Current Rheumatology Reviews - Volume 6, Issue 3, 2010

This is a very special issue of Current Rheumatology Reviews (CRR), which includes a topic that has fascinated me for years. In this issue, Dr. Bucala and his colleagues shed some light on a very important and relatively new disease, i.e., nephrogenic systemic fibrosis. This condition started appearing in the literature approximately 10 years ago with sporadic cases of fibrosis of the skin seen in patients who had renal failure. I remember with great clarity my first case of NSF and my interest in this disease peaked when I realized that we are dealing with a new disease entity. Subsequently, as more cases appeared, the search for a causative factor intensified. Causal relationship between the use of gadolinium-based contrast agents and nephrogenic systemic fibrosis was discovered in 2006. In this issue of CRR, Dr. Stenver describes the crucial role of health care professionals in the discovery of this association and his article provides us a reminder of the important role of pharmacovigilance in the discovery of potential drug toxicities. Reviews of this topic are not commonly present in the published literature and we are very pleased to provide a forum for leading researchers to provide unique and valuable viewpoints that will change the way we practice. For example, Dr. Thomsen and Dr. Morcos in their article shed light on the relatively low-incidence of NSF by using relatively stable gadolinium-based contrast agents. We tote up a mini-hot topic on pain in rheumatic diseases to augment this issue, by presenting an excellent review of the evidence for activation of peripheral and central pain pathways with particular focus on RA and osteoarthritis. Another study describes the neuroimaging studies that have improved our understanding of pain perception in RA, OA as well as fibromyalgia. The potential for an initial inflammatory stimulus leading to ongoing pain and activation is discussed in another article. These articles update us on the current understanding of pain perception in rheumatic disease, and hopefully these studies will have practical application in caring for patients with pain. Lastly, we are also presenting an article about the instruments that assess quality of life and disability levels of the patient with early rheumatoid arthritis, an area of interest to practicing clinicians. We look forward to any comments that you might have about the articles and will continue to strive to bring you high quality articles on important rheumatoid disease topics.

A little more than 10 years ago, the first cases of an unusual new fibrosing disorder emerged. The condition affected only individuals with significant renal insufficiency and was characterized by a rapid thickening and hardening of the skin of the extremities. Many of these patients experienced extreme disability and became wheelchair-dependent in as little as a few weeks. Biopsies of affected skin showed significant fibrosis, with increased dermal fibroblast-like cells and markedly increased collagen, elastin, and mucin production. There were few features of inflammation. With little insight into the cause of this disorder, it was given the initial descriptive name of “nephrogenic fibrosing dermopathy”; this was superceded by “nephrogenic systemic fibrosis” (NSF) once systemic features of the disease emerged, mostly on the basis of autopsy studies as these features were usually subclinical. By 2006, emerging observations from Europe suggested an epidemiologic link between the use of gadolinium-based magnetic resonance imaging agents and NSF. In June of 2006, the United States Food and Drug Administration released a public health advisory cautioning against the use of gadolinium-based contrast agents (GBCA) in patients with severe renal disease. Over the past year, significant new information has emerged that impacts the clinical care and magnetic resonance imaging decision-making of patients with kidney disease. This issue of Current Rheumatology Reviews features a selection of special reports from the 2007 Annual Scientific Symposium on NSF held at Yale University. These articles include the clinical spectrum of disease; current notions of pathogenesis, which appear to involve tissue persistence of GBCA and the activation and trafficking of circulating fibrocytes; the critical role of pharmacovigilence in the public health response to this new disease; and considerations of risk reduction strategies in the use of GBCA in at risk patients. The study of nosology, natural history, and medical experience of NSF is instructive not only for a better understanding of this particular disease but also for our approach to the currently idiopathic group of fibrosing disorders that afflict our patients.

Analysis of Gadolinium (Gd) in tissues has become important since the discovery of the relationship of Gd exposure to the development of nephrogenic systemic fibrosis (NSF). Microanalytical methods including Scanning Electron Microscopy with Energy Dispersive X-Ray Spectrometry (SEM/EDS), Secondary Ion Mass Spectrometry (SIMS) or X-Ray microscopy allow imaging and analysis of insoluble Gd deposits in routinely fixed and processed biopsy or autopsy tissues. Soluble chemicals may be detectable in frozen/unfixed tissue samples. In situ, non-destructive SEM/EDS analyses have demonstrated insoluble deposits containing Gd with P, Ca and Na in all cases of NSF examined, if sufficient biopsy is available. The presence of Gd bound to phosphate confirms the release of Gd ion from the chelated contrast agent formulation. Gd deposits tend to be more concentrated in deep subcutaneous fibrotic tissue, thus superficial biopsies may be false negative for Gd. SIMS or X-Ray microscopy can detect Gd at concentrations below the sensitivity of SEM/EDS. Inductively coupled plasma mass spectrometry (ICP-MS), a destructive technique, is optimal for determining gravimetric concentration of Gd in tissues, but cannot determine the molecular form of the Gd nor its spatial distribution. Differing analytical methods provide complementary information on Gd in tissues.

Recent studies have focused on the potential role of fibrocytes in the pathogenesis of nephrogenic systemic fibrosis (NSF). Advances in our understanding of the cellular and molecular biology of fibrocytes, which are reviewed herein, now allow for the exploration of specific hypothesis regarding fibrocyte function in NSF. We hypothesize that when the half-life of gadolinium-based MRI contrast agents (GBCA) is prolonged during renal insufficiency, these agents persist in tissues and trigger the recruitment or differentiation of fibrocytes. Ongoing experiments suggest that GBCA may promote fibrocyte differentiation by interfering with the physiologic inhibitory action of serum amyloid P (SAP) on circulating fibrocyte precursors. Further exploration of fibrocyte function in NSF may clarify not only the pathogenesis of this disorder but contribute to the explication of other idiopathic fibrosing diseases and lead to new therapeutic approaches.

Nephrogenic systemic fibrosis (NSF) is a serious and potentially life-threatening systemic fibrosing disorder. The condition is strongly linked to renal disease and significant evidence suggests an association with prior exposure to gadolinium-containing contrast agents, especially when used at higher doses for magnetic resonance angiography. This paper describes the clinical spectrum of disease as well as features that should suggest a diagnosis of NSF.

Effective drug safety surveillance - pharmacovigilance - is dependent on the careful and dedicated actions of many different stakeholders, in particular the pharmaceutical industry, the regulatory authorities and the health care professionals. Also the patients play a key role. The gadolinium-NSF case provides a unique experience, which not only highlights the ideal function of the international pharmacovigilance system, but also points out the weaknesses of the system. In particular this article focuses on the crucial role of the health care professionals, who prescribe the medicinal products. Different from the regulatory authorities the health care professionals are in direct contact with the patients and are therefore able to observe the side effects of drugs, as these occur. It is important to realize, though, that the health care professionals do not have the overview concerning side effects occurring in relation to the use of medicinal products, neither for a particular drug nor in general. The overview of the safety profile of medicinal products can however be achieved by the regulatory authorities, provided that the first line observers report what they observe. It is also important to emphasize, that the health care professionals are not able to take legally based actions towards the marketing authorisation holders, and health care professionals are not able to request the implementation of risk minimizing measures aiming at improving the safety of their patients. Appropriate regulatory actions can be taken by the authorities, provided that there is sufficient evidence justifying the action in relation to a particular drug or class of drugs.

About three and a half years ago, a causal relation between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium based contrast agents (Gd-CAs) was suggested. All evidence now suggests that low stability Gd-CAs can trigger the development of NSF. All studies indicate with no exception that macrocyclic Gd-CAs release significantly less free gadolinium than the linear agents, particularly the non-ionic ones which have the highest potential of gadolinium release. The longer the Gd-CA stays in the body the larger the amount of gadolinium that is retained in the body. The magnitude of the NSF problem remains uncertain; the condition seems to be underreported. The demonstration of a link between NSF and low stability Gd-CAs has had major consequences for patients with reduced renal function. Currently, if contrast administration is clinically deemed; necessary the preferred approach is contrast enhanced MRI using a macrocyclic Gd-CA. Contrast enhanced CT is at least as risky if not more as an enhanced MRI with low stability Gd-CAs.

Gadolinium based contrast agents (GBCAs) have been linked to nephrogenic systemic fibrosis (NSF) in patients with severe renal dysfunction. This article reviews strategies to prevent this condition in patients at risk. These include administering only single dose GBCA, scheduling MRI for just before the next routine dialysis in dialysis patients, delaying GBCA in acute renal failure while serum creatinine is rising, and making sure the best technologist is doing the case to ensure it will not need repeating. Most MRI centers have implemented at least some these NSF risk reduction strategies and as a result, NSF incidence is markedly decreased.

In this issue we have three articles discussing features of pain perception in rheumatic diseases. Dr. Inglis et al. review the evidence for activation of peripheral and central pain pathways from basic science using animal models with particular focus on rheumatoid arthritis and osteoarthritis. Drs. Shaikh and Shenker describe the clinical context of pain syndromes in rheumatic diseases and discuss how an initial inflammatory stimulus may lead to ongoing pain and activation of central pathways in the brain. An understanding of pain pathway activation is key to appreciating how pain symptoms impact on disability and loss of function in chronic disease. Dr. Sofat et al. then discuss the contribution that functional neuroimaging studies have made to our understanding of pain perception with specific reference to rheumatoid arthritis, osteoarthritis and fibromyalgia. Several techniques including functional magnetic resonance imaging and positron emission tomography have been used to unravel central brain mechanisms involved in pain perception in these conditions. A deeper understanding of pain mechanisms reviewed in these articles will hopefully provide new insights into the understanding of pain perception in rheumatic diseases which may lead to improved therapies for the future.

Rheumatoid arthritis (RA) and Osteoarthritis (OA) are both common diseases of the joints. RA is distinguished by inflammation and synovitis leading to joint destruction, whereas OA is typified by degenerative and mostly noninflammatory disease. Although differing in their pathology, both forms can elicit chronic disabling pain in patients. Relief from this pain is an unmet need for many patients, and this has lead to a drive to understand the pain mechanisms occurring in each disease in order to develop new analgesics. This necessitates the use of pre-clinical models. Here we discuss the methods and limitations of animal pain assessment, rodent models of RA and OA, and how these models have been used to investigate the genesis of pain. Specifically, we focus on processes studied in both RA and OA models, and how the mediators involved in the development of pain may differ between these two arthritic states and during acute and chronic pain. From this we have learnt that the key mediators of RA pain include inflammatory cells, inflammatory cytokines, astrocytes, substance P, and CGRP. Endogenous analgesic mediators in RA include β-endorphin, μ-opioid receptor, and various anti-inflammatory cytokines. Less is known of the mediators of OA pain, but important factors include CGRP, TRPV1, NGF, VIP and the μ-opioid receptor. Interestingly, several factors have been found not to play a role in OA pain, including glial cells, neutrophils and TNF. It must be noted that the vast majority of candidate drugs from animal research never reach the human clinic, in part due to false positives from animal models. This may be due to flaws in the models themselves, the methods used to assess pain, the physical properties of the candidate drug, or an inherent difference between animal and human pain pathways. By developing more clinically relevant models, novel diseasespecific analgesics are being developed with the hope of improving the quality of life for sufferers of arthritis pain.

Pain is a major symptom in rheumatic diseases. Understanding the nature of patients' pain symptoms in a rheumatology setting is integral to their assessment and optimising care. In recent years we have increasingly come to appreciate that not only is pain dependent on the underlying pathological process, but is also influenced by a number of additional factors that include genetics, the environment of the individual, previous pain experience and psychological status. Although local inflammation in the joint leads to the release of pro-inflammatory mediators including prostaglandins and cytokines that activate nociceptive signals in the joint, recent work has suggested that central activation of the brain is also important in mediating chronic pain in a number of rheumatic conditions including rheumatoid arthritis, fibromyalgia, osteoarthritis and back pain. A number of imaging modalities have been utilized in recent years to gain a deeper understanding of the pathways involved in the perception of pain in the rheumatic diseases. Functional Magnetic Resonance Imaging (fMRI), has been used to assess how the brain responds to and also mediates pain in the presence of arthritic disease. Positron emission tomography (PET) and Single photon emission computed tomography (SPECT) can produce blood flow images of the brain, or with the appropriate choice of radiopharmaceutical can also be used to image metabolic activity or specific neuroreceptors. Magnetoencephalography (MEG) can map cortical brain activity with high temporal resolution. These techniques have shown altered regional cerebral blood flow in areas of the brain in rheumatoid arthritis and fibromyalgia and have been used to determine pathways implicated in the perception of pain in specific conditions including complex regional pain syndrome and fibromyalgia. The information gained from functional imaging studies has improved our understanding of pain perception in rheumatic diseases and so may aid a more effective treatment for pain as will be discussed further in this review.

Although musculoskeletal pain is the commonest cause of chronic pain and one of the most common presenting features in rheumatology, it remains poorly managed. The burden of musculoskeletal pain is estimated to have increased between two and fivefold in the last 40 years. Pain in musculoskeletal disease can be inflammatory or degenerative and is often an essential part of the condition and is used by both patients and physicians to assess disease progress. The mechanisms of pain perception and pathology are varied and complex involving a distributed network from the periphery to the brain. This results in peripheral and central sensitisation following injury. In chronic pain this is further complicated by maladaptive neuroplasticity and psychological influences resulting in fear-avoidance. Recent advances in neuroimaging and genetics have aided a deeper understanding of the underlying processes. Both individual genes accounting for monogenic disorders and those with polygenic influences have been identified. The basic science of nociception, the current understanding of genetic influences, clinical aspects of pain management and evaluation and the practical application of these in understanding pain related to specific rheumatological conditions is reviewed.

Early rheumatoid arthritis (ERA) can be defined as the initial phase of the disease and can be considered as a “window of therapeutic opportunity”. It is essential to evaluate the quality of life in addition to the disability levels of these patients to better understand the evolution of the disease. Several instruments have been proposed to assess the quality of life of RA patients that involve detecting changes in health conditions over time as well as evaluating the prognosis, the risks and the benefits of a particular therapeutic intervention method. Generic instruments, such as the Medical Outcomes Study 36-Item Form Health Survey (SF-36), have been developed to reflect the impact of a disease in a wide variety of populations by evaluating the function, levels of disability and the degrees of physical and mental discomfort. Instruments designed for arthritis, such as the Stanford Health Assessment Questionnaire (HAQ), are used to obtain more specific information concerning the impact of this disease on the global evaluation of patients. Because there are few studies regarding instruments for assessing the quality of life in early RA, very little is known about the effect of generic instruments, such as the SF-36, on patients with ERA.