Summer CME: Behçet’s Disease in the United States
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Northeast Florida Medicine Vol. 65, No. 2 2014 1
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VOLUME 65, NUMBER 2 Rheumatology Summer 2014
EDITOR IN CHIEF Raed Assar, MD (Chair)
MANAGING EDITOR Laura Townsend ASSOCIATE EDITORS Sunil Joshi, MD (Vice Chair) Kim Barbel-Johnson, MD Mark Fleisher, MD Ruple Galani, MD James Joyce, MD
Daniel Kantor, MD Joseph Sabato, Jr., MD James St. George, MD
EXECUTIVE DIRECTOR Bryan Campbell DCMS FOUNDATION BOARD OF DIRECTORS President: Todd Sack, MD President-elect: Guy Benrubi, MD Secretary: Allen Seals, MD Treasurer: Malcom Foster, MD At Large Seat 1: Ruple Galani, MD At Large Seat 2: Eli Lerner, MD
2013 DCMS FOUNDATION DONORS Todd Sack, MD James Borland, MD Karen Ostergren, MD Marianne McEuen, MD J. Eugene Glenn, MD George Mayer, MD Jefferson Edwards, MD James St. George, MD R. Jay Cummings, MD Janet Betchkal, MD Jack Giddings, MD Cesar Gorospe, MD J. Timothy Walsh, MD H. Wade Barnes, MD David Boyd, MD Joe Ebbinghouse, MD Troy Guthrie, MD James Townsend, MD Kenneth Horn, MD N. H. Tucker, MD Chalermchai Punya, MD Allen Marks, MD
Northeast Florida Medicine is published by the DCMS Foundation, Jacksonville, Florida, in partnership with the County Medical Societies of Duval, Clay, Nassau, Putnam, and St. Johns. Except for official announcements from the County Medical Societies, no material or advertisements published in NEFM are to be seen as representing the policy or views of the DCMS Foundation or its colleague Medical Societies. All advertising is subject to acceptance by the Editor in Chief.
Disease in 27 Behçet’s the United States Ronald R. Butendieck, MD, McGregor N. Lott, MD and Kenneth T. Calamia, MD
Behçet’s Disease (BD) is an uncommon disorder in the United States, but the diagnosis is often considered in cases with recurrent aphthous stomatitis. It lies within the realm of immune mediated inflammatory diseases. This article focuses on the differential diagnosis of aphthosis, as well as other manifestations of BD that should lead to suspicion of its presence and support a diagnosis. Inflammatory eye disease, central nervous system manifestations and vascular problems may be distinctive, and are important clues to the presence of this disorder.
4 Patient Page From the Editor’s Desk
From the President’s Desk From the Executive 8 Vice President’s Desk 10 Residents’ Corner 42 DCMS Update
Features Rheumatology 2.0: Pain & Negative Serologies
Ghaith Mitri, MD, MMM, CPE, FACR Guest Editor
The Practicalities of Fibromyalgia Florentina Berianu, MD and Benjamin Wang, MD, FRCPC
Polymyalgia Rheumatica 17 Andy Abril, MD
Osteoarthritis: Nuts and Bolts of Joints that Ache
Fellipe Oliveira, MD and Andy Abril, MD
Gout: New Advances in an Old Disease Catherine Garcia, MD and John D. Carter, MD
Antiphospholipid Syndrome versus Multiple Sclerosis: “A common clinical dilemma?”
Karishma Ramsubeik, MD and Ghaith Mitri, MD, MMM, CPE, FACR
Address correspondence and advertising to: 1301 Riverplace Blvd. Suite 1638, Jacksonville, FL 32207 (904-355-6561), or email: firstname.lastname@example.org.
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Common Myths About Arthritis 1. Arthritis only affects old people. This is not true as arthritis comes in many shapes and forms and could affect people of all ages including children and infants. 2. You can control arthritis by food. This is not true. Even a disease like gout where certain foods such as red meat and beer could make it worse or trigger an attack, the majority of patients, more than 90%, have a problem with excreting even normal or low amounts of broken down or processed protein products in the body and some have a genetic defect in how they break down or process such products. A healthy diet and life style are recommended for all patients but arthritis can affect even those with very healthy life-styles and diet habits. Most patients with arthritis will need pharmacologic agents to control their disease and prevent any further progression. 3. Arthritis is a genetic disease. This is not true as certain types of arthritis could have a genetic or familial predisposition but certain environmental triggers are needed for such diseases to develop. 4. Pain is always due to arthritis. This is not true. Pain in limbs could be due to a diseases or injuries in the muscles, nerves, bones, joints or the tissues around or inside the joints such as tendons, ligaments or other soft tissues. 5. Exercise is always good for your joints. This is not true. Healthy and diversified amounts of exercise are good for your joints and muscles health but excessive repetitive exercise such as repeated marathon running could lead to early ware and tare arthritis in the knees even at a younger age. Your physician might also limit or recommend certain physical activities based on overall medical condition. 6. Cracking in the joint is always a sign of arthritis. This is not always true as such noises could be due to the sudden movement of the fluid inside the joints or some instability or excessive mobility in the joints. However, sometimes such noises are due to rough surfaces inside the joints or loss of cartilage which could be a sign of arthritis. 7. Once you develop arthritis it is only a matter of time before you become crippled. This is very not true as we currently have very effective medications that could achieve early remission and prevent any further worsening or damage. Today, arthritis patients could maintain normal physical activity and function especially if treated early before any joint damage.
You should always consult your physician about any weakness, joint pain, prolonged stiffness, redness or swelling of the joints or surrounding tissues.
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From the Editor’s Desk
Medicine in the New Era of Affordable Care Act (ACA) Accountable Care Organizations (ACOs) are becoming a reality and promise improved performance in terms of quality and cost. Last December, The Duval County Medical Society (DCMS), under the leadership of its Immediate Past President, Dr. Eli Lerner, provided a successful educational conference on the subject. This was an excellent primer on ACO initiatives for many physicians. The Northeast Florida Medicine (NEFM) Journal followed by publishing the ACO Forum presentations as CME articles worth 2.5 CME credits. This CME can be found at www.bit. ly/ACOForumCME.
Raed Assar, MD, MBA Editor-in-Chief Northeast Florida Medicine
In the opening editorial, Dr. Lerner shared his vision of the future of healthcare. He summarized the impact of Affordable Care Act (ACA) as far-reaching with implications affecting every patient and physician. He also identified the great need to better understand the changes in healthcare through physician education.
Pam Maxwell, Vice President of Orange Health Solutions provided an excellent ACO startup guide based on experience in the trenches, as she called it. She provided the realities: It requires appropriate funding, adequate provider network, well aligned financial incentives, and must create sustainable results by providing the appropriate care. She also emphasized the need to share best practices on how to manage over-utilization and waste in order to produce the required results. Dr. William Carrier, Vice President of Orange Health Solutions and long time champion of electronic medical records, presented his organization’s trailblazing experience in establishing an ACO in North Florida. He labeled four vital components in the recipe for a successful ACO. Learning from history and recognizing the current challenges in providing quality and cost effective healthcare was the first component. To solve failures in communication, coordination, quality and cost effectiveness, he suggested Information Technology (IT) as the second component. Establishing physician teams such as Patient Centered Medical Home (PCMH) was the
third component. The fourth component was to implement payment reform to incentivize change. Dr. Jonathan Gavras, Senior Vice President and Chief Medical Officer of Florida Blue, provided a payer’s perspective on Integrated Health Systems. To better manage the cost trends, which has outpaced overall inflation, payers are considering and implementing value based care models. As examples, he presented Florida Blue’s successful PCMH and Oncology ACO programs. He emphasized the need to further explore opportunities to improve patient engagement, physician satisfaction, and standardization of care in order to positively impact quality and cost. Chad Greeno from the Cerner Corporation provided examples of employer based ACOs. He highlighted proactive approaches by employers to decrease health care costs and improve quality. He emphasized need for worksite wellness programs, onsite clinics, and innovative direct provider organization contracts. He asked for physicians and employers to work closely to develop local solutions. Dr. Kenyatta Lee, Assistant Dean at the University of Florida and Associate Medical Director at First Coast Advantage, provided information on the role of the PCMH in ACOs and presented the concept of Ambulatory Intensive Care Units (A-ICU). Dr. Lee also emphasized that for better health care value, physicians need to morph into facilitators of improved quality at lower cost. The A-ICU provides more focused management of patients with higher costs of care by coordinating full access to physicians, social workers, and clinical pharmacists to reduce unnecessary emergency room and hospital utilization. The purpose of Dr. Lerner and DCMS’s efforts was to improve physicians’ understanding of the role of ACOs in our country’s health care delivery model and how we can contribute to and benefit from that change. Moving forward, NEFM and the Journal and Communication Committee stand ready to carry the torch of this education for DCMS members. Our patients are counting on us to work with hospitals, employers, health plans and the government to achieve the Triple Aim of improving the overall health of the population, improving quality and patient satisfaction, and reducing per capita costs of health care. Please let us know if you are interested in writing about the subject, remain involved, and stay tuned for future articles.
Dr. Assar is Aetna’s Medical Director for North Florida. Articles or opinions provided by Dr. Assar do not necessarily reflect the views of Aetna. DCMS online . org
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The value of our system is in the individualized care from our expert clinicians and our commitment to exceptional service, giving patients a great experience in every Brooks setting.
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From the President’s Desk
Thank you for your service and commitment The members of the Duval County Medical Society do so much for their patients and the citizens of northeast Florida, that their efforts would be sufficient for most other groups. Our members are committed to giving the best possible care to their patients. We also volunteer our talents and services to many medical and non-medical organizations. The best example of serving the citizens of northeast Florida is the We Care Clinics. However, our members are also very active in volunteering their time and provide their skills and talents to many programs globally. What amazes me is the extent of engagement in global volunteerism of our members. For examMobeen H. Rathore, MD ple, most have heard of 2014 DCMS President how our members volunteered after the Haiti earthquake. There is even a documentary made of our members’ heroic efforts. There are many other global programs that benefit from the volunteerism of our members. Of course, our Navy colleagues perform exemplary service worldwide serving many in need, including during times of natural disasters. I am certain that there are many global programs I am not aware of and will not be able to recount here. However, I do want to share with you some of the programs I am familiar with and even these programs represent just a very small part of our member’s global efforts. Our members have programs in Vietnam, treating children with craniofacial deformities and performing challenging surgeries. Others volunteer their time in HIV programs in South Africa and India serve the poor people of Ecuador. Society members not only serve the local underserved populations but also the un-served people in far-flung areas. Our members also want to extend this sentiment of global volunteerism to the next generation of physicians by taking students and trainees on many international trips so that they can learn first hand the issues and challenges of global health. This early exposure for
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budding physicians will make them not only more appreciative of what we have in our great country, but also the tremendous gaps and challenges that exist worldwide. We hope they will understand the true meaning of the saying, “those who have more, more is expected.” Personally, I have been privileged to work with children in mountains of northern Thailand where we were able to make a real difference in the lives of the children of the landless Akkha tribe, who would otherwise not receive healthcare services. By providing these children free healthcare, including immunizations, especially the Japanese Encephalitis vaccine, we were able to bring mortality secondary to Japanese Encephalitis to zero. Recently, I learned of an exceptional program in Nepal, where one of our longtime member’s spends his time every year serving hundreds of individuals, and another program in Magnolia. Not only do our members go to far-flung areas of the world to provide medical services, they have created unique programs that bring patients from the remotest parts of the world to Jacksonville and, in collaboration with the local hospitals, provide them with life saving medical intervention. One such program has been doing corrective surgery on children with congenital heart disease for years. I had personal exposure to this program when my two sons when they were in high school and college raised funds for the program. I was amazed at the difference this program makes. Many of our members have also provided their services in war torn parts of the world, including Afghanistan and Iraq. Once again the Afghanistan effort of one of our former longtime member’s was the subject of a documentary. I am certain that there are many others who provide these services quietly and effectively. All of these unsung heroes deserve our admiration and thanks. We would love to hear from you about your global efforts. Please e-mail us about what you or someone else is doing globally by e-mailing us information at email@example.com. Thank you members for doing so much above and beyond the call of duty for the people of northeast Florida and for those around the world. It warms my heart to be part of this Society with so many exceptional physicians, nay…exceptional people.
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From the Executive Vice President
Small Victories, Large Battles Small Victories, Long Battles One of the most difficult aspects of publishing a peer reviewed medical journal is the speed at which treatments and medical therapies can change. While the Northeast Florida Medicine Journal is not the New England Journal of Medicine (yet!), it still goes through a thorough vetting and peer-review process that can take a significant amount of time to complete. All the while, new treatments, procedures and techniques are being tested and coming to market. The constant battle to keep the Journal as upto-date and relevant as possible applies to our efforts to keep you up to Bryan Campbell date on key legislative efDCMS Executive Vice President forts as well. By the time this Journal has reached your desk, the 2014 Legislative Session in Tallahassee has drawn to a close. As of this writing, there are still a few weeks left in the Legislative Session, but there is one thing which we can convey with certainty… no one is certain what will happen next with scope of practice. What if it’s not a matter of “if ”, but rather “when”? The topic that has drawn the most interest during this Legislative Session is the matter of expansion of Scope of Practice for Nurse Practitioners. Measures introduced would create an Advanced Independent Practicing Registered Nurse (AIPRN) who could see patients without physician supervision. The measure was introduced as a solution to the access to care problem in Florida. DCMS and the Florida Medical Association strongly opposed the measure because of its implications for patient safety. Unfortunately, the proposal gained strong support from many in the Florida House, including Dr. Cary Pigman, an ER physician and Representative for the 55th District. In the end, the measure was combined with other bills
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involving Telemedicine and Trauma Center approvals, and did not pass through the House and Senate. The idea of expanding the scope of practice for Nurses has significant support, both from the large nursing community, and from several other factions. There is also tremendous support for the concept from future leaders of the Florida House of Representatives. Leaders have stated that even if the bill does not pass this year, they have several years to get the measure passed. If this sounds familiar, this is what happened over the past decade with the expansion of practice for Optometrists. After more than a decade of efforts for that expansion, organized medicine was unable to stop the groundswell of support for that expansion. This may be what we are facing over the next several years with the expansion of practice for nurses. Therefore, a victory this year may just be the beginning of a long and arduous battle. What’s Next? As soon as the 2014 Session ended, the FMA and physicians from around the state began working on how protect the integrity of the patient-physician relationship. The FMA has produced and distributed valuable information which specifically demonstrates the vast difference in education and training between physicians and ARNPs. The DCMS believes and advocates for an effective healthcare team, led by a physician, working together to ensure the best possible outcomes for their patients. As long as we are working together, within the House of Medicine, to make sure that your patients have access to the high quality care, those patients will benefit. Just as you are putting in the time and effort to read this journal, to strive to continue to improve the art and science of medicine in your practice, we are continuing to fight to protect your right to do so. We will continue to advocate and educate on behalf of physicians. Because together, we can help fulfill the mission of the Duval County Medical Society: Helping physicians improve the health of our community.
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Rheumatology 2.0: Pain & Negative Serologies In the previous Rheumatology issue in 2012, which is available in print and online, we provided a high level overview about this relatively new internal medicine sub-speciality despite its ancient roots, and the inverted pyramid approach to treatment in order to achieve early remission and better outcomes. We discussed inflammatory markers and some rheumatology serologies or auto anti-bodies with the typical suspect conditions such as rheumatoid arthritis (RA) and lupus or systemic lupus erythematosus (SLE), the new classification for juvenile Ghaith Mitri, MD, MMM, CPE, FACR idiopathic arthritis in Guest Editor children (JIA), which replaced the old misleading and inaccurate terminology of juvenile rheumatoid arthritis (JRA), Paget’s disease, and a clinical case describing the treatment challenges in a patient with severe neutropenia in the setting of RA and hepatitis C infection. In the majority of rheumatic diseases, the diagnosis is based on a very thorough history taking and supported by physical exam and appropriate testing. History of the presenting illness is very critical because many patients with rheumatic diseases are completely asymptomatic when they present for clinical evaluation. It is important to note that serologies in certain rheumatic conditions, such as RA and SLE, are never diagnostic but could support the diagnosis with the presence of other relevant criteria. Another critically important aspect of rheumatic conditions or syndromes is the significant overlap of clinical signs, symptoms, and even laboratory results among these conditions. Clinical diagnostic criteria for rheumatic conditions were developed for clinical trial purposes in order to include a homogeneous group of patients but could easily miss those with limited
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organ involvements or early in their disease course. Although overlapping autoimmune conditions such as SLE and RA are very uncommon but possible, a patient could easily have more than one cause for their pain such as osteoarthritis (OA), RA, and fibromyalgia all at the same time. In this issue we will focus on some rheumatic conditions associated with pain while having negative serologies and discuss a clinical case where clinically diagnostic criteria did not help in a patient with early or possibly atypical presentation. Dr. Florentina Berianu, and Dr. Benjamin Wang will discuss: “The Practicalities of Fibromyalgia”. Dr. Andy Abril will discuss: “Polymyalgia Rheumatica”. Dr. Fellipe Oliveira and Dr. Andy Abril will discuss: “Osteoarthritis”. Dr. Catherine Garcia and Dr. John Carter will discuss: “Gout: New Advances in an Old Disease”. Dr. Ronald R. Butendieck, Dr. McGregor N. Lott, and Dr. Kenneth T. Calamia will discuss: “Behçet’s Disease in the USA”, which will include a continuing medical education (CME) exercise. Dr. Karishma Ramsubeik and myself will discuss a clinical case: “Antiphospholipid Syndrome versus Multiple Sclerosis: A common clinical dilemma?”. With rising costs in healthcare, we have a mandate to cut costs, improve clinical outcomes and efficiencies while being patient-centric. This is very true in rheumatic conditions considering that the costs of biologic therapies for some rheumatic conditions compromise more than 50% of the total cost of care for the affected patients. Recent scientific advancement coupled with expanding big data supported by constant growth in EHR should lead in the near future to better outcomes through focused treatment to specific patient sub-sets and potentially identifying bio-markers for early diagnosis or to measure treatment response. There is a rapidly growing global interest in assessing patient reported outcomes (PROs) as we redesign our approach to a more cost-effective, efficient, and improved patient-centric healthcare model.
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Residents Corner: UF College of Medicine-Jacksonville
By: Marielle Connor, MD, UF Health Resident University of Florida College of Medicine-Jacksonville is a 695-bed academic health center with a busy graduate medical education department attracting residents and fellows from all regions of the United States. Overall, 50 to 70 percent of the graduates of UF College of Medicine-Jacksonville residency programs practice in Florida. Currently, UF Health- Jacksonville is training 279 residents in a variety of specialties including anesthesiology, diagnostic radiology, emergency medicine, internal medicine, neurology, obstetrics & gynecology, oral maxillofacial surgery, ophthalmology, orthopaedic surgery, pathology, pediatrics, psychiatry and general surgery. All University of Florida College of Medicine-Jacksonville GME programs have embraced the goal of instruction and assessment of resident/fellow competency in the six domains â€” patient care, medical knowledge, professionalism, interpersonal and communication skills, practice-based learning and improvement and systems-based practice. In addition, the residency programs all have a strong research component with large number of ongoing studies. Our residents have had a successful past year with several residents publishing or presenting their findings at both regional and national levels. Here are a few of the research highlights from the orthopaedic departments this past year: Kris Wheeler, MD and Marielle Connor, MD completed a clinical study looking at the potential for limb length discrepancy and angular deformities after all-transphyseal ACL reconstructions in skeletally immature patients. Retrospective chart and radiographic review found no evidence of limb length discrepancy or angular deformities at over 1 year post-surgery. These findings were accepted for a podium presentation at both the American Academy of Pediatrics National Conference in Orlando, FL, as well as the Eastern Orthopaedics Societyâ€™s annual meeting in Miami, FL. Corey Rosenbaum, MD and Anthony Bell, MD recently presented a poster at the American Academy of Orthopaedic Surgeons annual meeting in New Orleans, LA looking at the outcomes of retrograde negative pressure reaming for harvesting autologous bone graft in the treatment of tibial nonunions.
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In addition, Corey Rosenbaum, MD and Mark Elliot, MD recently completed a retrospective review of all traumatic knee dislocations presenting to UF Health in the past 10 years. Their findings will be presented at the upcoming Florida Orthopaedic Society annual meeting in Bonita Springs, FL as well as the Southern Orthopaedic Associationâ€™s annually meeting in Colorado Springs, CO. Lastly, the orthopaedic department has several ongoing studies which should be concluded within the year. These projects include a study of open calcaneus fractures and associated injuries, a review of the antibiotic prophylaxis regimen for open fractures, as well as a study looking at operative vs non-operative treatment for pediatric elbow medial epicondyle fractures. In conclusion, the University of Florida College of Medicine-Jacksonville is a great place to be in residency. The program teaches us to not only care for a variety of patients and conditions, but it has wonderful opportunities for us to pursue our research interests and thus help our respective fields continue to grow and develop.
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The Practicalities of Fibromyalgia Florentina Berianu, MD and Benjamin Wang, MD, FRCPC Division of Rheumatology, Mayo Clinic, Jacksonville, FL
Abstract: The understanding of the neurobiological pathogenesis of
fibromyalgia has led to an intensified research effort that has resulted in more therapeutic options for patients. Fibromyalgia is now seen mainly as a disorder based of sensory processing with defects at the peripheral, spinal cord, and central nervous levels. It shares pathogenic mechanisms with conditions such as irritable bowel syndrome, such that a broader syndrome can be conceptualized, known as the â€œcentral sensitization syndrome.â€? This article provides practical help on the recognition, evaluation, and treatment of fibromyalgia based upon such an understanding.
Table 1: Clinical entities currently considered parts of the spectrum of CSS (adapted from reference 2) Fibromyalgia Chronic Fatigue Syndrome (CFS)
Irritable Bowel Syndrome (IBS) and other functional GI disorders
Fibromyalgia is a common cause of chronic musculoskeletal pain that is not associated with tissue inflammation. Fibromyalgia, initially termed fibrositis, was initially described in France and England in the mid-nineteenth century.1 By the end of the twentieth century, many rheumatologists recognized fibromyalgia as a discrete syndrome.
Temporomandibular Disorder (TMD)
The cardinal feature of fibromyalgia is chronic, widespread pain that is not explained by another disorder. In fibromyalgia, the physical examination, other than tenderness in muscles and soft tissue (tender points), is unrevealing and laboratory and radiologic imaging are unremarkable. More recent insights have suggested that fibromyalgia is a disorder of the processing of sensory information by the nervous system. It has also become clear that fibromyalgia is not just fibromyalgia as an isolated entity. The more recent term Central Sensitization Syndrome (CSS) as established by M.B. Yunus is preferred. Yunus proposed that fibromyalgia is a member of a broader family of conditions associated with tension type headache, migraine, irritable bowel syndrome and primary dysmenorrheal syndrome among others, all of which share certain clinical and pathophysiologic features.2 (Table 1)
Restless Leg Syndrome (RLS) Periodic Limb Movements in Sleep (PLMS) Idiopathic Low Back Pain (LBP) Multiple Chemical Sensitivity (MCS) Primary Dysmenorrhea Headache (tension, migraine, mixed) Migraine Interstitial Cystitis/Chronic Prostatitis/ Painful Bladder Syndrome Chronic pelvic pain and endometriosis Myofascial Pain Syndrome Regional Soft Tissue Pain Syndrome
Address correspondence: Benjamin Wang, M.D., FRCPC. Mayo Clinic 4500 San Pablo Rd., Jacksonville, FL 32224. firstname.lastname@example.org
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The prevalence of fibromyalgia is approximately two percent and increases with age.3-5 Fibromyalgia is more common in females. According to a more recent study, fibromyalgia is the third most common rheumatic disease after low back pain and osteoarthritis, affecting up to five percent of women in the United States.6
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Fibromyalgia is a disorder of pain regulation. Fibromyalgia shares pathogenic features with other central pain disorders such as migraine, tension headaches, temporomandibular joint disorder and irritable bowel syndrome.7
Fibromyalgia is characterized by widespread musculoskeletal pain and fatigue, often accompanied by cognitive and mood disturbances.10 Physical examination reveals tenderness in multiple soft tissue anatomic locations. Laboratory testing is normal in the absence of other illnesses.
There is evidence for a genetic predisposition. First-degree relatives of patients with fibromyalgia are 8.5 times more likely to have fibromyalgia than relatives of patients with rheumatoid arthritis.8 Patients will often mention other affected family members or trace back their own symptoms into their younger years. A variety of biological stressors seem to be capable of either triggering or exacerbating fibromyalgia, including physical trauma, infections, early life trauma deployment to war, and other types of psychological stress. Groups of individuals with CSS (e.g., fibromyalgia, irritable bowel syndrome, headaches, temporomandibular joint disorder, etc.) display diffuse hyperalgesia. Many of these conditions have also been shown to demonstrate more sensitivity to many stimuli other than pain (e.g., auditory, visual), and the aggregate data suggest that these individuals have a fundamental problem with pain or sensory amplification rather than a structural, metabolic or inflammatory condition in the specific body region where the pain is being experienced.7 The understanding of fibromyalgia has increased substantially in recent years, suggesting a neurogenic origin for the chronic widespread pain. Neurochemical imbalances in the central nervous system are associated with central amplification of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). It is suggested that both the ascending and descending pain pathways operate abnormally, resulting in central amplification of pain signals, analogous to the “volume control setting” being turned up too high.7-9 In fibromyalgia, there are also changes in the levels of neurotransmitters that cause augmented central nervous system pain processing; levels of several neurotransmitters that facilitate pain transmission are elevated in the cerebrospinal fluid and brain (e.g., substance P, nerve growth factor and brain-derived neurotrophic factor); and levels of several neurotransmitters known to inhibit pain transmission are decreased (e.g. metabolites of serotonin, norepinephrine and dopamine).9 Levels of glutamate and other excitatory amino acids have also shown to be elevated in the CSF and brain in individuals with fibromyalgia. Glutamate acts on N-methyl-d-aspartate receptors to produce increased pain message signalling. Pharmacological agents that act centrally in ascending and/ or descending pain processing pathways, such as medications with approved indications for fibromyalgia, are effective in many patients with fibromyalgia and other conditions involving central pain amplification.7,9
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The musculoskeletal pain, involves both sides of the body and above and below the waist. Most common patient’s complaint is: “I feel as if I hurt all over.” Patients typically describe pain predominantly throughout the muscles, but often state that their joints hurt. Sometimes patients describe joint swelling, although synovitis is not present on examination.11,12 Patients often report numbness, tingling, burning especially in both arms and both legs, but a detailed neurologic evaluation or formal testing is usually unremarkable. The most common symptom of fibromyalgia is fatigue. Minor activities aggravate the pain and fatigue, although prolonged inactivity also makes symptoms worse. Patients are stiff in the morning and feel not rested, even if they have slept eight to 10 hours. Cognitive and mood disturbances are present in the majority of patients. The cognitive disturbances are often referred to as “fibro fog.” Patients typically describe problems with attention and difficulty doing tasks that require rapid thought changes. Neuropsychological testing reveals abnormalities.13 Headaches are present in more than 50 percent and include migraine and muscular (tension) types.6,14 Depression and/or anxiety are also very common by the time of diagnosis. Patients may have a variety of poorly understood pain symptoms, including abdominal and chest wall pain, and symptoms suggestive of irritable bowel syndrome, pelvic pain and bladder symptoms of frequency and urgency suggestive of the interstitial cystitis/ painful bladder syndrome.6
Physical Examination The physical examination in fibromyalgia is usually unremarkable unless the patient has other co-morbidities. In patients with fibromyalgia, the only reproducible finding on physical examination is tenderness in soft-tissue anatomic locations. The tender points used for the 1990 American College of Rheumatology Classification Criteria are at locations that most primary care physicians and specialists routinely evaluate in patients with soft tissue complaints. These locations include the upper mid-trapezius muscle, the lateral epicondyle (the so-called tennis elbow location), the second costochondral junction (the site of costochondritis) and the greater trochanter (the site of trochanteric bursitis of the hip). The amount of pressure should equal 4 kg/cm², which is enough to whiten the nail bed of the examiner’s finger tip. The 1990 ACR fibromyalgia classification criteria include:
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• Symptoms of widespread pain occurring both above and below the waist, and affecting the right and left sides of the body • Physical findings of at least 11 of 18 tender points These simple criteria had greater than 85 percent sensitivity and specificity for differentiating patients with fibromyalgia from those with other rheumatic diseases.15 Because the tender point examination can be inconsistent from patient to patient, especially being less prevalent in male patients with fibromyalgia, the 2010 American College of Rheumatology (ACR) preliminary diagnostic criteria for fibromyalgia provides an alternative approach to diagnosis. This accounts for chronic widespread pain in seven or greater defined body areas, common features such as fatigue, waking unrefreshed, cognitive and other somatic symptoms, but does not require a tender point examination.16 A complete physical examination, with a careful joint and neurologic examination, is necessary to exclude other illness presenting with similar symptoms.
Laboratory Fibromyalgia does not cause any abnormalities in laboratory testing or imaging, but the clinician needs to exclude associated disease or diseases with similar presentations to fibromyalgia. One should obtain a CBC, ESR and CRP for initial laboratory evaluation. Normal acute phase provide confidence that an occult inflammatory disorder is unlikely. Additional tests should only be obtained if the history and physical finding suggest a systemic disorder. The use of “screening” autoantibody tests (e.g. antinuclear antibody, rheumatoid factor) is not recommended unless definite symptoms of a connective tissue disorder are present. A careful history will help to identify sleep or mood disorders. Patients should be questioned for symptoms of sleep apnea and repetitive limb movements; if the history is suggestive, patients should be referred for an overnight polysomnogram.
Differential Diagnosis Patients with fibromyalgia present with multiple nonspecific symptoms and can mimic multiple disorders, but the patient’s history, physical examination and limited laboratory testing are sufficient to differentiate fibromyalgia from other systemic conditions, such autoimmune connective tissue diseases (CTD). Fibromyalgia can commonly coexist with CTD. Fibromyalgia should be considered the cause of diffuse pain and fatigue in a patient with RA/SLE who is under good control and without synovitis or elevated acute phase reactants.
Treatment Treatment of fibromyalgia must include non-pharmacologic modalities, as drugs seldom provide a comprehensive solution to symptoms, and can have a high frequency of side effects. Above all, “The physician must be friendly and interested—a resource the patient can rely on.” (Wolfe, 2008) Multiple classes of drugs have been used with varying efficacy in fibromyalgia, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrin reuptake inhibitors (SNRI), alpha-2-delta ligands and other centrally acting agents. Pregabalin, an alpha-2-delta ligand and antiepileptic drug, in 2007 was the first agent the FDA approved for fibromyalgia. In 2008, duloxetine, a selective serotonin norepinephrine reuptake inhibitor (SNRI), was the second FDA-approved agent for fibromyalgia. In 2009, milnacipran (also an SNRI) became the third drug FDA-approved for fibromyalgia.17 Interestingly, none of these agents have received regulatory approval for fibromyalgia in Europe, perhaps underscoring a limited therapeutic benefit. The classes of drugs which are quite effective for “peripheral” or somatic pain due to damage or inflammation in peripheral tissues, such as NSAIDs and opioids, are not nearly as effective analgesics in central pain states. Patients with fibromyalgia respond best to a multidisciplinary treatment program that incorporates the primary treating clinician and include physical medicine, rehabilitation and mental health specialists.18 Patient education regarding the disease, good sleep hygiene and enrolment in an exercise program are very important initial steps.19 High-intensity exercise has been shown to provoke pain compared with low intensity exercise.20 Therefore, patients should be advised not to exercise to the point of fatigue or exhaustion. This can be easy to do because of the limited stamina associated with the condition. The use of exercises in which it is easy to control intensity, such as walking, light yoga, tai chi, walking in a swimming pool or stationary bicycling for limited durations at low intensities are most the sustainable types of exercises. It appears that education is most effective in multimodal interventions. Cognitive behavioral therapy (CBT) combines interventions of both cognitive and behavioral aspects. Cognitive therapy is based on the premise that modifying maladaptive thoughts results in changes in affect and behavior.19 This may help to break the tendency toward either the lack of activity leading to deconditioning or forced overactivity leading to excess fatigue. Practically, patients should be helped to start a low intensity exercise habit, but avoid over-exercise. The goal should be a gradual increase in aerobic capacity, at which point symptomatic relief and function improve. Exercise at low to moderate intensity two or three times per week should be encouraged and supported to be sustained.18 Professional consultation for sleep disturbances should be obtained if needed. Patients who report waking up tired, daytime
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Rheumotology sleepiness or have clues to a sleep disturbance (snoring, restless legs, teeth grinding or sleepwalking) should be evaluated.
7. Schmidt-Wilcke T, Clauw DJ; Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol. 2011;7(9):518.
Psychological treatment also should be encouraged as a proven useful intervention and a crucial part of the overall treatment approach. Ideally, such therapies will help patients to pay attention to behavioral and emotional patterns, properly budget energy, and identify harmful moods, responses and attitudes.19
8. Arnold LM, Hudson JI, Hess EV, Ware AE, Fritz DA, Auchenbach MB, Starck LO, Keck PE Jr; Arthritis Rheum. 2004;50(3):944.
Medications should be carefully used, but not relied upon as the cornerstone of fibromyalgia treatment. It is often more beneficial to start at low doses as drug sensitivities (not true allergies) are common in fibromyalgia. Opiate analgesics should be avoided. Underlying sources of pain, most commonly an arthritic source, should be identified and treated. These serve as pain sources which are amplified by the “circuitry” of fibromyalgia.17
Conclusion The primary care physician would do well to assemble a multidiscipline team to assist fibromyalgia patients. This is often comprised of the following: a pain specialist, rheumatologist, sleep specialist, clinical psychologist and rehabilitation specialists such as physiatrists and therapists.
9. Daniel J. Clauw, MD; Lesley M. Arnold, MD; and Bill H. McCarberg, MD; The Science of Fibromyalgia; Mayo Clin Proc. 2011;86(9):907-911 10. Bennett RM. Clinical manifestations and diagnosis of fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):215.; 12:124. 11. Goldenberg DL. Diagnosis and differential diagnosis of fibromyalgia. Am J Med 2009; 122:S14. 12. Björkegren K, Wallander MA, Johansson S, Svärdsudd K. General symptom reporting in female fibromyalgia patients and referents: a population-based case-referent study. BMC Public Health 2009; 9:402 13. Glass JM. Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions. Curr Rheumatol Rep. 2006;8(6):425.
Recent insights into the pathogenesis of fibromyalgia have helped to validate this condition as not merely a condition of psychological disturbance, but also one of altered sensory processing with manifold manifestations and disease associations. Ongoing research into pharmacologic and non-pharmacologic methods of treatment offer hope for patients who are often misunderstood, mistreated and consequently suffer from the illness’ debilitating effects.v
14. Marcus DA, Bernstein C, Rudy TE. Fibromyalgia and headache: an epidemiological study supporting migraine as part of the fibromyalgia syndrome. Clin Rheumatol. 2005;24(6):595.
16. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010; 62:600.
1. Smythe HA, Moldofsky H, Two contributions to understanding of the “fibrositis” syndrome. Bull Rheum Dis 1977; 28:928–931. 2. Yunus MB. Primary fibromyalgia syndrome: Current concepts. Compr Ther 1984; 10:21-28. 3. Goldenberg DL. Fibromyalgia syndrome. An emerging but controversial condition. JAMA 1987; 257:2782. 4. Goldenberg DL. Fibromyalgia syndrome a decade later: what have we learned? Arch Intern Med 1999; 159:777. 5. Weir PT, Harlan GA, Nkoy FL, et al. The incidence of fibromyalgia and its associated comorbidities: a population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol 2006. 6. Berger A, Dukes E, Martin S, et al. Characteristics and healthcare costs of patients with fibromyalgia syndrome. Int J Clin Pract 2007;61:1498–508.
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15. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990; 33:160.
17. Howard S. Smith, Richard Harris, Daniel Clauw. Fibromyalgia: An Afferent Processing Disorder Leading to a Complex Generalized Pain Syndrome; Pain Physician 2011; 14:E217-E245. 18. Hauser W et al. Arthritis & Rheumatism (Arthritis Care & Research) 2009; 61:216–224. 19. Hassett AL, Gevirtz RN. Nonpharmacologic treatment for fibromyalgia: patient education, cognitive-behavioral therapy, relaxation techniques, and complementary and alternative medicine. Rheum Dis Clin North Am 2009; 35:393 20. Van Santen M, Bolwijin P, Landewe R, Verstappen F, Bakker C, Hidding A, Van Der Kemp D, Houben H, Van Der Linden S. High or low intensity aerobic fitness training in fibromyalgia: Does it matter? J Rheumatol 2002; 29:582–587.
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Polymyalgia Rheumatica Andy Abril, MD
Mayo Clinic Jacksonville, FL
Abstract: Polymyalgia rheumatica (PMR) is one of the most common inflammatory rheumatologic problems in the general population, especially in the elderly. It has many mimickers and it is not always easy to diagnose. This review provides the clinician with a basic understanding of the disease, and provides guidelines for the diagnosis and treatment of these patients
Introduction Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in the elderly population. It happens predominantly in people of Caucasian descent, especially of northern European extraction, although it can occur less frequently in patients of other ethnic groups. The incidence in patients of Scandinavian descent is >17 per 100.00, and in patients of southern European backgrounds is 12 per 100.000 individuals.1,2 Upon rendering a diagnosis of PMR, long term steroid use, although anathema to most clinicians, is indicated.1,2 Other autoimmune, infectious, endocrine and malignant disorders can present with similar symptoms. PMR is almost never seen in people younger than the age of 50 and prevalence increases with age. The average age of onset is 70 to 80 years of age, and 75 percent of patients are women. Giant cell arteritis (GCA) is seen in about 30 percent of patients with PMR, and about half of the patients with GCA have polymyalgia symptoms.2 The cause of polymyalgia rheumatica is unknown, although both genetic and environmental factors contribute to disease susceptibility and severity. Some studies show a cyclical pattern in incidence which suggests an environmental infectious trigger such as parvovirus B19, Mycoplasma pneumoniae, and Chlamydia pneumonia. Polymyalgia rheumatica has a modest familial aggregation. It is linked to the HLA DR4 allele in Caucasian populations.3 Epigenetic changes and differential expression of genes that regulate the expression of inflammatory cytokines have been postulated to account for the variable disease phenotypes.3
Clinical Presentation The most characteristic presenting feature of polymyalgia rheumatica is bilateral shoulder pain and stiffness of acute or sub-acute onset with bilateral upper arm tenderness. Patients often develop concomitant hip girdle pain and stiffness, as well as pain and stiffness in the posterior neck musculature.
Address correspondence: Andy Abril, MD, Division of Rheumatology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL
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Pain and stiffness are features of the disease more than weakness, although this can be difficult to assess in the presence of muscle pain. Disuse atrophy can occur, especially in patients who have gone untreated for a long time. Stiffness after periods of rest and morning stiffness of more than 45 to 60 minutes are typical. The stiffness may be intense; patients can have great difficulty turning over in bed or raising their arms above shoulder level. This makes it difficult to perform daily living activities such as rising from bed, a commode or a chair, or combing their hair. Mild synovitis may be seen in the wrists and knees, but the feet and ankles are rarely affected.1,2 Most patients have systemic symptoms including fatigue, loss of appetite, weight loss, low grade fever and sometimes depression, especially at the onset of the disease. In patients who present with polymyalgia symptoms, it is important to keep in mind that inflammatory rheumatic diseases that mimic PMR are more prevalent than polymyalgia rheumatica in people younger than 60 years of age. An erythrocyte sedimentation rate greater than 40 mm/h is a characteristic laboratory finding in polymyalgia rheumatica, but it may not be that high at presentation, and can even be normal. Even in this setting, C reactive protein is usually raised. During diagnosis, it is important to exclude other conditions such as active infections, inflammatory arthritis, thyroid disorders, cancer or even medication reactions such as statin induced arthralgia and myopathy.
Diagnostic Approach The presence of proximal shoulder or hip girdle pain with morning stiffness of more than 45 minutes in an elderly patient should raise suspicion for the disease. The absence of joint involvement, immunological markers such as rheumatoid factor, antinuclear and anti-cyclic citrullinated peptide (CCP) antibodies, and the presence of elevated inflammatory markers will confirm the diagnosis.4 The clinician should always look for symptoms of GCA such as jaw claudication, scalp tenderness, temporal headaches or visual changes, and rule out other problems such as cancer or infections. The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recently joined forces and published the 2012 provisional classification criteria for PMR. The two groups are also working on treatment guidelines.4 Imaging studies are not routinely done, but the presence of bilateral sub deltoid bursitis on MRI or ultrasonography is highly suggestive of the disease.4-6
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Treatment Glucocorticoids are the main medications used to treat PMR, typically at low-moderate dosages (prednisone, 15-20 mg a day). Rapid response within 24 to72 hours is expected. Unfortunately, corticosteroids are the only known effective treatment, and they often need to be continued for two to three years.7 Approximately 10 percent of patients relapse after 10 years, and the treatment may need to be extended or restarted in those situations.8 The clinician should be vigilant for corticosteroid related side effects, such as diabetes, glucocorticoid induced osteoporosis (GIO), edema, hypertension and insomnia. Theses hould be managed accordingly. Non-steroidal anti-inflammatories do not seem to help beyond mild pain relief (Reference needed?).Other agents such as methotrexate and anti-tumor necrosis factor agents have been used in small series without proven benefit, and should not be used routinely for this condition.9-11 Recently, the interleukin-6 antagonist, tocilizumab, has been reported in a small series to be effective in patients with refractory GCA and PMR.12 This agent is currently FDA approved for the management of rheumatoid arthritis. Further studies are needed to assess its utility and cost effectiveness.
Conclusion In essence, PMR is a very common rheumatologic illness of the elderly. Its presentation can be quite subtle and insidious, and it is frequently associated to temporal arteritis Treatment with glucocorticoids is the norm, but the clinician should be vigilant for potential side effects, and since this condition is in most cases self-limiting and goes in remission, gradual tapering should always take place as clinically tolerated. v
1. Michet CJ, Matteson EL. Polymyalgia Rheumatica. BMJ 2008;336:765-9 2. Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat. Rev. Rheumatol. 8, 509–521 (2012) 3. Weyand CE, Goronzy JJ. Giant Cell Arteritis and Polymyalgia Rheumatica. Ann Intern Med. 2003;139:505-515. 4. Dasgupta, B et al2012 Provisional classification criteria for polymyalgia rheumatica: A European League Against Rheumatism/American College of Rheumatology collaborative initiative. Vol. 64, No. 4, April 2012. 5. Cantini F, Salvarani C, Olivieri I, Niccoli L, Macchioni P, Boiardi L, et al. Inflamed shoulder structures in polymyalgia rheumatica with normal erythrocyte sedimentation rate. Arthritis Rheum 2001;44:1155–9. 6. Cantini F, Niccoli L, Nannini C, Padula A, Olivieri I, Boiardi L, et al. Inflammatory changes of hip synovial structures in polymyalgia rheumatica. Clin Exp Rheumatol 2005;23:462–8 7. Jones JG, Hazleman BL. Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis 1981;40:1-5. 8. Maradit Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based cohort of patients with polymyalgia rheumatica. J Rheumatol 2005;32:65-73. 9. Caporali R, Cimmino MA, Ferraccioli G,Gerli R, Klersy C, Salvarani C, et al; for the Systemic Vasculitis Study Group of the Italian Society for Rheumatology. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann InternMed 2004;141:493-500 10. Cantanoso CM, Macchioni P, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study. Arthritis Care Res 2007;57:1514-9. 11. Gabriel SE, Sunku J, Salvarani C, O’Fallon WM, Hunder GG. Adverse outcomes of and inflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum 1997;40:1873-8. 12. Unizony, S. Arias-Urdaneta, L. Miloslavsky, E. Arvikar, S. Khosroshahi, A. Keroack, B. Stone, J R. Stone, J H. Arthritis care & research. 64(11):1720-9, 2012 Nov.
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Osteoarthritis: Nuts and Bolts of Joints that Ache Fellipe Oliveira, MD and Andy Abril, MD Mayo Clinic Jacksonville, FL
Abstract: Osteoarthritis is the most common arthritic condition affecting humans. It is a frequent cause of chronic pain and disability. It has been for a long time considered mainly a degenerative condition, but there are many other biochemical factors involved in its pathogenesis. This review provides the clinician with recent concepts regarding pathogenesis, clinical aspects, diagnosis and therapeutic recommendations for patients with this condition.
Introduction Osteoarthritis (OA) is a disorder of the synovial joints. It does not typically affect the whole joint like the inflammatory arthropathies.1 It was previously thought to be part of the natural aging process; therefore, it was given the name Degenerative Joint Disease.2 OA is characterized by erosions of the articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis and many biochemical and morphological alterations of the synovial membrane and joint capsule.3 It is the leading cause of disability in industrialized countries. The prevalence increases with age, so that more than 80 percent of people older than 75 years of age are affected by OA.3 There are three basic types of OA: Primary idiopathic OA, Secondary OA and Erosive OA.
Primary Idiopathic OA Primary idiopathic OA can be localized or generalized; however, there is no universally accepted definition of generalized OA. Most commonly, generalized OA is known as more than three joint groups affected and frequently associated with Heberden`s nodes (enlargement of the distal interphalangeal joints). The most commonly affected joints are: DIP (distal interphalangeal), PIP (proximal interphalangeal), First CMC (car-
pometacarpal), cervical or lumbar spine, First MTP (metatarsal phalangeal), knees, and hips.2 There are numerous risk factors associated with primary OA. The prevalence increases with age. OA is more frequent in females, and it is more common in females with high bone mass index. There is also the mechanical factor contribution (e.g. repetitive use of the joint or a previously injured joint) which plays a role in the development of OA. OA may be inherited in 50 to 60 percent of cases (3). Nodal OA (presence of Heberden`s and Bouchard`s nodules) has been associated with HLA-A1 and HLA-B8.3
Secondary OA Secondary OA has many different etiologies and should be suspected whenever there is development of OA in atypical joints such as MCPs (metacarpal phalangeal), wrists, ankles, shoulders or elbows. Risk factors associated with secondary OA are: • Presence of metabolic disorder such as Acromegaly, Cushing, Wilson`s disease, Hemochromatosis, crystal arthropathy, Paget`s disease.2 • Bleeding dyscrasias seen in Hemophilia or iatrogenic due to the use of warfarin. • Inflammatory disorders like Rheumatoid arthritis, or any other inflammatory or infectious arthropathy. • Mechanical damage from surgery or joint trauma. • Neuropathic arthropathies; seen in conditions such as Diabetes, syphilis and spinal cord injury.
Erosive OA Erosive OA is a severe form of OA, affecting the DIPs and PIPs of the hands. Risk factors are not well defined; however, females are more affected than males.
Address correspondence: Andy Abril, MD, Division of Rheumatology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL
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Chondrocytes synthesize collagens, proteoglycans and proteinases. Failure to produce a good quality matrix of resistance, elasticity, and ability to maintain balance between synthesis and degradation of the extracellular matrix can lead to OA.1 The pathogenesis of OA is due to alteration of the chondrocyte differentiation process; in other words, the chondrocytes in OA are dysfunctional. The contributing factors to OA are multiple and complex. The abnormalities of chondrocyte synthesis are the result of tissue activation by cytokines and proteases. The cartilage loses its smooth aspect and microcracks appear which will deepen perpendicularly and form vertical clefts into the subchondral bone. Fissures lead to detachment of cartilage into the articular cavity. Synovial cells phagocytize the fragments of cartilage; those cells become capable of producing and releasing metalloproteinases and cytokines into the joint, which in turn, alternate the cartilage matrix and activate chondrocytes.1 Microcysts can develop in the exposed subchondral bone, and subchondral sclerosis increases as the disease progress.
Clinical Presentation OA most commonly presents in individuals older than 40 years of age. The main symptom related to OA is pain, which is exacerbated by activity and is relieved by rest. Stiffness is also a very prevalent complaint. This typically is reported to last less than 30 minutes after the patient awakens. Numerous findings can be present during the physical examination, but the most common of these are tenderness to palpation of the affected joint with or without sign of inflammation, mild effusions and crepitus. Osteophytes may be palpable as bony enlargements at the periphery of a joint. Characteristic clinical manifestations of OA are related to the compromise of a particular joint. It is common to see involvement of the DIPs, PIPs, and the first CMC joint in the hands.1 In the feet, typically the MTP joints are involved, which may lead to hallux valgus and/or rigidus. Compromise of the subtalar joint causes pain upon ambulation. Bursal inflammation occurs at the medial side of the metatarsal head and is commonly called a bunion.2
In the spine, the involvement is most common at the spinal levels C5, T8 and L3, which represent areas of great flexibility.2 The cervical spine shows spondylosis (osteophytes arising from the margin of the vertebral body). In advanced cases, it can cause spinal cord compression and impinge upon the nerve root. At the lumbar level, spondylosis (apophysial joint osteophytes) can cause spinal stenosis. The pain increases with exertion, and the physical exam is often unrevealing, except for the occasional presence of limited range of motion or local tenderness. Severe OA may lead to spondylolisthesis or the slipping of one vertebral body on another, which typically occurs at the apophysial joint at L4-L5. The shoulders are not commonly involved; however, compromise of the shoulders can be mild to severe leading to complete joint destruction. At the acromio clavicular joint, osteophytes can cause rotator cuff tear and/or tendinitis. Symptoms coming from the glenohumeral joint typically include anterior shoulder pain that gradually worsen over time and movement.
Diagnostic Approach The diagnosis of OA is based on the clinical picture, and is supported by radiologic and laboratory data. Among the clinical features of OA, none are completely sensitive or specific. The more features one finds, the more likely the diagnosis. Laboratory work up should include Sedimentation rate, Rheumatoid Factor, and radiographic study of the affected joint. Severe, acute pain is not a common manifestation of OA, and in those cases, joint aspiration is warned. The synovial fluid has few white cells <2000WBCs/uL indicating a noninflammatory process. Looking for crystals using polarized microscope is recommended. Compromise of joints that are uncommonly affected by idiopathic OA should prompt search for underlying secondary causes.
In the knees the presence of limited range of motion, osteophytes and effusions are common. As the disease advances, malalignment presents as genu varus or genu valgus. The cartilage loss begins most frequently in the medial aspect of the tibiofemoral joint. The patella can be involved, resulting in pain and tenderness on the anterior portion of the knee.
Radiographic evidence of OA is very common; however, it does not necessarily correlate with symptomatology of the patient.
When hips are involved, the pain is located in the outer groin or inner thigh area. It may irradiate to the medial knee, distal thigh, buttocks or sciatic region. One must differentiate pain caused by OA from throcanteric bursits OA, lumbosacral OA, knee OA, lumbar radiculopathy or vascular insufficiency.2
The American College of Rheumatology (ACR) has developed guidelines designed for clinical studies that are commonly used to assist the diagnosis of OA, however, there are limitations. The guidelines pertain to only certain joints,
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Radiological features include asymmetric joint space narrowing, subchondral sclerosis, osteophytes at the periphery of the joint and subchondral cysts.
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and as stated above, imaging does not necessarily correlate with the clinical presentation. Only patients with idiopathic OA are included in the guidelines.2 Knees: presence of pain plus osteophytes and one of the following - Older than 50 years of age, crepitus on motion and stiffness lasting less than 30 minutes.2 Hips: pain plus at least two of the following: ESR less than 20, acetabular or femoral osteophytes and joint space narrowing (predominantly in the superior and lateral aspect of the joint).2-4 Hands: pain, aching or stiffness, and at least three of the following - hard tissue enlargement of more than one of the subsequent joints (2nd, 3rd DIPs, PIPs, 1st CMC), hard tissue enlargement of more than one DIP, deformity of at least one of the selected joints, and fewer than three swollen MCP joints.2-5 Differential Diagnosis OA is not very difficult to diagnose, however, the main problem is to find out if the pain and disability are generated by the pathological changes seen in OA or are from another disease.1
Treatment The goals of the treatment are to control pain and swelling, minimize disability and improve quality of life. It is very important to establish that the patient symptoms are related to OA and not another pathology. The nonpharmacologic treatment includes physical and occupational therapy and weight reduction to reduce the stress and load on the affected joint. Results suggest that taking glucosamine sulphate does not add to the beneficial effects seen form exercise. Patients should be advised that the use of non- steroidal anti-inflammatory drugs (NSAIDs) or glucosamine while exercising will not decrease the benefits provided by physical activity.6 Patients should be proactive regarding their therapy and could be encouraged to contact organizations such as the Arthritis Foundation: 1-800-283-7800; www.arthritis.org. The pharmacological approach should be guided according to the severity of the pain. For mild to moderate pain, it is recommended to start treatment with acetaminophen. If the response to acetaminophen is not adequate, then the use NSAIDS is the next step. There is data suggesting that naproxen is the safest of all NSAIDS available on the market from the cardiovascular point of view.7 Due to the side effects of the chronic use of NSAIDS, it is recommended to take a proton pump inhibitor (PPI) while on NSAIDS for cases such as patients older than 65 years of age, a history of peptic ulcer disease, patients on anticoagulation, concomitant use of corticosteroids and be a positive status for H. Pylori.8
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If one type of NSAID does not produce an adequate response at its full safe dose for two weeks, then it is recommended to try another NSAID for another two weeks before classifying the patient as a non-responder to NSAID. The combination of acetaminophen with NSAID is not contraindicated and can be tried. The use of topical therapy with capsaicin or Diclofenac gel can also be used to help control the pain. Most recently, the FDA approved the use of Duloxetine in order to target central pain in OA. Studies have found that compared with placebo, Duloxetine demonstrated significant improvement in pain and function for people with painful knee OA already taking NSAIDs.9 In patients who do not respond to NSAIDS or are intolerant to them, intraarticular steroid injection is an option; however it should not be done more than three times per year in the same joint. In cases where all of the treatment options listed above failed, then low potency opioids or intraarticular hyaluronic acid, which is only FDA approved for OA of the knees, may be needed. Hyaluronic acid can be injected weekly for three to five weeks, depending on the specific commercial compound. The use of opioids in patients with OA requires careful attention. Those patients are usually elderly and the risks versus the benefits of the use of opioids needs to be discussed with the patient and the family members involved in the case. In individuals older than 65 years of age, the use of opioid is associated with an increased risk of bone fractures, cardiovascular events, a higher percentage of events leading to hospitalization and all-cause mortality.10-11 Tramadol should be the first to be introduced; codeine may be the next option due to its low potency. Failure to respond to both, prompt a difficult question to be answered: should the patient be given higher potency opioids or undergo surgical intervention. One must take into consideration all the comorbidities of the patient in order to decide if surgery is a safe option. The goal of the surgical intervention is to relieve pain and improve function of the affected joint. There are multiple surgical options available; therefore, referral to an experienced orthopedic surgeon is advisable.12
Conclusion Osteoarthritis is a very common cause of morbidity in the elderly population, it varies in intensity, localization and rate of progression, and all of these factors should be important in the evaluation and treatment of individual patients with this condition. As with all aspects of medicine, the treatment of OA must be multidisciplinary and individualized. Custom-made care is offered because an off-the-rack approach will not suit everyone. Extensive research is being conducted in several centers trying to elucidate pathogenic aspects of this disease and trying to find better therapeutic alternatives. v
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References: 1. Francis Berinbaum. Osteoarthritis, Pathology and Pathogenesis. Primer on Rheumatic diseases. New York: Springer; 2008.p.229-234 2. Rebeca M. Spheperd. Osteoathritis. The Washington Manual. New York: Lippincott Williams; 2004.p.85-91 3. Paul E.Di Cesare, Dominic R.Haudenschild, Jonathan Samuels, StevenB. Abramson. Pathogenesis of osteoarthritis. Kelley`s Text book of Rheumatology. Philadelphia: Elsevier, 2013.p.1617-1633 4. Altman R, etal. The American College of Rheumatology criteria for classification and reporting osteoarthritis of the hip. Arthritis Rheum 1991; 34: 505 5. Altman R, etal. The American College of Rheumatology criteria for classification and reporting osteoarthritis of the hand. Arthritis Rheum 1990; 33: 1601 6. Kenneth C.Kalunian. Initial pharmacologic therapy of osteoarthritis . Uptodate.
8. Bhala N. Emberson J. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant date from randomized trials. Lancet 2013. 9. Claire Y.J Wenham, Philip G. Conagan. New horizons in osteoarthritis. Age and ageing 2013; 42: 272-278 10. Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, Schnneeweiss S. The comparative safety of analgesics in older adults with arthritis, Arch Intern Med. 2010;170:1968-1978. 11. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of opioids for nonmalignant pain in older adults. Arch intern Med.2010;170:1979-1986. 12. E.M. Roos, C.B. Juhl. Osteoarthritis 2012 year in review: rehabilitation and outcomes. Osteoarthritis and Cartilage .2012; 20:1477-1483.
ame 1 e sets Foco Light n be up to two lines
7. Kenneth C.Kalunian. Treatment of osteoarthritis resistant to initial pharmacologic therapy. Uptdate.
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Gout: New Advances in an Old Disease Catherine Garcia, MD and John D. Carter, MD Abstract: Gout is the oldest known rheumatic disease that was first described over 4,000 years ago in Egypt. In Roman times, joint pain was classified as gout versus other. It has been known for many years that hyperuricemia is a necessary precursor for gout but not the sole disease determinant. In recent years, our knowledge of the pathophysiology of gout has expanded tremendously and new treatments have followed suit with more in the pipeline. Presently, treatments target the root cause of the disease, i.e. hyperuricemia. Hopefully, our newest therapies will be able to completely arrest the disease process of this oldest known rheumatic disease. Gout was reported in Egypt as early as 2640 BCE and later in Greece by Hippocrates in 500 BCE.1 During Roman times, it was felt that joint pain could be divided into one of two categories: gout and everything else.2 Historically it has been linked with wealthy, obese, middle-aged men.; It has afflicted historical figures such as Benjamin Franklin, Thomas Jefferson and King Henry VIII.1,3 In recent years though, it has affected an increasingly heterogeneous population, resulting in an estimated prevalence of gout among US adults of 3.9 percent (~8.3 million adults) in 2007-20084 and the prevalence is on the rise.5 The increasing prevalence of gout is a result of comorbidities that promote hyperuricemia, such as hypertension, obesity, metabolic syndrome, chronic kidney disease, dietary trends and certain medications (e.g. diuretics).6 Many of these same comorbidities make effective treatment of gout a challenge. Hyperuricemia is a primary risk factor and a necessary precursor to the development of gout, but it is not the sole determinant since many patients with elevated serum urate levels will never develop clinical gout.7 Gout is a progressive disease that can result in tophi deposition, chronic inflammatory arthritis and kidney stones (cardiovascular disease is a frequent co-morbidity but might not be caused by gout).8 It is characterized by elevated serum urate (>6.8 mg/dL in vitro) and deposition of monosodium urate crystals in tissues (joints, bursae, bone, ligaments, tendons and occasionally skin) clinically manifested as recurrent attacks of arthralgias or eventually, if left un-treated, development of tophi.9,10 It was thought that overproduction of uric acid due to dietary factors was nearly entirely responsible for gout, but research has shown that overproduction of uric acid accounts for only 10 to 25 percent of cases, whereas impaired renal excretion of uric acid is present in more than 90 percent of cases.9 Conditions resulting in impaired renal excretion of uric acid include inherited mutation in renal urate anion transporters; decrease in glomerular filtration rate (e.g. CKD); hypertension; insulin resistance (metabolic syndrome); lead toxicity and medi-
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cations such as diuretics, low dose aspirin, anti-tuberculosis drugs and anti-retroviral drugs.9 Uric acid metabolism is well understood and is the basis for the current therapeutic approaches. The purines in humans undergo enzymatic degradation by xanthine oxidases into hypoxanthine, xanthine and then uric acid. With human evolution, the expression of uricase (which oxidizes uric acid into highly soluble allantoin) was lost, resulting in serum urate levels in humans that are much higher than other mammals, and approaches the theoretical limits of solubility.11 The insoluble uric acid in humans is filtered at the glomerulus, undergoes reabsorption in the proximal tubule, secretion and postsecretory reabsorption; therefore, there is 90 percent net reabsorption and 10 percent renal clearance of the filtered urate. The renal urate anion transporters in charge of reabsorption have been identified as URAT1 [SCL22A12] and GLUT9 [SLC2A9], and the secretory transporter has been identified as ABCG2.9,11 Allopurinol and Febuxostat act as inhibitors of xanthine oxidase, thereby reducing generation of urate. PEGylated uricase (pegloticase) serves to oxidize the uric acid into soluble Allantoin, as previously mentioned. The uricosuric probenecid targets the reabsorption transporter URAT1 and GLUT9, thereby promoting the urinary excretion of uric acid. Other uricosurics with modest effects include losartan, fenofibrate and leflunomide.11 Recent advances have helped shed some light into the immunopathogenesis of gout and the inflammatory cascade. It is now known that the Toll-like receptor 2 (TLR2), TLR4, and the TLR adaptor protein MyD88 promote phagocytosis of MSU crystals.12 The intracellular assembly of the cytosolic NACHT-LRR-PYD containing protein NALP3 (also called cryopyrin) inflammasome protein complex is then triggered by these intracellular MSU crystals.13 This inflammasome protein complex assembly then activates caspase-1 culminating in the release of IL-1beta.13 The potent effect of the proinflammatory cytokine IL-1beta is responsible for the intense inflammatory response that is the hallmark feature of acute gouty attacks. Comprehension of these complex inflammatory pathways can serve as potential treatment targets in the future. Cryopyrin is known to be associated with other chronic autoimmune inflammatory conditions including familial cold autoinflammatory syndrome and Muckle-Wells syndrome. These NALP3 associated diseases are characterized by periodic inflammatory symptoms. However, it is also recognized that patients with these conditions have chronic low-grade inflammatory activity in between their attacks. Further, synovial tissue analysis of patients with rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease, has demonstrated upregulation of cryopyrin in comparison to the synovial tissue of patients with osteoarthritis.14 Taken together, these data suggest that cryopyrin
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Rheumotology associated diseases, including gout, are characterized by both acute and chronic inflammation. It is well recognized that elimination of chronic inflammation is the key to abrogating the pathologic sequelae of any chronic autoimmune inflammatory condition. Perhaps the classic example of this is borne out in the treatment of RA. For many years, it has been evident that methotrexate can slow the radiographic sequelae of RA. More recently, anti-tumor necrosis factor (TNF) therapy has been demonstrated to arrest the radiographic and clinical changes in many patients. These therapeutic successes have resulted in a profound effect in terms of improved patient physical function. As is the case with RA, gout can lead to severe radiographic destruction culminating in the loss of physical function. With gout specifically, clinical trial data and a large breadth of clinical experience demonstrates that effective lowering of the serum urate level below the threshold of solubility effectively reduces the number and frequency of acute gouty attacks. The more aggressive the serum urate lowering therapy, the less likely the patient will experience future attacks.15 Similar studies have demonstrated that serum urate lowering therapy can reduce, or even resolve, soft-tissue tophi.16 It would, therefore, seem logical that this same therapeutic approach would be effective at modifying or arresting the radiographic damage associated with chronic gouty arthropathy. Surprisingly, there are few data assessing the effect of lowering serum urate upon the radiographic progression of gout. The largest study to evaluate the effect of serum urate lowering therapy on radiographic progression demonstrated no correlation between radiographic changes and mean serum urate levels.17 Conversely, a recent exploratory study of eight patients with gout suggested that profound urate lowering therapy with pegloticase might lead to improvement in structural damage.18 Monosodium urate crystals can persist in the synovial materials of patients with gout even during the intercritical period.19,20 It has further been demonstrated that these same crystals can be detected in the synovial fluid of patients with gout from a joint that has never experienced a clinical attack of gout.21 More recent studies with advanced imaging modalities, such as ultrasound and MRI, also suggest that clinically silent synovial based inflammation persists in patients with gout during these same asymptomatic intercritical periods. Taken together, this data suggests that effective serum urate lowering therapy should eliminate these monosodium urate crystals and concomitant inflammation. This should be done not just as a means to prevent future clinical attacks, but also to eliminate the silent, but potentially important, synovial-based monosodium urate crystals and resulting inflammation. Because the threshold of solubility is 6.8mg/dL in vitro,22 the treatment target of <6.0mg/dL is often recommended.15 However, data is lacking to know if this is the correct target. The British Society of Rheumatology recommends <5.0mg/dL as the treatment target.23 More data is needed to know the most efficacious serum urate level target for the treatment of gout. It is also possible that this target could vary in individual patients depending on their disease severity and comorbidities.
Conclusion Gout is a disease that dates back to antiquity. Indeed, joint pain was classified many years ago as gout versus other. It was believed to be a disease of kings, but we now know it affects 24 Vol. 65, No. 2 2014
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the masses and the prevalence appears to be on the rise. Our knowledge of the pathophysiology of gout has expanded tremendously in recent years and new treatments have followed suit with more in the pipeline. Presently, treatments target the root cause of the disease. Hopefully, our newest therapies will be able to completely arrest the disease process of this oldest known rheumatic disease . v
References: 1. Schwartz SA. Disease of Distinction. Available from: [http://www. stephanaschwartz.com/PDF/disease_of_distinction.pdf.]. 2. Rodnan GP. Growth and development of rheumatology in the United States--a bicentennial report. Presidential address to the American Rheumatism Association. Arthritis and rheumatism. 1977;20(6):1149-68. 3. Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis research & therapy. 2006;8 Suppl 1:S1. 4. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis and rheumatism. 2011;63(10):3136-41. 5. Arromdee E, Michet CJ, Crowson CS, Oâ€™Fallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? The Journal of rheumatology. 2002;29(11):2403-6. 6. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis care & research. 2012;64(10):1431-46. 7. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. The American journal of medicine. 1987;82(3):421-6. 8. Bakris GL, Doghramji PP, Keenan RT, Silber SH. CaseBook challenges: Managing gout, hyperuricemia and comorbidities -- dialogue with the experts. The American journal of medicine. 2014;127(1):S1. 9. Terkeltaub R, Edwards NL. Gout: Diagnosis and Management of Gouty Arthritis and Hyperuricemia. Second Edition ed: Professional Communications Inc.; 2011. 272 p. 10. Cai Y, Peng YH, Tang Z, Guo XL, Qing YF, Liang SH, et al. Association of Toll-like receptor 2 polymorphisms with gout. Biomedical reports. 2014;2(2):292-6. 11. Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis and rheumatism. 2004;50(8):2400-14.
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Rheumotology 12. Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis and rheumatism. 2005;52(9):2936-46. 13. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-41. 14. Rosengren S, Hoffman HM, Bugbee W, Boyle DL. Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Annals of the rheumatic diseases. 2005;64(5):708-14. 15. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis and rheumatism. 2004;51(3):321-5. 16. Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis and rheumatism. 2002;47(4):356-60. 17. McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL. Influence of antihyperuricemic therapy on the clinical and radiographic progression of gout. Arthritis and rheumatism. 1991;34(12):1489-94.
18. Dalbeth N, Doyle AJ, McQueen FM, Sundy J, Baraf HS. Exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate-lowering therapy. Arthritis care & research. 2014;66(1):82-5. 19. Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout. Arthritis and rheumatism. 1991;34(2):141-5. 20. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Annals of internal medicine. 1999;131(10):756-9. 21. Bomalaski JS, Lluberas G, Schumacher HR, Jr. Monosodium urate crystals in the knee joints of patients with asymptomatic nontophaceous gout. Arthritis and rheumatism. 1986;29(12):1480-4. 22. Kippen I, Klinenberg JR, Weinberger A, Wilcox WR. Factors affecting urate solubility in vitro. Annals of the rheumatic diseases. 1974;33(4):313-7. 23. Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford, England). 2007;46(8):1372-4.
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Behçet’s Disease in the United States Background:
The Duval County Medical Society (DCMS) is proud to provide its members with free continuing medical education (CME) opportunities in subject areas mandated and suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). This issue of Northeast Florida Medicine includes an article, “Behçet’s Disease in the United States” authored by Ronald Butendieck, MD; McGregor Lott, MD and Kenneth Calamia, MD, which has been approved for 1 AMA PRA Category 1 credits.TM For a full description of CME requirements for Florida physicians, please visit www.dcmsonline.org.
Drs. Butendieck, Lott and Calamia work for Mayo Clinic, Division of Rheumatology.
To understand the varied presentations of Behçet’s Disease, its distinctive neurological, vascular and ophthalmological manifestations and have an approach to the disease diagnosis.
To appreciate the multiple causes of aphthosis and to recognize oral findings which should lead to suspicion of other disorders.
To gain an understanding of treatment options for Behçet’s Disease. Recognize the underlying vasculitis for which aggressive treatment should be considered for manifestations responsible for morbidity and mortality.
Date of release: June 1, 2014
Date Credit Expires: Expires: June 1, 2016
Estimated Completion Time: 1 hour
How to Earn this CME Credit: 1.
Read the “Behçet’s Disease in the United States” article, complete posttest following the article and email your test to Patti Ruscito at patti@ dcmsonline.org or mail it to 1301 Riverplace Blvd. Suite 1638, Jacksonville, FL 32207.
Go to www.dcmsonline.org to read the article and take the CME test online.
All non-members must submit payment for their CME before their test can be graded.
CME Credit Eligibility:
A minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted. A certificate of credit/completion will be emailed within four to six weeks of submission. If you have any questions, please contact Patti Ruscito at 904.355.6561 or email@example.com.
Drs. Butendieck, Lott and Calamia report no significant relations to disclose, financial or otherwise with any commercial supporter or product manufacturer associated with this activity.
Disclosure of Conflicts of Interest:
St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee and other individuals who are in a position to control the content of this educations activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations.
Joint Sponsorship Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare designates this educational activity for a maximum of 2 AMA PRA Category 1 credits.TM Physicians should only claim credit commensurate with the extent of their participation in the activity.
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Behçet’s Disease in the United States Ronald R. Butendieck, MD Mayo Clinic, Jacksonville, FL
McGregor N. Lott, MD and Kenneth T. Calamia, MD Mayo Clinic Health System, Waycross, GA
Abstract: Behçet’s Disease (BD) is an uncommon disorder in the United States (US), but the diagnosis is often considered in cases with recurrent aphthous stomatitis. It lies within the realm of immune mediated inflammatory diseases (IMID). This article focuses on the differential diagnosis of aphthosis, as well as other manifestations of BD that should lead to suspicion of its presence and support a diagnosis. Inflammatory eye disease, central nervous system manifestations and vascular problems may be distinctive, and are important clues to the presence of this disorder. The first description of Behçet’s Disease (BD) is attributed to Hulusi Behçet, who described cases of oral and genital ulcers with hypopyon uveitis. The disease has since been recognized as a vasculitis with multiple disease manifestations. BD is known to have a high prevalence along the ancient Silk Road, however, it occurs in other parts of the world including the United States, where patients lack the genetic and ancestral connections to the Silk Road. The prevalence and incidence of the disease in the population of Rochester, MN was found to be similar to that in European countries.1 In Western countries, there are a greater proportion of females diagnosed with the disease, and clinical features are primarily mucocutaneous and generally less severe. Clinicians should always seek to distinguish other diseases that can mimic BD, including inflammatory bowel disease, HLA-B27-associated disorders and systemic lupus. The presenting symptoms of most patients with BD are oral ulcers, which are clinically identical to the ulcers of recurrent aphthous stomatitis (Figure 1). The ulcerations of BD are recurrent, but individual ulcers typically heal in days or weeks; chronic ulcers lasting more than six weeks should prompt a biopsy and consideration of another disorder. Recurrent aphthous stomatitis is not unique to BD. Therefore, clues suggestive of inflammatory bowel disease, gluten enteropathy, HIV infection, IgA deficiency and hematologic disorders should be specifically
Address Correspondence to: Dr. Butendieck, Division of Rheumatology, 4500 San Pablo Road, Jacksonville, FL 32224. 904-953-2101. firstname.lastname@example.org
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Aphthous ulcers in BD
investigated. The purpose of a biopsy, which should include immunofluorescent staining, is to recognize other diseases that do not involve typical aphthous ulceration. The findings of more diffuse stomatitis or chronic mucositis (rather than discrete ulcers) should suggest an alternative diagnosis, such as lichen planus, mucous membrane pemphigoid, erythema multiforme and linear IgA disease. Recurrent aphthous stomatitis can occur as an isolated condition of unknown cause and can be severe. Some cases may be classified as “complex aphthosis,” which is characterized by multiple, painful lesions that are episodic or continuous and slow to heal; they may also be associated with genital ulcers. In the absence of any other symptom or finding suggestive of BD, these patients should not be diagnosed as “possible BD,” particularly in countries where the prevalence of BD is low. Along the Silk Road, such cases are followed expectantly, especially in younger male patients who are at risk for more serious manifestations.
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CME Figure 2: Scrotal ulcer in BD
Table 1 International Study Group Criteria for Behçet’s Disease2 • Recurrent oral ulceration (3x/yr) Plus 2 of the following: • Recurrent genital ulceration • Ocular lesions • Skin lesions
Figure 3: Positive pathergy test in distal two sites
• EN, pseudofolliculitis, papulopustules, acneform • Positive pathergy test
itis after cataract surgery or a flare of inflammation after joint injection. Pathergy is believed to be responsible for aneurysm formation after arterial puncture for diagnostic angiography in BD patients. Therefore, non-invasive testing is recommended if the disease is suspected.
Though symptomatic treatment can certainly proceed in the absence of a clear diagnosis, labeling patients as BD or “suspected BD” based on ulcers alone does them a disservice, as they may carry this diagnosis for years with subsequent, unexplained symptoms misattributed. The importance of the diagnosis of BD is related to the presence or risk of uveitis, CNS disease and vascular manifestations. Genital ulcers in BD affect the scrotum (Figure 2) or shaft of the penis in males and the labia in females. Deep ulcers may heal with scarring, a sign of previous ulceration in someone without active ulcers at the time of examination. A unique feature of BD is pathergy, which is the abnormal response of tissue to injury. It can be triggered by pricking the skin of the volar forearm with a 20-gauge needle at three locations. After 48 hours a palpable, erythematous lesion at the site indicates pathergy (Figure 3). While a positive test is not as common in areas away from the Silk Road, the test is easy to perform and positivity is highly supportive of the diagnosis of BD. Patients may report other phenomena that suggest pathergy, such as a nodule or thrombosis at the site of venipuncture, a flare of uve-
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The International Study Group (ISG) published “diagnostic” criteria for BD (Table 1) in 1990,2 though these are actually classification criteria used to assure similarity of patient groups in studies. As such, they lack sensitivity for the diagnosis in some patients. Vascular, gastrointestinal and central nervous system manifestations are not considered in these criteria, but should be considered in securing the diagnosis.3 More recently, data from 27 countries were pooled, leading to the International Criteria for Behçet’s Disease, in an attempt to improve sensitivity of criteria. Sensitivity was 90 percent and specificity was 91 percent.4 These criteria can serve as a guide, reminding the clinician of the multiple manifestations possible and supporting an educated clinical diagnosis. Rheumatology consultation is recommended for confirmation of the diagnosis before aggressive treatment is instituted. Skin manifestations are present in the majority of BD patients in the USA and are frequently helpful in supporting the diagnosis.5 The ISG criteria recognize erythema nodosum (EN), pseudofolliculitis, papulopustular lesions and acneiform nodules,2 but a variety of other skin lesions have also been reported. Biopsies of lesions may reveal a neutrophilic vascular reaction, but are non-specific; microthrombi in small vessels may also be seen. True vasculitis is infrequent. Vasculitis may be secondary to the infiltrate seen in nearby pustules or ulcers.6 The histopathologic findings of EN in BD are similar to those
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associated with other disorders.
Figure 4a: Parenchymal NBD
Ocular involvement occurs in approximately 50 percent of patients with BD from the US, but a higher percentage is noted in Silk Road countries.5 This primarily manifests as uveitis, inflammation of the iris, ciliary body or choroid. Although most instances of uveitis present with or after the onset of oral ulcers, ocular disease can be the first sign of BD. The age of onset is usually in the third to fourth decade, with men more commonly affected than women and the most severe cases typically seen in men between 15 and 25 years of age. Uveitis may initially be unilateral, but progression to bilateral disease occurs in nearly 70 percent of patients.7 Patients with ocular involvement commonly present with decreased vision, floaters, pain, redness and photophobia. A hypopyon (layered white blood cells in the anterior chamber) may be present, and a result from synechiae between the iris and lens may be a misshapen and poorly reactive pupil. Fundus examination may be unremarkable, though vitreous opacification, scattered yellow-white retinal exudates, retinal hemorrhages, optic nerve edema or pallor, or retinal detachment can be noted. The clinical course of ocular disease typically involves chronic-relapsing inflammation, with such long-term complications as glaucoma, cataract, retinal vascular occlusion, optic atrophy or phthisis bulbi. Left untreated, bilateral blindness has developed in up to 50 percent of affected males in older series, though the ocular prognosis has greatly improved with better treatment in recent years.7 Patients with suspected BD should receive a thorough baseline examination by an ophthalmologist. Vascular and neurologic manifestations may occur in BD patients and may be quite distinctive. These findings can be supportive of the diagnosis even when other symptoms or signs of the disease are limited. While overlap of involvement of the cardiovascular and neurologic systems is possible, patients often have recurrent or progressive symptoms in the system that first becomes involved. Mortality in BD is primarily related to major vessel disease and neurologic involvement, and is specifically increased in young males.8 In those with “vasculo-Behcet,” superficial thrombophlebitis may be followed by deep venous thrombosis, caval thrombosis, arterial stenosis or aneurysm, and pulmonary artery aneurysm.9,10 In cases of thrombosis, which can involve any venous system, clot is thought to be caused by a venous vasculitis rather than by any circulating factor, with implications for management. Progressive or recurrent thrombophlebitis, despite adequate anticoagulation, should raise suspicion for BD. Fever is unusual in BD patients, usually suggesting an infection, but may occur in those with large vessel disease.9 There are two major types of neurologic involvement in BD, each with distinctive clinical presentations, laboratory findings, imaging patterns, pathologies, and prognoses. “Neuro-Behçet disease” (NBD) may occur as a non-parenchymal form, that of cerebral venous thrombosis (CVT). Patients present with symptoms and signs of increased intracranial pressure, including headache and papilledema, or with an acute meningeal
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syndrome. Less commonly, patients can present with an acute stroke resulting from arterial thrombosis, dissection or aneurysm. MR venography is the imaging modality of choice when CVT is suspected. Lumbar puncture demonstrates a high CSF opening pressure, but fluid analysis is normal.11 Episodes of CVT are typically monophasic, but relapses can occur. Parenchymal involvement in NBD is a potentially devastating complication. In one review of several studies, the highest prevalence of neurological involvement was found in patients between the ages of 20 and 40 with men affected 2.8 times more frequently than women; the prevalence of NBD was 10 percent.12 Although NBD typically appears with or following other systemic symptoms of BD, neurologic involvement may be the initial manifestation of BD, posing a diagnostic challenge. Parenchymal NBD may present with a variety of clinical syndromes that follow relapsing or primary/secondary progressive courses. Most commonly, patients will exhibit the sub-acute onset of a brainstem syndrome resulting in ophthalmoparesis, cranial neuropathy, cerebellar or pyramidal dysfunction.12-14 A cerebral syndrome can present with encephalopathy, hemiparesis, hemisensory loss, seizures, dysphagia and mental status changes including cognitive dysfunction and psychosis. Patients with a diffuse or multifocal pattern can manifest a combination of signs and symptoms resulting from brainstem, cerebral or spinal cord involvement. CSF analysis demonstrates an increase in cells and protein in about 70-80 percent of patients, but glucose is typically normal and oligoclonal bands are absent.15 Patients who present with brainstem or spinal cord lesions, frequent relapses, early disease progression or high CSF pleocytosis have been shown to have a worse prognosis.12,14 Brain MRI is the gold standard for diagnostic imaging in NBD and radiographic location of lesions has been shown to correlate with clinical findings.16 Hyperintense lesions in the brainstem-thalamic-basal ganglia area on T2 and Fluid attenuated inversion recovery (FLARE) sequences are classic for parenchymal NBD.17,18 (Figure 4a) These lesions should raise the suspicion for parenchymal NBD even in the absence of other manifestations.19 Cerebral atrophy with subcortical lesions may
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CME also suggest NBD. While there is no pathognomonic lesion for NBD on brain biopsy, in an acute/subacute case, a perivasculitis prevails with infiltration of neutrophils, lymphocytes and macrophages, without fibrinoid necrosis.20,21
Figure 4b: NBD after 8 months of treatment with corticosteroids and cyclophosphamide
Headache is the most common neurological symptom described in patients with BD, but only about 10 percent are associated with an underlying neurological cause.12 While headaches have been described during flares of systemic features of BD, investigations have failed to show active CNS involvement during these episodes.22 The majority of headaches in patients with BD are migraine and tension headaches that have similar characteristics to headaches found in individuals in the general population.23,24 This awareness can be helpful in reducing unnecessary neurologic workup and inappropriate treatment. Laboratory tests are not frequently helpful in the diagnosis or measurement of disease activity in BD. An acute phase response may occur with large vessel involvement, arthritis or EN. Determination of HLA-B51 is not useful in the diagnosis of BD; positivity rates are similar in BD patients with and without neurological involvement.25,26
Treatment of BehĂ§etâ€™s Disease Evidence and consensus-based treatment recommendations for the various manifestations of BD have been presented,27 though controlled trials are limited especially for gastrointestinal, vascular, and neurological problems. Recalling that BD is a vasculitis, however, should remind the clinician that aggressive treatment must be considered for manifestations associated with morbidity or mortality.10 On the other hand, disease manifestations that are unlikely to be associated with serious consequences should be treated with restraint. First-line treatment of aphthosis includes topical corticosteroids in an appropriate vehicle to adhere to lesions for the longest possible period of time. Corticosteroid-containing gels can be applied by gently rubbing the preparation into the lesions for several minutes. Where multiple or diffuse lesions are present, a 50 percent combination of a high-potency corticosteroid and an antihistamine (such as diphenhydramine elixir, a mucous membrane anesthetic) can be used as a gargle, held in the mouth, and then spat. Treatment should be initiated at the first signs of ulcers in order to abort a full-blown outbreak. Colchicine has been used for ulcers and most other manifestations of BD for many years, though controlled studies have only supported its efficacy in genital ulcers, EN and arthritis.28 Recently, pentoxifylline and thalidomide have obtained orphan drug status for the treatment of BD-related aphthosis, but thalidomide is used infrequently because of toxicity.29 All patients with ocular inflammation involving the posterior segment should receive azathioprine and systemic corticosteroids. Cyclosporine A or infliximab is added in cases of severe or refractory ocular inflammation.27 Recent pharmacologic advances have significantly improved visual outcomes.30-38 Treatment of a CVT from any etiology typically includes anticoagulation.39 However, there is continued debate about
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whether treatment of a CVT associated with NBD should include anticoagulation, immunosuppressives or both;40 a final consensus has not been reached.41 Duration of anticoagulation therapy is three to six months, but is life-long if an underlying pro-thrombotic condition is identified.42 An international consensus paper with management recommendations for NBD was recently published.41 Treatment of acute episodes or relapses of parenchymal NBD in patients with brainstem or cerebral lesions includes methylprednisolone 1g IV daily for three to 10 days followed by a slow tapering dose of oral steroids for up to six months. The decision to include a disease-modifying therapy should be based on a patientâ€™s response to steroids, disease course, history of previous neurological relapses and other associated systemic BD features. Azathioprine is recommended as a first-line agent, though other treatments credited with some success include mycophenolate mofetil, methotrexate, chlorambucil43 and cyclophosphamide.44 (Figure 4b) Biologic therapies have shown promise and are recommended when first-line therapies have failed or are not tolerated, or if the disease shows more aggressive features or develops a relapsing course.41 The majority of available data, including one- and four-year follow-up studies, support the use of infliximab,38,45,46 which has been used successfully in a plethora of immune mediated inflammatory diseases (IMID). As with all IMIDs, disease modifying and steroid sparing agents need to be furtively sought and applied.
Conclusion In Western countries, symptoms suggesting the possibility of BD, including aphthosis, should cause the physician to consider other causes and should lead to a comprehensive evaluation of associated symptoms that can lead to a diagnosis. Published criteria can serve as a guide to the diagnosis of BD but ultimately the diagnosis is made on clinical grounds. Recognizing distinctive neurologic, vascular or ophthalmic manifestations will support the diagnosis of BD. Once recognized, aggressive treatment of the underlying vasculitis is a critical factor for successful control. v
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CME References: 1. Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behcet’s disease in the US: a population-based study. Arthritis Rheum. May 15 2009;61(5):600-604. 2. Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet. May 5 1990;335(8697):1078-1080. 3. Schirmer M, Calamia KT, O’Duffy JD. Is there a place for large vessel disease in the diagnostic criteria of Behcet’s disease? J Rheumatol. Dec 1999;26(12):2511-2512. 4. Davatchi F, Assaad-Khalil S, Calamia KT, et al. The International Criteria for Behcet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol. Mar 2014;28(3):338-347. 5. Balabanova M, Calamia KT, Perniciaro C, O’Duffy JD. A study of the cutaneous manifestations of Behcet’s disease in patients from the United States. J Am Acad Dermatol. Oct 1999;41(4):540-545. 6. Magro CM, Crowson AN. Cutaneous manifestations of Behcet’s disease. Int J Dermatol. Mar 1995;34(3):159-165. 7. Ozyazgan Y, Bodaghi B. Eye Disease in Behcet’s Syndrome. In: Yazici Y, Yazici H, eds. Behcet. New York: Springer; 1910. 8. Kural-Seyahi E, Fresko I, Seyahi N, et al. The long-term mortality and morbidity of Behcet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore). Jan 2003;82(1):60-76. 9. Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behcet’s disease: an update. Curr Opin Rheumatol. Jan 2011;23(1):24-31. 10. Hamuryudan V, Er T, Seyahi E, et al. Pulmonary artery aneurysms in Behcet syndrome. Am J Med. Dec 1 2004;117(11):867-870. 11. Wechsler B, Vidailhet M, Piette JC, et al. Cerebral venous thrombosis in Behcet’s disease: clinical study and longterm follow-up of 25 cases. Neurology. Mar 1992;42(3 Pt 1):614-618. 12. Al-Araji A, Kidd DP. Neuro-Behcet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. Feb 2009;8(2):192-204. 13. Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications in Behcet’s syndrome. Brain. Nov 1999;122 ( Pt 11):2183-2194. 14. Siva A, Kantarci OH, Saip S, et al. Behcet’s disease: diagnostic and prognostic aspects of neurological involvement. J Neurol. Feb 2001;248(2):95-103.
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15. Saruhan-Direskeneli G, Yentur SP, Mutlu M, et al. Intrathecal oligoclonal IgG bands are infrequently found in neuro-Behcet’s disease. Clinical and experimental rheumatology. May-Jun 2013;31(3 Suppl 77):25-27. 16. Joseph FG, Scolding NJ. Neuro-Behcet’s disease in Caucasians: a study of 22 patients. Eur J Neurol. Feb 2007;14(2):174-180. 17. Akman-Demir G, Bahar S, Coban O, Tasci B, Serdaroglu P. Cranial MRI in Behcet’s disease: 134 examinations of 98 patients. Neuroradiology. Dec 2003;45(12):851-859. 18. Borhani Haghighi A, Sarhadi S, Farahangiz S. MRI findings of neuro-Behcet’s disease. Clin Rheumatol. Jun 2011;30(6):765-770. 19. Coban O, Bahar S, Akman-Demir G, et al. Masked assessment of MRI findings: is it possible to differentiate neuro-Behcet’s disease from other central nervous system diseases? [corrected]. Neuroradiology. Apr 1999;41(4):255-260. 20. Arai Y, Kohno S, Takahashi Y, Miyajima Y, Tsutusi Y. Autopsy case of neuro-Behcet’s disease with multifocal neutrophilic perivascular inflammation. Neuropathology. Dec 2006;26(6):579-585. 21. Hirohata S. Histopathology of central nervous system lesions in Behcet’s disease. J Neurol Sci. Apr 15 2008;267(12):41-47. 22. Saip S, Siva A, Altintas A, et al. Headache in Behcet’s syndrome. Headache. Jul-Aug 2005;45(7):911-919. 23. Borhani Haghighi A, Aflaki E, Ketabchi L. The prevalence and characteristics of different types of headache in patients with Behcet’s disease, a case-control study. Headache. Mar 2008;48(3):424-429. 24. Aykutlu E, Baykan B, Akman-Demir G, Topcular B, Ertas M. Headache in Behcet’s disease. Cephalalgia. Feb 2006;26(2):180-186. 25. Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behcet’s disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford). May 2012;51(5):887-900. 26. Gul A, Uyar FA, Inanc M, et al. Lack of association of HLA-B*51 with a severe disease course in Behcet’s disease. Rheumatology (Oxford). Jun 2001;40(6):668-672. 27. Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the management of Behcet disease. Ann Rheum Dis. Dec 2008;67(12):1656-1662. 28. Yurdakul S, Mat C, Tuzun Y, et al. A double-blind trial of colchicine in Behcet’s syndrome. Arthritis Rheum. Nov 2001;44(11):2686-2692.
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CME 29. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. Mar 15 1998;128(6):443-450. 30. Yamada Y, Sugita S, Tanaka H, Kamoi K, Kawaguchi T, Mochizuki M. Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behcet disease. Br J Ophthalmol. Mar 2010;94(3):284-288. 31. Markomichelakis N, Delicha E, Masselos S, Fragiadaki K, Kaklamanis P, Sfikakis PP. A single infliximab infusion vs corticosteroids for acute panuveitis attacks in Behcet’s disease: a comparative 4-week study. Rheumatology (Oxford). Mar 2011;50(3):593-597. 32. Bawazeer A, Raffa LH, Nizamuddin SH. Clinical experience with adalimumab in the treatment of ocular Behcet disease. Ocul Immunol Inflamm. Jun 2010;18(3):226-232. 33. Sobaci G, Erdem U, Durukan AH, et al. Safety and effectiveness of interferon alpha-2a in treatment of patients with Behcet’s uveitis refractory to conventional treatments. Ophthalmology. Jul 2010;117(7):14301435.
40. Tayer-Shifman OE, Seyahi E, Nowatzky J, Ben-Chetrit E. Major vessel thrombosis in Behcet’s disease: the dilemma of anticoagulant therapy - the approach of rheumatologists from different countries. Clinical and experimental rheumatology. Sep-Oct 2012;30(5):735-740. 41. Kalra S, Silman A, Akman-Demir G, et al. Diagnosis and management of Neuro-Behcet’s disease: international consensus recommendations. J Neurol. Dec 24 2013. 42. Aguiar de Sousa D, Mestre T, Ferro JM. Cerebral venous thrombosis in Behcet’s disease: a systematic review. J Neurol. May 2011;258(5):719-727. 43. O’Duffy JD, Robertson DM, Goldstein NP. Chlorambucil in the treatment of uveitis and meningoencephalitis of Behcet’s disease. Am J Med. Jan 1984;76(1):75-84. 44. Ait Ben Haddou EH, Imounan F, Regragui W, et al. Neurological manifestations of Behcet’s disease: evaluation of 40 patients treated by cyclophosphamide. Rev Neurol (Paris). Apr 2012;168(4):344-349. 45. Al-Araji A SA, Saip S, Constantinescu C, Akman-demir G, Arayssi T, et al. Treatment of neuro-Behçet’s disease with infliximab: an international muticentre case-series of 18 patients [abstract]. Clin Exp Rheumatol. 2010;28(Suppl 60):S119. 46. Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behcet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum. Aug 2011;41(1):61-70.
34. Deuter CM, Zierhut M, Mohle A, Vonthein R, Stobiger N, Kotter I. Long-term remission after cessation of interferon-alpha treatment in patients with severe uveitis due to Behcet’s disease. Arthritis Rheum. Sep 2010;62(9):2796-2805. 35. Onal S, Kazokoglu H, Koc A, et al. Long-term efficacy and safety of low-dose and dose-escalating interferon alfa-2a therapy in refractory Behcet uveitis. Arch Ophthalmol. Mar 2011;129(3):288-294. 36. Davatchi F, Sadeghi Abdollahi B, Shams H, et al. Combination of pulse cyclophosphamide and azathioprine in ocular manifestations of Behcet’s disease: longitudinal study of up to 10 years. Int J Rheum Dis. Dec 8 2013. 37. Davatchi F, Shams H, Rezaipoor M, et al. Rituximab in intractable ocular lesions of Behcet’s disease; randomized single-blind control study (pilot study). Int J Rheum Dis. Aug 2010;13(3):246-252.
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38. Giardina A, Ferrante A, Ciccia F, Vadala M, Giardina E, Triolo G. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behcet’s disease refractory to standard immunosuppressive drugs. Rheumatol Int. Jan 2011;31(1):33-37. 39. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol. Feb 2007;6(2):162-170.
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1. What are the classic MRI findings for parenchymal Neuro-Behçet’s disease? a. Periventricular high–signal intensity lesions on MRI FLAIR sequences. b. Hyperintense lesions in the brainstem-thalamic-basal ganglia area on T2-weighted MRI and FLARE sequences. c. Hypointense lesions in the corpus callosum on T1-weighted MRI sequences d. Atrophy of the caudate nuclei and putamen. e. Isointense to hypointense nodule or mass on T1-weighed MRI sequences and isointense to hyperintense mass on T2-weighted MRI sequences that tend to enhance intensely and diffusely on post-gadolinium-enhanced T1-weighted MRI sequences. 2. All the following are true concerning cerebral venous thrombosis (CVT) in patients with Behçet’s disease except? a. Patients may present with papilledema and headache. b. A high CSF opening pressure is noted. c. CSF analysis demonstrates a pleocytosis. d. MRV is the imaging modality of choice for diagnosis when CVT is suspected. e. Episodes of CVT are typically monophasic, but relapses may occur.
3. Evaluation of a patient with parenchymal neuro-Behçet’s disease is most likely reveal which of the following except? a. A sub-acute onset of a brainstem syndrome resulting in ophthalmoparesis, cranial neuropathy, cerebellar or pyramidal dysfunction. b. CSF analysis with increased cells and protein, but normal glucose levels. c. Brain biopsy identifying perivasculitis without fibrinoid necrosis. d. CSF analysis with increased cells, low protein, oligoclonal bands, and low glucose levels. e. A cerebral syndrome with encephalopathy, hemiparesis, hemisensory loss, seizures, dysphagia and mental status changes. 4. Regarding skin lesions in Behçet’s disease, all of the following are true, except: a. The International Study Group criteria recognize a variety of lesions b. True vasculitis is infrequent, though microthrombi in small vessels may be seen c. The histopathologic features are similar to those seen in non-Behçet’s lesions d. A lymphocytic infiltrate is typically noted e. Lesions are present in a majority of Behçet’s patients 5. Aphthous ulcers in Behçet’s disease are characterized by all of the following except: a. Chronicity, with individual ulcers persisting 6 weeks or longer b. Location on the scrotum or penile shaft in males and the labia in females c. Recurrence, though this finding is not specific to Behçet’s d. A positive response to topical corticosteroids e. A typical lack of diffuse mucosal involvement
6. All of the following are ophthalmic findings in Behçet’s disease except: a. Chronic-relapsing uveitis b. Bilateral blindness c. Female predilection d. Hypopyon e. Unremarkable fundus 7. Which statement is true about Behçet’s disease? a. The highest prevalence of the disease is in the Scandinavian countries. b. In the USA, the disease is more common in females c. Is associated with HLA-B27 d. May be diagnosed by biopsy of an aphthous lesion 8. The following are possible vascular manifestations of Behçet’s Diseaset: a. Superficial thrombophlebitis b. Recurrent deep venous thrombosis despite adequate anticoagulation c. Pulmonary artery aneurysms d. Cerebral venous thrombosis e. Femoral artery aneurysm f. All of the above 9. The following statements are true about pathergy, except: a. Pathergy represents and excessive tissue response to trauma b. Pathergy is suggested by a flare of arthritis after intra-articular injection c. Pathergy is common in several autoimmune conditions d. Pathergy can be provoked by needle stick of the skin.
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Antiphospholipid Syndrome versus Multiple Sclerosis: â€œA common clinical dilemma?â€? Karishma Ramsubeik, MD and Ghaith Mitri, MD, MMM, CPE, FACR
Abstract: Patients early in their disease presentations may not have
the full criteria for a specific clinical diagnosis or a clinical syndrome. In fact some of these clinical syndromes in autoimmune or rheumatic disease have several shared clinical manifestations as in this case, where the patient had an acute neurological presentation but did not fully meet the diagnosis criteria for antiphospholipid syndrome, despite responding to warfarin therapy. As the case continued to evolve she met the diagnosis criteria for multiple sclerosis. We will describe her case presentation and discuss literature about such an overlap between these clinical syndromes. The full criteria may not be met initially but it is always important to assess the risk vs. benefit of treatment as the case continues to evolve.
Case Presentation A 19-year-old woman with no significant past medical history presented to the emergency room with a two-week history of weakness on her right side. The patient had a normal vaginal delivery four months prior and had no previous history of miscarriages. On examination, power was 3/5 in her right hand, 4/5 in right deltoid and 4/5 in the right lower extremity. There was also decreased sensation to all modalities on the right side. The remainder of the neurological examination was normal. She was admitted to the neurology service. Laboratory test results were as follows: WBC 7.4, Hgb 13.9, platelets 335, BUN 9, creatinine 0.7, albumin 4.1 alkaline phosphatases (ALP) 66, ALT 17, AST 17, PTT 41.3, PT 13.8, 1NR 1.2, folate 720, B12 531, HIV negative, HTLV I, II antibodies negative, RPR non-reactive, TSH 1.22, CK 107, ESR 41, ANA positive 1: 320 (speckled pattern), lupus anticoagulant (LAC) 1.5 (weakly present), CSF revealed 49 RBC, 115 WBC. CSF was negative for oligoclonal bands, and myelin CSF > 8(0-1). CT of the head was performed without contrast and revealed the following: no focal cerebral lesions, no mass effect or midline shift, normal ventricular size and no hemorrhage, mass lesion or acute infarction. MRI of
Address Correspondence to: Ghaith Mitri, MD at Ghaith.email@example.com
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cervical spine revealed diffuse abnormal intramedullary T2 signal intensity in the cervical spinal cord. Specifically, swelling extending from the level of C2 to C7 without any significant contrast enhancement was noted. MRI of the brain and thoracic spine did not reveal any abnormalities. A diagnosis of tranverse myelitis was made and the patient was treated with Solumedrol 1g IV for five days. Her weakness dissipated promptly and she was discharged on a tapering regimen of prednisone. Eight weeks later she represented to the emergency department with a two-day history of right upper and lower extremity weakness. On examination, there was 3/5 power in her right hand, 4/5 power in the right deltoid and 4/5 power in right lower extremity, as well as decreased sensation to all modalities on the right. She was admitted to the neurology service and rheumatology was consulted. Laboratory test results were as follows: WBC 7.5, Hb 13.5, platelets 309, BUN 12, creatinine 0.7, albumin 4.1 ALP 66, ALT 17, AST 17, PTT 46, PT 14.2, INR 1.2, C3 133 (90-180), C4 39.9(10-40), anti dsDNA 21(0-99), anti-smith (SM) 28 (0-99), Ro antibody 28( 0-99), La antibody 8(0-99), anti-RNF 34(0-99), anticardiolipin IgM antibody <11 (1-10), anticardiolipin IgG antibody <10 ( 1-9), cANCA <1:20, pANCA<1:20, serum NMO IgG antibody was negative. Mixing studies were performed and the PT failed to correct. Beta glycoprotein IgA antibody 37(0-20), beta glycoprotein IgG antibody<5(0-20), beta glycoprotein IgM antibody 11 (0-20), MRI of the brain revealed multiple high signal abnormalities within the brain with primary involvement of the region of the thalamic nuclei bilaterally, as well as the periaqueductal parenchyma, left posterior longitudinal fasciculus and cervical medullary junction. The largest was in the left foreamen measuring 10 x 14 mm. There was also focal high signal abnormality involving the periaqueductal region and adjacent to the floor of the fourth ventricle on the left side. There was a faint three by five mm high signal abnormality involving the thalamus posteriorly on the right side. No abnormalities were seen in the corpus callosum. MRI of the cervical spine demonstrated an abnormal signal within the cervical spine which began caudally at the C6 level with heterogeneous signal extending through the level of C3. A relative gap and abnormal signal extended to C2 where
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there was abnormal signal extending to the top of the dens. MRI was repeated in two days and demonstrated multiple lesions within the brain with primary involvement of the region of the thalamic nuclei bilaterally, as well as the periaqueductal parenchyma, left posterior longitudinal fasciculus and cervical medullary junction. The patient was treated with Solumedrol 1g IV for five days; her weakness improved once again and she was discharged. Based on the laboratory data we recommended anticoagulation, however, this was not started. Beta glycoprotein IgA antibody was repeated 12 weeks later and found to be 21 (0-20), beta glycoprotein IgG antibody 6 (0-20), beta glycoprotein IgM antibody 15 (0-20). Lupus anticoagulant (LAC) was repeated 12 weeks later and found to be 1.8 (moderately present). The patient was not treated with aspirin or non-steroidal anti-inflammatory agents. She had repetitive episodes of weakness on a monthly basis which prompted multiple admissions to the hospital. Ten months after her initial presentation, the patient was started on warfarin. For eight months while on warfarin, she remained in remission without any acute neurological exacerbations or any new complaints after her last hospital admission.
Discussion According to the International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS),1 a person is considered to have antiphospholipid syndrome if at least one of the clinical criteria and one of the laboratory criteria are present (classification of APS should be avoided if less than 12 weeks or more than five years separate the positive antiphospholipid test and the clinical manifestation). The clinical criteria are as follows: • Vascular thrombosis One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (e.g. unequivocal findings of appropriate imaging studies or histopathology). Thrombosis should be present without significant evidence of inflammation in the vessel wall for histo-pathologic confirmation. Superficial venous thrombosis is not included in the clinical criteria. • Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the tenth week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (b) One or more premature births of a morphologically normal neonate before the thirty-fourth week of gestation because of: (i) eclampsia or severe pre-eclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency, which include abnormal or
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non-reassuring fetal surveillance test(s) (e.g. a non-reactive non-stress test, suggestive of fetal hypoxemia), abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g. absent end-diastolic flow in the umbilical artery), oligo-hydramnios (e.g. an amniotic fluid index of 5 cm or less), or a postnatal birth weight less than the tenth percentile for the gestational age or (c) Three or more unexplained consecutive spontaneous abortions before the tenth week of gestation with maternal anatomic or hormonal abnormalities, and paternal and maternal chromosomal causes excluded. Laboratory criteria are as follow: • Lupus anticoagulant (LA) present in plasma on two or more occasions at least 12 weeks apart detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/ phospholipid-dependent antibodies) • Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma present in medium or high titer (i.e. >40 GPL or MPL, or >the ninety-ninth percentile) on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA • Anti-o2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the ninety-ninth percentile) present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA according to recommended procedures The revised McDonald criteria2 have been extensively used since 2005 for the diagnosis of multiple sclerosis. These criteria are shown in Table 1 and Table 2 (page 38). Based on the International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS), our patient did not meet the criteria for antiphospholipid syndrome. Despite the fact that she had previous cerebrovascular accidents, imaging never confirmed thrombosis, and as a result she did not meet the clinical criteria. Regarding the laboratory criteria for the antiphospholipid syndrome, this criterion is met since lupus anticoagulant was found to be present in the plasma on two occasions at least 12 weeks apart. It is interesting to note that even though the beta glycoprotein IgA antibody was present in the plasma on two occasions at least 12 weeks apart, this is not included in the revised Sapparo criteria1 for diagnosis of antiphospholipid syndrome. According to these guidelines, there is a paucity of information on beta glycoprotein IgA antibody in antiphospholipid syndrome, and a number of positive beta glycoprotein IgA antibody tests had no apparent association with any clinical manifestations of antiphospholipid syndrome. In 2008, Shen et al3 retrospectively evaluated the thrombotic significance of beta glycoprotein IgA antibody and found that it is a significant independent risk factor for thrombosis. The initial 1999 Sapporo criteria4 did not include other tests frequently used in antiphospholipid syndrome, such as beta
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Rheumotology Table 1: International Panel Criteria (McDonald Criteria) for the Diagnosis of Multiple Sclerosis (MS)2 Clinical Presentation
Additional Date Needed for MS Diagnosis
Two or more attacks; objective clinical evidence of two or more lesions
Dissemination in space demonstrated by: Two or more attacks; objective clinical evidence of 1 lesion
• MRI † , or • Two or more MRI lesions consistent with MS plus positive CSF ‡ , or • Await further clinical attack implicating a different site.
One attack; objective clinical evidence of two or more lesions
Dissemination in time demonstrated by: • MRI † , or second clinical attack.
Dissemination in space demonstrated by: One attack; objective clinical evidence of one lesion (clinically isolated syndrome)
Insidious neurologic progression suggestive of MS
• MRI † or • Two or more MRI lesions consistent with MS plus positive CSF ‡ • And dissemination in time, demonstrated by: MRI † or Second clinical attack
One year of disease progression and dissemination in space, demonstrated by two of the following: • ≥9 T2 lesions in brain, or four to eight T2 lesions in brain with positive visual-evoked potentials, or • ≥2 T2 focal lesions in spinal cord Positive CSF ‡
* Brain MRI is recommended to help exclude other etiologies † MRI criteria for dissemination in space or time are described in Table 2. ‡ Positive CSF defined as oligoclonal bands different from those in serum or raised IgG index.
Table 2: MRI Criteria for Brain Abnormality: Space and Time Dissemination2 MRI Lesions Disseminated in Space At least three of the following criteria must be met: 1. One gadolinium-enhancing lesion or nine T2-hyperintense lesions in the brain or spine 2. At least one infratentorial or spine lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions MRI Lesions Disseminated in Time At least one criterion must be met: 5. Gadolinium-enhancing lesion ≥3 months after initial presentation, but in a different location from the initial event. 6. New T2 lesion, compared with a reference MRI done ≥30 days after onset of initial event
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glycoprotein antibodies. In 2004, a general consensus decided that the detection of beta glycoprotein antibodies will be added to the Sapporo criteria. This was based on data which indicated that beta glycoprotein antibodies are associated with APS. Beta glycoprotein antibody assay was found to be more specific than anticardiolipin antibody in antiphospholipid determination in APS, and the combination of beta glycoprotein antibody and anticardiolipin assays increased the sensitivity of antiphospholipid determination in APS.5 In addition, there were reports that the test for beta glycoprotein antibodies may be found positive in a small percentage of patients with APS who were negative for anticardiolipin and lupus anticoagulant. Results have shown that anti beta glycoprotein may be the sole antibody present in up to 10 percent of the patients with clinical features of antiphospholipid syndrome.6, 7 NMO-IgG has not been reported in patients with APS who develop recurrent myelitis, but it is present in up to 25 percent of patients with Sjogren’s syndrome (SS) and SLE.8
Conclusion Our patient had two or more attacks, therefore meeting the criteria for multiple sclerosis. In 1995 Ijdo et al9 showed that eight percent of patients with antiphospholipid symptoms or events also carried a diagnosis of multiple sclerosis (MS) or MS-like illnesses (MSL). As a result, they suggested that the antiphospholipid syndrome (APS) should be strongly considered as an alternative diagnosis to multiple sclerosis. The prevalence of antiphospholipid syndrome amongst multiple sclerosis patients has been an area of controversy. Furthermore, the relationship of multiple sclerosis to antiphospholipid syndrome is yet to be elucidated. It is important to make the distinction between these two conditions as treatment modalities for one may adversely affect the other. Multiple sclerosis is commonly treated with beta-interferon, which can potentially exacerbate antiphospholipid syndrome. Anticoagulation is the mainstay of antiphospholipid syndrome management; however its efficacy for managing multiple sclerosis is unknown. In 2006 Paran et al10 compared evoked potential studies in antiphospholipid syndrome patients and patients with multiple sclerosis, and found visual evoked potentials were uncommon in antiphospholipid syndrome patients compared to those with multiple sclerosis. Perhaps our patient presented early in the course of her disease. Evoked potential testing may be useful to help render the correct diagnosis.v
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References: 1. Miyakis S, Lockshin MD, Atsumi T et al. International
consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS. Journal of Thrombosis and Haemostasis 2006;4:295-306.
2. Polman CH, Reingold SC, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Annals of Neurology 2005; 58:840-846. 3. Shen YM, Lee R, Frenkel E et al. IgA antiphospholipid antibodies are an independent risk factor for thromboses. Lupus 2008;17(11):996-1003 4. Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome report of an International Workshop. Arthritis Rheum. 1999;42:1309-1311 5. Marai I, Gilburd B, Blank M et al. Anti-cardiolipin and anti-beta2-glycoprotein I (beta2GP-I) antibody assays as screening for anti-phospholipid syndrome. Hum Antib 2003;12:57-62. 6. Nash MJ, Camilleri RS, Kunka S et al. The anticardiolipin assay is required for sensitive screening for antiphospholipid antibodies. J Thromb Haemost 2004; 2:1077-1081 7. Kaplan V, Erkan V, Derksen WL. Real world experience with antiphospholipid antibodies (APL): how useful is anti-o2glycoprotein (o2GPI) test? Arthritis Rheum 2004; S67 8. Weinshenker B, De Seze J, Vermersch P et al. The relationship between neuromyelitis optica and systemic autoimmune disease. Program and abstracts of the American Academy of Neurology 58th Annual Meeting; April 1-8, 2006; San Diego, California. Abstract S52.003. 9. Ijdo JW, Conti-Kelly AM, Greco P et al. Anti-phospholipid antibodies in patients with multiple sclerosis and MS-like illnesses: MS or APS? Lupus.1999;8(2):109-115. 10. Paran D, Chapman J, Korczyn AD et al. Evoked potential studies in the antiphospholipid syndrome:differential diagnosis from multiple sclerosis. Ann Rheum Dis. 2006;65(4):525-528.
Northeast Florida Medicine Vol. 65, No. 2 2014 41
DCMS Update These physicians’ applications for membership in the Duval County Medical Society are now being processed. Any information or opinions you may have concerning the eligibility of the applicants listed here may be directed at firstname.lastname@example.org or 904.355.6561. New Active Members: Desai Ankit, MD Florida Plastic Surgery Group Plastic Surgery Doreen Dargon, MD Emergency Resources Group Emergency Medicine Edward Jedd Roe III, MD UF Health Emergency Medicine Leslie Stevens, MD Community Hospice Hospice & Palliative Medicine Mary Alizadeh, MD VA HealthCare Gastroenterology
Mark Clayman, MD Clayman Plastic Surgery Plastic Surgery
Kyle Contini, MD St. Vincent’s Family Medicine
Pablo Pella, MD Infectious Disease Consultants Infectious Disease
Monique Gray-Jefferson, MD St. Vincent’s Family Medicine
Staci Tanyue, MD North Florida OBGyn Obstetrics & Gynecology
William Palfrey, MD UF Health Internal Medicine
Sumra Rathore, MD Aurora Diagnostics Bernhardt Lab Anatomical/Clinical Pathology
Jinny Gunn, MD Mayo Clinic General Surgery
New Resident Members:
New Retired Members:
Kristin Barrie, MD UF Health Anesthesiology
Miriam Turner, MD
DCMS hosts Dr. Robert Wah, AMA President-elect A more than 25 year tradition continued on May 19, 2014 as we hosted Dr. Robert Wah, the President-elect of the American Medical Association. Dr. Wah’s visit included a visit to the UF Proton Therapy Institute, a presentation to Downtown Rotary, an editorial board meeting with The Florida Times-Union, a meeting with Florida Blue, and finally a DCMS membership reception and dinner. The dinner was hosted at The University Club on the top floor of the Gate Riverplace Tower, the new headquarters of the DCMS. Dr. Wah presented the AMA’s strategic plan, goals for the future and how they are working on behalf of physicians. DCMS President, Dr. Mobeen Rathore proudly presented Dr. Wah with a copy of the DCMS history book, The Pioneer Medical Society. We look forward to continuing this tradition in the years to come. Thank you to all the Members, sponsors (The Doctors Company, Maserati of Jacksonville and Brooks Rehabilitation) and supporters who made this event a success.
1. (from left to right) Eugene Rawson Griffin, III, MD; Bryan Campbell, DCMS EVP; W. Alan Harmon, MD, President, Florida Medical Association; Randal Henderson, MD; Robert Wah, MD, President-Elect AMA; Stuart Klein; Mobeen Rathore, MD, DCMS President; Eli Lerner, MD, DCMS Immediate Past President; John Montgomery, MD, DCMS Past President 2. Dr. Wah speaking to DCMS Membership 3. Dr. Wah, AMA President-elect and Dr. Mobeen Rathore, DCMS President 4. Cocktail reception with Dr. Robert Wah, AMA President-elect
42 Vol. 65, No. 2 2014
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Your patients have a guide to walk with, listen to and help them find quality time through all stages of advanced illness—Community Hospice of Northeast Florida. Ask us how we can help your patients find that quality time. Call Community Hospice today.
904.407.6500 • 866.253.6681 toll free • CommunityHospice.com Community Focused • Community Supported DCMS online . org Serving Baker, Clay, Duval, Nassau and St. Johns Northeast Florida since Medicine1979 Vol. 65, No. 2 counties
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does your medical malpractice insurerWe know We hate lawsuits. We loathe litigation. which drugs lead to pass. lawsuits help doctors head off claims at the We in internal medicine? track new treatments and analyze medical advances. We are the eyes in the back of your
the doctors company does. We do extra homework. We protect good head. We make CME easy, free, and online. medicine. We are your guardian angels.
Donald J. Palmisano, MD, JD, FACS Board of Governors, The Doctors Company Former President, American Medical Association
We are The Doctors Company.
drugs most frequently involved in medication-related malpractice claims against internists The Doctors Company is devoted to helping doctors avoid potential lawsuits. For us, this starts with patient safety. In
Source: The Doctors Company
fact, we have the largest Department of Patient Safety of any medical malpractice insurer. And, local physician advisory As the across nation’s malpractice insurer, have an unparalleled understanding boards thelargest country.physician-owned Why do we go thismedical far? Because sometimes the bestwe way to look out for the doctor is to start
of liability claims internists. This givesmalpractice us a significant advantage incall theour courtroom. It also with the patient. Toagainst learn more about our medical insurance program, Jacksonville officeaccounts at for our741-3742 ability to anticipate emerging trends and provide innovative patient safety tools to help physicians (800) or visit www.thedoctors.com. reduce risk. When your reputation and livelihood are on the line, only one medical malpractice insurer can give you the assurance that today’s challenging practice environment demands—The Doctors Company. Endorsed by
To learn more, call our Jacksonville office at 800.741.3742 or visit www.thedoctors.com.
We relentlessly defend, protect, and reward the practice of good medicine. 44 Vol. 65, No. 2 2014 Northeast Florida Medicine Duval_8x8_color.indd 1
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Published on Jun 2, 2014
Our Summer 2014 issue on Rheumatology is guest edited by DCMS member Dr. Ghaith Mitri. It offers CME credit on Behcet's Disease in the Unite...