CME Overcoming Challenges in the Diagnosis and Management of Axial Spondyloarthritis: New Insights and Implications for Clinical Practice

Chair Abhijeet Danve, MD, FACP, FACR Yale School of Medicine New Haven, Connecticut

What’s Inside 3 A Closer Look at Strategies to Improve the Timely Recognition of Axial Spondyloarthritis 15 Expert Insight on the Treatment of Axial Spondyloarthritis

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Media: Enduring Material Content/Peer Reviewer Disclosures Accredited Activity Release Date: August 28, 2020 The following Content/Peer Reviewer has nothing to disclose: Accredited Activity Expiration Date: August 27, 2021 Time to Complete Activity: 60 minutes Matthew A. Goodman, MD

Activity Description Disclosure of Unlabeled Use In this activity, an expert in rheumatology discusses practical strategies for This educational activity may contain discussions of published and/or identifying and managing axial spondyloarthritis (axSpA) in clinical practice. investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled Target Audience indications. The opinions expressed in the educational activity are those of This activity has been designed to meet the educational needs of internists and the faculty and do not necessarily represent the views of the planners. Please other clinicians involved in the identification and care of patients with axSpA. refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Educational Objectives Upon completion of this activity, participants should be better able to: Disclaimer • Identify axSpA in patients with inflammatory back pain via assessment of Participants have an implied responsibility to use the newly acquired medical history, musculoskeletal symptoms and findings, and extra-articular information to enhance patient outcomes and their own professional manifestations and comorbidities development. The information presented in this activity is not meant to serve • Apply classification criteria and diagnostic tests into clinical practice to as a guideline for patient management. Any procedures, medications, or other support early detection of axSpA courses of diagnosis or treatment discussed or suggested in this activity should • Assess efficacy and safety data related to novel biologic options for axSpA, not be used by clinicians without evaluation of their patient's conditions and recognizing the potential clinical impact on the management of patients possible contraindications and/or dangers in use, review of any applicable who do not respond well to traditional pharmacologic therapies manufacturer's product information, and comparison with recommendations • Employ treatment plans for individual patients with axSpA in accordance of other authorities. with current evidence, expert recommendations, and patient needs and preferences Method of Participation • Recognize the importance of collaborating with rheumatologists to provide There are no fees for participating in or receiving credit for this accredited optimal treatment and longitudinal support for patients with axSpA activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing Providership, Credit, and Support board. This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. A statement of credit will be issued only upon receipt of a completed activity evaluation form and will be emailed to you upon completion. You will receive This activity is supported by an educational grant from Novartis your certificate from [email protected]. If you have questions Pharmaceuticals Corporation. regarding the receipt of your emailed certificate, please contact via email at [email protected]. Physician Continuing Medical Education This activity has been planned and implemented in accordance with About This CME Activity the accreditation requirements and policies of the Accreditation PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Council for Continuing Medical Education (ACCME) through the joint Inc. are responsible for the selection of this activity’s topics, the preparation providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for of editorial content, and the distribution of this activity. Our activities may Medical Education. The Medical Learning Institute, Inc. is accredited by the contain references to unapproved products or uses of these products in ACCME to provide continuing medical education for physicians. certain jurisdictions. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and The Medical Learning Institute, Inc. designates this enduring material for a enforce the editorial independence of PVI and Medical Learning Institute, Inc. maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of Faculty Disclosures PeerView or any of its partners, providers, and/or supporters. Chair Abhijeet Danve, MD, FACP, FACR Assistant Professor of Medicine Director Spondyloarthritis Clinic Yale School of Medicine New Haven, Connecticut

Abhijeet Danve, MD, FACP, FACR, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Janssen Pharmaceuticals, Inc. Grant/Research Support from Novartis Pharmaceuticals Corporation. Stock Shareholder in Novartis Pharmaceuticals Corporation.

Planning Committee Disclosures The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited activity during the past 12 months unless listed below.

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A Closer Look at Strategies to Sacroiliitis Grade 0 (Normal)a Improve the Timely Recognition of Axial Spondyloarthritis

Dr. Danve: Hello, this is Dr. Abhijeet Danve, Assistant Professor and Rheumatologist from the Yale School of Medicine in New Haven, Connecticut. Welcome to this educational activity focused on managing axial spondyloarthritis in the internal medicine setting.

We’ll begin with a quote. “Learn to see. Learn to hear. Learn to a Image courtesy of Dr. Abhijeet Danve. feel. Learn to smell. And know that by practice alone can you become expert." The practice of rheumatology is all about pattern An x-ray of the pelvis was performed that did not show sacroiliitis. recognition”

Patient Casea (Cont’d) Patient Case

Back pain is worse with prolonged rest and improves with exercise and activity

Patient referred Wakes up because of back pain; NSAIDs provide significant relief 44-year-old to a rheumatologist woman who had high suspicion with chronic of spondyloarthritisb low back Needs to visit her podiatrist for recurrent plantar fasciitis pain (CLBP) for 6-8 years Normal ROM at L spine, mild tenderness at insertion of plantar fascia on calcaneus; otherwise, normal joint examination

a Image courtesy of Dr. Abhijeet Danve. Labs show normal ESR and CRP, but positive for HLA-B27 b MRI of pelvis confirmed sacroiliitis; subchondral marrow inflammation shown by increased MRI signal on fat suppressed T2 weighted image (STIR; as shown by white arrows) and joint cavity (as shown by yellow arrows).

An MRI of the pelvis without contrast was performed. As you can Dr. Danve: We’ll begin with a case. A 44-year-old, otherwise see, it showed inflammatory changes on both sides of the bilateral healthy woman presents with chronic low back pain that has been SIJs. Here you can see the bone marrow edema in the subchondral ongoing for 6 to 8 years. The back pain is worse with prolonged aspect of the right, as well as the left, SIJ on the T2-weighted STIR rest, and it improves with exercises, as well as activities. Sometimes image. the back pain wakes the patient up in the middle of the night. She reports that NSAIDs provide significant relief from the back pain. The patient also needs to visit her podiatrist often for recurrent plantar fasciitis. On examination, she has normal range of movement at lumbar spine, and she has mild tenderness at the insertion of plantar fascia on the left side. The rest of the joint So what can we call patients who do not have examination, as well as systemic examination, is normal. Blood definitive sacroiliitis but have other features tests show normal sed rate and normal CRP, but she’s positive suggestive of spondyloarthritis? HLA-B27 gene.

So what can we call patients who don’t have definitive sacroiliitis but have other features suggestive of spondyloarthritis?

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divided axial spondyloarthritis into two main subtypes: ankylosing Spectrum of Spondyloarthritis1 spondylitis, also called radiographic axial spondyloarthritis; and nonradiographic axial spondyloarthritis. The ASAS classification is Axial Peripheral spondyloarthritis spondyloarthritis also validated for patients with peripheral spondyloarthritis.

PsA Defining AS and nr-axSpA1,2 Undifferentiated Nonradiographic AS ReA peripheral axial spondyloarthritis spondyloarthritis AS (r-axSpA) nr-axSpA

Arthritis • Clear evidence of sacroiliitis on plain • No radiographic evidence of sacroiliitis of IBD radiographs (x-rays) • Inflammation of sacroiliac joints may be • Spinal involvement is more extensive detected by MRI • Structural abnormalities of vertebrae • Severity of symptoms usually similar often present 1. Raychaudhuri SP, Deodhar A. J Autoimmun. 2014;48-49:128-133.

• Emerging thinking is that axSpA is a single disease continuum with radiographic severity increasing over time The term spondyloarthritis is used for a group of interrelated • Sacroiliitis is now considered a late or alternative finding in the disease course; inflammation precedes structural spinal damage conditions that share similar genetic, pathophysiologic, and • Of patients with nr-axSpA, 5%-10% develop radiographic evidence of AS within 2 years and 20% after 5 years clinical features. Largely, the spondyloarthritis would be axial or peripheral. The axial disease affects the spine, hips, and the SIJs. 1. van der Heijde et al. Ann Rheum Dis. 2017;76:978-991. 2. Sieper J et al. Arthritis Rheum. 2013;65:534-551. Peripheral spondyloarthritis mainly affects the peripheral joints in the extremities. However, this classification is not absolute, In patients who have ankylosing spondylitis, there is clear evidence and significant overlap is seen among patients with axial of sacroiliitis on plain x-rays. The spinal involvement is more spondyloarthritis and peripheral spondyloarthritis. extensive. The structural abnormalities of vertebrae often present on x-rays, whereas in nonradiographic axial spondyloarthritis Main types of axial spondyloarthritis are nonradiographic axial by definition, the x-ray does not show definite radiographic spondyloarthritis and ankylosing spondylitis. Prominent diseases sacroiliitis. The inflammation in the SI joints may be detected by that come under the peripheral spondyloarthritis umbrella are MRI. The severity of symptoms is similar between nonradiographic psoriatic arthritis, reactive arthritis, and arthritis of inflammatory axial disease and ankylosing spondylitis. The emerging thinking bowel disease. is that axial spondyloarthritis is a single disease continuum with radiographic severity increasing over the time. Therefore, Axial spondyloarthritis is an expanded concept of ankylosing radiographic sacroiliitis is now considered a late finding in the spondylitis. In the past we used to wait until patients developed disease course, because inflammation precedes structural damage structural changes in the spine and SIJs on x-ray to formally in the SIJs and the spine, too. diagnose them with ankylosing spondylitis and start treatment. But now we realize that ankylosing spondylitis is an advanced What is axSpA?1 stage, and patients have been suffering with back pain and other symptoms for many years before the radiographic changes • Immune-mediated chronic inflammatory disease affecting the axial occur. To include the earlier stages of the disease, the term axial and peripheral skeleton, as well as extra-articular organs such as skin, gut, and eyes spondyloarthritis was introduced. • Mainly affects young individuals in their third or fourth decade

• Frequently leads to significant pain, loss of function, work disability, 1 Nomenclature and impaired quality of life

• axSpA became the standard nomenclature in 2009 based on a • Heterogeneous presentation and progression multinational study by ASAS1,2 • ASAS divided axSpA into 2 main subtypes

– AS (r-axSpA) 1. Danve A, Deodhar A. Curr Rheumatol Rep. 2017;19:22. – nr-axSpA • ASAS classification is also validated for patients with peripheral, rather Overall, axSpA, or axial spondyloarthritis, is an immune-mediated than axial, SpA3 chronic inflammatory disease affecting the axial, as well as – Patients whose symptoms are not predominantly back pain but PsA, reactive arthritis, and arthritis-associated IBD peripheral, skeleton, and extra-articular organs such as skin, intestines, and eyes. It mainly affects young individuals in their

1. Rudwaleit M et al. Ann Rheum Dis. 2009;68:770-776. 2. Rudwaleit M et al. Ann Rheum Dis. 2009;68:777-783. 3. Rudwaleit M et al. Ann Rheum Dis. 2011;70:25-31. third or fourth decade and frequently leads to significant pain, loss of function, work disability, and impaired quality of life. Patients Axial spondyloarthritis became the standard nomenclature in with this condition have a heterogeneous presentation, as well as 2009 based on a multinational study done by The Assessment progression. of a Spondyloarthritis International Society called ASAS. ASAS

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Why Care About axSpA? How Common Is axSpA in the United States?1,2

• NHANES 2009-2010 of 5,103 participants in the United States showed – CLBP in 19.4% Not every Associated with Much more Frequently patient’s comorbidities – Inflammatory back pain (IBP) in 7% common than missed by back pain is such as HTN, we think internists – HLA-B27 prevalence of 6% mechanical CAD, and CVA  Non-Hispanic whites (Caucasians): 7.5%

axSpA has great treatment options,  Mexican Americans: 4.6% and if treated early future progression may be prevented – axSpA in 1% (0.9%-1.4%) – AS in 0.5%

1. Weisman MH et al. Ann Rheum Dis. 2013;72:369-373. 2. Reveille JD et al. Arthritis Rheum. 2012;64:1407-1411.

Why should internal medicine doctors care about axial The National Health and Nutrition Examination Survey, which spondyloarthritis? Because not every patient’s back pain is was performed in 2009 with 5,103 participants in the United mechanical. Axial spondyloarthritis is much more common States, showed that the prevalence of axial spondyloarthritis than we think. It is frequently missed in internists’ offices. was about 1% and ankylosing spondylitis was 0.5%. This survey Now axial spondyloarthritis has a great treatment options, also showed that chronic back pain is reported by almost 20% and if treated early it may prevent future progression, as well of the population, out of which 7% of them can have features of as the complications. For internal medicine in particular, axial inflammatory back pain. Overall, the prevalence of HLA-B27 in spondyloarthritis being an inflammatory disease can be associated United States is 6%. In non-Hispanic whites, it’s about 7.5%, and in with comorbidities such as hypertension, coronary artery disease, Mexican Americans, it’s about 4.6%. In African Americans, it ranges sleep apnea, and an increased risk of stroke. between 2% and 4%. Prevalence of HLA-B27 is proportionate to the prevalence of axial spondyloarthritis in that particular population, so the higher the prevalence of HLA-B27, the higher How Common Is axSpA in Clinical Practice? the prevalence of axial spondyloarthritis.

axSpA May Be More Common Than Rheumatoid Arthritis in the United States1-4

1.6 1.4

1.4 1.2 1.01 0.92 France 0.8 0.62 0.6 US 0.6 0.55

Prevalence, % Prevalence, Lithuania 0.4 0.31 0.31 0.2 0.15 0 AS SpA RA This begs the next question, how common is axial 1. Saraux A et al. Ann Rheum Dis. 2005;64:1431-1435. 2. Guillemin F et al. Ann Rheum Dis. 2005;64:1427-1430. spondyloarthritis in clinical practice? We think that this is one of 3. Adomaviciute D et al. Scand J Rheumatol. 2008;37:113-119. 4. Helmick CG et al. Arthritis Rheum. 2008;58:15-25. the commonly underdiagnosed and misdiagnosed disorders for various reasons. Studies show that axial spondyloarthritis may be more common than rheumatoid arthritis in the United States. The prevalence of rheumatoid arthritis is 0.6%, and that of axial spondyloarthritis is 1.4%. While these data show that axial spondyloarthritis is more common than rheumatoid arthritis, we don’t see this in clinical practice.

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Reasons for Missed and Delayed Diagnosis of rheumatoid arthritis and examination findings make the diagnosis quite obvious. Moreover, we all are more familiar with • Patients with axSpA are seen by other clinicians before rheumatologists its symptoms, examination findings, and the ways of diagnosis of – Family practice, internal medicine, chiropractors, osteopaths, physical rheumatoid arthritis. therapists, orthopedic surgeons, spine surgeons, neurosurgeons, physiatrists, dermatologists, ophthalmologists, gastroenterologists We just saw that the population prevalence of axial • X-rays take 8 to 10 years to show radiographic sacroiliitis spondyloarthritis is 1.4%, and that of ankylosing spondylitis is • Most common MRI scan ordered is L Spine, so SIJs are missed 0.5%. But in actual clinical practice, the diagnostic prevalence • Lack of reliable biomarkers other than HLA-B27 of axial spondyloarthritis is very low, as compared with that of population prevalence.

Insufficient Awareness of AS in the Primary Care Setting1

There are several reasons for missed and delayed diagnosis of this condition. The patients with axial spondyloarthritis are seen by Truven Healthcare Database: nonrheumatology doctors, like family practice, internal medicine, 127 million patients chiropractors, osteopaths, physical therapists, spine surgeons, 63% of AS diagnoses made and orthopedic surgeons. These patients may not be referred to by nonrheumatologists rheumatologists, because we do not think about this condition When patients with a diagnosis of AS are referred to a rheumatologist, when we are assessing patients with back pain. the diagnosis is confirmed in only 42% of cases

Another limitation is physical examination findings. There’s a lack of specific physical examination findings in patients with 1. Deodhar A et al. Clin Rheumatol. 2016;35:1769-1776. axial spondyloarthritis. There are no reliable markers available for diagnosis of axial spondyloarthritis other than HLA-B27, In this study, done using the Truven Healthcare Database that which is a sensitive test but not as specific for the diagnosis of has 127 million patients, about 63% of the time an ankylosing axial spondyloarthritis. The x-rays take 8 to 10 years to show spondylitis diagnosis was made by nonrheumatologists. When radiographic sacroiliitis, and during this time, the disease may be these patients were referred to rheumatologists, the diagnosis was missed. Also commonly, a lumbar spine MRI is ordered for patients confirmed only in 40% of the patients. with chronic back pain, and this does not include the sacroiliac joint cuts, so the sacroiliac joint findings are missed on MRI. Kaiser Permanente Northern California: Underrecognition and Lack of Referral of Patients With AS by PCPs1

Diagnostic Challenges

Kaiser Permanente Northern California Database 3,4 • Interval between onset of symptoms Average Time to Diagnosis and diagnosis is 4 to 9 years on average1 Point prevalence of “any” spondyloarthritis was 0.2%, AS was 0.1% – Multiple nuanced presentations mean that is one-tenth of real prevalence diagnosis is never straightforward axSpA ~7.4 y – axSpA is rarely diagnosed early Less than 50% of patients diagnosed – Majority of affected people are were referred to rheumatology not yet diagnosed RA ~9 mo • Some studies indicate as many as 25% of

patients who present to primary care offices 1. Curtis JR et al. Perm J. 2016;20:15-151. with CLBP may have axSpA2

1. Davis JC et al. Ann Rheum Dis. 2006;65:1518-1520. 2. van Hoeven L et al. Arthritis Care Res (Hoboken). 2014;66:446-453. 3. Chan KW et al. Arthritis Rheum. 1994;37:814-820. 4. Redeker I et al. 2018 American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting (2018 ACR/ARHP). Abstract 1658. A large study performed in the Kaiser Permanente Northern California Database found the point prevalence of ankylosing The average delay between symptom onset and diagnosis of axial spondylitis was 0.1%, as compared with the population prevalence spondyloarthritis ranges from 4 to 9 years, depending on different of 0.5%. The point prevalence of any spondyloarthritis was 0.2%, studies. Some studies indicate that as many as 25% of patients as compared with 1%, which may explain how this diagnosis is not who present to primary care offices with chronic low back pain picked up in the regular clinical practice. Also in this study, less may indeed have axial spondyloarthritis. Axial spondyloarthritis than 50% of the patients who were diagnosed to have ankylosing can be missed in rheumatology offices as well. Overall, a high spondylitis were indeed referred to rheumatology. index of suspicion is required for diagnosis.

In comparison, the average delay in the diagnosis of rheumatoid arthritis otherwise is only 9 months, because the symptoms

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Frequency of axSpA Diagnosis in Patients Seen Typical Clinical Features of axSpA by Rheumatologists for Evaluation of Chronic Back Pain1 Musculoskeletal Nonmusculoskeletal • IBP • Uveitis Referral strategy: If patients with CBP starting before aged 45 years • Peripheral arthritis • IBD with either IBP, HLB-B27 positivity, or sacroiliitis • Dactylitis • PsO • Enthesitis Prevalence of axSpA was 46% • Anterior chest wall pain

Other features specific to spondyloarthritis There is a 14-year delay in the diagnosis of axSpA • Strong association with HLA-B27 in the United States • Familial aggregation • Osteoproliferation • Negative RF

1. Deodhar A et al. Arthritis Rheumatol. 2016;68:1669-1676.

The PROSpA was performed in the United States to evaluate the The typical clinical features of axial spondyloarthritis could frequency of axial spondyloarthritis diagnoses among patients be divided as musculoskeletal and nonmusculoskeletal. The seen by rheumatologists, and it showed that about 40% of musculoskeletal symptoms include inflammatory back pain, patients in rheumatology practices did have axial spondyloarthritis peripheral arthritis, dactylitis, enthesitis, and anterior chest that was not identified in the past. wall pain. The nonmusculoskeletal symptoms, also called extra-articular symptoms, include uveitis, inflammatory This study used a referral strategy of referring the patients or bowel disease, and psoriasis. Some features that are specific evaluating the patients with chronic back pain starting before age to spondyloarthritis in general are strongly associated with of 45 who had either inflammatory back pain, positive for HLA-B27, HLA-B27, familial aggregation, presence of new bone formation or or had imaging evidence of sacroiliitis. Among subsequently osteoproliferation, and negative rheumatoid factor. That’s why this referred patients using this strategy, the prevalence of axial disease used to be called seronegative spondyloarthropathy. spondyloarthritis was 46%. This study also reported that the delay in an axial spondyloarthritis diagnosis in the United States is 14 Cohort Studies: years, which is unacceptable. Key Differences Between AS and nr-axSpA1-6 Variable AS vs nr-axSpA Age at onset Similar Combined Conclusions of Epidemiologic Studies AS: men more frequently afflicted (up to 3:1 vs women) 1-3 Sex on axSpA in the United States nr-axSpA: similar rates, but may be slightly more likely in women HLA-B27 positive Similar • Population-based studies show that the prevalence of axSpA is 1%, while the prevalence of AS and RA is 0.5% and 0.6%, respectively CRP Higher for patients with AS Pain scores Similar • Diagnostic prevalence of axSpA is one-tenth of population prevalence, indicating that axSpA (diluted amongst mechanical back pain [MBP]) is underrecognized BASDAI Similar BASFI Higher for patients with AS • Delay in diagnosis from onset of symptoms is 14 years BASMI Higher for patients with AS • 63% of patients with AS are diagnosed by nonrheumatologists; when re-examined TNFi response Similara by rheumatologists, only 40% of diagnoses are confirmed a Similar TNFi response if CRP elevation or MRI positive. TNFi response in normal CRP; MRI-negative nr-axSpA similar to placebo. 1. Baraliakos X et al. RMD Open. 2015;1:e000053. 2. Kiltz U et al. Arthritis Care Res (Hoboken). 2012;64:1415-1422. 3. Rudwaleit M et al. Arthritis Rheum. 2009;60:717- • axSpA diagnosis is also missed by rheumatologists 727. 4. Wallman JK et al. Arthritis Res Ther. 2015;17:378. 5. Callhoff J et al. Ann Rheum Dis. 2015;74:1241-1248. 6. Sieper J et al. Ann Rheum Dis. 2013;72:815-822. – 47% of patients were existing patients of rheumatologists who remained undiagnosed for a long time There are some key differences between ankylosing spondylitis 1. Deodhar A et al. Clin Rheumatol. 2016;35:1769-1776. 2. Curtis J et al. Perm J. 2016;20:15-151. 3. Deodhar A et al. Arthritis Rheumatol. 2016;68:1669-1676. and nonradiographic axial spondyloarthritis. Ankylosing spondylitis is seen more frequently in men, whereas Overall, we saw that population prevalence of axial nonradiographic axial spondyloarthritis tends to be [seen in similar spondyloarthritis is about 1%, and that of ankylosing spondylitis numbers] among men and women. The CRP is more frequently is 0.5%. However, diagnostic prevalence is one-tenth of the elevated in patients with ankylosing spondylitis. The functional population prevalence. This confirms our suspicion that axial impairment, as well as the limited range of movement, tends to spondyloarthritis is a widely underdiagnosed condition. And this occur more frequently with ankylosing spondylitis as compared underscores the importance of having a high suspicion when you with nonradiographic axial spondyloarthritis. However, the pain see patients with chronic low back pain, especially young adults scores and the disease activity as measured with different indices, who also have some other features that would suggest axial such as Bath Ankylosing Spondylitis Disease Activity Index, are spondyloarthritis. similar among the two stages of axial spondyloarthritis. The age of onset is also similar, so is the response to TNF inhibitors and positive HLA-B27 status.

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Inflammatory Back Pain (IBP)1-3 IBP vs MBP

• Cardinal symptom particularly in patients with axSpA IBP MBP • Usually starts before aged 45 years and lasts >3 months Onset Insidious Variable

• Prevalence of low back pain in general population is ~20% Morning stiffness Usually >30 min Usually minor Early morning and Maximum pain/stiffness Late in day – Only 5% of these patients have axSpA second half of night (OR = 20) • Sensitivity of IBP for diagnosis of axSpA is 70%-80%, and specificity variable is 20% Exercise/activity Improves symptoms (OR = 23) Worsens symptoms Duration Chronic Acute or chronic • In large cohorts of patients with back pain, up to 30% patients without axSpA may have IBP Age at onset Before aged 45 y Variable Response to NSAIDs Significant Variable

1. Underwood et al. Br J Rheumatol. 1995;34:1074-1077. 2. Reveille JD et al. Am J Med Sci. 2013;345:431-436. 3. Poddubnyy D et al. J Rheumatol. 2011;38:2452-2460.

Inflammatory back pain is the most common symptom in axial Overall, inflammatory back pain is insidious as opposed to spondyloarthritis. More than 85% of patients with axSpA have mechanical back pain where the onset is variable. Morning chronic inflammatory back pain. Of the patients who have stiffness is prolonged in patients with inflammatory back pain, chronic back pain in general population, only 5% have axial whereas it’s minor in patients who have mechanical back pain. spondyloarthritis. The inflammatory back pain is sensitive but The pain is also worse in the morning and second half of night not a specific feature of axial spondyloarthritis. Sensitivity of in patients with inflammatory back pain, whereas in those with inflammatory back pain is 70% to 80%, and specificity varies mechanical back pain, it’s worse late in the day. between 30% to 50%. In large cohorts of patients with back pain, up to 30% of patients without axial spondyloarthritis may fulfill the Exercises or activities improve the inflammatory back pain but inflammatory back pain criteria. So, in short, inflammatory back may make the mechanical back pain worse. The age of onset for pain is sensitive, but it is not a specific feature. inflammatory back pain is mostly before aged 45 years, while it can be variable in patients with mechanical back pain. Patients with inflammatory back pain respond very well to NSAIDs as opposed Characteristics of IBP1 to those with mechanical back pain.

Age at onset <45 y

Duration >3 mo Extra-Articular Manifestations1,2 Insidious onset

Morning stiffness >30 min • Major musculoskeletal manifestations include pain and inflammation in Improvement with exercise (OR = 23) – SIJs and spine Uveitisa No improvement with rest – Low back and neck; pain may improve with exercise Awakening from pain, especially during second half of night, but not with rest with improvement on arising (OR = 20) – Shoulders PsO – Hips and buttocks Alternating buttock pain IBD – Fingers and toes Subclinical IBDb IBP if 4 or more are positive • Disease can result in – Impaired mobility Dactylitis – Postural abnormalities 1. Taurog JD et al. N Engl J Med. 2016;374:2563-2574. Peripheral arthritis  Hyperkyphosis can appear within the first 10 years Enthesitis – Extra-articular manifestations in organs outside the spine Characteristics of inflammatory back pain include age of onset a Prevalence includes all axial and peripheral spondyloarthritis disease states. b Prevalence includes all axial and peripheral spondyloarthritis disease states. Subclinical is defined as relating to or denoting a disease that is not severe enough to present definite or readily observable symptoms. before aged 45 years, duration more than 3 months, usually 1. Rudwaleit M et al. Arthritis Rheum. 2009;60:717-727. 2. Kopylov U et al. J Rheumatol. 2018;45:498-505. insidious onset, morning stiffness lasting more than 30 minutes, pain improving with exercise but not with the rest, and the back Coming to the peripheral arthritis, it’s usually acute in onset, pain waking the patient up during the second half of the night intermittent. It is asymmetrical and oligoarthritis, meaning it with improvement on arising. Also, alternating buttock pain is one involves four or less joints. of the specific features of inflammatory back pain. The diagnosis of inflammatory back pain is usually clinical and depends on Peripheral arthritis usually favors joints of the lower extremities, obtaining the right information when assessing patients. and the frequency depends on the type of spondyloarthritis. For example, patients with psoriatic arthritis more frequently have peripheral arthritis as compared with patients who have axial spondyloarthritis.

Enthesitis is one of the specific features of this family of the diseases. Enthesitis is the site of insertion of ligaments, tendons, and joint capsule to the bone. Common sites for enthesitis in patients with axial spondyloarthritis include Achilles tendon

Go online to complete the post-test and evaluation for CME credit PeerView.com/WXC900 8 Overcoming Challenges in the Diagnosis and Management of Axial Spondyloarthritis: New Insights and Implications for Clinical Practice insertion, plantar fascia insertion, iliac crest, and lateral epicondyle. Spondyloarthritis is strongly associated with the HLA-B27 gene. In the clinical research studies, various enthesitis indices are used. Prevalence of HLA-B27 in Caucasians ranges between 6% to Dactylitis is a characteristic feature of spondyloarthritis, especially 9%. About 90% to 95% of patients with ankylosing spondylitis psoriatic arthritis and reactive arthritis. It occurs because of diffuse are HLA-B27 positive. However, if you look at 100 patients with swelling of flexor tendon sheath and adjacent soft tissue. It may a HLA-B27-positive status, only about 5 patients will go on to also involve the joints. develop ankylosing spondylitis. That means over 90 people with a positive HLA-B27 status will never develop ankylosing spondylitis. Among the extra-articular manifestations, uveitis is the most In summary, HLA-B27 forms about 40% of the overall risk for common, and it affects about 25% of patients with axial spondyloarthritis. spondyloarthritis. Uveitis in axial spondyloarthritis is usually acute anterior uveitis. Of the patients who present to their eye doctor Prevalence of AS with acute anterior uveitis, about 50% have spondyloarthritis and 50% are positive for the HLA-B27 gene. Anterior uveitis involves iris and ciliary body. Acute anterior uveitis is intermittent and Population AS Prevalence, % HLA-B27 Prevalence, % 1,2 self-limiting. Only less than 5% of patients develop chronic visual United States 0.52 6 impairment. Psoriasis is seen in about 10% of patients with axial The Netherlands3 0.1 8 spondyloarthritis. Germany4 0.55 9 Norway5 1.1-1.4 14

Haida Indians6 6.1 50 Burden of Disease in AS and nr-axSpA Is Similar1

1. Helmick CG et al. Arthritis Rheum. 2008;58:15-25. 2. Reveille JD et al. Arthritis Rheum. 2012; 64:1407-1411. 6 AS 5-10 y (n = 117) 3. van der Linden S et al. Arthritis Rheum. 1984; 27:241-249. 4. Braun J et al. Arthritis Rheum. 2005;52:4049-4050. 5. Gran T et al. Ann Rheum Dis. 1985;44:359-367. 6. Gofton JP et al. Ann Rheum Dis. 1966;25:525-527. 5.1 AS <5 y (n = 119) 5 4.8 4.8 nr-axSpA <5 y (n = 226) 4 4 3.9 3.9 3.1 3.1 The prevalence of ankylosing spondylitis mirrors the prevalence 3 2.5 of HLA-B27 in a particular geographic area. For example, among 2 2 2 Haida Indians, the HLA-B27 prevalence is 50% and prevalence 1.1 1 of ankylosing spondylitis is 6%. Whereas in United States, the 0 prevalence of HLA-B27 is 6%, and that of ankylosing spondylitis is BASDAI Pain BASFI BASMI 0.5%.

1. Rudwaleit M et al. Arthritis Rheum. 2009;60:717-727.

Prevalence of AS and axSpA1-6 Although we say nonradiographic disease is an earlier stage, the burden of disease activity is similar in ankylosing spondylitis. Data from the German Spondyloarthritis Inception Cohort show that patients with nonradiographic disease, early ankylosing spondylitis, and late ankylosing spondylitis have similar pain and disease activity scores. The functional limitation tends to be higher in patients with ankylosing spondylitis.

AS in the AS in SpA in the Genetics of AS1 population HLA-B27+ population

1. Gran JT et al. Ann Rheum Dis. 1985;44:359-367. 2. Braun J et al. Arthritis Rheum. 2005;52:4049-4050. 3. van der Linden SM et al. Arthritis Rheum. 1984;27:241-249. 4. Saraux A et al. Ann Rheum Dis. 2005;64:1431-1435. • Prevalence of HLA-B27 in Caucasians is 6%-9% 5. Adomaviciute D et al. Scand J Rheumatol. 2008;37:113-119. 6. Helmick CG et al. Arthritis Rheum. 2008;58:15-25.

• 90%-95% of patients with AS are HLA-B27+ In summary, only about 5% to 8% patients who are HLA-B27 • Less than 5% of patients who are HLA-B27+ develop AS; however, 20% of relatives of HLA-B27+ patients with AS will develop some kind positive will develop axial spondyloarthritis. This underlines the of spondyloarthritis fact that we should not be sending HLA-B27 gene tests for all • HLA-B27 forms about 40% of the overall risk for spondyloarthritis patients with chronic back pain. We should have a high suspicion

• MZ twin concordance rate for AS is 63% compared with DZ concordance of the patient having axial spondyloarthritis before ordering the rate of 12.5% HLA-B27 test.

1. Reveille J. Ann Rheum Dis. 2011;70(suppl 1):i44-i50.

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Frequency of HLA-B27 in Patients With SpA with back pain and at a nonradiographic stage, during which their x-ray may be normal but their MRI may be abnormal. And all of these patients then progressed to a radiographic stage Disorder Frequency, % AS 80-90 or ankylosing spondylitis in 6 to 10 years. The risk factors for Reactive arthritis 30-50 progression include high CRP, extensive MRI changes, male sex, Psoriatic arthritis 25 and smoking. Psoriatic spondylitis 60 Enteropathic arthritis 7 1 Enteropathic spondylitis 70 Natural History of axSpA: Newer Trends General US population 6.1

• IBP occurs in 6% of the US population, but only a small percentage develop nr-axSpA HLA-B27 tends to be positive whenever a patient with • Up to 12% of patients spondyloarthritis has spinal involvement or axial involvement as with nr-axSpA will develop AS compared with peripheral involvement. within 2 years

Pathogenesis of axSpA1 1. https://www.the-rheumatologist.org/article/rheumatologists-make-progress-defining-spectrum-of-axial-spondyloarthritis/3/.

But now, we think differently. The newer studies show that not every patient with inflammatory back pain will go on to develop nonradiographic disease or ankylosing spondylitis. Some of them may spontaneously remit. Among patients who have nonradiographic axial spondyloarthritis, some of the patients will develop radiographic changes over time, and others may remain in the nonradiographic stage.

1. Watad A et al. Front Immunol. 2018;9:2668. Radiographic Progression in nr-axSpA

The exact pathogenesis of axial spondyloarthritis is not clear. We think that among patients with risk factors such as altered microbiome, mechanical stress, smoking, male sex, and HLA-B27 Estimated that 10%-40% of patients with nr-axSpA progress to radiographic axSpA (AS) over a period of 2-10 years positivity, there is inflammation brought on by innate immune mechanisms with subsequent involvement of adaptive immunity, leading to inflammation, bone marrow edema, causing osteitis Patients with nr-axSpA who do not progress to AS do not necessarily remit—they just do not develop radiographic changes and new bone formation, and subsequently leading to the fusion. despite persistence of the IBP

Natural History of axSpA: Previous Concept1

Nonradiographic stage Radiographic stage 6-10 years The longitudinal studies in patients with nonradiographic disease modified New York Criteria (1984) show that 10% to 40% of patients progress to the radiographic

Back pain Back pain stage over a period of 2 to 10 years. Back pain Sacroiliitis Radiographic Syndesmophytes on MRI sacroiliitis The patients at the nonradiographic stage who do not progress

Time, y to ankylosing spondylitis do not necessarily remit. Rather, they do

Risk factors for progression: high CRP, extensive MRI changes, male sex, smoking not develop the radiographic changes despite the persistence of the inflammatory back pain, as well as other symptoms.

1. Rudwaleit M et al. Arthritis Rheum. 2005;52:1000-1008.

Previously, we used to think about axial spondyloarthritis in a linear fashion. What I mean is we thought that patients started

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Cardiovascular Comorbidities in Patients With AS: Risk Factors Associated With Progression to AS Integrated US Health Plan Data1

Consistent Inconsistent 30 a Controls (n = 7,372) AS (n = 1,843) a 27.1 Risk Factors Risk Factors 25.4 25 • Baseline low-grade x-ray • HLA-B27 positivity inconsistent 22 21.7 2,3 sacroiliitis1,2 between studies 20 3 • Male sex predictive for nr-axSpA • Baseline MRI inflammation 15 but protective for AS2 • Elevated CRP2 4 10 b • Buttock pain 8.3 Prevalence, % Prevalence, 7.1 6.6 5,6 a 5.3 a • Smoking 5 a 3.9 2.8 2.3 2.2 1.8 0.7 1.0 1.2 0 Athero CHF PVD CVD IHD T2DM Hyperlipid HTN Cardiovascular Comorbidities 1. Huerta-Sil G et al. Ann Rheum Dis. 2006;65:642-646. 2. Poddubnyy D et al. Ann Rheum Dis. 2011;70:1369-1374. 3. Bennett AN et al. Arthritis Rheum. 2008;58:3413-3418. 4. Sampaio-Barros PD et al. J Rheumatol. 2010;37:1195-1199. a P < .01. b P < .005. 5. Machado P et al. Arthritis Rheum. 2011;63(suppl 10):1650. 6. Poddubnyy D et al. Arthritis Rheum. 2012;64:1388-1398. 1. Han C et al. J Rheumatol. 2006;33:2167-2172.

The risk factors associated with progression to ankylosing Patients with ankylosing spondylitis are at a higher risk of spondylitis can be classified into consistent risk factors and cardiovascular comorbidities, including hypertension, coronary inconsistent risk factors. The consistent risk factors include artery disease, and stroke as compared with those without baseline mild x-ray changes, baseline MRI inflammation, and ankylosing spondylitis. elevated CRP. The inconsistent risk factors include positive HLA-B27, male sex, buttock pain, and smoking. How Do We Make the Diagnosis of axSpA?

Natural History and Disease Progression1 Gold standard for diagnosis of axSpA is clinician’s judgement

No specific biomarker yet

CRP, HLA-B27, x-ray SIJs, and MRI SIJs

1. Little H et al. Am J Med. 1976;60:279-285. So how do we make the diagnosis of axial spondyloarthritis? The gold standard for diagnosis of axial spondyloarthritis is clinician’s As you can see, if left untreated, patients with nonradiographic judgment. There is no specific biomarker yet, but we take help disease may develop ankylosing spondylitis, which leads to from C-reactive protein, HLA-B27, x-ray, and an MRI of the sacroiliac structural changes in the spine and joints and causes deformities. joint.

Late Complications of axSpA1 How Do Rheumatologists Diagnose axSpA in Practice?1

Not explained by other CBP for >3 months, onset <45 years causes, such as MBP or fibromyalgia Extra-Articular Manifestations Clinical Manifestations AS SIJs x-ray

Aortitis; aortic insufficiency; conduction disorders; Cardiac bundle-branch and atrioventricular blocks Presence of SpA features Renal Secondary amyloidosis; IgA nephropathy ≥4 SpA features <4 SpA features Pulmonary Fibrosis of the upper lobe and pleural thickening

Neurologic Cauda equina syndrome SpA features Confirmatory tests Consider • IBP • HLA-B27 another • Inflammatory arthritis • MRI diagnosis • IBD, PsO, uveitis nr-axSpA • Enthesitis • F/H of IBD and PsO

1. Ewerton Maia Rodrigues C et al. Rev Bras Rheumatol. 2012;52:375-383. 1. van den Berg R et al. Ann Rheum Dis. 2013;72:646-653.

Late complications of axial spondyloarthritis include osteoporosis, Among the patients with chronic back pain that started before aortic valve incompetence, apical fibrosis in the lungs, IgA aged 45 years that is not explained by other causes, such as nephropathy, amyloidosis, and rarely cauda equina syndrome. mechanical back pain or fibromyalgia, we prefer to get a plain

Go online to complete the post-test and evaluation for CME credit PeerView.com/WXC900 11 Overcoming Challenges in the Diagnosis and Management of Axial Spondyloarthritis: New Insights and Implications for Clinical Practice film of the pelvis. If there is sacroiliitis, that patient has ankylosing Diagnostic vs Classification Criteria1 spondylitis. If there is no sacroiliitis, we look into specific spondyloarthritis features. These spondyloarthritis features Diagnostic Criteria Classification Criteria include inflammatory back pain, inflammatory peripheral arthritis, Used by a physician to make a diagnosis Applied to patients in whom the diagnosis has already been made When making the diagnosis, the value of diagnostic uveitis, psoriasis, inflammatory bowel disease, enthesitis, and tests/parameters depends on the prevalence Prevalence of the disease is not important, since all patients of the disease (pretest probability) should have the disease (have been previously diagnosed) family history. If they have less than four spondyloarthritis features, Purpose of classification criteria is to provide a unique language The purpose of diagnostic criteria/algorithms for researchers to evaluate homogenous groups of patients, is to help diagnose individual patients we proceed to get the HLA-B27 status, as well as an MRI to further which facilitates comparisons of clinical or experimental studies Criteria for diagnosis should have a high sensitivity in order Criteria for classification should have a high specificity evaluate for the presence of axial spondyloarthritis. to identify as many patients with the disease as possible (close to 100%) in order to avoid misclassification (inclusion of patients who do not have the disease) Should allow for flexibility in diagnostic confidence (definite, probable, possible) Gives a yes or no answer (criteria fulfilled or not fulfilled) Modified New York Criteria (1984) for AS1 Applies to the individual patient Applies to groups of patients

Clinical Criteria 1. Deodhar A. Clin Rheumatol. 2014;33:741-747. a. Low back pain and stiffness for more than 3 months that improves with exercise but is not relieved by rest b. Limitation of motion of the lumbar spine in both the sagittal and As I said, the classification criteria are not supposed to be used for frontal planes diagnostic criteria; it is mainly for clinical research studies. c. Limitation of chest expansion relative to normal values correlated for age and sex Radiologic Criterion Imaging in Spondyloarthritis1 a. Sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally

Definition of AS Grade I Grade III If the radiologic criterion is associated with at least one clinical criterion

1. van der Linden S et al. Arthritis Rheum. 1984;27:361-368.

There are two widely used classification criteria for patients with axial spondyloarthritis: the Modified New York Criteria and the recent ASAS classification criteria. These criteria are used mainly in clinical research studies and are not supposed to be used for Grade II diagnosis. Grade IV

1. Sudoł-Szopinska I, Urbanik A. Pol J Radiol. 2013;78:43-49. To fulfill the Modified New York Criteria, a patient must have radiographic sacroiliitis with at least one additional clinical Imaging has particular importance in evaluation of patients with criterion, which includes inflammatory back pain, limitation of suspected spondyloarthritis, mainly because of a lack of specific motion at lumbar spine, and limitation of chest expansion. examination findings and biomarkers. On a plain x-ray, the sacroiliitis can be graded from grade I, where there are suspicious changes, to grade IV, where there is complete ankylosis or fusion in ASAS Classification Criteria for axSpA1 the joint. On spinal films, we look for syndesmophytes. Sometimes it can be difficult to distinguish between syndesmophytes in In patients with ≥3 mo back pain and age at onset <45 y ankylosing spondylitis from osteophytes from degenerative Sacroiliitis on imaging HLA-B27 or plus ≥1 SpA feature plus ≥2 other SpA features disease. Syndesmophytes tend to have vertical orientation, whereas osteophytes have a horizontal orientation. • SpA features – IBP; arthritis; enthesitis (heel); uveitis; dactylitis; PsO; Crohn’s disease/colitis; good response to NSAIDs; family history for SpA; HLA-B27; elevated CRP • Sacroiliitis on imaging 1 • Active (acute) inflammation on MRI highly suggestive of sacroliitis Bamboo Spine associated with SpA • Definite radiographic sacroliitis according to modified New York criteria

1. Rudwaleit M et al. Ann Rheum Dis. 2011;70:25-31.

The ASAS classification criteria have two arms: an imaging arm and a HLA-B27 arm. The patients in the imaging arm need to have sacroiliitis on x-ray or MRI plus one of the spondyloarthritis features, whereas patients who have a positive HLA-B27 status need to have two or more spondyloarthritis features to be classified as axial spondyloarthritis. 1. Sudoł-Szopinska I, Urbanik A. Pol J Radiol. 2013;78:43-49.

In advanced ankylosing spondylitis, patients can have extensive fusion between the vertebrae, leading to bamboo spine.

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Because rheumatologists cannot see all patients with back pain, 1 Imaging in Spondyloarthritis several different referral strategies have been introduced to help clinicians decide when to refer a patient with chronic back pain to T1W T2W rheumatology. These contain various spondyloarthritis features with good sensitivity, specificity, and likelihood ratio of having T2W axial spondyloarthritis.

Probability of axSpA Diagnosis 1 T1W Based on Clinical Features and Imaging

Insidious onset, Among patients with CBP chronicity (>3 mo), in GP/PCP office 5% association with morning stiffness, Presence of IBP 1. Baraliakos X et al. Best Pract Res Clin Rheumatol. 2016;30:608-623. improvement with 15% exercise but not rest, and alternating Presence of 1 or 2 additional SpA features: buttock pain enthesitis, dactylitis, uveitis, positive family history, Crohn’s disease, alternating buttock pain, 30%-70% PsO, asymmetrical arthritis, positive The use of MRI has revolutionized the assessment and evaluation response to NSAIDs, acute phase reactants (raised ESR/CRP) of patients with spondyloarthritis. With the help of MRI, we Probability HLA-B27+ (59%-90%) of axSpA can diagnose the axial spondyloarthritis much earlier. The >90% Imaging X-ray SIJ+ = AS specific findings on MRI include bone marrow edema on the X-ray SIJ- and MRI SIJ+ = nr-axSpA T2-weighted image and erosion and sclerosis on T1-weighted 1. Rudwaleit M et al. Ann Rheum Dis. 2004;63:535-543. images. We perform an MRI of the pelvis without contrast to look for sacroiliitis. We do not routinely do MRI of the lumbar spine in Among the patients with chronic back pain presenting to patients with suspected axial spondyloarthritis. the primary care doctors’ offices, 5% are going to have axial spondyloarthritis. If their back pain is inflammatory in nature, the probability goes up to 15%. If they have one or two additional Differential Diagnoses spondyloarthritis features, the likelihood goes up to 30% to 70%. If they have a positive HLA-B27 status, there is more than a 90% AS and nr-axSpA are commonly misdiagnosed as probability that they have axial spondyloarthritis. • Acute or chronic MBP or strain • Fibromyalgia • Diffuse idiopathic skeletal hyperostosis Candidate Parameters Used in the Referral Strategies • Vertebral compression facture • SIJ infection • IBP—an integral part of all the strategies • Osteitis condensans ilii • Erosive osteochondrosis • Evidence of sacroiliitis on available imaging (x-ray or MRI) • Familial Mediterranean fever • Presence of HLA-B27

• Family history of AS or axSpA

• Good response to NSAIDs

Differential diagnosis for patients with axial spondyloarthritis • Extra-articular manifestations of spondyloarthritis (PsO, IBD, and uveitis) include mechanical back pain; fibromyalgia; diffuse idiopathic • Family history of AS, IBD, and PsO skeletal hyperostosis; vertebral compression fracture; infections, especially when there is unilateral sacroiliitis; osteitis condensans ilii; and rarely familial Mediterranean fever. In general, in primary care doctors’ offices, the evaluation should Clinical Utility of the Clinical Parameters start with focusing on identification of inflammatory back pain. of Spondyloarthritis1 The candidate parameters used in referral strategies include

Sensitivity, % Specificity, % +LR inflammatory back pain, evidence of sacroiliitis on available IBP (updated information) 80 72 2.9 imaging, presence of HLA-B27, family history of spondyloarthritis, Enthesitis (heel pain) 37 89 3.4 good response to NSAIDs, and extra-articular manifestations. Peripheral arthritis 40 90 4.0 Dactylitis 18 96 4.5 Acute anterior uveitis 22 97 7.3 Positive family history for AS, AAU, IBD, ReA 32 95 6.4 PsO 10 96 2.5 IBD 4 99 4.0 Good response to NSAIDs 77 85 5.1  acute phase reactants 50 80 2.5

1. Rudwaleit M et al. Ann Rheum Dis. 2004;63:535-543.

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Single Center, Multicenter, and International Studies Evaluating extra-articular manifestations, positive family history, good Strategies for the Screening and Referral of axSpA1 response to NSAIDs, or elevated acute phase reactants. Referring Author and Year Strategy N Male, % axSpA, % AS, % nr-axSpA, % Physicians • LBP >3 mo, onset at <45 y ≥1 of IBP, + HLA-B27, Brandt 2007 Ortho primary care 350 48.6 45.4 50.3 49.7 sacroiliitis on available imaging Hermann 2009 GP • Calin criteria (4/5) 92 41 33 53.3 46.7 1,2 • LBP >2 mo < 10 y, onset at <45 y, ≥1 of AM stiffness, Disease Activity Braun 2011 Ortho improvement with exercise, not rest, waking at night, 322 50 35 41.6 58.4 improvement with NSAID • LBP >3 mo, onset <45 y • Strategy 1: ≥1 of IBP, + HLA-B27, sacroiliitis on available Poddubnyy 2011 imaging 318 53 41.8 61.6 38.4 BASDAI ASDAS GP and ortho (MASTER study) • Strategy 2: 2 of 5 IBP, + HLA-B27, sacroiliitis on available 242 55 36.8 61.8 38.2 imaging, positive family history for AS, 1. Fatigue 1. Total back pain good response to NSAID • LBP >3 mo, onset <45 y 2. Axial pain 2. Patient global • Strategy 1: ≥1 of IBP, + HLA-B27, sacroliitis on available Primary care Sieper 2012 imaging 504 47 35.6 77 23 Other (GP, 3. Peripheral joint pain/swelling 3. BASDAI q3 (RADAR study) • Strategy 2: 2 of 6 IBP, + HLA-B27, sacroliitis on available 568 55 39.8 78 22 neuro, ortho) imaging, positive family history for AS, good response 4. Entheses 4. BASDAI q6 to NSAID, EAM GP, eye, van den Berg 2013 • LBP >3 mo but <2 y, onset <45 y 157 33 41.4 18 82 5. AM stiffness intensity 5. CRP or ESR gastroenterology Deodhar 2014 Self rheumatology • LBP >3 mo, onset <45 y, ≥1 of IBP, + HLA-B27, sacroliitis 751 50 46 31 69 6. AM stiffness duration (ProSpA study) Other physicians on available imaging

1. Danve A et al. Clin Rheumatol. 2015;34:987-993.

The studies have shown that about 30% to 45% of patients who are referred using one of the referral strategies are diagnosed with 1. van der Heijde D et al. Ann Rheum Dis. 2009;68:1811-1818. 2. Sieper J et al. Ann Rheum Dis. 2009;68(suppl II):ii1-ii44. axial spondyloarthritis. Among patients with axial spondyloarthritis, we use composite Possible Screening Approach for axSpA indices to monitor the disease activity. The prominent disease in Patients With Chronic Low Back Pain1 activity indices include the Bath Ankylosing Spondylitis Disease CBP (>3 mo) Activity Index and Ankylosing Spondylitis Disease Activity Score. first symptoms in patients aged <45 years

IBP Sacroiliitis on any imaging HLA-B27+ • Sensitivity: 80%-90% • Sensitivity: 75% • Only if available • Specificity: 90% • Specificity: 75% • Not recommended • If positive, 1 in 3 patients • ~1 in 5 patients has for screening has axSpA axSpA, if positive • Simple to apply: yes • Simple to apply: yes • Costs: moderate (only • Costs: low once)

Refer to a rheumatologist With this approach, a rheumatologist will need to see three patients with back pain to be able to diagnose one patient with axSpA

1. Sieper J et al. Ann Rheum Dis. 2005;64:659-663.

One of the practical strategies could be sending a patient with chronic back pain to rheumatologists if they have inflammatory back pain, sacroiliitis on imaging, or HLA-B27 positivity. With this approach, rheumatologists will need to see three patients with back pain to be able to diagnose one patient with axial spondyloarthritis.

ASAS-Endorsed Recommendation for Early Referral of Suspected axSpA by PCPs or Nonrheumatologists1

• Patients with CLBP (duration ≥3 months) with onset before 45 years of age should be referred to a rheumatologist if at least one of the following parameters is present – IBPa – HLA-B27 positivity – Sacroiliitis on imaging, if available (on x-rays or MRI)b – Peripheral manifestations (arthritis, enthesitis, and/or dactylitis)c – Extra-articular manifestations (PsO, IBD, and/or uveitis)c – Positive family history for spondyloarthritisc – Good response to NSAIDsc – Elevated acute phase reactantsd

a Any set of criteria, preferably ASAS definition of IBP. b Only if imaging is available, not recommended as routine screening parameter. c According to the definition applied in the classification criteria for axSpA. d C-reactive protein serum concentration or erythrocyte sedimentation rate above upper normal limit after exclusion of other causes for elevation. 1. Poddubnyy D et al. Ann Rheum Dis. 2015;74:1483-1487.

According to the ASAS recommendations, patients with chronic back pain with onset before aged 45 years should be referred to a rheumatologist if at least one of the following parameters is present: inflammatory back pain, HLA-B27 positivity, imaging evidence of sacroiliitis, peripheral arthritis, enthesitis or dactylitis,

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Expert Insight on the Treatment The American College of Rheumatology (ACR) along with Spondyloarthritis Research and Treatment Network of Axial Spondyloarthritis (SPARTAN) published recommendations for treatment of axial spondyloarthritis in 2019.

Goals of axSpA Management Initial Therapy: Nonpharmacologic Interventions

Patient education • Nature of disease and advice about need for a lifelong exercise and posture-training program and about their working and leisure habits relevant to axSpA Reduce Maintain spinal Reduce functional • Importance of regular follow-up and management of comorbidities symptoms flexibility and posture limitations • Medication compliance and monitoring of disease activity and for potential AEs of therapies Counseling regarding smoking cessation

Depression screening and psychosocial support

Physical therapy • Newly diagnosed patients should be referred to a physical therapist for an initial evaluation Maintain Decrease and training ability to work complications • Exercises include postural training, range of motion exercises, stretching, recreational activities, and sometimes hydrotherapy • Spinal manipulation should be avoided in patients with spinal fusion or advanced spinal osteoporosis

Dr. Danve: The goals of management in axial spondyloarthritis According to these recommendations, the management of include reducing the patient’s symptoms, maintaining spinal patients with axial spondyloarthritis includes nonpharmacological flexibility and posture, reducing functional limitations, interventions and pharmacotherapy. The nonpharmacological maintaining the ability to work, and decreasing long-term interventions are of particular importance in patients with axial complications. spondyloarthritis in the long term. It should start with patient education, where patients should be advised about the nature of their disease and the need for lifelong exercises and a posture Primary Goals of Management for Patients With axSpA1 training program. The importance of regular follow-ups and management of comorbidities should be explained. Patients Optimize short- and long-term HRQOL through the following: should be educated about medication compliance, monitoring of their disease activity, and the potential adverse events of the Prevention of Minimization Maintenance Relief of Maintenance complications of extraspinal of effective therapies. symptoms of function of spinal and extra-articular psychosocial disease manifestations functioning and comorbidities Smoking cession is strongly recommended. As with other chronic To eliminate To reduce To preserve the impact symptoms To maintain To prevent social such as pain, flexion of axSpA- participation, the best associated diseases, patients should be screened for depression, and stiffness, and possible contractures, prevent fatigue or to especially disorders job loss, functional such as reduce them capacity dorsal and improve psychosocial support should be provided. Patients with newly to the minimal kyphosis uveitis and health status possible level aortic valve and function insufficiency diagnosed axial spondyloarthritis should be referred to physical 1. van der Heidje D et al. Ann Rheum Dis. 2017;76:978. therapists for initial evaluation and training of exercises, which include postural training and range-of-motion exercises. Spinal Overall, we would like to preserve social participation, prevent manipulation should be avoided in patients with spinal fusion or job loss, improve health-related quality of life, and function of the advanced spinal osteoporosis because of the risk of fracture. patients.

Exercise and Physical Therapy1

Cochrane review of 11 trials with 763 participants • Individualized home-based or supervised exercise programs are better than no exercise • Supervised group PT is better than home exercise • Combined in-patient spondyloarthritis exercise followed by group PT is better than group PT alone

ACR/SAA/SPARTAN • PT has been strongly recommended in both active and stable AS • Recommendations – Supervised PT + unsupervised back exercises – Both land-based and aquatic PT are very effective

1. Dagfinrud H et al. Cochrane Database Syst Rev. 2008:CD002822.

A Cochrane review of 11 trials with 763 participants showed that individualized a home-based or supervised exercise program was

Go online to complete the post-test and evaluation for CME credit PeerView.com/WXC900 15 Overcoming Challenges in the Diagnosis and Management of Axial Spondyloarthritis: New Insights and Implications for Clinical Practice better than no exercise. Supervised group physical therapy was In patients with axial spondyloarthritis, sulfasalazine works better better than home exercises, and combined inpatient exercises than methotrexate for peripheral arthritis. If the patient has followed by group physical therapy were better than group isolated sacroiliitis or enthesitis despite NSAIDs, you could consider physical therapy alone. The ACR guidelines strongly recommend local glucocorticoid injections. The steroid injections should physical therapy in patients with both active and stable ankylosing be avoided at sites like Achilles tendon, patellar tendon, and spondylitis. The recommendations include supervised physical quadriceps enthesis because of the risk of tendon rupture. therapy and unsupervised back exercises. The recommendations state that both land-based, as well as aquatic physical therapy, are Multiple RCTs Support Efficacy of NSAIDs in axSpA1,2 effective for patients with ankylosing spondylitis. • NSAIDs as first-line therapy in axSpA/AS – Various NSAIDs are equally effective Pharmacological Treatment Options – Should use two full strength NSAIDs before advancing to a biologic – Data show no benefit of continuous treatment vs on-demand treatment – Unclear if NSAIDs prevent radiographic progression in AS NSAIDs csDMARDS

TNF IL-17 inhibitors inhibitors

1. Ward MM et al. Arthritis Rheumatol. 2016;68:282-298. 2. Kroon FP et al. Cochrane Database Syst Rev. 2015;7:CD010952. JAK inhibitors and IL-23 inhibitors are in development Various NSAIDs are equally effective. One should use two different NSAIDs in full dose over 2 to 4 weeks before advancing to biologic therapy. It is not clear if NSAIDs prevent radiographic progression These are exciting times in regard to the pharmacotherapy for axial in patients with axial spondyloarthritis. spondyloarthritis; treatment options include NSAIDs, conventional DMARDs—mainly sulfasalazine and methotrexate—TNF inhibitors, How Effective Are NSAIDs?1 and IL-17 inhibitors. In development, there are JAK inhibitors and IL-23 inhibitors. • German cross-sectional study of 1,080 patients • 78% of patients with AS had regularly taken NSAIDs for their disease 12 months prior to the study Of the TNF inhibitors, certolizumab has been approved by the FDA • Most patients with AS commonly used diclofenac, naproxen, and for use in nonradiographic disease. Recently, the IL-17 inhibitors indomethacin secukinumab and ixekizumab have been approved by FDA for • Response rates nonradiographic disease. – 20% had complete pain response – 35% had a 50% response – 25% had a 25% response First-Line Treatment of Active AS: 2019 ACR/SAA/SPARTAN Recommendations1 – 20% had minimal response

1. Zochling J et al. Clin Rheumatol. 2006;25:794-800. Active AS and nr-axSpA Determine Isolated Sacroiliitis (Axial Disease) additional or Enthesitis disease NSAIDs manifestations NSAIDs In a cross-sectional study from Germany of 1,080 patients with • Continuous • No preferred NSAID ankylosing spondylitis, 20% of patients had complete response Isolated Sacroiliitis Physical therapy Peripheral Arthritis or Enthesitis Despite to NSAIDs, 20% of patients had no response to NSAIDs, and the Despite NSAIDs • Active over passive NSAIDs if ≤2 joints remaining had variable response. • Land-based over aquatic Local GC Local GC SSX Against systemic GCs • SSZ over MTX Avoid Achilles, patellar, and quadriceps Against LEF, APR, THL, ACR/SAA/SRTN entheses GC injections and PAM Treatment Recommendations 2019: NSAIDs1

1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613. Recommendation Level of Evidence In adults with active AS, NSAIDs are strongly recommended over no Low Patients with active ankylosing spondylitis should be started on treatment with NSAIDs Continuous treatment with NSAIDs over on-demand treatment with Low to moderate NSAIDs and sent for physical therapy. Continuous NSAIDs are NSAIDs is conditionally recommended preferred. The guidelines recommend against using systemic No particular NSAID is recommended as the preferred choice for treatment Low to moderate glucocorticoids for patients with active ankylosing spondylitis. Depending on the additional disease manifestations, those with peripheral predominant arthritis, despite NSAIDs, should be considered for sulfasalazine if more than two joints are involved or local glucocorticoid injections if less than two joints are involved. 1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613.

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Overall, the guidelines strongly recommend using NSAIDs for TNFi Therapy initial therapy in patients with ankylosing spondylitis. Continuous ASAS20 response rates at week 24 for infliximab, week 14 for golimumab, treatment with NSAIDs is preferred over on-demand treatment. and week 12 for adalimumab, certolizumab pegol, and etanercept The guidelines do not recommend any particular NSAID as the preferred choice.

ACR/SAA/SRTN Treatment Recommendations 2019: DMARDs1

Recommendation Level of Evidence

1. van der Heijde D et al. Arthritis Rheum. 2006;54:2136-2146. 2. Davis JC Jr et al. Arthritis Rheum. 2003;48:3230-3236. 3. Inman RD et al. Arthritis Rheum. 2008;58:3402-3412. 4. van der Heijde D et al. Arthritis Rheum. 2005;52:582-591. 5. Landewé R et al. Ann Rheum Dis. 2014;73:39-47. In patients with active AS despite NSAIDs, sulfasalazine, methotrexate, or tofacitinib are conditionally recommended over no treatment with these Very low medications—sulfasalazine or methotrexate should be considered only in to moderate patients with prominent peripheral arthritis when TNFis are not available There are five TNF inhibitors that have been approved for ankylosing spondylitis. The response rates as measured by ASAS20 and ASAS40 criteria tend to be similar.

1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613. Certolizumab Pegol in nr-axSpA: Phase 3 C-axSpAnd Study1 The role of conventional DMARDs in axial spondyloarthritis is mainly limited to patients with peripheral arthritis, because these Proportion of Patients Achieving Proportion of Patients Achieving Major Improvement in ASDAS-MI ASAS40 by Week 52 DMARDs usually are not effective for axial disease.

Active AS Despite NSAIDs: 2019 ACR/SAA/SPARTAN Recommendations1

Active AS despite NSAIDs 2L Therapy TNFi • Over TOF, SEC/IXE AS with unclear activity No preferred TNFi, except while on biologic AS + recurrent uveitis for AS + IBD or uveitis Spinal or pelvis MRI or AS + IBD

TNFi monoclonal antibodies over other biologics 1. Deodhar A et al. Arthritis Rheumatol. 2019;71:1101-1111. 3L Therapy Active AS on TNFi Against co-treatment with low-dose MTX

Active AS despite TNFi Active AS despite TNFi Recently, certolizumab has been approved for use in non- (1° nonresponder) (2° nonresponder) SEC/IXE (over TOF) Alternative TNFi radiographic disease, based on the data from C-axSpAnd study. TOF Against biosimilar of 1st TNFi Against biosimilar of 1st TNFi Against non-TNFi/non-SEC/ Against non-TNFi/non-SEC/ IXE or adding SSZ, MTX IXE or adding SSZ, MTX Prolonged Treatment With TNFis 1 1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613. Reduces Spinal Radiographic Progression in AS

• Objective: Evaluate spinal radiographic progression in a large cohort of patients For patients who active ankylosing spondylitis despite NSAIDs, with AS (n = 210) who are on TNFis; 8-year follow-up – GLAS cohort starting a TNFi 2004-2012 we use TNF inhibitors. Depending on the patient preferences and – X-rays at baseline and every 2 years scored by mSASSS comorbidities, the choice of TNF inhibitor is decided. For those – Baseline mean mSASSS was 10 who have active ankylosing spondylitis on TNF inhibitors, we see • During first 4 years, x-ray progressed linearly (estimated mean progression rate if they had primary nonresponse or secondary nonresponse. If 1.7 for 0-2 and 2-4 years) • However after 2 years, estimated mean progression rate was reduced from 2.3 they had primary nonresponse to the TNF inhibitor, we switch to 0.8 in patients who completed 8 years of treatment them to IL-17 inhibitor, either secukinumab or the ixekizumab. • Conclusions: Patients with AS on long-term TNFi showed reduction in spinal Those who had secondary nonresponse to the TNF inhibitor— radiographic progression after >4 years of follow-up meaning they initially responded but over the period they stopped 1. Maas F et al. Arthritis Care Res (Hoboken). 2017;69:1011-1019. responding—for those patients, we use an alternative TNF inhibitor before switching them to IL-17 inhibitors. Now we know that prolonged treatment with TNF inhibitors reduces the spinal radiographic progression. In this study from the GLAS cohort to evaluate the spinal radiographic progression in patients with ankylosing spondylitis had 8-year follow-up data. The x-rays were performed at baseline and every 2 years and scored with an index called modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). This study was done from 2004 to 2012.

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The researchers found that during the first 4 years, the x-ray TNFi: axSpA1 progressed linearly. However after that, the mean progression rates were reduced in patients who completed 8 years of treatment. In short, patients with ankylosing spondylitis who had Variables associated with TNFi response been on long-term TNF inhibitors showed a reduction in the spinal radiographic progression after more than 4 years of follow-up. Elevated Short duration Inflammation CRP/ESR of symptoms noted by MRI Studies also showed that the TNF retention in patients with axial spondyloarthritis tends to be about 90% at 6 months, 80% at 12 months, and 75% at 2 years. 30%-40% of patients with AS continue with active disease despite NSAIDs/TNFi therapy

TNFis: Contraindications and Adverse Events 1. Sieper J et al. Lancet. 2017;390:73-84.

• Active infection Overall, 30% to 40% of patients with ankylosing spondylitis • Latent TB Contraindications • Demyelinating disease continued to have active disease despite treatment with NSAIDs or • Heart failure TNF inhibitors and need something else. • Malignancy

• Injection-site reactions • HF • Infusion reactions • Cutaneous reactions IL-17 Inhibitors for axSpA AEs • Neutropenia • Malignancy • Infections • Induction of autoimmunity • Demyelinating disease

Secukinumab Ixekizumab Bimekizumab Netakimab The contraindications for TNF inhibitors include active infection, (approved) (approved) (in development) (in development) latent tuberculosis, demyelinating disease, heart failure, and malignancies—mainly melanoma or hematologic malignancies. The common adverse effects to TNF inhibitors include injection- site reactions, neutropenia, various serious or nonserious infections, demyelinating disease, exacerbation of underlying heart failure, induction of autoimmunity, and increased risk of skin cancers. And that something else now is IL-17 inhibitors. Of the IL-17 inhibitors, secukinumab and ixekizumab have been approved ACR/SAA/SRTN for use in AS, as well as nonradiographic disease. The other IL-17 Treatment Recommendations 2019: TNFis1 inhibitors in development include bimekizumab and netakimab.

Recommendation Level of Evidence Role of IL-17A in Bone Erosion In adults with active AS despite treatment with NSAIDs, a TNFi is strongly High 1 recommended over no treatment with a TNFi and Bone Formation in Spondyloarthritis

No particular TNFi is considered the preferred choice of treatment Moderate

In adults with active AS despite treatment with NSAIDs, treatment with a Very low TNFi over treatment with secukinumab or ixekizumab is recommended In adults with active AS despite treatment with NSAIDs, treatment with a Very low TNFi over treatment with tofacitinib is recommended

1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613.

The ACR guidelines recommend TNF inhibitors as the next option for patients whose disease is not adequately controlled with 1. McGonagle et al. Ann Rheum Dis. 2019;78:1167-1178. NSAIDs. No particular TNF inhibitor is preferred as such. IL-17A is an important cytokine secreted by Th17 cells and plays major role in inflammation, osteoproliferation, as well as osteoclastogenesis, in patients with axial spondyloarthritis.

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ACR/SAA/SPARTAN A Closer Look at the Approved IL-17 Inhibitors for axSpA Treatment Recommendations 2019: IL-17 Inhibitors1

Indication Dosage and Administration Adverse Reactions Recommendation Level of Evidence • AS recommended dosages, ± loading dosage – With a loading dosage: 150 mg at weeks 0, 1, 2, 3, • Adults with and 4, and every 4 weeks thereafter Most common adverse • In patients with AS despite treatment with NSAIDs, secukinumab active AS – Without a loading dosage: 150 mg every 4 weeks reactions (>1%) are • Adults with or ixekizumab is strongly recommended over no treatment High – If a patient continues to have active AS, consider a nasopharyngitis, Secukinumab1 active nr-axSpA with secukinumab or ixekizumab dosage of 300 mg every 4 weeks diarrhea, and upper with objective • nr-axSpA recommended dosages, ± loading dosage respiratory tract signs of – With a loading dosage: 150 mg at weeks 0, 1, 2, 3, infection inflammation • In patients with active AS despite treatment with TNFi, secukinumab and 4, and every 4 weeks thereafter or ixekizumab is conditionally recommended over treatment Very low – Without a loading dosage: 150 mg every 4 weeks with a different TNFi in patients with a primary nonresponse to TNFi • Adults with • AS recommended dose Most common (≥1%) active AS – 160 mg by subcutaneous injection (two 80 mg adverse reactions are • Adults with • In adults with active AS despite treatment with NSAIDs who have injections) at week 0, followed by 80 mg injection-site reactions, Ixekizumab2 active nr-axSpA contraindications to TNFis, secukinumab or ixekizumab are every 4 weeks upper respiratory tract with objective Low • nr-axSpA recommended dose infections, nausea, and conditionally recommended over treatment with methotrexate, signs of – 80 mg by subcutaneous injection every 4 weeks tinea infections. inflammation sulfasalazine, or tofacitinib

1. Cosentyx (secukinumab) Prescribing Information. https://www.novartis.us/sites/www.novartis.us/files/cosentyx.pdf. 2. Taltz (ixekizumab) Prescribing Information. https://uspl.lilly.com/taltz/taltz.html#pi. 1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613.

Based on several randomized controlled studies, now we The ACR guidelines recommend using secukinumab or ixekizumab know that IL-17 inhibitors, including secukinumab and in patients who had primary nonresponse to TNF inhibitors. ixekizumab, improve the disease activity in patients with axial Some patients with axial spondyloarthritis may respond well spondyloarthritis, including ankylosing spondylitis, as well as to TNF inhibitors for initial months or years, and then they lose nonradiographic disease. These two medications now have been the response. In such patients, we use alternative TNF inhibitor approved by FDA for use in nonradiographic disease, as well as before switching them to IL-17 inhibitors. Patients who had ankylosing spondylitis. contraindications to TNF inhibitors are candidates for IL-17 inhibitor therapy. Forest Plot of the Efficacy of IL-17 Inhibitors in the Treatment of AS: ASAS201 JAK Inhibitors for axSpA1-3

Tofacitinib Filgotinib Upadacitinib

1. Yin Y et al. Arthritis Res Ther. 2020;22:111. .

1. van der Heijde D et al. Ann Rheum Dis. 2017;76:1340-1347. 2. van der Heide D et al. Lancet. 2018;392:2378-2387. 3. van der Heijde D et al. 2019 ACR/ARP Annual Meeting (ACR 2019). Abstract 2728. In a recent systematic review and meta-analysis to assess the efficacy and safety of IL-17 inhibitors in active ankylosing Clinical trials are underway for JAK inhibitors in axial spondylitis, the researchers included data from six studies spondyloarthritis. These include tofacitinib, upadacitinib and including 1,733 patients of which 1,153 patients received IL-17 filgotinib. inhibitors, whereas 580 patients who received placebo were included. At week 16, the IL-17 inhibitor regimen produced Treatment of Stable AS: significant increase in ASAS20 response rate and ASAS40 response 2019 ACR/SAA/SPARTAN Recommendations1 rate. With respect to the safety profile, patients treated with IL-17 Stable AS Determine additional Spinal fusion or advanced (axial disease) disease manifestation osteoporosis inhibitors are at increased risk of infections, including reactivation NSAIDs Avoid spinal manipulation • On-demands of latent tuberculosis. Physical Therapy Severe kyphosis Advanced hip arthritis Avoid spinal osteotomy Total hip arthroplasty

Stable AS on biologic Stable AS on TNFi + NSAID Stable AS on TNFi Stable AS on TNFi + oral small molecule • Against discontinuation If on originator TNFi, do not Continue TNFi alone; Continue TNFi alone; of biologic switch to stop NSAID stop csARD biosimilar TNFi • Against biologic tapering as a standard approach as a standard approach Against cotreatment with low-dose MTX

1. Ward MM et al. Arthritis Rheumatol. 2019;71:1599-1613.

For patients who have stable disease, the guidelines recommend continuing NSAIDs as required. All the patients should continue physical therapy and exercises at home. Spinal manipulation

Go online to complete the post-test and evaluation for CME credit PeerView.com/WXC900 19 Overcoming Challenges in the Diagnosis and Management of Axial Spondyloarthritis: New Insights and Implications for Clinical Practice should be avoided in patients who have advanced osteoporosis or spinal fusion, especially in the thoracal spine. In patients who have severe kyphosis, osteotomy usually is recommended against. In those who have stable disease, the guidelines recommend using on-demand NSAIDs and continuing physical therapy.

For patients who have stable disease on biologic, the guidelines recommend against discontinuation of biologics or tapering the dose of biologics. If a patient is doing well with a TNF inhibitor and NSAID, you can stop the NSAID and continue only the TNF inhibitor. We used to give methotrexate in addition to TNF inhibitors to improve the retention of TNF, but now the studies show that this may not be required, so we can stop the conventional DMARDs if they are on them. The guidelines for using biosimilars in United States are not clear as yet.

Summary1,2

• axSpA (AS and nr-axSpA) is the most frequent type of spondyloarthritis • Average delay in diagnosis is 8-11 years • Disease activity (BASDAI) is similar in AS and nr-axSpA • Patients with nr-axSpA respond as well to TNF inhibitors as well as patients with AS • Differentiating features of nr-axSpA from AS – M:F 1:1 – Less frequent CRP elevation and MRI lesions – Less impaired mobility • Osteoporosis, apical fibrosis, IgA nephropathy, and amyloidosis are complications of AS

1. Taurog JD et al. N Engl J Med. 2016;375:1303. 2. Sieper J, Poddubnyy D. Lancet. 2017;390:73-84.

In summary, axial spondyloarthritis is most frequent type of spondyloarthritis. It contains AS, as well as its earlier stage, nonradiographic disease. The average delay in diagnosis is 8 to 11 years, which is unacceptable. The disease activity, as well as response to the treatment, is similar in earlier stages and later stages of the disease. This condition is associated with many other comorbidities. It is recommended that internal medicine physicians evaluate patients with chronic back pain with the focus of identifying if the back pain is inflammatory in nature. If the back pain is inflammatory in nature, please look for other spondyloarthritis features. You could start with a plain pelvic x-ray to look for sacroiliitis and start the patients on full-dose NSAIDs. Patients should be educated regarding seeing a rheumatologist and following nonpharmacological interventions. Now we have good treatment options, and if started early patients’ disease activity, their function, and quality of life improves as well. We are able to prevent long-term complications, including fusion of the spine. Thank you very much.

Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

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This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.

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