Proceedings of the 2013 Rheumatology Winter Clinical Symposia

CONFERENCE PROCEDINGS

Proceedings of the 2013 Rheumatology Winter Clinical Symposia Arthur Kavanaugh, MD,* Roy Fleischmann, MD, MACR,y Martin Jan Bergman, MD, FACR FACP, FCPP,z Eric Ruderman, MD,y Orrin Troum, MD,z Alvin F. Wells, MD, PhD,J George Martin, MD,** Leonard H. Calabrese, DO,yy Allan Gibofsky, MD, JD, FACP, FCLM,zz Vibeke Strand, MD,yy and John J. Cush, MDzz

Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com. & 2013 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:667–673 Keywords: Rheumatology

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he introduction of novel therapeutic agents has dramatically improved outcomes for patients with various rheumatic diseases, including rheumatoid arthritis (RA) [1,2]. Successes achieved with newer therapies have helped drive the introduction of innovative treatment paradigms, such as ‘treat-to-target’. They have also elevated the goals of treatment such that remission is now considered both desirable and

n University of California, San Diego, CA. yMetroplex Clinical Research Center, Dallas, TX. zDrexel University College of Medicine, Philadelphia, PA. yDivision of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL. zKeck School of Medicine, University of Southern California, Los Angeles, CA. yRheumatology & Immunotherapy Center, Franklin, WI. nn Dermatology and Laser Center of Maui, Kihei, HI. yyCleveland Clinic Lerner College of Medicine, Cleveland, OH. zzHospital of Special Surgery, NY. yyDivision of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, CA. zzBaylor Research Institute, Baylor University Medical Center, Dallas, TX. Address reprint requests to John J. Cush, MD, Baylor Research Institute, Baylor University Medical Center, Dallas, TX. Tel.: þ1 214 373 4321; fax: þ1 214 373 4326. E-mail: [email protected].

0049-0172/12/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.04.001

achievable. However, because the costs of newer therapies tend to far exceed those of older therapies, questions have been raised about the “value” of new treatments. Pharmacoeconomics can provide some answers in that regard. In order to accurately assess the value of treatments for RA and other rheumatic diseases, a comprehensive approach must be undertaken. For direct costs, in addition to the costs of the medicines themselves, costs that need to be considered include those related to monitoring for toxicity, treating toxicity should it occur, and costs related to toxicities of alternate agents needed to treat active disease (e.g. steroid-induced osteoporosis). In rheumatic diseases, indirect costs often exceed direct costs. An abundance of evidence over the past half century has clearly shown that untreated, conditions like RA exert a tremendous economic toll on affected patients, their families, and society. With greater disability comes less ability to work: this includes ‘absenteeism’, where patients do not feel well enough to attend their jobs, as well as ‘presenteeism’, where patients may go to work, but are much less productive than they had been. Highly effective therapies that improve patients’ functional 667

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status incur some cost savings by obviating these indirect costs. There is some debate about the optimal methods to perform pharmacoeconomic studies. However, this is an area rheumatologists must be well versed in so that they can help define the optimal therapeutic approaches to patients with rheumatic diseases.—Arthur Kavanaugh NEW AGENTS FOR RHEUMATOID ARTHRITIS The annual American College of Rheumatology (ACR) 2012 meeting was eventful with respect to reporting of data of new biologic agents, other than TNFa inhibitors and molecules in development. Among approved biologic medications, tocilizumab has been studied as a subcutaneous biologic. The MUSASHI trial showed that patients originally treated with tocilizumab, 8 mg/kg IV, maintained response when switched to the subcutaneous formulation, 162 mg q week, each as monotherapy (Ogata A, et al. EULAR 2012, Berlin, #FRI0180). Similar findings were confirmed in patients on background DMARDs in the SUMMACTA trial presented by Burmester at the 2012 ACR meeting in Washington DC. The BREVACTA trial was also presented at the ACR 2012 meeting and studied tocilizumab 162 mg subcutaneously given every 2 weeks on background DMARDs in DMARD-incomplete responders compared to continued DMARDs and found that the clinical, radiographic, and functional responses were superior with subcutaneous tocilizumab. Long-term data from the 12month ACT-RAY study suggested that although tocilizumab monotherapy was equally clinically efficacious to tocilizumab plus methotrexate (MTX), radiographic progression was inhibited to a greater extent with combination therapy. Head-to-head trials with biologics have just recently been reported. The AMPLE study compared subcutaneous abatacept 125 mg a week and adalimumab 40 mg every other week, both on background MTX; there was no difference in the clinical response, kinetics of response, radiographic progression, or improvement in function with either therapy. The study was too small to show differences in safety (Weinblatt M, et al. ACR 2012, Washington DC, #2449). A report of tofacitinib studied in MTX-naı¨ve patients with MTX compared to tofacitinib 5 and 10 mg BID as monotherapy was presented at the ACR 2012 meeting (Fleischmann R, et al. ACR 2012, Washington DC, #2486). Both doses of tofacitinib were more effective than MTX with respect to clinical, radiographic, and functional outcomes. With respect to safety, it was reported that in the phase 3 and extension studies, a higher incidence of Herpes zoster (HZ) was seen with tofacitinib than with biologic therapies (Cohen S, et al. ACR 2012, Washington DC, #2485); the FDA-approved product insert suggests that patients, no matter what age,

Proceedings of the 2013 Rheumatology Winter Clinical Symposia

should be vaccinated against HZ prior to the initiation of tofacitinib therapy. A report of baricitinib, an oral JAK1/ 2 inhibitor, was presented that showed that a dose of 4 or 8 mg given orally q day was effective, with a reasonable safety profile for the 4-mg daily dose which is now in phase 3 trials. An MRI substudy suggested that baricitinib may be effective in limiting structural damage (Genovese M, et al. ACR 2012, Washington DC, #2487; Smolen J, et al. Ibid. #490; Peterfy C, et al. Ibid. #2488). A very preliminary report of a more specific JAK1 inhibitor, GLPG0634, showed initial efficacy in a small number of patients over 1 month; further trials are being planned (Vanhoutte F, et al. EULAR 2012, Berlin, #OP0263). 2013 should be interesting as well with further data expected from the kinase inhibitors discussed here as well as the results of key studies with other kinase inhibitors in development.—Roy Fleischmann HYDROXYCHLOROQUINE While the use of the bark of the Cinchona tree dates back to the time of the Incas, its use as the derivative hydroxychloroquine (HCQ) in rheumatologic conditions did not become commonplace until the latter half of the 20th century. The exact mechanism of action of this medication remains poorly understood. It exerts an effect on the lysosome, where it stabilizes the intracellular membrane and leads to acidification of the contents of the organelle. This, in turn, leads to deactivation of proteases, inhibition of protein and cytokine production, and interference with the function of ERK and MAP. New evidence points to the interaction between HCQ and Toll-like receptors (TLR7,9) as another potential mechanism of action [3]. The most common uses for HCQ are in the treatment of RA and Systemic Lupus Erythematosus (SLE). Most commonly used in combination therapies for the treatment of RA, most notably “Triple Therapy,” recent studies have also demonstrated an effect of HCQ in RA on the risk of development of diabetes and on cardiovascular disease. Similar effects have been seen in SLE, where HCQ has also demonstrated the ability to reduce the number and severity of flares, to increase the rate of remission (including from lupus nephritis), to decrease the need for oral prednisone, and to decrease the incidence of thromboembolic events [4,5]. Its use in other diseases has been somewhat disappointing, showing little benefit in either Sjogren’s syndrome or inflammatory osteoarthritis. HCQ is generally a well-tolerated medication, although it is not without toxicities. The best known is its effect on the retina. Traditionally given as a weightbased medication, a recent report has suggested that the duration of therapy is a more important predictor of retinopathy, with a 41% incidence after 5–7 years of therapy. Standards for ocular monitoring have been

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proposed to decrease this likelihood [6]. Other toxicities include myopathy/cardiomyopathy, with a characteristic vacuolar appearance on biopsy, neuropathy, ototoxicity, and abnormal cartilage pigmentation. A category C drug, it is nevertheless often continued in pregnancy, particularly in SLE due to a positive risk/benefit ratio. Overall, HCQ is a remarkably effective medication in multiple disease states. Toxicities are relatively uncommon and easily managed. While its effects may not appear dramatic, they are often underestimated and underappreciated. This interesting medication clearly has a welldeserved place in the rheumatologic pharmacopeia.—Martin J. Bergman

RAYNAUD’S PHENOMENON Raynaud’s phenomenon, first described by Maurice Raynaud in 1862, is a common syndrome manifested by episodic attacks of cold-induced digital pallor and cyanosis. It may present as a primary syndrome or as a secondary phenomenon in conjunction with atherosclerosis, drugs, hyperviscosity, and, importantly, connective tissue diseases such as primary systemic sclerosis (PSS). Abnormal nailfold capillary loops in a patient with Raynaud’s can help to identify those with underlying connective tissue disease. In association with sclerodermaspecific autoantibodies, this finding has been found to be highly predictive of the development of PSS. Initial management of Raynaud’s phenomenon is conservative and involves avoiding cold exposure or other triggers. For patients requiring medical therapy, first-line therapy usually involves treatment with calcium channel blockers (typically nifedipine) or angiotensin receptor blockers. The alpha-adrenergic blocker prazosin was shown to be effective in two small trials. Patients with secondary Raynaud’s phenomenon may develop digital ischemia and ulceration. The dual endothelin receptor antagonist bosentan was shown in two separate trials to reduce the development of new digital ulcers, although it had no effect on healing of existing ulcers. The phosphodiesterase 5 inhibitors sildenafil and tadalafil have been studied in a number of small trials; in a controlled trial in secondary Raynaud’s, sildenafil reduced the frequency of attacks. For refractory cases of secondary Raynaud’s, the intravenous prostaglandin analog iloprost has been shown to reduce the frequency and severity of attacks and improve ulcer healing. Surgical management, with thoracic or digital sympathectomy, has been successful in some cases, although the data remains largely anecdotal. Future directions for therapy that are of interest include novel nitrate formulations and botulinum toxin. A controlled trial of fasudil, an oral inhibitor of rho kinase, which plays a role in vascular smooth muscle function and vasoconstriction, was disappointingly negative.—Eric Ruderman

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NON-ARTICULAR USES OF MRI MRI is the most versatile of diagnostic technologies. It provides unique spatial resolution. Emerging in 1970s when nuclear magnetic resonance was being investigated, it rapidly expanded to permeate most areas of clinical science and research. Several modalities now utilize magnetic resonance. Magnetic resonance spectroscopy complements MRI to characterize tissue noninvasively. MRI uses signals from hydrogen protons to form anatomic images, while MRS uses this information to determine the concentration of brain metabolites in central nervous system tissue. It is most widely used in CNS disorders such as neuropsychiatric systemic lupus erythematosus. As MRS shows spectral tracings of metabolites, it is also useful in inflammatory myositis. Phosphorus MRS (31P-MRS) evaluates metabolic disturbances in dermatomyositis as it quantifies ATP and other energy-rich phosphates. Magnetic Resonance Angiography is also a safe, reliable, and accurate tool in assessing hand vascular pathology in systemic sclerosis. Magnetic Resonance Elastography (MRE) mimics tissue or organ palpation and quantitatively determines tissue elasticity. It propagates low-frequency shear waves (acoustically or via mechanical vibration) combined with phase-contrast MRI to measure tissue motion, therefore determining shear modulus and viscosity. It is useful in early detection and extent of liver fibrosis and assessment of chronic liver disease, and it is a safe, reliable, and noninvasive alternative to liver biopsy for staging hepatic fibrosis. MRI also identifies focal RA cerebral vasculitis, cerebral lesions in Sjogren’s syndrome, evaluation of the parotid gland, promising biopsy sites for muscle in inflammatory myopathies, and provides standardized image quality, comparable to CT, in interstitial lung disease. —Orrin Troum AN UPDATE ON OSTEOARTHRITIS Our current understanding of the pathophysiology and treatment of osteoarthritis has been revolutionized over the last several years. Osteoarthritis is no longer considered to simply be a degenerative type of arthritis. In some patients, degeneration of the meniscus may be a precursor to cartilage damage. Indeed, the loss of the meniscus may lead to stress on the cartilage, which results in subchondral bone changes as well as synovitis and bone marrow lesions. Both of these may set up an inflammatory response resulting in a cascade effect giving the clinical picture of osteoarthritis. As with any disease, a multiple prong approach to its treatment is paramount. This includes patient education, physical therapy, and lifestyle changes that are unknown to exacerbate osteoarthritis especially of the weightbearing joints such as the knee and hip. Newer topical anti-inflammatory medications as well as intra-articular

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injections may result in significant pain relief in many patients. Current research on therapeutic options for patient with osteoarthritis is exciting. New data are evolving on the use of biologic medications, some of which target cytokines as well as nerve cell growth factors. The possibility of regenerating cartilage to the use of stem cells is also exciting. Efforts to develop safer nonsteroidal antiinflammatory medications involve the use of a combination of gastro-protective agents (e.g. H2-blockers and proton pump inhibitors) with NSAIDs as well as developing newer delivery systems and micro particles of these agents.—Alvin F. Wells

ADVANCES IN MORPHEA MANAGEMENT Little is known about the diagnosis, evaluation, and treatment practices of rheumatologists and dermatologists who treat morphea (localized scleroderma). Of importance is the accepted observation that there is a therapeutic window in morphea after which the sclerosis is irreversible. A recent prospective 3-year cohort study of 224 patients examined several critical issues regarding morphea: who diagnosed and treated morphea; what was the interval duration between the onset of clinical symptoms and diagnosis/treatment; what did the initial evaluation consist of; and what therapy was initiated [7]. The study divided patients into 3 categories: circumscribed, linear and generalized morphea. Children accounted for 95/224 patients, with the overall majority (84%) being female. Overall 63% of subjects were diagnosed 46 months after the onset of the disease and 25.5% were diagnosed 42 years. Children were diagnosed earlier than adults, with linear scleroderma (predominantly in children) being leading to an earlier diagnosis. Dermatologists made the diagnosis in 83.5% of patients while rheumatologists diagnosed only linear and generalized psoriasis. The biopsy rate between each subtype did not significantly differ but children were less likely to be biopsied (60%) than adults (88.4%). Despite the lack of evidence, 48% of patients had laboratory testing likely inclined to r/o systemic disease. Imaging studies were performed in o15% of patients. Rheumatologists generally saw more severe forms of scleroderma (linear and generalized) and treated more aggressively with MTX and systemic steroids than dermatologists, even when treating the same subtype (i.e. linear scleroderma). Dermatologists used more topical steroids (lacking in evidence for their efficacy) and phototherapy (evidence supports its efficacy). Evidence supporting the use of oral MTX (15 mg/m2 up to 20 mg weekly) in active juvenile scleroderma was confirmed in a 2-year follow-up study [8]. MTX use in 65 patients resulted in a 73.8% response with complete remission in 72.9% and complete remission on meds in 27.1% of those patients.

Proceedings of the 2013 Rheumatology Winter Clinical Symposia

Run out of ideas on morphea-related joint contractures? In a single-patient case study [9], the use of fractional ablative carbon dioxide laser resurfacing increased the range of motion on a morphea-related wrist contracture. Generally, dermatologists treat wrinkles using these devices but their utility in treating burn scar-related joint contractures is being widely adopted. Hopefully, these studies will lead to consensus-based multidisciplinary studies utilizing outcome measures and comparative studies.—George Martin RHEUMATOLOGY AND CHRONIC VIRAL HEPATITIS Chronic viral hepatitis B and C are two infections that afflict over 500 million people worldwide and are both capable of causing a variety of rheumatic disorders. While these diseases (cryoglobulinemia, polyarteritis, etc.) are clinically fascinating, they are rare. Alternatively, both hepatitis C (HCV) and hepatitis B (HBV) present formidable problems to the rheumatologist as comorbidities in patients with inflammatory diseases that require immunosuppressive therapies. Knowledge of both the underlying rheumatologic disorders as well as the underlying infection in terms of its activity and severity is essential for optimal management [10]. HCV is a global pathogen infecting an estimated 200 million people worldwide. Following primary infection, as many as 80% or more of patients will develop a chronic persistent infection for the rest of their lives [11]. In this group, about one-quarter will progress to cirrhosis, endstage liver disease, or hepatocellular carcinoma. In patients with RA, SLE, vasculitis, or other conditions requiring immunosuppressives, rheumatologists must work closely with hepatologists to determine whether these patients are candidates for antiviral therapy, which can be successful in curing the infection in as many as 75% of those initiating therapy. From the perspective of the underlying rheumatic disease, selecting drugs with the minimal toxic effects on the liver is essential. Avoiding methotrexate and leflunomide is important. In the 2012 RA treatment guidelines, we have been given the first guidance of DMARD therapy with C level evidence suggesting that etanercept may be both safe and effective. Clinical trials of other DMARDS are still needed. HBV is a global infection affecting over 500 million people, and in contrast to HCV, the major concern in this disease is reactivation of silent chronic infection that can be potentially fatal. All patients being put on high-risk immunosuppressives and all patients with risk factors for HBV should be screened with antibodies to hepatitis B surface and core as well as be tested for the presence of HbsAg. Studies where physicians, including rheumatologists, dermatologists, and gastroenterologists, used these drugs have demonstrated suboptimal screening practices, and revision of our current screening guidelines is

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urgently needed [12]. Treatment of HBV-infected patients is possible when they are maintained on effective long-term antiviral therapy.—Leonard Calabrese LAW FOR THE CLINICAL RHEUMATOLOGIST: AN OVERVIEW The American legal system has three major divisions: Criminal Law, Civil Law and Administrative Law. Criminal Law is that division of the legal system that deals with punishment of individuals who engage in conduct proscribed by the Penal Code. In contrast, Civil Law deals with the resolution of disputes (between private individuals and between private individuals, between private individuals and a governmental entity, and even between two governmental entities). Administrative Law covers the regulation of specialized areas by special entities called “agencies” and is a hybrid of criminal law and civil law: not only does it cover the resolution of disputes in that specialized area (e.g. traffic and parking), but provides for punishment if the rules generated by an administrative agency are not followed (e.g. penalties for underpayment of taxes). Administrative agencies are created by a legislature, and thus are found in municipalities, states, and the federal government. The same act can result in a criminal prosecution, a civil lawsuit, and an administrative hearing. The Civil Law can also be thought of as having three major divisions: Contract Law (the specialized area dealing with formal obligations between parties, usually defined in a document), Property Law (the specialized area dealing with defining ownership rights), and Tort Law (disputes between parties that deal with harm or damages as a result of conduct by one or more parties). The clinical Rheumatologist may become involved with the legal system as a result of an allegation of the tort of Professional Liability, or Medical Malpractice. The tort of Medical Malpractice has four elements: Duty (the obligation to do something or the obligation to refrain from doing something), Breach (something was done that should not have been done or something was not done that was required), Causation (the events resulted in an outcome), and Damages (harm that can be physical and/or economic). All of these elements must be proven for a malpractice case to be successful. Most allegations of medical misconduct are usually settled as a result of the business judgment of the insurance company, and thus the truth or falseness of the allegations is generally never determined. Related to the tort of Medical Malpractice (and often claimed as well as part of litigation against a clinical Rheumatologist) is the tort of Lack of Informed Consent. Informed Consent is NOT a signed piece of paper; rather, it is a process whereby the risks, benefits, and alternatives of a proposed therapy together with the risks and benefits of the alternatives are presented to the patient. For there to be valid informed consent, there

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must be (1) disclosure of information (2) to a competent patient (3) who understands the information presented (e.g. in his/her native language and at a comprehensible reading or conversational level) and then (4) voluntarily (5) decides. If any of these five elements are missing, there is no informed consent, regardless of whether or not the patient has signed a form. Finally, the law imposes significant responsibility on the clinical Rheumatologist for diagnostic and therapeutic decisions, not withstanding limitations placed by an insurance company on whether or not the procedure or therapy is therapeutic is “covered.” As noted in a major decision: “the physician who compiles without protest with the limitations imposed by a third party payor, when his medical judgment dictates otherwise, cannot avoid his ultimate responsibility for his patient’s care. He cannot point to the health care payor as the liability scapegoat when the consequences of his own determinative medical decisions go sour. (Wickline v. State of California, 192 Cal. App. 3d 1630).—Allan Gibofsky TREAT-TO-TARGET IN GOUT Treat-to-target (T2T) has become a lightning rod issue in rheumatology—some pledging allegiance, while others refute that disease metrics are best path to quality care. Metrics that guide therapy may be routine in lupus, osteoporosis, hypertension, diabetes, and hyperlipidemia, where aggressive management to achieve optimal thresholds of control has yielded better short- and long-term outcomes. Thus, the belief that T2T is well suited to treating gout where an easily obtained biomarker can guide therapy. The presumption is that therapeutic lowering of serum uric acid (sUA) levels to below the saturation point of monosodium urate (o6 mg/dl or o360 mmol/l) will prevent crystal formation and promote tophus resolution. The net effect should be fewer gouty attacks, less tophi, and less of the comorbid consequences of hyperuricemia and gout (renal disease, hypertension, metabolic syndrome, etc.). The frequency of gout has risen sharply in the last 4 decades. Hence the need for effective interventions is evident. However, there are disappointments for those advocating for T2T in gout. While 495% of rheumatologists monitor sUA levels in gout, only 33–74% of primary care physicians will do the same. While T2T mandates periodic and frequent visits, only two-thirds of gout patients are seen every 6 or 12 months by rheumatologists [13]. Lastly, it appears that despite new drug advances in gout, sUA o6.0 mg/dl is achieved in less than half of patients in clinical trials. Nevertheless, there is data showing that with urate-lowering therapy (ULT), 45% those with a sUA 48 mg/dl had flares but only 23% flared if the sUA was o6.0 mg/dl [14]. There are several studies documenting the rates of tophus reduction to be inversely proportional to the sUA level

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[15] and that MSU crystals disappear from synovial fluid with the reduction in sUA levels [16]. Nonetheless, there is no data on whether tight control of gout, with sUA o6.0 will reduce the comorbidities that plague these patients. Clearly, the advent of novel therapies to inhibit xanthine oxidase and block uric acid formation (i.e. pegloticase) have increased the tools whereby T2T in gout can be achieved in all. Although tighter control of this urate deposition disease is sorely needed to improve the functional and articular outcomes of those afflicted, there are growing concerns of the comorbidities of gout and hyperuricemia and what can be done to avert these problems. The links between gout or hyperuricemia and hypertension, diabetes, obesity, metabolic syndrome, and cardiovascular events have been motivating to take gout more seriously. Trends to be more aggressive about gout management are evident in those who will adopt a T2T approach in gout.—John J. Cush FDA ISSUES RELEVANT TO RHEUMATOLOGISTS Many issues addressed by FDA, Center for Drug Evaluation and Research (CDER) during the calendar year 2012 were specifically of interest to rheumatologists. These included Arthritis Advisory Committee (AAC) meetings that addressed the following: (1) Serious adverse joint events observed in randomized controlled trials (RCTs) of anti-Nerve Growth Factor monoclonal antibodies (anti-NGF mAbs) [17]; (2) Treatment of acute gout attacks with an anti-IL-1 Receptor mAb (anti-IL-R mAb) Rilonacept [Regeneron] [18]; and (3) Treatment of active rheumatoid arthritis (RA) with the JAK 3/1/2 inhibitor, Tofacitinib [Pfizer] [19]. All anti-NGF mAb clinical programs were placed on hold in Dec 2010 attributed to “unexpected cases of joint destruction presumably due to avascular necrosis (AVN) (and/or) rapidly progressive osteoarthritis (RPOA) at a rate that was inexplicably high compared to what was expected in the population as a whole.” These included 3 products, Tanezumab [Pfizer], Fulranumab [Janssen], and REGN475 [Regeneron], in RCTs in OA among other indications. The Pfizer product database was most extensive: E 6400 patients and 45000 treated for Z6 months, and offered best estimates of potential risks. The majority of events with sufficient data [65%], were blindly adjudicated by external experts and revealed increased risks with (1) doses 45 mg and (2) concomitant use of NSAIDs. Regardless, the clinically significant benefits reported in all RCTs indicated to the AAC that development should continue with appropriately included restrictions. Regarding Rilonacept for treatment of acute gout attacks, the AAC voted that further demonstration of efficacy against a “standard of care” was necessary, that

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safety had been evaluated over too short a timeframe [16 weeks], and that the optimal patient population for this treatment and its long-term safety profile remained to be confirmed. Tofacitinib, as the first of a “class” of JAK/STAT inhibitors has generated a great deal of interest as an effective DMARD with rapid onset. Data presented at the AAC meeting were from 5-phase 3 RCTs including 47000 patient years of exposure, the largest database ever submitted in support of a new therapy in RA. The overall vote was positive, and in November 2012, the FDA approved this product for treatment of patients with an inadequate response to DMARDs as monotherapy or combination treatment but only for the 5 mg BID dose. A labeling indication for “inhibition of structural damage” will await submission of additional data from the MTXnaı¨ve population in the START protocol, no decision regarding approval of the 10 mg BID dose has been made. Finally, the development of biosimilars continues, with at least several monoclonal antibody products currently under review at EMA [20]. FDA has issued 4 recent guidance documents and presented a session at ACR 2012 explaining their review process.—Vibeke Strand REFERENCES [1] Solomon DH, Kavanaugh A. The economics of rheumatoid arthritis management. Int J Adv Rheumatol 2008;6:2-5. [2] Her M, Kavanaugh A. Critical analysis of economic tools and economic measurement applied to rheumatoid arthritis. Clin Exp Rheumatol 2012;30(Suppl. 73):S107-S111; [Epub 2012 Oct 16]. [3] Katz SJ, Russell AS. Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action. Curr Opin Rheumatol 2011;23(3): 278-81. [4] Alarcon GS, McGwin G, Bertoli AM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66(9):1168-72. [5] Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69(1):20-8. [6] Marmor MF, Kellner U, Lai TYY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118(2):415-22. [7] Johnson W, Jacobe H. Morphea in adults and children cohort II: patients with morphea experience delay in diagnosis and large variation in treatment. J Am Acad Dermatol 2012;67:881-9. [8] Zulian F, et al. A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea). J Am Acad Dermatol 2012;67:1151-6. [9] Kineston D, et al. Novel use of a fractional CO2 resurfacing laser in morphea. Arch Dermatol 2011;147(10):1148-50. [10] Vassilopoulos D, Calabrese LH. Management of rheumatic disease with comorbid HBV or HCV infection. Nat Rev Rheumatol 2012;8:348-57. [11] Singh JA, Furst DE, Bharat A, et al. 2102 Update of the 2008 American College of Rheumatology recommendations for the use of disease modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64:625-39.

A. Kavanaugh et al. [12] Yazdany J, Calabrese L. Preventing hepatitis B reactivation in immunosuppressed patients: is it time to revisit the guidelines? Arthritis Care Res 2010;62(5):585-9. [13] Cush JJ, Keenan RT. The diagnosis and management of gout in 2012: Survey of US and Canadian rheumatologists. Abstract #1914 American College of Rheumatology annual meeting; 2012. [14] Sarawate CLJ. Clin Rheumatol 2006;12:61-5. [15] Perez-Ruiz FJ. Rheumatology 2007;34:1888-93. [16] Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66:1056-8.

673 [17] /http://www.fda.gov/downloads/AdvisoryCommittees/Com mitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommitteeS. [18] /http://www.fda.gov/downloads/AdvisoryCommittees/Com mitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ UCM302882.pdfS. [19] /http://www.fda.gov/downloads/AdvisoryCommittees/Com mitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ UCM302958.pdfS. [20] Doerner T, Strand V, Castanedo-Hernandez G, Ferracciolo G, Isaacs J, Kvein T, et al. The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 2012. http://dx.doi.org/ 10.1136/annrheumdis-2012-202715.