was developed using human gamma-1 immunoglobulin (IgG)-expressing transgenic mice, which created a molecule with endogenous IgG(1) biologic properties and low immunogenicity. Ustekinumab was well tolerated in clinical studies and yielded rapid, significant, and sustained efficacy plus improved quality of life/work performance and reduced depression/anxiety. Its pharmacologic properties afford the most convenient dosing regimen among approved biologics, representing a significant advancement in the treatment of moderate to severe psoriasis. Ustekinumab also holds promise for other immune-mediated disorders with significant unmet need., (© 2011 New York Academy of Sciences.)

IL-27 is a heterodimeric cytokine bridging innate and adaptive immunity by playing a role in the activation of naive T cells and in development of Th1 cells. Additionally, recent evidence supports a role for IL-27 in the activation of monocytic cells. Both pro-inflammatory and anti-inflammatory activities have been attributed to IL-27; however, the role played by IL-27 in the activation of human monocytic cells in terms of cytokine production has not been well described. Our results show that IL-27 is a strong inducer of proinflammatory cytokine and chemokine expression, including enhancement of IL-6, IP-10, MIP-1alpha, MIP-1beta, and TNF-alpha expression in human primary monocytes. Furthermore, we observed that IL-27-induced cytokine and chemokine production was mediated by STAT1, STAT3, and NF-kappaB activation. Understanding how IL-27 exerts its effects on monocytic cells will identify important molecular mechanisms in the regulation of immune responses, particularly in the modulation of monocyte activation.

Thymoquinone (TQ) derived from the nutraceutical black cumin oil has been reported to be a novel agonist of Neu4 sialidase activity in live cells (Glycoconj J DOI 10.1007/s10719-010-9281-6). The activation of Neu4 sialidase on the cell surface by TQ was found to involve GPCR-signaling via membrane targeting of Gαi subunit proteins and matrix metalloproteinase-9 activation. Contrary to other reports, TQ had no anti-inflammatory effects in vitro. Here, we show that MyD88/TLR4 complex formation and subsequent NFκB activation are induced by the Neu4 activity associated with TQ-stimulated live primary bone marrow (BM) macrophage cells from WT and Neu1-deficient mice, HEK-TLR4/MD2 cells and BMC-2 macrophage cell line but not with primary macrophage cells from Neu4-knockout mice. Tamiflu (oseltamivir phosphate), pertussis toxin (PTX), a specific inhibitor of Gαi proteins of G-protein coupled receptor (GPCR) and the broad range inhibitor of matrix metalloproteinase (MMP) galardin applied to live primary BM macrophage cells completely block TQ-induced MyD88/TLR4 complex formation. Using immunocytochemistry and western blot analyses, Tamiflu, galardin and PTX inhibit NFκB activation induced by Neu4 activity associated with TQ-stimulated BMC-2 cells, HEK-TLR4/MD2 cells and primary BM macrophages from WT mice. EMSA analyses on HEK-TLR4/MD2 nuclear cell extracts confirm the nuclear localization and DNA binding of TQ-induced NFκB activation in a biphasic manner within 30 min. Co-immunoprecipitation experiments reveal for the first time that MMP-9 may be an important intermediate link in the TQ-induced Neu4 activity circuitously targeting TLR4 receptors. Central to this process is that Neu4 forms a complex with MMP-9, which is already bound to TLR4 receptors. Fluorescence spectrophotometer analyses of live CD14-THP1 cells treated with TQ show Neu4 sialidase activity over 5 min. Using flow cytometry analyses, CD14-THP1 cells treated with TQ express stable protein levels of Neu4, TLR4 and MMP9 on the cell surface over 30 min except for a marked diminution of MMP9 at 15 min. Using cytokine array profiling analyses of serum, Neu4-knockout mice respond poorly to TQ in producing pro-inflammatory cytokines and chemokines after 5-h treatment compared to the wild-type or hypomorphic cathepsin A mice with a secondary 90% Neu1 deficient mice. Our findings establish an unprecedented signaling paradigm for TQ-induced Neu4 sialidase activity. It signifies that MMP-9 forms an important molecular signaling platform in complex with TLR4 receptors at the ectodomain and acts as the intermediate link for TQ-induced Neu4 sialidase in generating a functional receptor with subsequent NFκB activation and pro-inflammatory cytokine production in vivo.

A newly described cytokine, interleukin-27 (IL-27), that activates naive CD4 T cells, has recently been shown to be an anti-HIV cytokine. However, the effect of HIV infection on IL-27 expression has not been characterized. We found that clinical characteristics, including HIV viral load, hepatitis C virus coinfection, and CD4 T cell counts, were associated with changes in serum IL-27. Overall, our results suggest circulating HIV may suppress IL-27, a critical concept in treatment development with this cytokine.

Anti-inflammatory activities of thymoquinone (TQ) have been demonstrated in in vitro and in vivo studies. However, the precise mechanism(s) of TQ in these anti-inflammatory activities is not well understood. Using a newly developed assay to detect sialidase activity in live macrophage cells (Glycoconj J doi: 10.1007/s10719-009-9239-8 ), here we show that TQ has no inhibitory effect on endotoxin lipopolysaccharide (LPS) induced sialidase activity in live BMC-2 macrophage cells. In contrast, the parent black seed oil (BSO) and another constituent of BSO para-cymene (p-CY) completely block LPS induced sialidase activity. All of these compounds had no effect on cell viability. On the other hand, TQ induces a vigorous sialidase activity in live BMC-2 macrophage cells in a dose dependent manner as well in live DC-2.4 dendritic cells, HEK-TLR4/MD2, HEK293, SP1 mammary adenocarcinoma cells, human WT and 1140F01 and WG0544 type I sialidosis fibroblast cells. Tamiflu (oseltamivir phosphate) inhibits TQ-induced sialidase activity in live BMC-2 cells with an IC(50) of 0.0194 microM compared to an IC(50) of 19.1 microM for neuraminidase inhibitor DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid). Anti-Neu1, -2 and -3 antibodies have no inhibition of TQ-induced sialidase activity in live BMC-2 and human THP-1 macrophage cells but anti-Neu4 antibodies completely block this activity. There is a vigorous sialidase activity associated with TQ treated live primary bone marrow (BM) macrophage cells derived from WT and hypomorphic cathepsin A mice with a secondary Neu1 deficiency (NeuI KD), but not from Neu4 knockout (Neu4 KO) mice. Pertussis toxin (PTX), a specific inhibitor of Galphai proteins of G-protein coupled receptor (GPCR) and the broad range inhibitors of matrix metalloproteinase (MMP) galardin and piperazine applied to live BMC-2, THP-1 and primary BM macrophage cells completely block TQ-induced sialidase activity. These same inhibitory effects are not observed with the GM1 ganglioside specific cholera toxin subunit B (CTXB) as well as with CTX, tyrosine kinase inhibitor K252a, and the broad range GPCR inhibitor suramin. The specific inhibitor of MMP-9, anti-MMP-9 antibody and anti-Neu4 antibody, but not the specific inhibitor of MMP-3 completely block TQ-induced sialidase activity in live THP-1 cells, which express Neu4 and MMP-9 on the cell surface. Neu4 sialidase activity in cell lysates from TQ-treated live THP-1 cells desialylates natural gangliosides and mucin substrates. RT-PCR and western blot analyses reveal no correlation between mRNA and protein values for Neu3 and Neu4 in human monocytic THP-1 cells, suggesting for the first time a varied post-transcriptional mechanism for these two mammalian sialidases independent of TQ activation. Our findings establish an unprecedented activation of Neu4 sialidase on the cell surface by thymoquinone, which is derived from the nutraceutical black cumin oil. The potentiation of GPCR-signaling by TQ via membrane targeting of Galphai subunit proteins and matrix metalloproteinase-9 activation may be involved in the activation process of Neu4 sialidase on the cell surface.

Background: Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit-risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor alpha), for the treatment of psoriasis., Methods: We randomly assigned 903 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-and-severity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physician's global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12., Results: There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physician's global assessment, as compared with 49.0% of those who received etanercept (P<0.001 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab., Conclusions: The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT00454584.), (2010 Massachusetts Medical Society)

Cytokines are critical coordinators of the immune response necessary for resolving bacterial and viral assaults on the immune system. In particular, the IL-12 family of cytokines are key players in the regulation of T cell responses. These responses are orchestrated by monocytes, macrophages, and dendritic cells which produce the members of the IL-12 family of cytokines in response to infection. IL-27 and IL-23 are two cytokines that are related to IL-12; these cytokines share homology at the subunit, receptor, and signalling levels. IL-12 is composed of p35 and p40 subunits, which, when combined together form the bioactive IL-12p70. IL-23 is composed of the IL-12p40 subunit as well as the IL-23p19 subunit, which shares homology with IL-12p35. IL-27 is composed of EBI3 and p28. These three cytokines activate similar members of the JAK/STAT signalling pathways as a result of homology in their receptor components. Production of these cytokines by activated monocytes, macrophages, and dendritic cells results in the activation and differentiation of T cells. In spite of their similarity, each of these cytokines has specific roles in the regulation of immune responses. IL-12 is required for the induction of IFN-gamma production, critical for the induction of Th1 cells. IL-27 has been shown to play a role in the induction of Th1 cells from naive T cells, whereas IL-23 has been demonstrated to play a key role in the induction of the newly described Th17 cells. Recently, a novel heterodimeric and anti-inflammatory cytokine composed of the IL-12p35 and EBI3 subunits has been identified as IL-35. The biological properties of the IL-12 family of cytokines, the signalling pathways mediated by these cytokines and their role in infection, inflammation, and autoimmune diseases will be the focus of this review.

Background: Since some patients with psoriatic arthritis do not respond to typical drug treatments, alternatives are needed. Findings suggest that interleukins 12 and 23 might affect clinical symptoms and pathological joint changes of psoriatic arthritis. Ustekinumab is a human monoclonal antibody that inhibits receptor-binding of these cytokines. We aimed to assess the efficacy and safety of ustekinumab for psoriatic arthritis in this phase II study., Methods: We undertook a double-blind, randomised, placebo-controlled, crossover study at 24 sites in North America and Europe. Patients with active psoriatic arthritis were randomly allocated via interactive voice response system to either ustekinumab (90 mg or 63 mg) every week for 4 weeks (weeks 0-3) followed by placebo at weeks 12 and 16 (n=76; Group 1) or placebo (weeks 0-3) and ustekinumab (63 mg) at weeks 12 and 16 (n=70; Group 2). The first 12 weeks of the study were placebo-controlled. Masking was maintained to week 16, and patients were followed up to week 36 [corrected]. The primary endpoint was ACR20 response at week 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00267956., Findings: At week 12, 32 (42%) patients in Group 1 and ten (14%) in Group 2 achieved the primary endpoint (difference 28% [95% CI 14.0-41.6]; p=0.0002). Of 124 (85%) participants with psoriasis affecting 3% or more body surface area, 33 of 63 (52%) in Group 1 and three of 55 (5%) in Group 2 had a 75% or greater improvement in psoriasis area and severity index score at week 12 (47% [33.2-60.6]; p<0.0001). During the placebo-controlled period (weeks 0-12), adverse events arose in 46 (61%) patients in Group 1 and 44 (63%) in Group 2; serious adverse events were recorded in three (4%) Group 2 patients (none in Group 1)., Interpretation: Ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo, and the drug was well tolerated. Larger and longer term studies are needed to further characterise ustekinumab efficacy and safety for treatment of psoriatic arthritis.

Introduction: Infliximab is indicated for severe plaque psoriasis (PsO). The investigators compared safety event rates in infliximab PsO trials with those of the general United States and PsO populations., Methods: Integrated data (n=1373 patients) were compared with external databases., Results: The analyses reported here are based on 1106 patient years and 116 patient years of follow-up in the infliximab group and the placebo group, respectively. The standardized mortality ratio in infliximab-treated patients (0.17 [95% confidence interval [CI]: 0.00-0.92], 1 patient died) was lower than that of the general PsO population. No death occurred in the placebo group. Comparing with the psoriasis population, the standardized incidence ratios (SIRs) for hospitalization were 1.16 (95% CI: 0.92-1.43) in infliximab-treated patients and 1.07 (95% CI: 0.46-2.11) in placebo-treated patients. For serious infection, the SIRs were 1.28 (95% CI: 0.78-1.97) in infliximab-treated patients and 1.47 (95% CI: 0.18-5.32) in placebo patients. The incidence of tuberculosis (TB) among infliximab-treated patients was 0.18 per 100 patient-years (95% CI: 0.02-0.65). No TB occurred in the placebo group. Standardized incidence ratio for malignancy (excluding nonmelanoma skin cancers) was 0.39 (95% CI: 0.05-1.42; 2 malignancies) in infliximab-treated patients. No malignancy occurred in the placebo group., Limitations: Exclusion criteria in clinical studies may bias selection of subjects who are healthier than the general population. Additionally, the limited number of patients followed over a maximum of 1 year can limit the ability to detect infrequent events or those events that require prolonged follow-up to detect. Nonmelanoma skin cancers were excluded from the analysis. Finally, populations and adverse event definitions may have differed in external databases and studies., Conclusion: Based on the data from external databases, mortality, hospitalization, and serious infection rates in infliximab-treated patients were generally comparable to or less than that of the PsO population. Internal malignancy rates were similar to that expected in the general US population. However, the limitations of these data must be considered when compared with the totality of the safety profile of infliximab generated across all indications.

Background: Although nail psoriasis occurs frequently in patients with psoriatic skin lesions, effective treatments are limited., Objective: Occurrence of nail psoriasis by type and incidence of nail clearance using the Nail Psoriasis Severity Index were evaluated., Methods: This was a 50-week, phase III study in which 378 patients with moderate to severe psoriasis were randomized 4:1 to infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and every 8 weeks through week 46, with placebo crossover to infliximab at week 24., Results: Of the 373 evaluated patients, 305 (81.8%) had baseline nail psoriasis. The right thumbnail was most often the worst involved nail, and pitting and onycholysis were the most common lesions. Among patients with baseline nail psoriasis, 6.9%, 26.2%, and 44.7% in the infliximab group had nail disease clearance at weeks 10, 24, and 50, respectively, versus 5.1% in the placebo group at week 24 (P < .001). Mean percent improvements in Nail Psoriasis Severity Index score at weeks 10 and 24 were 26.8% and 57.2%, respectively, in the infliximab group versus -7.7% and -4.1%, respectively, in the placebo group (both P < .001). At week 24, mean percent improvements in nail matrix and nail bed features were 52.9% and 69.2%, respectively (vs -1.9% and 18.4% for placebo; P < .001)., Limitations: The study did not evaluate nail response beyond 1 year., Conclusions: Patients with psoriasis receiving infliximab experienced marked and sustained nail improvement.

This study examined the impact of infliximab maintenance therapy on productivity in patients with moderate-to-severe psoriasis. Patients from the multicentre, double-blind, placebo-controlled EXPRESS study (n = 378) were randomised to receive infusions of placebo or infliximab 5 mg/kg at weeks 0, 2, and 6 and every 8 weeks through week 46, with placebo crossover to infliximab at week 24. Main outcome measures were a 10-cm productivity visual analog scale (VAS), role-physical and role-emotional domain scores of the Short Form 36-Item questionnaire (SF-36), and Dermatology Life Quality Index (DLQI) scores. The productivity VAS score was 5.9 cm at baseline. Mean change through week 10 with infliximab was significantly greater than that with placebo (2.7 cm vs. - 0.1 cm) and was sustained through week 24. Similar trends were observed for SF-36 scores. The proportion of patients whose skin condition prevented them from working and/or studying per DLQI scores decreased through week 10 with infliximab (12.1% and 1.4%, respectively), but increased slightly with placebo (9.1% and 11.6%, respectively). At week 50, improvements in productivity and SF-36 scores were sustained with infliximab. In placebo patients who crossed over to infliximab, these scores improved and approached those seen with infliximab at week 50. Infliximab significantly improved productivity and ability to work in psoriasis patients.

Background: Previous studies of infliximab in psoriasis have demonstrated rapid improvement with induction therapy and sustained response with regularly administered maintenance therapy., Objective: The efficacy and safety of continuous (every-8-week) and intermittent (as-needed) maintenance regimens were compared., Methods: Patients with moderate-to-severe psoriasis (n = 835) were randomized to induction therapy (weeks 0, 2, and 6) with infliximab 3 mg/kg or 5 mg/kg or placebo. Infliximab-treated patients were randomized again at week 14 to continuous or intermittent maintenance regimens at their induction dose., Results: At week 10, 75.5% and 70.3% of patients in the infliximab 5 mg/kg and 3 mg/kg groups, respectively, achieved PASI 75; 45.2% and 37.1% achieved PASI 90 (vs 1.9% [PASI 75] and 0.5% [PASI 90] for placebo; P < .001). Through week 50, PASI responses were better maintained with continuous compared with intermittent therapy within each dose, and with 5 mg/kg compared with 3 mg/kg continuous therapy., Limitations: Longer term (>1 year) maintenance therapy and further study of infliximab serum concentrations over this period, in both PASI 75 responders and non-responders, would be preferable., Conclusions: Through week 50, response was best maintained with continuous infliximab therapy. Infliximab was generally well-tolerated in most patients.

Objective: To examine the effect of infliximab on employment status, time lost from work, and productivity in a double-blind, placebo-controlled study of patients with active psoriatic arthritis (PsA)., Methods: Two hundred adult patients with PsA were randomized to intravenous infusions of either infliximab 5 mg/kg or placebo at Weeks 0, 2, 6, 14, and 22, with early escape at Week 16. Employment status, workdays missed, and productivity were assessed at baseline and at Week 14. The effect of PsA on daily productivity was assessed using a visual analog scale., Results: At baseline, similar percentages of patients in both treatment groups were employed and similar percentages missed workdays; the mean productivity score at baseline was similar between groups (roughly 3 on a scale of 0 to 10). At Week 14, median productivity increased significantly in the infliximab group compared with the placebo group (67.5% vs 9.2%; p < 0.0001). Compared with the placebo group, higher proportions of patients in the infliximab group improved employment status from unemployed at baseline to employed at Week 14 (11.5% vs 0%; p = 0.084) and from part-time to full-time employment (30.0% vs 10.0%; p = 0.582). Among patients employed at baseline and Week 14, a lower proportion of patients in the infliximab group than in the placebo group had missed workdays in the 4 weeks prior to Week 14 (p = 0.138)., Conclusion: After 14 weeks of treatment, infliximab improved productivity in patients with active PsA. There was also a trend toward increased employment and reduced time lost from work for patients treated with infliximab.

The effect of within-household reinfestation on design sensitivity is investigated through statistical modeling of the reinfestation process. When reinfestation is present, household randomization tends to magnify treatment differences when compared with individual randomization or a randomized blocking design in the simple setting of two patients per household. The effect of reinfestation under more general household randomization settings is investigated by determining the relationship between the treatment effect and the number of patients per household. In an actual clinical study of treatment for head lice infestation, household randomization with proper stratification was adopted. The results from the study were consistent with theoretical expectations. This seeming contradiction to the blocking principle demonstrates the need to check whether all conditions are met before applying standard design principles.

Background: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established., Objective: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis., Methods: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels., Results: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions., Conclusions: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

Background: Tachyphylaxis, defined as a rapidly decreasing response to a physiologically active agent after administration of a few doses, can be well demonstrated in the experimental setting. However, tachyphylaxis in the clinical setting lacks clear demonstration., Objective: Our purpose was to identify dermatologists' perception of the clinical incidence of tachyphylaxis and then design a prospective study that would estimate the clinical incidence of tachyphylaxis., Methods: Clinical and academic dermatologists completed a survey questionnaire about the incidence of tachyphylaxis and the time course to its occurrence. Subjects with plaque psoriasis applied topical corticosteroid twice daily for 12 weeks to their plaques, leaving an isolated plaque untreated for comparison. Plaques were evaluated every 2 weeks. By means of a 9-point scale, an end point for clinical detection of tachyphylaxis was defined as "an increase in plaque elevation of at least 2 occurring after a detectable decrease in plaque elevation with topical steroid.", Results: The survey found that 57% of dermatologists perceived that tachyphylaxis occurred after 8 weeks of therapy with topical corticosteroid. In the 12-week clinical study, none of 32 patients exhibited detectable signs of tachyphylaxis., Conclusion: What accounts for the commonly held belief of tachyphylaxis in the clinical setting may be related to the therapeutic efficacy of topical corticosteroids. Failure of topical corticosteroids to clear psoriasis after an initial improvement may give the impression of tachyphylaxis. The common clinical perception of tachyphylaxis may also be related to issues of compliance outside a study setting or a psoriasis flare unrelated to therapy.

Background: Therapy with aromatic retinoids for psoriasis is associated with abnormal liver function test findings and toxic hepatitis (in 1.5% of patients)., Objective: Our purpose was to determine the safety of acitretin with respect to liver function, on the basis of biopsy., Methods: We treated 128 adults (with chronic, stable psoriasis) with oral acitretin (25-75 mg/day) for four 6-month intervals in a prospective, open-label, 2-year multicenter study. Liver biopsies were performed before and after study completion (2 years)., Results: Eighty-three available pairs of pretreatment and posttreatment liver biopsies demonstrated no change in 49 patients (59%), improvement in 20 (24%), and worsening in 14 (17%). Of these 14 patients with decrements in biopsy status, most changes were mild. There was no correlation between liver function test abnormalities or cumulative acitretin dose and changes in liver biopsy status., Conclusion: Acitretin therapy elicited no biopsy-proven hepatotoxicity in this prospective 2-year study. These findings suggest that periodic liver biopsy may not be necessary with acitretin treatment.

Clinical manifestations of mastocytosis are mediated, at least in part, by release of the mast cell mediators histamine and prostaglandin D2. It has been previously reported that in addition to prostaglandin D2, mast cells produce other eicosanoids, including thromboxane. Nonetheless, little information exists regarding the formation of other prostanoids in vivo. The most accurate method to examine the systemic production of eicosanoids in vivo is the quantitation of urinary metabolites. We previously developed a highly accurate assay employing mass spectrometry to measure a major urinary metabolite of thromboxane, 11-dehydro-thromboxane B2, in humans. We utilized this assay to quantitate thromboxane production in 17 patients with histologically proven mastocytosis. We report that thromboxane formation was significantly increased (>2 SD above the mean) in at least one urine sample from 65% of patients studied. Of these, 91% of patients with documented systemic involvement had elevated thromboxane generation. In addition, endogenous formation of thromboxane was highly correlated with the urinary excretion of the major urinary metabolite of prostaglandin D2 (r = 0.98) and Ntau-methylhistamine (r = 0.91), suggesting that the cellular source of increased thromboxane in vivo could be the mastocyte. Enhanced thromboxane formation in patients with this disorder is unlikely to be of platelet origin as other markers of platelet activation, platelet factor 4 and beta-thromboglobulin, were not increased in three patients with marked overproduction of thromboxane. Furthermore, the recovery of 11-dehydro-thromboxane B2 excretion in two patients after the administration of aspirin occurred significantly more rapidly than the recovery of platelet thromboxane generation. These studies, therefore, report that thromboxane production is significantly increased in the majority of patients with mastocytosis that we examined and provide the basis to elucidate the role of this eicosanoid in disorders of mast cell activation.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Various endogenous factors such as stress and infection are known to influence psoriasis. Previous data suggest that pregnancy has a significant influence on the course of psoriasis. This study explores the effect of pregnancy as well as other hormonal events on psoriasis in women.

Objective: To determine the safety and efficacy of topically applied tazarotene gel in the treatment of mild to moderate psoriatic plaques., Design: Two multicenter, double-blind, randomized studies of 6- and 8-week duration, with an 8-week follow-up in the second study., Setting: Medical center outpatient dermatology services., Participants: One hundred fifty-three adults with 2 bilateral target plaques on the trunk, legs, or arms., Interventions: Vehicle gel or 0.01% and 0.05% tazarotene gel administered twice daily to 45 patients (study A), or 0.05% and 0.1% tazarotene gel administered either once or twice daily to 108 patients (study B)., Main Outcome Measures: Treatment success and plaque elevation, scaling, and erythema vs time., Results: The 0.01% tazarotene gel showed minimal efficacy. Applications of 0.05% and 0.1% tazarotene gels administered once or twice daily, resulted in significant improvements in plaque elevation, scaling, erythema, and overall clinical severity as early as 1 week. Treatment success rates (defined as > 75% improvement from baseline) were 45% with 0.05% tazarotene gel vs 13% with vehicle gel after 6 weeks of treatment (P < .05; study A) and ranged from 48% to 63% with the various tazarotene treatment regimens after 8 weeks of treatment (study B). These improvements were evident at the 8-week follow-up. Treatment-related adverse effects were generally limited to mild or moderate local irritation and were less frequent with the treatment regimen administered once daily., Conclusion: The 0.05% and 0.1% tazarotene gels demonstrated significant efficacy in the treatment of mild to moderate psoriatic plaques that persisted after cessation of treatment.

We have seen great progress in the past decade in our understanding of the pathogenesis of psoriasis. The fruits of this knowledge are being realized in many of the exciting immunologic therapies currently in development. The potential for astute clinical observation to produce effective therapies and to change the direction of research has been proven in the past and still remains as an avenue for the future. Although individual treatments were discussed in this article, combination therapy is likely to continue to play a major role. Additionally, because future therapeutic developments are not likely to be free of toxicity, rotational therapy may still be necessary. Many questions remain unanswered. Substantial progress is just beginning into the.

Background: The biologically active form of vitamin D3, calcitriol, is effective in the treatment of psoriasis but can alter calcium metabolism. Calcipotriene is an analog of calcitriol that has low calcemic activity and aids in clearing psoriasis., Objective: The purpose of this study was to determine the safety of topical therapy with calcipotriene particularly in relation to calcium and bone metabolism., Methods: In a double-blind, randomized, parallel, vehicle-controlled trial, 78 adults with plaque psoriasis were treated twice daily with topical calcipotriene ointment (50 microgram/gm, maximum usage, 120 gm per week) or vehicle for 8 weeks. After a screening visit, patients were admitted to the hospital at weeks 0 (baseline), 1,2,4, and 8. Blood and urine chemistry analysis included parathyroid hormone, serum calcium, bone-specific alkaline phosphatase, urinary hydroxyproline, and 24 hour urinary calcium excretion. Bone densitometry measures were performed at baseline and week 8., Results: No incidences of calcipotriene treatment-related hypercalcemia, calcium mobilization from bone, or clinically significant changes in bone density wer noted during this study., Conclusion: Topical application of up to 120 gm per week of calcipotriene ointment for 8 weeks is safe and effective for plaque psoriasis. There were no adverse effects on calcium and bone metabolism during this 8 week study.

Cylindromas are rare benign adenexal tumors that classically arise on the head and neck, thus earning the name of turban tumor. They are usually benign, but may be multiple and recurrent. A 78-year-old woman noted an abdominal cylindroma, an unusual presentation of this rare cutaneous tumor. The clinical presentation, histologic characteristics, and variations of the dermal cylindroma are reviewed.

The efficacy and pharmacokinetic profiles of two oral formulations of cyclosporine A (Sandimmune and Neoral; Sandoz Pharmaceuticals, East Hanover, NJ) were evaluated in 37 patients with moderate to severe plaque psoriasis in a randomized, double-blind, modified, crossover study. Cyclosporine A (150 mg twice daily), administered in either formulation, reduced the severity of plaque lesions: 94% of all patients reported at least moderate improvement and 70% reported complete clearing. Approximately 2 weeks of therapy were required for drug exposure to stabilize on either formulation. Cyclosporine A exposure from Neoral was significantly greater relative to that from Sandimmune across all study weeks. At the eighth week (before crossover), AUC and Cmax values for Neoral and Sandimmune were 5618 +/- 1705 versus 3202 +/- 596 ng.h/mL and 1283 +/- 337 versus 623 +/- 173 ng/mL, respectively. In crossover analysis at steady state, the relative oral bioavailability of cyclosporine from the Neoral formulation was 54% greater than that from Sandimmune. Some pharmacokinetic parameters showed less variability both between and within groups of patients taking Neoral versus Sandimmune. Both formulations were well tolerated, in that most adverse events were of mild severity.

Symptoms of mastocytosis have been attributed to the overproduction of both histamine and prostaglandin (PG) D2. Recently, we developed an assay for the major urinary metabolite of PGD2 (PGD-M), 9 alpha,11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid, and demonstrated that urinary excretion of this compound is markedly increased in patients with mastocytosis. It had been shown previously that measurement of the urinary excretion of histamine metabolites provides a more sensitive biochemical diagnostic indicator of systemic mastocytosis than does measurement of unmetabolized histamine. Therefore, we examined the correlation between the urinary excretion of the histamine metabolite, NT-methylhistamine, and PGD-M in urine samples from patients with mastocytosis. Urinary excretion of NT-methylhistamine and PGD-M was measured in 46 urine samples from 17 patients with histologically documented mastocytosis. Both compounds were quantified by mass spectrometry. In all urine collections showing an increase above normal (2 SD above the mean) in the excretion of NT-methylhistamine, the fold increase above normal in the urinary excretion of PGD-M was substantially greater. Further, in some urine samples from four patients whose excretion of NT-methylhistamine was consistently normal, the excretion of PGD-M was increased above normal by as much as 300%. These data indicate that quantification of the urinary excretion of PGD-M is a more sensitive biochemical diagnostic indicator of mastocytosis than is the quantification of NT-methylhistamine.

Background: Cyclosporine has been used to treat a variety of cutaneous and immune-mediated diseases. Nephrotoxicity is the most common major adverse side effect., Objective: The study was designed to investigate the frequency of alterations in serum creatinine in patients with psoriasis receiving 5 mg/kg/day of cyclosporine., Methods: Sixteen patients with severe refractory psoriasis received cyclosporine, 5 mg/kg/day, for 12 weeks. Serum creatinine was evaluated with respect to each patient's baseline., Results: Serum creatinine levels remained in the normal range, but 10 of 16 patients had a 30% elevation and 5 of 16 patients had a 50% elevation of serum creatinine compared with the patient's baseline value., Conclusion: These results indicate that a significant elevation in serum creatinine occurs in many patients who receive cyclosporine for psoriasis.

The efficacy and safety of 0.05% halobetasol propionate ointment were evaluated in patients with chronic atopic or other eczematous dermatoses in two vehicle-controlled, double-blind studies: a paired-comparison study in 124 patients (study A) and a parallel-group study in 100 patients (study B). In study A, patients applied both treatments twice daily for 2 weeks and were evaluated by investigators on days 0, 7, and 14 with 0 to 3 severity scales and by self-assessment with two 5-step end-of-treatment rating scales. In study B, patients applied treatments twice daily for 2 weeks, and investigators made evaluations on days 0, 3, 7, and 14 with 0 to 6 scales and also made a 5-step end-of-treatment physician's global assessment. In study A, both severity scores and patient ratings favored halobetasol propionate significantly on days 7 (p less than or equal to 0.0013) and 14 (p less than 0.0001); in study B, severity scores on days 3 (p less than or equal to 0.045, pruritus, erythema, and overall lesion severity), 7, and 14 (p less than 0.001, all comparisons) also favored halobetasol propionate significantly, and global assessments showed complete resolution or marked improvement for 83% of patients using halobetasol propionate versus 28% of those using vehicle (p less than 0.0001). No instances of systemic effects or skin atrophy were reported in either study. We conclude that 0.05% halobetasol propionate ointment is highly effective and well tolerated in the treatment of the conditions studied, with the rapid action and high degree of clearing associated with superpotent corticosteroid formulations.

The results of two studies are presented that reveal the efficacy and safety of 0.05% halobetasol ointment in the treatment of patients with plaque psoriasis of at least moderate severity. Both multicenter studies were randomized, double-blind, and vehicle controlled, and study medications were applied twice daily for 2 weeks. One study was a paired-comparison (PC); the other study was of parallel-group (PG) design. Both studies called for evaluations at entry (week 0) and after 1 and 2 weeks of treatment. The PC study enrolled 100 patients; the PG study enrolled 110 patients; 204 patients provided efficacy data over both studies. In the PC study, plaque elevation, erythema, and scaling, at least moderately severe at entry, showed at the end of treatment both statistical (p less than or equal to 0.0003) and clinical significance (all greater than 1-unit difference on the rating scale) favoring 0.05% halobetasol ointment over vehicle. Pruritus (initially mild) and total score also showed statistically significant treatment differences favoring halobetasol at the final evaluation. Patient global responses for "effectiveness" and "overall rating" favored 0.05% halobetasol ointment over vehicle. In the PG study, induration, erythema, and scaling, at least moderately severe at entry, showed at the end of treatment both statistically and clinically significant differences favoring 0.05% halobetasol ointment over vehicle. Physician's global evaluation favored 0.05% halobetasol ointment over vehicle after 2 weeks of use. No patients were released from either study because of adverse events. No systemic adverse events or findings of skin atrophy were reported in these studies. Reports of "stings" or "burns" were equally divided between halobetasol and its vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)