ACR. Chicago. Conference Highlights & Insights for Rheumatology Specialists

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1 ACR Chicago American College of Rheumatology/ Association of Rheumatology Health Professionals 2018 Annual Meeting October 19 24, 2018 Chicago, IL Conference Highlights & Insights for Rheumatology Specialists

2 ACR 2018 Annual Meeting ACR American College of Rheumatology/ Association of Rheumatology Health Professionals 2018 Annual Meeting October 19 24, 2018 Chicago, IL Table of Contents 1 Making Medication Adherence the Fifth Vital Sign 6 Genetic Risk Score May Identify Ankylosing Spondylitis Earlier 1 De-Hyping Artificial Intelligence and Machine Learning in Health Care 7 A Divorce Between Psoriatic Arthritis and Rheumatoid Arthritis 2 Questions to Consider When Collecting Patient-Generated Data 15 Treatment of Patients with AS, PsA, and PsO 3 American College of Rheumatology Prepares Guideline on Reproductive Health in Rheumatic Disease 6 IQ-Lupus Program Decreases Hospitalizations Among High-Risk Patients 16 Women Abused During Childhood Have Significantly Higher Risk of Lupus 17 Study Finds That Intensity of Walking Affects Risk of Knee Replacement 630 Madison Avenue 2nd Floor Manalapan, NJ PUBLISHER Gene Conselyea WRITER Keightley Amen, BA, ELS EDITOR Kerri Fitzgerald ART DIRECTOR Ari Mihos GRAPHIC DESIGNER Lisa Adamitis PROJECT MANAGER Stephanie Maloney ACCOUNT MANAGERS Ron Gordon Gene Conselyea 2018 American Medical Communications, Inc, Manalapan, NJ 07726

3 Making Medication Adherence the Fifth Vital Sign During an afternoon of specialized pre-meeting sessions at the annual meeting, speakers addressed various aspects of health technology. One presenter, Bernard Vrijens, PhD, of AARDEX Group, stressed to attendees that Medication Adherence Is a Key Element to Integrate in e-health. The speaker began by quoting former U.S. Surgeon General C. Everett Koop: Drugs don t work in patients who don t take them. Adherence is key to therapeutic success, Dr. Vrijens said. He outlined three steps along the adherence journey: Patients must initiate therapy, implement the dosing regimen, and then persist. However, he cited studies that have found 20% to 30% of patients do not initiate prescriptions, 15% do not implement doses as prescribed daily (due to missing a dose, taking an extra dose, or missing a dose), and 40% discontinue treatment by the twelfth month, demonstrating problems all along the adherence journey. Variable adherence creates drug-specific issues of efficacy, safety, and drug resistance, Dr. Vrijens continued. Suboptimal adherence leads to treatment failure, disease progression, and adverse events, then more complex treatments to address the ensuing issues. It is a complex and expensive loop, he stated, so healthcare practitioners must abandon the struthian approach of burying our heads in the sand. Instead, they must better capture true adherence rates and understand the consequences. Medication adherence is a vital sign to measure and manage, he concluded. Next, Dr. Vrijens reviewed the weaknesses of the available methods to assess adherence in ambulatory patients, including direct methods (measuring pharmacokinetics and pharmacodynamics), self-report, pill counts, and prescription and refill databases (currently the gold standard). He encouraged the audience to consider the utility of electronic monitoring and institute knowledge at all points of care. He said a systems approach is the only way to successfully combat the problem. Such an approach would involve adjusting health care and prescribing policies; involving the community and other institutions; and educating healthcare practitioners, prescribers, patients, their families, and their friends. One study cited found that awareness of adherence patterns is the best way to change patient behavior, so he proposed using patients social networks to make patients aware and more adherent. Finally, Dr. Vrijens acknowledged that physicians and other healthcare practitioners have heavy workloads and limited resources, so algorithms and systems can help alleviate the adherence problem. However, he stressed that technological solutions do not replace physicians; rather, they redefine their role and require a multidisciplinary approach. Healthcare systems must evolve to meet the challenge of achieving satisfactory adherence to therapeutic drug regimens, he said, guiding attendees to consider patienttailored approaches, measurement-guided interventions, and e-health. Medication adherence is a vital sign to measure and manage. Bernard Vrijens, PhD De-Hyping Artificial Intelligence and Machine Learning in Health Care Prior to the annual meeting, the ACR Clinical Research Conference focused on technology advances that are changing the landscape of medicine and rheumatology. Beyond electronic health records, there is a broad range of digital and mobile technologies. One of the sessions addressed artificial intelligence (AI). Geoffrey Tison, MD, MPH, a cardiologist at the University of California San Francisco, framed the discussion by acknowledging how physicians and other healthcare providers are overworked. They are being asked to do more with less time and fewer resources, he said. So, can AI help? The topic is surrounded by a fair amount of hype, he said. And I d like to demystify that somewhat today. Simply put, he said, machine learning has taken the best of computer science and statistics and married the two. To perform machine learning, one defines a task, takes a large amount of data, puts it into a model, and then allows the machine to provide output. For example, in his research applying AI to identify atrial fibrillation (AF), Dr. Tison and his team entered many 1

4 ACR 2018 Annual Meeting Humans no longer have a monopoly on complex problem solving, but in the age of machine learning, epidemiology remains as important as ever. Geoffrey Tison, MD, MPH electrocardiogram results (EKGs) some that showed AF and some that did not and labeled them as such, so that the machine could learn to recognize future EKGs as positive or negative for AF. Although Dr. Tison described his work using applications of machine learning in cardiology, he believes the model is applicable to rheumatology and many other specialties within medicine. He cited examples of image recognition and machine learning to identify skin cancer and detect diabetic retinopathy. Despite the possibilities, Dr. Tison cited limitations as well. Such models are very data hungry, needing thousands or tens of thousands of data points. Data must be labeled by humans first, which is cost prohibitive and time consuming. In addition, there is a potential lack of interpretability. He concluded, Humans no longer have a monopoly on complex problem solving, but in the age of machine learning, epidemiology remains as important as ever. Questions to Consider When Collecting Patient-Generated Data Prior to the start of the annual meeting, an afternoon of presentations focused on Applications of Mobile Health Technologies. Eric M. Ruderman, MD, of the Feinberg School of Medicine at Northwestern University, encouraged participants to consider many essential questions during his talk, Efficient Collection of Patient-Generated Data. The overarching question, he said, is to decide which data to collect and for what goal, such as research, clinical care, or target a particular issue. Focusing on patientgenerated data in the clinical settings, Dr. Ruderman said practitioners must make sure that data patient-reported outcome measures are: feasible (able to be collected and used effectively) meaningful minimal (presenting a low collection burden) Furthermore, Dr. Ruderman said, practitioners should consider how much data they want to collect, taking into account the complexity of tools, how precise the tools are and whether precision will actually be used in clinical care, and patients willingness to complete instruments, including questionnaire fatigue. Ultimately, for data to contribute to clinical care, the information must be collected in real time and must be concise, meaningful, and actionable, otherwise you re spinning your wheels, he said. Once these larger questions are addressed, many important considerations remain. For example, Dr. Ruderman specifically reviewed three times when patients can provide data. When collecting data during patient visits, practitioners must weigh when to collect data, whether to collect it from every patient at every visit, how data collection with affect workflow, and who will be responsible for data collection and entry. How much time will data collection realistically take? Dr. Ruderman asked, and when will it be done during the appointment when the patient and physician are face to face, or on a tablet when the patient is in a waiting room? Alternatively, when practices ask patients to provide such information before a visit, logistical questions arise, such as whether to use paper, web-based systems, or apps. One of the more difficult aspects of pre-visit data collection is deciding who ensures that it occurs, sends reminders to patients, and delivers the data to the physician. Some practices are starting to collect between-visit data, using apps or web-based solutions. Again, Dr. Ruderman asked participants to consider who will be responsible for entering the data, tracking changes longitudinally, and making sure the data actually adds to the next visit. Finally, practitioners must think about how to integrate patient-generated data with objective data such as joint counts, physical exams, and laboratory results. Ideally, he said, patient-generated data, objective data, visit notes, and changes over time should all be on the same system. Although there are many questions to consider and challenges to address including patient acceptance, patient 2

5 capabilities, clinical capacity, and infrastructure Dr. Ruderman said patient-generated data has many potential benefits, including better outcomes, patient engagement, and improved patient understanding of the importance of adherence. The next steps in the efficient collection of patient-generated data will be demonstrating value; integrating tools into the electronic health record; and crossing practice domains among care, research, and registries. American College of Rheumatology Prepares Guideline on Reproductive Health in Rheumatic Disease At its annual meeting, the American College of Rheumatology (ACR) presented a draft of a clinical practice guideline to help rheumatologists and obstetricians/gynecologists manage the reproductive health of patients with rheumatic disease. According to ACR, the guideline, known as the Reproductive Health in Rheumatic Diseases Guideline, is the first evidence-based clinical practice guideline related to the management of all reproductive health issues for patients across the spectrum of rheumatic diseases. Lisa R. Sammaritano, MD, of Hospital for Special Surgery Weill Cornell Medicine in New York, N.Y., and one of the experts involved in the guideline s development, said that managing pregnancy, especially in women with conditions such as lupus or antiphospholipid antibody syndrome, can be challenging. Our patients have particular needs and challenges during pregnancy, and the obstetrician/gynecologist may not always be aware of these, said Dr. Sammaritano. In addition, rheumatologists may not be aware of updates in contraception, fertility therapies, and pregnancy management. With the expansion of new therapies available for rheumatic diseases in recent years, especially in rheumatoid arthritis, we need to learn more about which of these new treatments are compatible with pregnancy. Some of the important considerations in the reproductive health of patients with rheumatic disease are: planning pregnancies ahead of time conceiving during periods of low disease activity conceiving when neither the mother nor father are using teratogenic medications, which could put a fetus at risk In preparing the guideline, the panel of experts met with a panel of patients who stressed that they wanted to talk with their rheumatologist about family planning, early and often, according to Dr. Sammaritano. In fact, patients often seek guidance from their rheumatologists about safe contraception, fertility issues, and safe medication use during pregnancy and breastfeeding. This guideline will help rheumatologists when their patients ask these important questions about family planning. To develop the guideline, a panel of rheumatologists, obstetricians/gynecologists, reproductive medicine specialists, epidemiologists, and patients with rheumatic diseases conducted a systematic review of current, evidence-based literature on all aspects of reproductive health in rheumatic disease. They applied standard GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology to assess the quality of the evidence. ACR plans three papers on the following topics once the guideline is complete: 1. Reproductive health in general, including contraception, assisted reproductive technology, preservation of fertility for women using cytotoxic medications, and menopause, including estrogen replacement therapy 2. Pregnancy counseling and management. 3. Medication management for men and women Our patients have particular needs and challenges during pregnancy, and the obstetrician/gynecologist may not always be aware of these. Lisa R. Sammaritano, MD 3

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8 ACR 2018 Annual Meeting IQ-Lupus Program Decreases Hospitalizations Among High-Risk Patients Systemic lupus erythematosus (SLE), or lupus, is a chronic disease that causes systemic inflammation and affects multiple organs, including kidneys, lung, heart, and brain, as well as the skin and joints. The condition is far more common in women than in men, and it is more prevalent among African-Americans and Latinos than non-hispanic whites. Furthermore, the disease is often diagnosed late or misdiagnosed, and it requires careful management during pregnancy. Research presented at the annual meeting shows that patients with high-risk SLE may have a decreased risk of hospitalization and shorter length of stay when they have improved access to rheumatologic care. Previous research from a team at the University of Rochester Medical Center in New York found that a small group of high-risk, high-cost patients account for most hospitalizations, the majority of length of stay, and most overall cost. Specifically, high-risk, high-cost patients spent three times as many days in the hospital, and such patients often were young women from lower socioeconomic backgrounds. Allen P. Anandarajah, MBBS, the study s presenting author, said, These patients often were unable, or unwilling, to come to outpatient clinics. We organized focus group meetings with patients from within the high-risk group and recognized that the lack of easy access was a major impediment to routine clinical care. Therefore, the researchers decided to evaluate the impact of interventions to improve access to rheumatology care. The study defined high-risk, high-cost patients with lupus as those who required three or more hospital admissions over a three-year period between 2013 and Most of the patients were African-Americans from poor, urban communities. The medical center launched a program called IQ-LUPUS (Improve Quality in Low-income, Underserved, Poor, Underprivileged, SLE) to improve quality of care for the target population and to enhance their access to rheumatology care. IQ-LUPUS opened a rheumatology clinic in a local urban neighborhood, and it offers patients direct access to a nurse care coordinator and social worker. Researchers examined data from fiscal year (FY) 2017 to compare no-show rates for the high-risk, high-cost patients at the outpatient clinic with no-show rates of all other lupus patients, as well as all rheumatology patients systemwide. They also determined hospitalization rates and length of stay for all medical center admissions among study participants, comparing data from the first 10 months of FY 2017 to the first 10 months of FY Fifty-four patients enrolled in IQ-LUPUS. In FY 2017, the no-show rate for high-risk, high-cost patients was 12.1% compared with 5.8% for all patients with lupus and 4.3% for all rheumatology patients. The no-show rate for the high-risk, high-cost patients decreased 1.3% in FY 2018 but increased 0.8% in all patients with lupus and 0.7% in all rheumatology patients. Furthermore, hospital admissions and length of stay decreased in the high-risk, high-cost group from 52 admissions and 231 days to 36 admissions and 159 days. The number of 30-day admissions also decreased from 21 in 2017 to 14 in The researchers concluded that improved access to rheumatology care through programs such as IQ-LUPUS can decrease hospitalizations and length of hospital stay for high-risk, vulnerable patients. Genetic Risk Score May Identify Ankylosing Spondylitis Earlier At the annual meeting, a team of researchers presented a new method to accurately assist in the early diagnosis of ankylosing spondylitis (AS). Their study found that a genetic risk score can help clinicians identify the condition earlier and at lower cost than current testing methods. AS is a common cause of chronic back pain and may affect the skin, intestines, and eyes. The disease commonly begins during patients teens or 20s, is far more common in men than women, and has a strong genetic risk. Zhixiu Li, PhD, of Queensland University of Technology Institute of Health and Biomedical Innovation in Australia, said the typical delay between the onset of AS symptoms and diagnosis is eight to 10 years and that patients often receive inappropriate treatment during the delay. Early diagnosis and intervention have been shown to improve outcomes, but early diagnosis can be challenging. In early disease, magnetic resonance imaging (MRI) imaging is the current gold standard for diagnosis, but it is very expensive, and many patients with early changes on an MRI scan don t go on to get AS, said Dr. Li. Thus, we 6

9 think genetic profiling may even be informative, particularly in early disease, but also potentially prior to onset of symptoms. Genetic risk score (GRS) uses thousands of genetic variants to calculate a person s susceptibility for a particular disease. Dr. Li s team of researchers examined two models of GRS to determine whether they could serve as an early diagnostic tool in AS. The first model was based on samples of European descent (n=7,742 patients with AS and n=14,542 controls). The second model was based on samples of East Asian descent (n=6,001 patients with AS and n=4,943 controls). The researchers compared their models with standard testing for AS and reported results using area under the curve (AUC). In the European GRS model, the AUC was 0.92, with 83% sensitivity and 92% specificity compared with 0.87 with human leukocyte antigen-b27 alone. In the East Asian GRS model, the AUC was 0.95, with 91% sensitivity and 95% specificity. Our findings show that GRS has high discriminatory capacity and could be of clinical utility in early diagnosis at [a] lower cost than MRI, said Dr. Li. In addition, [it] could also be applied to identify individuals with [a] substantial risk of developing AS before major symptoms appear. It could also be applied to patients with arthritic symptoms but without a clear diagnosis. The researchers are working to improve their models and examining how GRS performs when combined with other clinical features or test results. At a dinner symposium hosted by Novartis at the annual meeting, a panel of experts explained the irreconcilable differences between psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The presentation, titled PsA: Is It Time to Divorce from RA? Identifying Clinical Signs and Symptoms, and Gaining New Insights into Pathophysiology and Management, highlighted the many important distinctions between PsA and RA despite the fact that they can have similar presentation and have historically been treated the same. Philip J. Mease, MD, of the University of Washington School of Medicine in Seattle, introduced the topic, stressing that PsA and RA are distinct diseases. PsA often goes undiagnosed, he said, but early diagnosis is important to outcomes. DISTINGUISHING PSA FROM RA Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, said, The divorce actually happened a long time ago, we just have to get with the program. PsA is part of the spondyloarthritis group of diseases, and she outlined its specific clinical hallmarks, in comparison with RA: PsA involves the axial skeleton and distal interphalangeal joints, as opposed to the metacarpophalangeal joints and wrist joints in RA. PsA can be mono-, oligo-, or polyarticular, as opposed RA, which is polyarticular. PsA joints are often asymmetrical, whereas RA joints are mostly symmetrical. PsA leads to enthesitis, but RA does not. Dactylitis is a hallmark of PsA, but it is rare in RA. Patients with PsA do not have a high titer rheumatology factor, as opposed to those with RA. PsA often leads to nail lesions, as opposed to RA. A Divorce Between Psoriatic Arthritis and Rheumatoid Arthritis PsA involves psoriasis, which can appear before other signs and symptoms; RA does not. When we look at PsA, we are not just looking at joints, Dr. Wright said, adding that innate and adaptive immune responses contribute to the pathogenesis of both PsA and RA, but RA joints are enriched with a range of inflammatory cytokines. In PsA, there is inflammatory activation at multiple sites, and PsA joints are enriched with interleukin- 17-producing cells. Therefore, Even if they look the same at presentation, we have to look at the activation to understand and treat. If left untreated, PsA can have a significant impact on patients functional status and quality of life, she said. Because of some of the disease manifestations, patients often are seen by their primary care physicians and specialists such as dermatologists long before they are referred to rheumatology. Continued on page 8 7

10 ACR 2018 Annual Meeting Continued from page 7 PSA S IMPACT ON PATIENTS Dr. Mease focused his presentation on PsA s effects on patients lives. Peripheral arthritis can lead to irreversible deformities, pain, stiffness, and loss of function, he said, and the damage is progressive in most patients. Enthesitis, he continued, also has a significant impact on patients, who report diffuse aches and pains and often present with a swollen joint or digit but have endured months or years of pain and tenderness. Importantly, he said, the presence of enthesitis is a biomarker of increased disease severity and poorer functional status. Its true prevalence is underestimated, because it may mimic mechanical stress injury or tendonitis, and quantification by physical examination is difficult due to the location of the sites. Dactylitis is also a marker of disease severity, Dr. Mease said if it is present, it is associated with greater disease burden. Spine disease is present in 50% of patients with PsA, he continued, but presentation is variable. Patients with this manifestation have poorer physical function and health-related quality of life (HRQOL) than patients with more peripheral involvement. However, about 20% of patients with evidence of axial involvement may not be symptomatic, he said. Regarding the skin, even a moderate amount of psoriatic skin involvement is associated with greater disease burden, greater reported pain, fatigue, impairment, discomfort, and self-consciousness. Therefore, it is very important to acknowledge the skin with patients and evaluate its involvement. In fact, psoriasis often develops into PsA. Nail disease is also important, for similar reasons, but it is difficult to treat. Like the skin, nail psoriasis is closely associated with PsA development. ASSESSMENT OF PSA Dr. Mease discussed PsA assessment tools but stressed that one size does not fit all. For clinical trials, he said researchers should assess every item in the inner circle of the OMERACT (Outcome Measures in Rheumatology): musculoskeletal disease activity (including peripheral joints, enthesitis, dactylitis, and spine symptoms), skin diseases activity, and pain. Global assessment, physical function, HRQOL, fatigue, and systemic inflammation. He said the American College of Rheumatology 20 Criteria tend to be the primary endpoint in PsA studies and has served researchers reasonably well in deciphering between treatment and placebo, but new composite measures are being developed to better elucidate disease severity and treatment effectiveness. They are being used more commonly in trials but not quite ready for use in clinical practice, he added. No patient who comes to see you with this disease will be like another patient with the same disease. Take into account the different disease domains for individualized diagnosis and management. Philip J. Mease, MD Finally, Dr. Mease said, No patient who comes to see you with this disease will be like another patient with the same disease. Take into account the different disease domains for individualized diagnosis and management, referring attendees to guidelines created by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (otherwise known as GRAPPA). PRACTICAL USE OF IMAGING Clinical examination may not provide an accurate or complete picture of PsA, said presenter Catherine J. Bakewell, MD, RhMSUS, of Intermountain Medical Group in Salt Lake City, Utah. She offered many images from her practice to demonstrate how imaging can help with diagnosis, proper prognosis, and better disease management. The main modalities to visualize disease activity in PsA are radiography, ultrasound, and magnetic resonance imaging (MRI). Although radiography is fast, inexpensive, and reproducible, it cannot help researchers or clinicians visualize soft tissue or active inflammation, Dr. Bakewell said. MRI can show peripheral arthritis, enthesitis, dactylitis, and nail effects, and it is effective in detecting early disease. However, it cannot detect axial disease and is expensive. Therefore, she recommends ultrasound, which can detect all of those manifestations, including joints during movement, at a low cost. In the future, researchers and clinicians may find themselves using new imaging modalities even artificial intelligence to diagnose, assess, manage, and monitor patients with PsA. 8

11 Learn about Actual patients who have taken COSENTYX and have been compensated for their time. Individual results may vary. WITH EXPERIENCE IN REAL-WORLD US PATIENTS 1 * INDICATIONS COSENTYX (secukinumab) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. COSENTYX is indicated for the treatment of adult patients with active psoriatic arthritis. COSENTYX is indicated for the treatment of adult patients with active ankylosing spondylitis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS COSENTYX is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients. Please see additional Important Safety Information on adjacent pages. Please see Brief Summary of full Prescribing Information on adjacent pages.

12 IL-17A is an important mediator in the inflammatory process 2 There are a variety of cell types that can produce IL-17A 3 TNFα Activated dendritic cells Mast cells Innate lymphoid cells IL-23 T H 17 cells Other T cells Neutrophils IL-17A IL-17A is a naturally occurring cytokine involved in normal inflammatory and immune response. Selectively targeting IL-17A with COSENTYX (secukinumab) inhibits release of pro-inflammatory cytokines and chemokines which are implicated in the development of certain types of psoriatic disease. 2 Clinical significance of the COSENTYX mechanism of action is unknown. Images not drawn to scale. The above graphic has been simplified. The immune pathophysiology of psoriatic disease involves complex molecular mechanism feedback loops not shown in this graphic. 4,5 The understanding of the pathophysiology of plaque psoriasis and psoriatic arthritis continues to evolve. This represents a current theory of the role of IL-17A in the disease. IMPORTANT SAFETY INFORMATION (cont d) WARNINGS AND PRECAUTIONS Infections COSENTYX may increase the risk of infections. In clinical trials, a higher rate of infections was observed in subjects treated with COSENTYX compared to placebo-treated subjects. In placebo-controlled clinical trials in patients with moderate to severe plaque psoriasis, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%), and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with COSENTYX compared with placebo. A similar increase in risk of infection was seen in placebo-controlled trials in patients with psoriatic arthritis and ankylosing spondylitis. The incidence of some types of infections appeared to be dose-dependent in clinical studies. Exercise caution when considering the use of COSENTYX in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and COSENTYX should be discontinued until the infection resolves. Please see additional Important Safety Information on adjacent pages. Please see Brief Summary of full Prescribing Information on adjacent pages.

13 COSENTYX clinical data backed by real-world experience Active comparator data in moderate to severe plaque PsO vs two different comparators Efficacy and safety data in robust clinical trials 11+ years of clinical trial experience worldwide 6 12,600+ unique prescribers to date in the US 1 Go deeper into the body of evidence for COSENTYX visit PsO, psoriasis. IMPORTANT SAFETY INFORMATION (cont d) WARNINGS AND PRECAUTIONS (cont d) Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with COSENTYX. Do not administer COSENTYX to patients with active TB infection. Initiate treatment of latent TB prior to administering COSENTYX. Consider anti-tb therapy prior to initiation of COSENTYX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving COSENTYX should be monitored closely for signs and symptoms of active TB during and after treatment. Inflammatory Bowel Disease Caution should be used when prescribing COSENTYX to patients with inflammatory bowel disease. Exacerbations, in some cases serious, occurred in patients treated with COSENTYX during clinical trials in plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. In addition, new onset inflammatory bowel disease cases occurred in clinical trials with COSENTYX. In an exploratory study in 59 patients with active Crohn s disease, there were trends toward greater disease activity and increased adverse events in the secukinumab group as compared to the placebo group. Patients who are treated with COSENTYX should be monitored for signs and symptoms of inflammatory bowel disease.

14 is the #1 prescribed interleukin antagonist across PsO, PsA, and AS 7 * AS, ankylosing spondylitis; PsA, psoriatic arthritis; PsO, psoriasis. * Based on new biologic prescription (NBRx) IMS data week of 9/21/2018. Interleukins include COSENTYX, Stelara (ustekinumab), Taltz (ixekizumab), and Tremfya (guselkumab). IMPORTANT SAFETY INFORMATION (cont d) WARNINGS AND PRECAUTIONS (cont d) Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in patients treated with COSENTYX in clinical trials. If an anaphylactic or other serious allergic reaction occurs, administration of COSENTYX should be discontinued immediately and appropriate therapy initiated. The removable cap of the COSENTYX Sensoready pen and the COSENTYX prefilled syringe contains natural rubber latex which may cause an allergic reaction in latex-sensitive individuals. The safe use of the COSENTYX Sensoready pen or prefilled syringe in latex-sensitive individuals has not been studied. Vaccinations Prior to initiating therapy with COSENTYX, consider completion of all age appropriate immunizations according to current immunization guidelines. Patients treated with COSENTYX should not receive live vaccines. Non-live vaccinations received during a course of COSENTYX may not elicit an immune response sufficient to prevent disease. MOST COMMON ADVERSE REACTIONS Most common adverse reactions (>1%) are nasopharyngitis, diarrhea, and upper respiratory tract infection. References: 1. Data on file. Cosentyx Tracker Data. Novartis Pharmaceuticals Corp; February Cosentyx [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; Miossec P, Kolls JK. Targeting IL-17 and T H17 cells in chronic inflammation. Nat Rev Drug Disco. 2012;11(10): Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol. 2014;71(1): Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5): Data on file. AIN457A2102 Clinical Study Report. Novartis Pharmaceuticals Corp; December Data on file. Cosentyx Weekly Dashboard. Novartis Pharmaceuticals Corp; September 21, Please see additional Important Safety Information on previous pages. Please see Brief Summary of full Prescribing Information on adjacent pages. Novartis Pharmaceuticals Corporation East Hanover, New Jersey Novartis 10/18 T-COS

15 COSENTYX (secukinumab) injection, for subcutaneous use COSENTYX (secukinumab) for injection, for subcutaneous use Initial U.S. Approval: 2015 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis COSENTYX is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. 1.2 Psoriatic Arthritis COSENTYX is indicated for the treatment of adult patients with active psoriatic arthritis. 1.3 Ankylosing Spondylitis COSENTYX is indicated for the treatment of adult patients with active ankylosing spondylitis. 4 CONTRAINDICATIONS COSENTYX is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients [see Warnings and Precautions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Infections COSENTYX may increase the risk of infections. In clinical trials, a higher rate of infections was observed in COSENTYX treated subjects compared to placebo-treated subjects. In placebo-controlled clinical trials in patients with moderate to severe plaque psoriasis, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with COSENTYX compared with placebo. A similar increase in risk of infection was seen in placebocontrolled trials in patients with psoriatic arthritis and ankylosing spondylitis [see Adverse Reactions (6.1)]. The incidence of some types of infections appeared to be dose-dependent in clinical studies [see Adverse Reactions (6.1)]. Exercise caution when considering the use of COSENTYX in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and COSENTYX should be discontinued until the infection resolves. 5.2 Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with COSENTYX. Do not administer COSENTYX to patients with active TB infection. Initiate treatment of latent TB prior to administering COSENTYX. Consider anti-tb therapy prior to initiation of COSENTYX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving COSENTYX should be monitored closely for signs and symptoms of active TB during and after treatment. 5.3 Inflammatory Bowel Disease Caution should be used when prescribing COSENTYX to patients with inflammatory bowel disease. Exacerbations, in some cases serious, occurred in COSENTYX treated patients during clinical trials in plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. In addition, new onset inflammatory bowel disease cases occurred in clinical trials with COSENTYX. In an exploratory study in 59 patients with active Crohn s disease, there were trends toward greater disease activity and increased adverse events in the secukinumab group as compared to the placebo group. Patients who are treated with COSENTYX should be monitored for signs and symptoms of inflammatory bowel disease [see Adverse Reactions (6.1)]. 5.4 Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in COSENTYX treated patients in clinical trials. If an anaphylactic or other serious allergic reaction occurs, administration of COSENTYX should be discontinued immediately and appropriate therapy initiated [see Adverse Reactions (6.1)]. 5.5 Risk of Hypersensitivity in Latex-sensitive Individuals The removable cap of the COSENTYX Sensoready pen and the COSENTYX prefilled syringe contains natural rubber latex which may cause an allergic reaction in latex-sensitive individuals. The safe use of COSENTYX Senso ready pen or prefilled syringe in latex-sensitive individuals has not been studied. 5.6 Vaccinations Prior to initiating therapy with COSENTYX, consider completion of all age appropriate immunizations according to current immunization guidelines. Patients treated with COSENTYX should not receive live vaccines. Non-live vaccinations received during a course of COSENTYX may not elicit an immune response sufficient to prevent disease. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the labeling: Infections [see Warnings and Precautions (5.1)] Inflammatory Bowel Disease [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis A total of 3430 plaque psoriasis subjects were treated with COSENTYX in controlled and uncontrolled clinical trials. Of these, 1641 subjects were exposed for at least 1 year. Four placebo-controlled phase 3 trials in plaque psoriasis subjects were pooled to evaluate the safety of COSENTYX in comparison to placebo up to 12 weeks after treatment initiation, in Trials 1, 2, 3, and 4. In total, 2077 subjects were evaluated (691 to COSENTYX 300 mg group, 692 to COSENTYX 150 mg group, and 694 to placebo group) [see Clinical Studies (14) in the full prescribing information]. Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the COSENTYX groups than the placebo group during the 12-week placebo-controlled period of the placebo-controlled trials. Table 1: Adverse Reactions Reported by Greater Than 1% of Subjects with Plaque Psoriasis Through Week 12 in Trials 1, 2, 3, and 4 COSENTYX 300 mg 150 mg Placebo Adverse Reactions (N = 691) (N = 692) (N = 694) n (%) n (%) n (%) Nasopharyngitis 79 (11.4) 85 (12.3) 60 (8.6) Diarrhea 28 (4.1) 18 (2.6) 10 (1.4) Upper respiratory tract infection 17 (2.5) 22 (3.2) 5 (0.7) Rhinitis 10 (1.4) 10 (1.4) 5 (0.7) Oral herpes 9 (1.3) 1 (0.1) 2 (0.3) Pharyngitis 8 (1.2) 7 (1.0) 0 (0) Urticaria 4 (0.6) 8 (1.2) 1 (0.1) Rhinorrhea 8 (1.2) 2 (0.3) 1 (0.1) Adverse reactions that occurred at rates less than 1% in the placebocontrolled period of Trials 1, 2, 3, and 4 through Week 12 included: sinusitis, tinea pedis, conjunctivitis, tonsillitis, oral candidiasis, impetigo, otitis media, otitis externa, inflammatory bowel disease, increased liver transaminases, and neutropenia. Infections In the placebo-controlled period of the clinical trials in plaque psoriasis (a total of 1382 subjects treated with COSENTYX and 694 subjects treated with placebo up to 12 weeks), infections were reported in 28.7% of subjects treated with COSENTYX compared with 18.9% of subjects treated with placebo. Serious infections occurred in 0.14% of patients treated with COSENTYX and in 0.3% of patients treated with placebo [see Warnings and Precautions (5.1)]. Over the entire treatment period (a total of 3430 plaque psoriasis subjects treated with COSENTYX for up to 52 weeks for the majority of subjects), infections were reported in 47.5% of subjects treated with COSENTYX (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of subjects treated with COSENTYX (0.015 per patient-year of follow-up). Phase 3 data showed an increasing trend for some types of infection with increasing serum concentration of secukinumab. Candida infections, herpes viral infections, staphylococcal skin infections, and infections requiring treatment increased as serum concentration of secukinumab increased. Neutropenia was observed in clinical trials. Most cases of secukinumabassociated neutropenia were transient and reversible. No serious infections were associated with cases of neutropenia. Inflammatory Bowel Disease Cases of inflammatory bowel disease, in some cases serious, were observed in clinical trials with COSENTYX. In the plaque psoriasis program, with 3430 patients exposed to COSENTYX over the entire treatment period for up to 52 weeks (2725 patient-years), there were 3 cases (0.11 per 100 patient-years) of exacerbation of Crohn s disease, 2 cases (0.08 per 100 patient-years) of exacerbation of ulcerative colitis, and 2 cases (0.08 per 100 patient-years) of new onset ulcerative colitis. There were no cases in placebo patients (N = 793; 176 patient-years) during the 12 week placebo-controlled period. One case of exacerbation of Crohn s disease was reported from longterm non-controlled portions of ongoing clinical trials in plaque psoriasis [see Warnings and Precautions (5.3)]. Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in COSENTYX treated patients in clinical trials [see Warnings and Precautions (5.4)].

16 Psoriatic Arthritis COSENTYX was studied in two placebo-controlled psoriatic arthritis trials with 1003 patients (703 patients on COSENTYX and 300 patients on placebo). Of the 703 patients who received COSENTYX, 299 patients received a subcutaneous loading dose of COSENTYX (PsA1) and 404 patients received an intravenous loading dose of secukinumab (PsA2) followed by COSENTYX administered by subcutaneous injection every four weeks. During the 16-week placebo-controlled period of the trials in patients with psoriatic arthritis, the overall proportion of patients with adverse events was similar in the secukinumab and placebo-treatment groups (59% and 58%, respectively). The adverse events that occurred at a proportion of at least 2% and at a higher proportion in the COSENTYX groups than the placebo groups during the 16-week placebo-controlled period were nasopharyngitis, upper respiratory tract infection, headache, nausea, and hypercholesterolemia. The safety profile observed in patients with psoriatic arthritis treated with COSENTYX is consistent with the safety profile in psoriasis. Similar to the clinical trials in patients with psoriasis, there was an increased proportion of patients with infections in the COSENTYX groups (29%) compared to placebo group (26%) [see Warnings and Precautions (5.1)]. There were cases of Crohn s disease and ulcerative colitis that include patients who experienced either exacerbations or the development of new disease. There were three cases of inflammatory bowel disease, of which two patients received secukinumab and one received placebo [see Warnings and Precautions (5.3)]. Ankylosing Spondylitis COSENTYX was studied in two placebo controlled ankylosing spondylitis trials with 590 patients (394 patients on COSENTYX and 196 patients on placebo). Of the 394 patients who received COSENTYX, 145 patients received a subcutaneous load of COSENTYX (study AS1) and 249 received an intravenous loading dose of secukinumab (study AS2) followed by COSENTYX administered by subcutaneous injection every four weeks. During the 16-week placebo-controlled period of the trials in patients with ankylosing spondylitis, the overall proportion of patients with adverse events was higher in the secukinumab groups than the placebo-treatment groups (66% and 59%, respectively). The adverse events that occurred at a proportion of at least 2% and at a higher proportion in the COSENTYX groups than the placebo groups during the 16-week placebo-controlled period were nasopharyngitis, nausea, and upper respiratory tract infection. The safety profile observed in patients with ankylosing spondylitis treated with COSENTYX is consistent with the safety profile in psoriasis. Similar to clinical trials in patients with psoriasis, there was an increased proportion of patients with infections in the COSENTYX groups (31%) compared to the placebo group (18%) [see Warnings and Precautions (5.1)]. In the ankylosing spondylitis program, with 571 patients exposed to COSENTYX there were 8 cases of inflammatory bowel disease during the entire treatment period [5 Crohn s (0.7 per 100 patient-years) and 3 ulcerative colitis (0.4 per 100 patient-years)]. During the placebo-controlled 16-week period, there were 2 Crohn s disease exacerbations and 1 new onset ulcerative colitis case that was a serious adverse event in patients treated with COSENTYX compared to none of the patients treated with placebo. During the remainder of the study when all patients received COSENTYX, 1 patient developed Crohn s disease, 2 patients had Crohn s exacerbations, 1 patient developed ulcerative colitis, and 1 patient had an ulcerative colitis exacerbation [see Warnings and Precautions (5.3)]. 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immuno - genicity. The immunogenicity of COSENTYX was evaluated using an electrochemiluminescence-based bridging immunoassay. Less than 1% of subjects treated with COSENTYX developed antibodies to secukinumab in up to 52 weeks of treatment. However, this assay has limitations in detecting anti-secukinumab antibodies in the presence of secukinumab; therefore the incidence of antibody development might not have been reliably determined. Of the subjects who developed antidrug antibodies, approximately one-half had antibodies that were classified as neutralizing. Neutralizing antibodies were not associated with loss of efficacy. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to COSENTYX with the incidences of antibodies to other products may be misleading. 7 DRUG INTERACTIONS 7.1 Live Vaccines Patients treated with COSENTYX may not receive live vaccinations [see Warnings and Precautions (5.6)]. 7.2 Non-Live Vaccines Patients treated with COSENTYX may receive non-live vaccinations. Healthy individuals who received a single 150 mg dose of COSENTYX 2 weeks prior to vaccination with a non-u.s. approved group C meningococcal polysaccharide conjugate vaccine and a non-u.s. approved inactivated seasonal influenza vaccine had similar antibody responses compared to individuals who did not receive COSENTYX prior to vaccination. The clinical effectiveness of meningococcal and influenza vaccines has not been assessed in patients undergoing treatment with COSENTYX [see Warnings and Precautions (5.6)]. 7.3 CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4. Upon initiation or discontinuation of COSENTYX in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed [see Clinical Pharmacology (12.3) in the full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available human data with COSENTYX use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In an embryo-fetal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of secukinumab during organo - genesis at doses up to 30 times the maximum recommended human dose (MRHD) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal Data An embryo-fetal development study was performed in cynomolgus monkeys with secukinumab. No malformations or embryo-fetal toxicity were observed in fetuses from pregnant monkeys that were administered secukinumab weekly by the subcutaneous route during the period of organogenesis at doses up to 30 times the MRHD (on a mg/kg basis at a maternal dose of 150 mg/kg). A pre- and post-natal development toxicity study was performed in mice with a murine analog of secukinumab. No treatment related effects on functional, morphological or immunological development were observed in fetuses from pregnant mice that were administered the murine analog of secukinumab on gestation days 6, 11, and 17 and on postpartum days 4, 10, and 16 at doses up to 150 mg/kg/dose. 8.2 Lactation Risk Summary It is not known whether secukinumab is excreted in human milk or absorbed systemically after ingestion. There are no data on the effects of COSENTYX on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for COSENTYX and any potential adverse effects on the breastfed child from COSENTYX or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of COSENTYX in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 3430 plaque psoriasis subjects exposed to COSENTYX in clinical trials, a total of 230 were 65 years or older, and 32 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects. 10 OVERDOSAGE Doses up to 30 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey US License No Novartis T /18 COS