Perinatal use and discontinuation of disease-modifying anti-rheumatic drugs and biologics in women with rheumatoid arthritis: a cohort study.

OBJECTIVES: To characterize the utilization and discontinuation of medications before, during and after pregnancy among women with RA. METHODS: We used population-based administrative data to identify women with RA who had a singleton pregnancy ending in delivery between 1 January 2002 and 31 December 2012. We assessed the utilization of RA medications, namely, conventional synthetic DMARDs, biologics, glucocorticosteroids and NSAIDs, across six windows spanning 24 and 12 months before the start of pregnancy, each trimester of pregnancy and 12 months post-pregnancy. We defined medication discontinuation as no prescription in a given window following a prescription in the preceding window and evaluated predictors using logistic regression models, calculating adjusted odds ratios (ORs) and 95% CIs. RESULTS: We studied 1730 pregnancies in 1301 women with RA (mean age at delivery 31.4 ± 5.4 years). We observed substantial medication discontinuation, particularly in the first trimester, with discontinuation of antimalarials in 57.3% of patients, azathioprine 59.1%, sulfasalazine 69.5% and biologics 50.8%. Factors inversely associated with discontinuation of antimalarials in the first trimester were maternal age [OR 0.90 (95% CI 0.86, 0.95)] and number of rheumatology visits [OR 0.86 (95% CI 0.75, 0.97)] and for biologics, prior adverse birth outcome [OR 0.22 (95% CI 0.05, 0.95)]. CONCLUSION: Our population-based study shows frequent discontinuation of medications for RA, particularly in the first trimester. Findings indicate a need to educate women with RA who are planning pregnancy on the benefits and risks of medications during pregnancy.

Gold Nanoparticles in Glioma Theranostics.

Despite many endeavors to treat malignant gliomas in the last decades, the median survival of patients has not significantly improved. The infiltrative nature of high-grade gliomas and the impermeability of the blood-brain barrier to the most therapeutic agents remain major hurdles, impeding an efficacious treatment. Theranostic platforms bridging diagnosis and therapeutic modalities aim to surmount the current limitations in diagnosis and therapy of glioma. Gold nanoparticles (AuNPs) due to their biocompatibility and tunable optical properties have widely been utilized for an assortment of theranostic purposes. In this Review, applications of AuNPs as imaging probes, drug/gene delivery systems, radiosensitizers, photothermal transducers, and multimodal theranostic agents in malignant gliomas are discussed. This Review also aims to provide a perspective on cancer theranostic applications of AuNPs in future clinical trials.

Light therapies for acne: abridged Cochrane systematic review including GRADE assessments.

We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light-based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and grey literature sources (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QoE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QoE) showed little or no difference in effectiveness on participants' assessment of improvement between 20% aminolaevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, vs. vehicle plus blue light, whereas another study (n = 180) comparing ALA-PDT (red light) concentrations showed that 20% ALA-PDT was no more effective than 15% ALA-PDT but better than 10% and 5% ALA-PDT. Pooled data from three studies (n = 360, moderate QoE) showed that methyl aminolaevulinate PDT, activated by red light, had a similar effect on changes in lesion counts vs. placebo cream with red light. Several studies compared yellow light with placebo or no treatment, infrared light with no treatment, gold microparticle suspension with vehicle and clindamycin/benzoyl peroxide (C/BPO) combined with pulsed dye laser with C/BPO alone. None of these showed any clinically significant effects. Most studies reported adverse effects, but inadequately, with scarring reported as absent, and blistering only in studies on intense pulsed light, infrared light and PDT (very low QoE). Carefully planned studies, using standardized outcome measures and common acne treatments as comparators, are needed.

[Lichenoid drug reactions]. / Lichenoide Arzneimittelreaktionen.

Lichenoid drug reactions are rare compared to typical morbilliform drug exanthema or urticaria. They are associated with specific drugs or drug families like gold, antimalarial drugs, ß­blockers and angiotensin-converting-enzyme inhibitors. Recent observations included associations with novel drugs such as biologics (e. g. tumour necrosis factor antagonists) and immune checkpoint inhibitors (anti-programme cell death protein 1 antibodies). Lichenoid drug reactions most often resemble lichen planus mainly in areas of ultraviolet-light exposed skin, but also mucosal lichen planus and even bullous lesions may occur.

Cancer targeting with biomolecules: a comparative study of photodynamic therapy efficacy using antibody or lectin conjugated phthalocyanine-PEG gold nanoparticles.

The functionalisation of therapeutic nanoparticle constructs with cancer-specific biomolecules can enable selective tumour accumulation and targeted treatment. Water soluble gold nanoparticles (ca. 4 nm) stabilised by a mixed monolayer of a hydrophobic zinc phthalocyanine photosensitiser (C11Pc) and hydrophilic polyethylene glycol (PEG) have been prepared. The C11Pc-PEG gold nanoparticle constructs were further functionalised with jacalin, a lectin specific for the cancer-associated Thomsen-Friedenreich (T) carbohydrate antigen, or with monoclonal antibodies specific for the human epidermal growth factor receptor-2 (HER-2). The two biofunctionalised nanoparticle conjugates produced similar levels of singlet oxygen upon irradiation at 633 nm. Importantly, both nanoparticle conjugates demonstrated extensive, yet comparable, phototoxicity in HT-29 colorectal adenocarcinoma cells (80-90%) and in SK-BR-3 breast adenocarcinoma cells (>99%). Non-conjugated C11Pc-PEG gold nanoparticles were only minimally phototoxic. Lysosomal colocalisation studies performed with the HT-29 colon cancer cells and the SK-BR-3 breast cancer cells revealed that both nanoparticle conjugates were partially localised within acidic organelles, which is typical of receptor-mediated endocytosis. The similarity of the targeted PDT efficacy of the two biofunctionalised C11Pc-PEG gold nanoparticles is discussed with respect to targeting ligand binding affinity and cell surface antigen density as key determinants of targeting efficiency. This study highlights how targeting small cell-surface molecules, such as the T antigen, can mediate a selective photodynamic treatment response which is similar to that achieved when targeting overexpressed protein receptors, such as HER-2. The high prevalence of the T antigen present on the cellular surface of primary tumours emphasises the broad potential applications for lectin-targeted therapies.

The testing of Sanocrysin: science, profit, and innovation in clinical trial design, 1926-31.

This article provides a detailed analysis of the origins and significance of the 1926 clinical trial of Sanocrysin, a gold compound thought at the time to be useful in the treatment of tuberculosis. This experiment is generally considered to be the first clinical trial in the United States that used a formal system of randomization to divide research subjects into treatment and nontreatment groups; it was probably also the first clinical trial in the United States to use placebo shams in a nontreatment control group to overcome the problem of what researchers at the time called "psychic influence." As such, it was an extremely important moment in the history of clinical trial design. Yet, as I argue, the Sanocrysin experiment also needs to be understood in terms of both the regulatory environment at the time and the commercial interests of Parke, Davis & Company, the pharmaceutical manufacturer that was intent on introducing the drug. Although some historians argue that therapeutic reformers in the twentieth century used experimental science to rein in the commercial forces of the market, this article suggests that, at least in this case, the promotion of rigorous clinical science and the pursuit of corporate profit were deeply intertwined.

Protein metalation by metal-based drugs: reactions of cytotoxic gold compounds with cytochrome c and lysozyme.

Protein metalation processes are crucial for the mechanism of action of several anticancer metallodrugs and warrant deeper characterisation. We have explored the reactions of three cytotoxic gold(III) compounds-namely [(bipy(2Me))(2)Au(2)(µ-O)(2)][PF(6)](2) (where bipy(2Me) is 6,6'-dimethyl-2,2'-bipyridine) (Auoxo6), [(phen(2Me))(2)Au(2)(µ-O)(2)][PF(6)](2) (where phen(2Me) is 2,9-dimethyl-1,10-phenanthroline) (Au(2)phen) and [(bipy(dmb)-H)Au(OH)][PF(6)] [where bipy(dmb)-H is deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine] (Aubipyc)-with two representative model proteins, i.e. horse heart cytochrome c and hen egg white lysozyme, through UV-visible absorption spectroscopy and electrospray ionisation mass spectrometry (ESI MS) to characterise the inherent protein metalation processes. Notably, Auoxo6 and Au(2)phen produced stable protein adducts where one or more "naked" gold(I) ions are protein-coordinated; very characteristic is the case of cytochrome c, which upon reaction with Auoxo6 or Au(2)phen preferentially forms "tetragold" adducts with four protein-bound gold(I) ions. In turn, Aubipyc afforded monometalated protein adducts where the structural core of the gold(III) centre and its +3 oxidation state are conserved. Auranofin yielded protein derivatives containing the intact auranofin molecule. Additional studies were performed to assess the role played by a reducing environment in protein metalation. Overall, the approach adopted provides detailed insight into the formation of metallodrug-protein derivatives and permits trends, peculiarities and mechanistic details of the underlying processes to be highlighted. In this respect, electrospray ionisation mass spectrometry is a very straightforward and informative research tool. The protein metalation processes investigated critically depend on the nature of both the metal compound and the interacting protein and also on the solution conditions used; thus, predicting with accuracy the nature and the amounts of the adducts formed for a given metallodrug-protein pair is currently extremely difficult.

Brucella species-induced brucellosis: Antimicrobial effects, potential resistance and toxicity of silver and gold nanosized particles.

Brucellosis is an endemic zoonotic disease caused by Brucella species, which are intramacrophage pathogens that make treating this disease challenging. The negative effects of the treatment regime have prompted the development of new antimicrobials against brucellosis. A new treatment modality for antibiotic-resistant microorganisms is the use of nanoparticles (NPs). In this study, we examined the antibacterial activities of silver and gold NPs (SNPs and GNPs, respectively), the resistance developed by Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) strains and the toxicity of both of these NPs in experimental rats. To test the bactericidal effects of the SNPs and GNPs, we used 22 multidrug-resistant Brucella isolates (10 B. melitensis and 12 B. abortus). The minimal inhibitory concentrations (MICs) of both types of NPs were determined utilizing the microdilution technique. To test the stability of resistance, 7 B. melitensis and 6 B. abortus isolates were passaged ten times in culture with subinhibitory concentrations of NPs and another ten times without NPs. Histopathological analysis was completed after rats were given 0.25, 0.5, 1, and 2 mg/kg NPs orally for 28 consecutive days. The MIC values (µg/ml) of the 10-nm SNPs and 20-nm GNPs against B. melitensis were 22.43 ± 2.32 and 13.56 ± 1.22, while these values were 18.77 ± 1.33 and 12.45 ± 1.59 for B. abortus, respectively. After extensive in vitro exposure, most strains showed no resistance to the 10-nm SNPs or 20-nm GNPs. The NPs and antibiotics did not cross-react in any of the evolved Brucella strains. SNPs and GNPs at doses below 2 mg/kg were not harmful to rat tissue according to organ histopathological examinations. However, a greater dose of NPs (2 mg/kg) harmed all of the tissues studied. The bactericidal properties of NPs are demonstrated in this work. Brucella strains develop similar resistance to SNPs and GNPs, and at low dosages, neither SNPs nor GNPs were hazardous to rats.

[Pemphigus: a review]. / Pemphigus: revue de la littérature.

BACKGROUND: Pemphigus is a rare autoimmune bullous disorder. Numerous treatment regimens have been proposed in the literature. OBJECTIVE: To assess the efficacy and tolerance of treatment regimens proposed in pemphigus vulgaris (PV) and pemphigus foliaceus (PF), from a systematic review of the literature. METHODS: Randomized control trials have been identified using the PubMed and Embase databases up to April 2009. Uncontrolled prospective and retrospective studies have also been analyzed. RESULTS: Eleven randomized control trials having included a total number of 421 patients (377 PV, 44 PF) have been analyzed. Most studies had a limited statistical power due to the rather low number of cases included. Results from ten different treatment regimens have been analyzed: different dosages of prednisone and prednisolone, pulse intravenous dexamethasone, azathioprine, cyclophosphamide, cyclosporine, dapsone, mycophenolate mofetil, plasmapheresis, topical applications of epidermal growth factor (EGF), and intravenous immune globulins (IVIG). Inclusion criteria were: (i) consecutive patients in nine studies, (ii) patients who did not respond to low doses of corticosteroids in one study, and (iii) patients with relapsing type of pemphigus in one study. None of these studies allowed identifying the best effective and well tolerated regimen. Mycophenolate mofetil was more effective than azathioprine for disease control (from one study; n=40; OR=0.72; 95% CI=0.52-0.99). However, no difference in the rate of clinical remission was evidenced between these drugs. Azathioprine and cyclophosphamide seem to have a corticosteroid sparing effect. CONCLUSION: Data from the literature did not allow identifying the best therapeutic regimen, mainly because of the lack of statistical power of most studies. The usefulness of immunosuppressant added to systemic corticosteroids as the first line of treatment is not clearly established.

Jacques Forestier: Forgotten Contributions of a Rheumatologist to Spine Surgery.

Jacques Forestier (1890-1978) was a well-known rheumatologist and radiologist whose innovations have revolutionized spinal neurosurgery and rheumatology. He was well known as "Doctor Lipiodol" for his accidental discovery of spinal myelography, which he later extrapolated for use in many body cavities and their pathologies. He was the first to describe "senile ankylosing hyperostosis of the spine," which was later renamed "diffuse idiopathic skeletal hyperostosis." Furthermore, he is credited with the first use of gold salts as a disease-modifying therapy for rheumatoid arthritis. We have presented a historical vignette to chronicle the life of Jacques Forestier and his contributions to the field of spinal neurosurgery.

HIV therapeutic possibilities of gold compounds.

Highly active antiretroviral therapy (HAART) has resulted in decreased mortality and morbidity from the acquired immune deficiency syndrome caused by the human immunodeficiency virus (HIV). Drug resistance and toxicity of HAART has led to the search for novel inhibitors of HIV infection. Gold-based compounds have shown promising activity against a wide range of clinical conditions and microorganism infections including HIV-1. A typical example is auranofin which resulted in an elevated CD4+ T-cell count in an HIV patient being treated for psoriatic arthritis. In addition, reports exist on gold-based inhibitors of reverse transcriptase (RT), protease (PR) and viral entry of host cells. These and other characteristics of gold-based HIV drugs are reviewed here.

[Corneal tatoo--art or science?]. / Tatuajul corneean--arta sau stiinta?

The permanent colouring of disfigured corneal scars is known for almost 200 years. Because of improvement in surgical reconstructive techniques, corneal tattoing is used today only with a restricted group on carefully chosen patients, and merely for esthetique reasons.

Enhancement of linear energy transfer in gold nanoparticles mediated radiation therapy.

OBJECTIVE: The metric dose enhancement ratio (DER) has been widely used to assess the enhancing capability of gold nanoparticles (GNPs). However, there is a large disparity between the observed radiobiological outcome and DER values. A new metric, linear energy transfer enhancement ratio (LETER), is introduced to bridge the gap between theoretical predictions and the experimentally measured sensitization. METHODS: The radiation transport code SCEPTRE is used to examine the efficacy of the proposed new metric. Different clusters of GNPs irradiated with x-ray photons generated at 120 kVp and therapeutic 6 MV photon beams are investigated. For each pattern, two GNPs sizes are examined 50 and 100 nm. RESULTS: An enhancement in the linear energy transfer has been observed for both energies. In the case of 120 kVp, LETER is substantially lower than DER; moreover, it decreases with increasing GNP size. On the other hand, the results of 6 MV show that LETER is relatively higher than DER, and it increases with the size of GNP. For the studied energies, LETER is in good agreement with the sensitization reported in the literature. CONCLUSION: The results indicate the merit of LETER as a better indicator of the radiobiological outcome of GNP aided radiotherapy.

Theranostic Gold Nanomicelles made from Biocompatible Comb-like Polymers for Thermochemotherapy and Multifunctional Imaging with Rapid Clearance.

A new generation of photothermal theranostic agents based on assembling 6 nm gold nanoparticles (AuNPs) is developed by using a novel comb-like amphipathic polymer as the template. The small AuNPs are assembled into DOX@gold nanomicelles, which show strong absorbance in the near-infrared region, for multimodal bioimaging and highly effective in vivo chemotherapy and photothermal therapy.

Gold derivatives for the treatment of cancer.

The cytotoxicity and anti-tumour activity screening trials for both gold(I) and gold(III) are summarised. Gold(I) thiolates employed clinically in the treatment of rheumatoid arthritis display some potency against various tumours but a greater potential is found in their analogues. In particular, analogues featuring a linear P-Au-S arrangement in which the thiolate ligand is derived from a biologically active thiol display high potency. Further, targeting mitochondria with tetrahedrally coordinated gold(I) phosphine compounds with enhanced hydrophilicity is a research direction with exciting potential. Recent research has shown that gold(III) compounds featuring square-planar geometries, as found in cisplatin, may target DNA and may provide new anti-tumour agents.

Commonly used disease-modifying antirheumatic drugs in the treatment of inflammatory arthritis: an update on mechanisms of action.

Although disease-modifying drugs are extensively used in the treatment of inflammatory arthritides such as rheumatoid arthritis (RA), the actual underlying mechanisms of action of these agents remains somewhat unclear. Many investigators have studied the effects of these agents, often with particular attention being paid to alterations in inflammatory cytokine production, cell proliferation and activation, signal transduction pathways, and enzyme inhibition. By gaining a more complete understanding of these mechanisms, further information may be had regarding the pathophysiology of RA as well as other autoimmune diseases. In the following review we will examine some of the more recent studies of drug mechanisms, focusing on the most commonly used anti-rheumatic medications in the treatment of RA.

The association between ocular cicatricial pemphigoid and rheumatoid arthritis.

PURPOSE: To assess the pathogenesis, symptomatology, and severity of rheumatoid arthritis (RA) in patient's with concomitant ocular cicatricial pemphigoid (OCP). METHODS: We retrospectively analyzed the charts of eight patients seen at a single institution between the years 1972 and 1997 with concomitant RA and OCP. Patients with OCP secondary to medical therapy, radiation, or chemical burns, or Stevens-Johnson syndrome were excluded. RESULTS: The female-to-male ratio was 7:1. All patients had positive serum rheumatoid factors and immunohistochemical confirmation of OCP. The mean number of years of RA prior to OCP diagnosis was 19. The number of patients with stage II OCP was three of eight (37.5%). The number of patients with stage III OCP was five of eight (62.5%). All patients had radiologic evidence of degenerative joint disease and synovial thickening. All eight patients had keratoconjunctivitis sicca, five of eight patients (62.5%) had Sjögren's syndrome, and five of eight patients (62.5%) developed rheumatoid cornea necrosis leading to corneal perforation. CONCLUSIONS: The implication exists that RA and OCP may be linked via an immunologically mediated mechanism and that patients with severe extraarticular symptoms associated with RA may be more likely to develop OCP. Prompt recognition of overlying symptoms may facilitate proper therapy for control of both diseases.

Cutaneous lupus erythematosus.

Lupus erythematosus (LE) has many different clinical manifestations including a variety of cutaneous findings. Some of the cutaneous manifestations are not specific for LE, such as photosensitivity reactions, oral ulcers, alopecia, urticaria, vasculitis, vesiculo-bullous lesions, acral changes, cutaneous mucinoses, and cutaneous calcinosis. Other findings are specific for LE in that they are found only in patients who have lupus erythematosus. These LE-specific disorders include acute cutaneous LE, subacute cutaneous LE, and several forms of chronic cutaneous LE, including discoid LE. Skin biopsies are often helpful in differentiating LE-specific skin lesions from other disorders that can mimic them. Photoprotective measures and a number of drugs are useful in treating cutaneous LE.

[The role of the conventional drugs in the treatment of rheumatoid arthritis]. / Il ruolo dei farmaci "tradizionali" nella terapia dell'artrite reumatoide.

Rheumatoid arthritis (RA), the most frequent systemic connective tissue disease, is characterized by polyarticular symmetric chronic synovitis. It is generally a progressive disease with radiographic evidence of joint damage, functional status decline and premature mortality. Pharmacologic therapy for RA often consists of combination of non steroidal antiinflammatory drugs (NSAIDs), glucocorticoids and disease modifying antirheumatic drugs (DMARDs). Although NSAIDs and glucocorticoids may alleviate symptoms, joint damage may continue to occur and to progress. DMARDs should have the potential to reduce or prevent joint damage, preserve joint function and achieve remission. Many efforts have been taken in the past years to standardize the assessment of RA aiming at making study results comparable. Response criteria have been developed by the American College of Rheumatology and the European League against Rheumatism. These criteria have permitted the evaluation of the efficacy of the old and new therapies. The first one have been illustrated in this review. The second one will be treated in a next article.