Current Rheumatology Reviews - Volume 10, Issue 1, 2014

Improved understanding of the molecular mechanisms leading to autoimmunity have resulted in advances toward the diagnosis, management, and treatment of rheumatologic diseases. Many of these mechanisms overlap with inflammatory disease states and cancer, where nanoscience is increasingly being applied for pharmacologic and diagnostic purposes [1-6]. Additionally, nanoscience has furthered the study of cellular interactions within the in situ environment, thereby increasing the understanding of these complex, multi-system disorders [1, 7-9]. This Hot Topics review series intends to provide an overview of nanoscience, as it pertains to rheumatology and immunology, highlighting emerging technologies applied to rheumatologic models and with the potential for human use. This mini-series has a particular focus on imaging and drug delivery applications pertinent to autoimmune conditions as well as reviewing the pharmacology, clearance, and biodistribution of nanomaterials in inflammatory conditions and by immune cells. Nanotechnology involves the synthesis and utilization of materials – including but not limited to metals, oxides, lipids, polymers -- in the nanoscale range (1 to 1000 nm). Nanomaterial composition as well as the size, shape, charge, and surface coating contribute to unique nanomaterial characteristics that can be used for a variety of biomedical applications [1, 10]. Each of these independent variables influences the application, biodistribution, metabolism, and as anticipated, bystander toxicity. In the current era of biologic and monoclonal antibody-directed therapy for autoimmune disease, clinical and radiographic markers are becoming less sensitive to detect subtle disease activity, and there is an increasing demand for improved diagnostic imaging techniques and contrast agents. Because of the large surface to volume ratio and ease of functionalization, nanoparticles are particularly well suited for advanced imaging [1, 11] and may fill this gap. In the review by Rogers et al., the authors cite several examples of novel nanoparticle-based imaging strategies to identify inflammation and rheumatic disease in the early, pre-clinical stages and even at the cellular level [7, 12, 13]. Coupled with targeted molecular markers, multimodal nanoparticles carrying larger payloads than traditional contrast materials have the ability to increase the sensitivity and specificity of disease monitoring while retaining the anatomic detail of traditional imaging. In addition to the advantages nanomaterials provide as novel contrast agents in imaging, they can also be utilized in vaccination strategies or as drug carriers for targeted delivery to tissues [1, 14, 15]. This technology may improve upon current treatments or could provide therapies for some rheumatic illness, such as systemic lupus erythematosus or scleroderma, for which there are limited therapeutic options. In the review authored by Henderson and colleagues, a wide range of nanoparticle platforms including varied material composition and conjugated strategies are described as approaches to control the processes of drug release, targeted delivery, and degradation [16-19]. There is precedence for FDA approval of nanoparticle-based drug delivery for the treatment of infection and cancer in humans, and in some instances, this has decreased systemic toxicity while improving efficacy [20]. This same balance between targeted therapy and untoward side effects will need to be applied to medications designed for the rheumatic illnesses as the field advances. Many nanomaterials in the living organism are phagocytized by cells of the reticuloendothelial system, and in particular, these include the monocyte/macrophage cellular lineage [21]. In the review by Song et al., the authors discuss the complex interactions between nanoparticles and immune cells since this interplay can affect particle distribution, clearance, and potentially lead to off-target effects such as immune stimulation. Ultimately, these relationships between nanoparticles and immune system activation versus suppression will need to be clarified if their applications extend into treating primary disorders of the immune system such as autoimmunity. In Rheumatology, the role of nanoparticle based imaging, treatment-derived strategies, and pharmacokinetics and biodistribution has largely been conducted in preclinical models. Further in depth studies are needed to translate these exciting findings from animals to patients with rheumatologic or autoimmune conditions. Although some extrapolation can be made from the cancer and infectious disease arena, the chronicity of rheumatic disease will make clarifying the potential effects of nanomaterials in both short- and long-term applications germane to those patients as well as to others with chronic illness.

A variety of imaging modalities assists in the diagnosis and assessment of rheumatoid arthritis and of other rheumatic disorders; however, the definitive diagnosis of inflammatory arthritides can be challenging, especially in the early stages of disease. Consequently, there is significant research underway in expanding imaging sensitivity and specificity to aid in diagnostics of early stage inflammation and management of subclinical disease activity. Nanotechnology, the manipulation of materials in the nanoscale range (1 to 1000nm), is increasingly utilized in the biomedical field to meet this need, particularly as novel contrast agents in imaging. In this review, the use of superparamagnetic iron oxide (SPIO), gold, and chitosan glyco-nanoparticles will be discussed in their imaging capabilities pertaining to rheumatic diseases as well as emerging multimodal nanomaterials that could have future biomedical applications in the imaging of inflammation.

Nanotechnology, or the use of technology at the submicron scale, and its application to medicine (nanomedicine) draws from many ideas and technological advancements across myriad fields of materials technology and has improved biomedical understanding. Nanotechnology puts current materials science on the same physical scale as classic immune mediating substances, including viruses, moieties found on prokaryotic bacteria, and antigen presenting cells. Functionalized nanoparticles, fullerenes, liposomes, nanogels, and virus-like particles, are several examples of nanotechnology that are currently being applied to the treatment of oncologic and infectious diseases. However, the majority of the current commercial utilization of nanomedicine has been directed towards creating improved vaccines in order to prevent infectious diseases. These processes may have direct applications toward the creation of vaccines used to treat autoimmune disease as well. Current therapeutics utilizing nanotechnology, are gaining traction in treatments for gout and rheumatoid arthritis, and experimental animal models have demonstrated success in using the above technologies to improve the effectiveness and safety of current standard treatment of rheumatologic illnesses. Here we review many of the common forms of nanoparticles used in medical applications as well as where they have found a role in rheumatology. Continued technical feasibility, ongoing safety studies, and lingering questions on cost are all issues that have not yet been resolved in regards to widespread application in rheumatology and immunology.

Nanoparticles (NPs) provide several advantages over the small molecule drugs including prolonged circulation time and enhanced delivery to targeted sites. Once a NP enters the body, it interacts with host’s immune system and is engulfed by cells of the mononuclear phagocyte system (MPS). The interaction between NPs and the immune cells can result in immunosuppression or immunostimulation, which may enhance or reduce the treatment effects of NPs. Therefore, it is critical to understand the interactions between NPs and the immune system in order to optimize the treatment benefit and minimize the undesirable toxicities of NPs. This review elaborates on the interaction between NP and the MPS and its impacts on the pharmacokinetics (PK) and pharmacodynamics (PD) of NPs and applications for inflammatory diseases. This review also encompasses an overview of NPs being developed for treatment of inflammatory diseases.

The diagnosis of Fixed Sagittal Imbalance (FSI), previously known as Flat Back Syndrome, requires the measurement of spinal curvatures on a lateral radiograph in the standing position (C7-S1). It can be difficult to position a spastic patient, sometimes repeated exposure are required, at separate thoracic and lumbar levels, increasing the radiation dosage. CT Scanography is suggested as an alternative radiological diagnostic method since it is rapid to perform. The patient is comfortably positioned (horizontal) and it combines both prone and supine positions, therefore acting as a functional examination. This test was performed on 34 consecutive patients with fractured vertebrae (lumbar, dorsal) and with back pain persisting beyond the bone healing period. The functional scanogram was found to be accurate in diagnosing sagittal imbalances, but more importantly it offered reduction in radiation: in Entrance dose; in Effective dose and Absorption dose. Scanogram is therefore proposed as an alternative method for the diagnosis of FSI.

For many years observational studies and clinical trials on systemic sclerosis (SSc) have been carried out only on patients who met the 1980 American College of Rheumatology-ACR preliminary classification criteria. However, this lead to the exclusion from all those studies of subset patients, particularly those with a limited cutaneous SSc-sine scleroderma subset, because, despite a diagnosis of SSc based on Raynaud’s phenomenon (RP) associated with digital pitting scars/ulcers, or by sclerodactyly and telangiectasia and/or typical esophagopathy and/or interstitial fibrosis detected by High Resolution Computed Tomography of the lungs, they did not satisfy the classification criteria. In that setting, LeRoy and Medsger proposed to label as affected by limited SSc (lSSc) or early SSc, cases presenting with RP associated with an SSc-type nailfold capillary pattern and/or SSc-selective autoantibodies. In 2008, Koenig et al. validated these criteria and proposed to name early SSc, or pre-scleroderma, patients with RP and either a scleroderma marker autoantibody or typical capillaroscopy abnormalities or both, who had been clearly shown to have high probabilities but not the certainty to develop definite SSc during a 20-year follow-up. This definition has been recently challenged by the development of the new ACR/EULAR criteria for the classification of SSc. At present, to be labeled as affected by early SSc, or pre-scleroderma, a patient should suffer from RP associated with either scleroderma marker autoantibodies or typical capillaroscopy findings and should not meet the 2013 ACR/EULAR criteria for the classification of SSc nor should he/she meet the criteria for SSc sine scleroderma.

The objective of this umbrella systematic review was to identify, evaluate, and synthesize systematic reviews of physical activity interventions for adults with fibromyalgia (FM) focussing on four outcomes: pain, multidimensional function (wellness or quality of life), physical function (self-reported physical function or measured physical fitness) and adverse effects. A further objective was to link these outcomes with details of the interventions so as to guide and shape future practice and research. Electronic databases including Medline, EMBASE, CINAHL, AMED, the Cochrane Library, and DARE, were searched for the January 1st 2007 to March 31st 2013 period. Nine systematic reviews (60 RCTs with 3816 participants) were included. Meta-analysis was not conducted due to the heterogeneity of the sample. We found positive results of diverse exercise interventions on pain, multidimensional function, and self-reported physical function, and no supporting evidence for new (to FM) interventions (i.e., qigong, tai chi). There were no serious adverse effects reported. The variability of the interventions in the reviews prevented us from answering important clinical questions to guide practical decisions about optimal modes or dosages (i.e., frequency, intensity, duration). Finally, the number of review articles is proliferating, leading researchers and reviewers to consider the rigor and quality of the information being reviewed. As well, consumers of these reviews (i.e., clinicians, individuals with FM) should not rely on them without careful consideration.