Christopher M. Burns

Gout therapeutics: new drugs for an old disease

The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and the US Food and Drug Administration heralds a new era in the treatment of gout. The use of modified uricases to rapidly reduce serum urate concentrations in patients with otherwise untreatable gout is progressing. Additionally, advances in our understanding of the transport of uric acid in the renal proximal tubule and the inflammatory response to monosodium urate crystals are translating into potential new treatments. In this Review, we focus on the clinical trials of febuxostat. We also review results from studies of pegloticase, a pegylated uricase in development, and we summarise data for several other pipeline drugs for gout, such as the selective uricosuric drug RDEA594 and various interleukin-1 inhibitors. Finally, we issue a word of caution about the proper use of the new drugs and the already available drugs for gout. At a time of important advances, we need to recommit ourselves to a rational approach to the treatment of gout.

Latest evidence on gout management: what the clinician needs to know:

Until recently, the last drug approved for the treatment of gout by the United States Food and Drug Administration was allopurinol in 1966. Since 2008, two new drugs for the treatment of gout, febuxostat and pegloticase, have been approved in the US. Febuxostat has been approved in the EU and pegloticase approval is anticipated. A new single-ingredient colchicine preparation is available in the US, and the treatment recommendations for the use of colchicine in acute gout have evolved, now favoring a low-dose regimen. Several other exciting drugs are in development. Herein, we review some of basic principles in the diagnosis and staging of gout. We then examine current treatment principles, with particular attention to febuxostat and pegloticase, offering suggestions as to where they might fit into a modern therapeutic algorithm for gout treatment. We then present available data on several exciting new agents in development, including interleukin-1 inhibitors, and relate them to advances in our understanding of gout pathogenesis. We conclude with some important nonpharmacologic principles for optimal management of this ancient and eminently treatable disease. Dedicated gout research, going on quietly in the background of other breathtaking advances in rheumatology, is now paying off. This comes at a time when the number of patients affected by gout continues to rise, mainly due to an epidemic of obesity. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes.

Immune checkpoint receptors in regulating immune reactivity in rheumatic disease

Immune checkpoint regulators are critical modulators of the immune system, allowing the initiation of a productive immune response and preventing the onset of autoimmunity. Co-inhibitory and co-stimulatory immune checkpoint receptors are required for full T-cell activation and effector functions such as the production of cytokines. In autoimmune rheumatic diseases, impaired tolerance leads to the development of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogrens syndrome. Targeting the pathways of the inhibitory immune checkpoint molecules CD152 (cytotoxic T lymphocyte antigen-4) and CD279 (programmed death-1) in cancer shows robust anti-tumor responses and tumor regression. This observation suggests that, in autoimmune diseases, the converse strategy of engaging these molecules may alleviate inflammation owing to the success of abatacept (CD152-Ig) in rheumatoid arthritis patients. We review the preclinical and clinical developments in targeting immune checkpoint regulators in rheumatic disease.

All-trans retinoic acid-induced focal myositis, synovitis, and mononeuritis.

All-trans retinoic acid has revolutionized the treatment of acute promyelocytic leukemia, but this therapy is often complicated by the all-trans retinoic acid syndrome. Here we report a patient with newly diagnosed acute promyelocytic leukemia who developed acute focal myositis, synovitis, and possible vasculitis, after receiving all-trans retinoic acid therapy. We review the existing literature on this rare clinical entity, all-trans retinoic acid-induced myositis. This condition can manifest as fever, myalgia, arthralgia, and Sweet syndrome, accompanied by distinct magnetic resonance findings involving the lower extremity musculature. Treatment consists of discontinuation of the offending drug and often high dose corticosteroids.

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis

The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V‐domain Ig–containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1α) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus‐prone mouse strain.

Fatal aortic dissection due to a fulminant variety of isolated aortitis.

Aortitis is typically a chronic, progressive disease manifestation associated with large vessel vasculitidies, most notably giant cell, Takayasu arteritis, and a newly described entity, isolated aortitis. The aortitis may lead to aneurysm formation and symptoms associated with branch vessel occlusion in these diseases, but aortic dissection is rare and usually a late complication of smoldering, incompletely treated disease. We present a case of aortitis in a previously healthy 39-year-old man who succumbed to aortic dissection hours after the onset of symptoms. No aneurysm or fibrosis was found on postmortem examination. The inflammation was characterized by disruption of the media with patchy transmural chronic and focally acute inflammatory infiltrate. We review case reports of other individuals with aortitis, who initially or very early in their course presented with aortic dissection in the absence of known rheumatic disease and most without evidence of aneurysm formation. We believe that this represents a process characterized by an aggressive vasculitis of the aorta with its own clinical features, a fulminant variety of isolated aortitis.

Rheumatologic manifestations in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous group of stem-cell disorders leading to ineffective hematopoiesis in 1 or more bone marrowYderived lineages. Clinically, MDS presents as peripheral cytopenias, in some cases with subsequent progression to acute myeloid leukemia (AML). Myelodysplastic syndrome can occur de novo, but also as a secondary condition in patients who have previously received radiation or chemotherapy, where the risk reaches 2% to 10%. A small number of cases are related to exposure to organic solvents, particularly benzene, and other putative exposures, including hair dyes and pesticides. It has long been known that patients with MDS frequently have associated autoimmune phenomena. Up to 10% of patients satisfy criteria for well-defined rheumatic diseases, including rheumatoid arthritis and polymyalgia rheumatica. In some series, the incidence of autoimmune disorders, most commonly dermal, that is, vasculitis and arthritis, is as high as 56%. The increasing incidence with age and occurrence after carcinogenic exposures, iatrogenic and otherwise, suggests accumulated genetic damage and failure of repair as a key component in disease initiation and/or progression.1 However, recent advances in our understanding of the pathogenesis of MDS suggest that, in many patients, the cytopenias and bone marrow failure are immune mediated, resulting in the killing or apoptosis of hematopoietic precursors within the marrow. It is also theorized that this bone marrow immune activation may ‘‘spill over’’ into the systemic autoimmunity and rheumatic manifestations so common in MDS. Finally, with the advent of stimulating factor therapy to treat cytopenias, treatment-related autoimmune conditions are becoming common as well. We reviewed the rheumatologic findings in MDS patients in our institution and found a strikingly high prevalence of auto immunity not localized to the bone marrow. We conducted an IDX (238.75 MDS)Ybased search of the records from Dartmouth-Hitchcock Medical Center from 2006 to 2008 to identify patients with MDS and then reviewed each chart for rheumatologic phenomena. Six of 7 patients were seen by a rheumatologist (not patient 1). We found 7 patients with bone marrow biopsy-proven MDS (Table). All patients were older, 58 to 87 years of age, and 5 of 7 have died. Features of their cases are shown in the Table. Only 1 patient fulfilled the American College of Rheumatology criteria for a specific diagnosis (patient 6), Wegener granul matosis or granulomatosis with polyangiitis. However, patient 7 appeared to have a disorder consistent with necrotizing vasculitis (Figure). An immune mechanism for MDS has been postulated for over 2 decades now, largely stemming from evidence for immune activation within the MDS bone marrow milieu and the clinical observation that a subset of patients responds to immunosuppressive agents with reduced transfusion requirements and progression to AML. Multiple components of the immune system can be aberrant in the MDS bone marrow milieu, including cytokines, cytotoxic CD8 cells, and natural killer cells. Aberrant cytokines and growth factors in the marrow include increased interleukin (IL) 1> or A, IL-6, IL-8, granulocytemacrophage colony-stimulating factor, erythropoietin, transforming growth factor A, interferon regulatory factor 1, and IL-17.9Y14 A FAS-mediated proapoptic mechanism has also been characterized. More recently, a T cellY and natural killer cellYmediated

When should a rheumatologist suspect a mitochondrial myopathy

Metabolic myopathies consist of inborn errors of glycogen, lipid, and mitochondrial respiratory chain enzymes (1). They result in weakness with or without muscle breakdown and in the case of mitochondrial disease, a bewildering array of multisystem abnormalities. Rheumatologists are usually comfortable with the diagnosis and management of dermatomyositis, polymyositis, connective tissue disease–associated myositis, malignancy-associated myositis, and inclusion body myositis. Because the signs and symptoms that distinguish the metabolic myopathies are less common, the recognition of these myopathies is more difficult and the diagnosis is often missed or delayed. These disorders are easily confused with other rheumatic diseases or neurologic conditions, including functional disorders, and are therefore difficult to diagnose. Since this heterogeneous group of diseases with protean manifestations is relatively common (between 1 in 11,000 and 1 in 24,000, although there are estimates as frequent as 1:8,000) (2), and because rheumatologists see patients with diagnostic dilemmas, we suspect that most rheumatologists encounter several such cases over years of practice. The mitochondrial myopathies fall into 4 different categories of clinical presentation, 3 of which we will demonstrate with case reports. The fourth, infantile hypotonia, is a complex syndrome that presents most frequently in early infancy and is usually fatal by 1 year of age. It presents with severe hypotonia (floppy infant syndrome) as well as brain, heart, and kidney disease that lead to a fatal outcome. This disorder is very rare in later childhood and it is unlikely that a rheumatologist would see this condition. The other syndromes discussed below may be seen by rheumatologists.

Re: Letter to the editor (ACR-11-0828) when should a rheumatologist suspect a mitochondrial myopathy?

In a recent article in Arthritis Care & Research, Albert et al provided a concise and interesting review for rheumatologists on mitochondrial myopathies (1). The authors described 4 different categories of patient presentation, highlighted by 3 short cases. The article outlined clinical features compatible with a mitochondrial myopathy, a differential diagnosis, and tests to consider in such patients with an emphasis on muscle histology. The authors, however, did not include fibromyalgia syndrome in the differential diagnosis, which is particularly relevant to case 3 (1). Fibromyalgia syndrome is a common disorder characterized by widespread pain in the muscles, bones, and joints, often with additional symptoms including fatigue, poor sleep, headaches and dizziness, irritable bowel syndrome, and cognitive difficulties (2–4). Elaborations on the original 1990 American College of Rheumatology criteria for the classification of fibromyalgia (2) have been published recently in Arthritis Care & Research (3). Many of the clinical features of fibromyalgia syndrome are not unlike those that the patient in case 3 presented with (1–5). In practice, the clinical suspicion for a diagnosis of fibromyalgia syndrome is often supported by the negative results of testing such as routine laboratory studies, imaging, and, when ordered, electromyogram studies (4). Clinicians familiar with this syndrome can diagnose the condition easily and confidently and usually do not order expensive or exhaustive diagnostic testing. Treatment is effective for the majority of patients (4–5). Fibromyalgia is thought to affect somewhere between 0.5% and 4% of the general population (4–5). Fibromyalgia syndrome is a common diagnosis among patients referred to a rheumatology clinic (4,5), whether as a primary syndrome or a diagnostic dilemma, and more frequently encountered than rare disorders like the idiopathic inflammatory myopathies, systemic lupus erythematosus, vasculitis, and, it would appear, mitochondrial myopathies. Therefore, we suggest that fibromyalgia syndrome should be included in the differential diagnosis of mitochondrial myopathies. On a practical level, advice for rheumatologists on how to differentiate these 2 conditions and when to consider additional testing for mitochondrial myopathies in patients labeled as “fibromyalgia syndrome” would be very helpful. John J. Carey, MBBChBAO, MS Robert J. Coughlan, MBBChBAO, MD Muiris O’Sullivan, MBBChBAO Galway University Hospitals Galway, Ireland