Leonard H. Calabrese

Virally associated arthritis 2008: clinical, epidemiologic, and pathophysiologic considerations

Several viruses have been associated with the development of inflammatory arthritis, including the hepatitis viruses (hepatitis B virus and hepatitis C virus), HIV, the parvovirus B19, the human T-cell lymphotropic virus-I, and the alphaviruses. Here, we review the epidemiology, the pathophysiological mechanisms, the pertinent clinical and laboratory findings as well as the principles of therapy of the most common virus-associated arthritides. We believe that the knowledge of these key diagnostic and therapeutic features of virus-associated arthritides is important for the rheumatologist of the 21st century.

Diagnosis and classification of central nervous system vasculitis.

Central nervous system vasculitis is one of the foremost diagnostic challenges in rheumatology. It results in inflammation and destruction of the vasculature within the CNS. When vasculitis is confined to brain, meninges or spinal cord, it is referred to as primary angiitis of the CNS. Secondary CNS vasculitis occurs in the setting of a systemic vasculitis, auto-inflammatory or infectious disease. Prompt and accurate diagnosis of CNS vasculitis is essential to prevent irreversible brain damage, and to secure precise treatment decisions. Progressive debilitating and unexplained neurological deficits, associated with abnormal cerebrospinal fluid is the typical picture of the disease. Biopsy of the brain remains the gold standard diagnostic test. The differential diagnosis of CNS vasculitis is highly diverse with a broad array of mimics at the clinical, radiographic and angiographic levels.

Tumor necrosis factor inhibitors and lung disease: a paradox of efficacy and risk.

OBJECTIVE Tumor necrosis factor inhibitors (TNFi) are being increasingly used for a wide range of indications. There are increasing reports of pulmonary toxicity related to the use of TNFi. In this review, we have attempted to synthesize the available literature regarding noninfectious complications related to TNFi use. METHODS We reviewed case reports, case series, and clinical trials accessed from the PubMed database (www.pubmed.gov), European League Against Rheumatism web archive (http://www.abstracts2view.com/eular/index.php), and the British Society of Rheumatology Biologics Register Newsletter website (http://www.rheumatology.org.uk/publications) using 23 search terms. RESULTS There are increasing data available about use of TNFi in treatment of systemic inflammatory rheumatologic disorders and their attempted use for various pulmonary indications. Currently reported noninfectious pulmonary complications related to TNFi use include most commonly granulomatous disease and pulmonary fibrosis/interstitial lung disease and rarely alveolar hemorrhage and antisynthetase syndrome. De novo granulomatous disease seems to be mostly reversible, whereas pulmonary fibrosis carries the worst prognosis especially in the setting of prior lung fibrosis. CONCLUSIONS Serious and potentially fatal pulmonary toxicity has been reported during the use of TNFi, specifically from pulmonary fibrosis. Increased awareness during trial design and increased postmarketing surveillance is needed to provide more information about the epidemiology of these complications. Early recognition of these complications may help avert therapeutic misadventures.

The role of IL-6 in host defence against infections: immunobiology and clinical implications

IL-6 is a pleiotropic cytokine with broad-ranging effects within the integrated immune response. One of the roles of IL-6 is to support immunocompetence, defined as the ability of a host to respond to infections. Understanding the precise role of this cytokine in immunocompetence requires a critical appraisal of data derived from both preclinical and clinical studies. Primary immunodeficiency diseases involving IL-6 or its signalling pathways reveal that IL-6 is critical in the defence against numerous types of pathogens. Studies of IL-6 signalling in preclinical models reveal that selective inhibition of either classic IL-6 signalling or IL-6 trans-signalling has differential effects on the host response to different types of infections. Knowledge of such variation might inform bioengineering of new IL-6-targeting molecules and potentially enable modulation of their toxicity. Clinical studies of IL-6 inhibitors, mainly tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies. Targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases.

For patients with rheumatic disease and hepatitis C infection: the end of interferon

Hepatitis C virus (HCV) is a global pathogen and is the cause of rare but complex rheumatic complications but more commonly exists as a challenging comorbidity for patients with existing rheumatic diseases. Until recently, the standard of care of HCV has been the use of interferon-based regimens, which not only have limited effectiveness in curing the underlying viral illness but are poorly tolerated and in patients with rheumatic diseases especially problematic given their association with a wide variety of autoimmune toxicities. Numerous and other more effective and better tolerated regimens are rapidly emerging incorporating direct acting antiviral agents that do not require the use of interferon, that is, interferon free. The potential of interferon free treatment of HCV makes screening for this comorbidity more important than ever. Rheumatologists need to be knowledgeable about these therapeutic advances and partner with hepatologists to craft the most efficacious and toxicity-free regimes possible.

SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krüppel-like Factor 2 and Endothelial Dysfunction

BACKGROUND Human immunodeficiency virus (HIV) infection is associated with increased risk of thromboembolic and cardiovascular comorbid conditions. Although systemic inflammation is linked to cardiovascular risk, direct evidence of vascular inflammation and endothelial dysfunction is lacking. METHODS We examined by immunofluorescence microscopy thoracic aortas from 16 simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected and 16 uninfected rhesus macaques. RESULTS Focal endothelial proliferation and subendothelial inflammatory cells were found in sections of all infected animals, compared with minimal changes in sections from the 16 uninfected controls. In the infected animals, we detected increased endothelial levels of bacterial 16s ribosomal DNA as well as increased subendothelial accumulation of CD68(+) monocytes/macrophages (P< .001) and CD8(+) T lymphocytes (P< .001). Endothelial dysfunction was manifested by decreased levels of endothelial nitric oxide synthase (P< .005) and Krüppel-like factor 2 (KLF2) (P< .005). KLF2 expression was decreased in primary human aortic endothelial cells exposed to bacterial lipopolysaccharide or to oxidized low-density lipoprotein in vitro, and this could be prevented by simvastatin. CONCLUSIONS SIV and SHIV infection lead to endothelial inflammation, dysfunction, and decreased KLF2 expression reflecting early atherosclerotic changes. Translocated bacterial components and lipid oxidation products may induce endothelial dysfunction in HIV infection that could be prevented by statin treatment.

Emerging Viral Infections in Rheumatic Diseases

OBJECTIVES To review the current literature regarding emerging viral pathogens in the context of rheumatic diseases with the intent of increasing awareness among rheumatologists and treating physicians, aiming at early recognition and treatment of these patients. METHODS We reviewed case reports, case series, review articles, and original reports from PubMed (www.pubmed.gov) regarding various aspects influencing spread of infectious diseases including epidemiology and viral and human factors that are potentially responsible for the emergence of new viral pathogens. By consensus, we generated a list of emerging viral pathogens pertinent regarding presentation with rheumatologic manifestations and then short-listed several with particular clinical relevance including hepatitis B, human immunodeficiency virus, and Chikungunya viruses for discussion in greater detail. RESULTS There has been a change in the epidemiology and clinical rheumatic manifestations of previously known viral pathogens as well as the emergence of new viral pathogens as a consequence of factors such as changes in environmental temperature and its consequences, changes in vector and parasite biology, and human influences such as treatment and immunization. CONCLUSIONS Rheumatologists need to be cognizant of the changing landscape of emerging viral pathogens as they may present with myriad clinical features. Recognition of these pathogens is important to guide correct treatment and prognosis. Given the current scenario of global epidemiologic factors that influence viral emergence, we should expect a growing number of future emerging pathogens. Ongoing research directed at understanding pathogenesis and transmission as well as developing better preventive strategies may help counter the threat posed by emerging pathogens.

Rheumatic immune-related adverse events from cancer immunotherapy

Immunotherapy has revolutionized the treatment of cancer, but a rapid rise in the use of the family of therapeutic agents known as checkpoint inhibitors (CPIs) is associated with a new group of immune-related adverse events (irAEs) in almost any organ system. Among these irAEs, rheumatic complications are common and seem to have features that are distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indefinitely, even after cessation of CPI therapy. In this Review, mechanisms of action of CPIs and how they might cause rheumatic irAEs are described. Also covered are epidemiology and clinical descriptions of rheumatic irAEs, plus guiding principles for managing irAEs. Finally, we outline future directions that must be taken in response to a series of unanswered questions and unmet needs that now confront rheumatologists who are, or will be, engaged in this new area of rheumatology.Cancer immunotherapies that function as checkpoint inhibitors are an exciting development but are associated with immune-related adverse events that can occur in almost any organ. Among these events are complications that mirror established rheumatic diseases, so oncologists and rheumatologists must work together.Key pointsCancer immunotherapy with checkpoint inhibitors (CPIs) has revolutionized the treatment of cancer but presents the risk of developing autoimmune or autoinflammatory complications know as immune-related adverse events (irAEs).irAEs are clinically common and can occur in almost any organ system during and/or after treatment with a CPI.Treatment of irAEs often requires immunosuppression with glucocorticoids, which are sometimes administered with conventional synthetic or biologic disease-modifying drugs.Rheumatic irAEs are not as common as some other irAEs but are underdiagnosed and less well recognized.Rheumatic irAEs seem to be nosologically distinct, occurring both early and late in response to CPI therapy, and a substantial proportion of them are chronic, persisting even after cessation of CPI therapy.Rheumatologists must be prepared for irAEs and contribute to inter-professional teams in managing immunotherapy for patients with cancer.

Proceedings of the 2013 Rheumatology Winter Clinical Symposia.

Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com.