Do new biologics meet the unmet medical need in rheumatoid arthritis? Safety and efficacy of abatacept following B-cell depletion

Sir, anti TNF-α agents (aTNFs) are the most commonly prescribed biological agents in RA. More recently abatacept (ABA), a T-cell costimulation modulator, and rituximab (RTX), a monoclonal antibody directed against CD20, have become available. Observational studies suggest that switching to a new drug class may be more effective in uncontrolled RA than switching to a class of biologics to which the patient had unsuccessfully been exposed [1]. Information about the efficacy and safety of cycling strategies through third-line biologics is lacking. This study aimed to analyse the effectiveness and safety of switching patients to ABA as the third biological class after failure of aTNF plus RTX. The Swiss Clinical Quality Management (SCQM) programme for RA is a longitudinal population-based cohort, which has been approved by the local ethics committees of all participating centres [2]. For this analysis, we collected all the …

Plant immunostimulants-Scientific paradigm or myth?

In traditional medicine, numerous plant preparations are used to treat inflammation both topically and systemically. Several anti-inflammatory plant extracts and a few natural product-based monosubstances have even found their way into the clinic. Unfortunately, a number of plant secondary metabolites have been shown to trigger detrimental pro-allergic immune reactions and are therefore considered to be toxic. In the phytotherapy research literature, numerous plants are also claimed to exert immunostimulatory effects. However, while the concepts of plant-derived anti-inflammatory agents and allergens are well established, the widespread notion of immunostimulatory plant natural products and their potential therapeutic use is rather obscure, often with the idea that the product is some sort of "tonic" for the immune system without actually specifying the mechanisms. In this commentary it is argued that the paradigm of oral plant immunostimulants lacks clinical evidence and may therefore be a myth, which has originated primarily from in vitro studies with plant extracts. The fact that no conclusive data on orally administered immunostimulants can be found in the scientific literature inevitably prompts us to challenge this paradigm.

Evolution of radiographic joint damage in rituximab-treated versus TNF-treated rheumatoid arthritis cases with inadequate response to TNF antagonists

Observational studies have suggested that patients with rheumatoid arthritis (RA) who experience inadequate response to anti-tumour necrosis factor (anti-TNF) agents respond more favourably to rituximab (RTX) than to an alternative anti-TNF agent. However, the relative effectiveness of these agents on long-term outcomes, particularly in radiographic damage, remains unclear.

Targeting the insulin-like growth factor-1 receptor in human cancer

The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or IGF-2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon, and prostate cancer. Anti-cancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this mini review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.

Antisense molecules for targeted cancer therapy

The efficacy of traditional anti-cancer agents is hampered by toxicity to normal tissues, due to the lack of specificity for malignant cells. Recent advances in our understanding of molecular genetics and tumor biology have led to the identification of signaling pathways and their regulators implicated in tumorigenesis and malignant progression. Consequently, novel biological agents were designed which specifically target key regulators of cell survival and proliferation activated in malignant cells and thus are superior to unspecific cytotoxic agents. Antisense molecules comprising conventional single-stranded antisense oligonucleotides (ASO) and small interfering RNA (siRNA) inhibit gene expression on the transcript level. Thus, they specifically target the genetic basis of cancer and are particularly useful for inhibiting the expression of oncogenes the protein products of which are inaccessible to small molecules or inhibitory antibodies. Despite the somewhat disappointing results of recent antisense oncology trials, the identification of new cancer targets and ongoing progress in ASO and siRNA technology together with improvements in tumor targeted delivery have raised new hopes that this fascinating intervention concept will eventually translate into enhanced clinical efficacy.

First clinical experience with anecortave acetate (Retaane)

BACKGROUND: Anecortave acetate is an angiostatic cortisene which is injected as a posterior juxtascleral depot and has been shown to be effective in the treatment of exudative age-related macular degeneration (AMD). The compound is not yet approved in Switzerland but can be used as "compassionate use" in individual cases. PATIENTS AND METHODS: An uncontrolled case series with standardised documentation of ETDRS visual acuity, near acuity, need for magnification and fluorescein angiography was performed. RESULTS: 22 eyes of 19 patients (8 male, 11 female, average age 78.8 years) were treated with a posterior juxtascleral depot injection (PJD) of 15 mg anecortave acetate. The mean change in visual acuity after 3 months in eyes treated with anecortave acetate was -2.6 ETDRS letters corresponding to 0.52 Snellen lines. 3/20 eyes gained more than 1 line. 11/20 eyes showed stable visual acuity (+/- 1 Snellen line, +/- 5 ETDRS letters). 5/20 eyes developed moderate vision loss (one to two Snellen lines, 6-10 ETDRS letters). 1/20 lost 18 ETDRS letters (> 3 Snellen lines). There were no moderate or severe adverse events. CONCLUSIONS: A PJD of 15 mg anecortave acetate is safe and well tolerated. In eyes with occult CNV without recent progression or with residual neovascular activity after photodynamic therapy anecortave acetate may be an alternative therapeutic option before considering intravitreal anti-VEGF agents due to the much less invasive character and lower risk profile.

Brain edema and increased intracranial pressure in the pathophysiology of bacterial meningitis

A number of advances in our understanding of the pathophysiology of bacterial meningitis have been made in recent years. In vivo studies have shown that bacterial cell wall fragments and endotoxins are highly active components, independent of the presence of viable bacteria in the subarachnoid space. Their presence in the cerebrospinal fluid is associated with the induction of inflammation and with the development of brain edema and increased intracranial pressure. Antimicrobial therapy may cause an additional increase of harmful bacterial products in the cerebrospinal fluid and thereby potentiate these pathophysiological alterations. These changes may contribute to the development of brain damage during meningitis. Some promising experimental work has been directed toward counteracting the above phenomena with non-steroidal or steroidal anti-inflammatory agents as well as with monoclonal antibodies. Although considerable advances have been made, further research needs to be done in these areas to improve the prognosis of bacterial meningitis.

Acute coronary syndromes: management and secondary prevention

Acute coronary syndromes represent a broad spectrum of ischemic myocardial events including unstable angina, non-ST elevation myocardial infarction and acute ST elevation myocardial infarction, which are associated with high morbidity and mortality. They constitute the most frequent cause of hospital admission related to cardiac disease. Early diagnosis and risk stratification are essential for initiation of optimal medical and invasive management. Therapeutic measures comprise aggressive antiplatelet, antithrombotic, and anti-ischemic agents. In addition, patients with high-risk features, notably positive troponin, ST segment changes and diabetes, benefit from an early invasive as compared to a conservative strategy. Importantly, lifestyle interventions, modification of the risk factor profile, and long-term medical treatment are of pivotal importance in reducing the long-term risk of recurrence.

The effect of monoalkyl phosphates and fluoride on dissolution of hydroxyapatite, and interactions with saliva

The aims were to investigate the effect of monoalkyl phosphates (MAPs) and fluoride on dissolution rate of native and saliva-coated hydroxyapatite (HA). Fluoride at 300 mg/l (as NaF) inhibited dissolution of native HA by 12%, while potassium and sodium dodecyl phosphates (PDP, SDP), at 0.1% or higher, inhibited dissolution by 26-34%. MAPs, but not fluoride, also showed persistence of action. MAPs at 0.5% and fluoride at 300 mg/l were then tested separately against HA pre-treated with human saliva for 2 or 18 h. Agents were applied with brushing to half the specimens, and without brushing to the other half. In control (water-treated) specimens, pre-treatment of HA with human saliva reduced dissolution rate on average by 41% (2 h) and 63% (18 h). Brushing did not have a statistically significant effect on dissolution rate of saliva-coated specimens. In brushed specimens, fluoride significantly increased the inhibition due to 2- or 18-hour saliva pre-treatment. It is hypothesised that brushing partially removes the salivary film and allows KOH-soluble calcium fluoride formation at the surfaces of HA particles. Inhibition was reduced by PDP in 2-hour/non-brushed specimens and in 18-hour/brushed specimens. PDP did not affect dissolution rates in the remaining groups and SDP did not affect dissolution rate in any group. Possible reasons for these variable results are discussed. The experiments show that pre-treatment with saliva can significantly modify results of tests on potential anti-erosive agents and it is recommended that saliva pre-treatment should be a routine part of testing such agents.

Organoleptic assessment of halitosis for dental professionals - general recommendations

An organoleptic assessment of an odor is defined as a method that can measure the strength of target odors and expresses the value in terms of a point or number with reference to a pre-defined organoleptic scale. Organoleptic assessments are performed using different scales and are used widely in industry (e.g. for measuring the effectiveness of anti-odor agents), in research (to discover relationships between bad breath and microbiology of the tongue, or the generation of particular volatile compounds), but it is also a prerequisite for the diagnosis of halitosis in individual patients required before directing appropriate treatment. An organoleptic assessment of halitosis patients may be carried out in specialized institutions but--based on the fact that in most cases the odor originates from oral structures--also by dental professionals including general dental practitioners (GDPs). Thus, this paper describes the scientific background for recommendations on how a GDP or dental hygienist or general practitioner with cases of bad breath should use organoleptic methods as a valid approach to assess malodor in patients, with a view to diagnosis and treatment, and subsequent treatment monitoring.

Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis: comparison between private rheumatology practices and academic centers in a large observational cohort

OBJECTIVE To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. METHODS We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort. RESULTS All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0). CONCLUSION With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.

Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis

BACKGROUND Anti-TNFα agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. METHODS We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFα agents. Appropriateness of the first-line anti-TNFα treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. RESULTS Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. CONCLUSION Appropriateness of first-line anti-TNFα therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFα agents.

Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.

Periodontal and peri-implant wound healing following laser therapy

Laser irradiation has numerous favorable characteristics, such as ablation or vaporization, hemostasis, biostimulation (photobiomodulation) and microbial inhibition and destruction, which induce various beneficial therapeutic effects and biological responses. Therefore, the use of lasers is considered effective and suitable for treating a variety of inflammatory and infectious oral conditions. The CO2 , neodymium-doped yttrium-aluminium-garnet (Nd:YAG) and diode lasers have mainly been used for periodontal soft-tissue management. With development of the erbium-doped yttrium-aluminium-garnet (Er:YAG) and erbium, chromium-doped yttrium-scandium-gallium-garnet (Er,Cr:YSGG) lasers, which can be applied not only on soft tissues but also on dental hard tissues, the application of lasers dramatically expanded from periodontal soft-tissue management to hard-tissue treatment. Currently, various periodontal tissues (such as gingiva, tooth roots and bone tissue), as well as titanium implant surfaces, can be treated with lasers, and a variety of dental laser systems are being employed for the management of periodontal and peri-implant diseases. In periodontics, mechanical therapy has conventionally been the mainstream of treatment; however, complete bacterial eradication and/or optimal wound healing may not be necessarily achieved with conventional mechanical therapy alone. Consequently, in addition to chemotherapy consisting of antibiotics and anti-inflammatory agents, phototherapy using lasers and light-emitting diodes has been gradually integrated with mechanical therapy to enhance subsequent wound healing by achieving thorough debridement, decontamination and tissue stimulation. With increasing evidence of benefits, therapies with low- and high-level lasers play an important role in wound healing/tissue regeneration in the treatment of periodontal and peri-implant diseases. This article discusses the outcomes of laser therapy in soft-tissue management, periodontal nonsurgical and surgical treatment, osseous surgery and peri-implant treatment, focusing on postoperative wound healing of periodontal and peri-implant tissues, based on scientific evidence from currently available basic and clinical studies, as well as on case reports.