CME Overcoming Challenges in the Diagnosis and Management

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Abhijeet Danve, MD, FACP, FACRYale School of Medicine New Haven, Connecticut

Chair

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CME

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

What’s Inside

3

15

A Closer Look at Strategies to Improve the Timely Recognition of Axial Spondyloarthritis

Expert Insight on the Treatment of Axial Spondyloarthritis

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Activity Information

Media: Enduring MaterialAccredited Activity Release Date: August 28, 2020Accredited Activity Expiration Date: August 27, 2021Time to Complete Activity: 60 minutes

Activity Description In this activity, an expert in rheumatology discusses practical strategies for identifying and managing axial spondyloarthritis (axSpA) in clinical practice.

Target Audience This activity has been designed to meet the educational needs of internists and other clinicians involved in the identification and care of patients with axSpA.

Educational Objectives Upon completion of this activity, participants should be better able to:• Identify axSpA in patients with inflammatory back pain via assessment of

medical history, musculoskeletal symptoms and findings, and extra-articular manifestations and comorbidities

• Apply classification criteria and diagnostic tests into clinical practice to support early detection of axSpA

• Assess efficacy and safety data related to novel biologic options for axSpA, recognizing the potential clinical impact on the management of patients who do not respond well to traditional pharmacologic therapies

• Employ treatment plans for individual patients with axSpA in accordance with current evidence, expert recommendations, and patient needs and preferences

• Recognize the importance of collaborating with rheumatologists to provide optimal treatment and longitudinal support for patients with axSpA

Providership, Credit, and SupportThis 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.

Physician Continuing Medical EducationThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint

providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

The Medical Learning Institute, Inc. designates this enduring material for a 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.

Faculty DisclosuresChair 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.

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Content/Peer Reviewer DisclosuresThe following Content/Peer Reviewer has nothing to disclose:

Matthew A. Goodman, MD

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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 feel. Learn to smell. And know that by practice alone can you become expert." The practice of rheumatology is all about pattern recognition”

Patient Case

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

Wakes up because of back pain; NSAIDs provide significant relief

Needs to visit her podiatrist for recurrent plantar fasciitis

Normal ROM at L spine, mild tenderness at insertion of plantar fascia on calcaneus; otherwise, normal joint examination

Labs show normal ESR and CRP, but positive for HLA-B27

44-year-old woman

with chronic low back

pain (CLBP) for 6-8 years

Dr. Danve: We’ll begin with a case. A 44-year-old, otherwise healthy woman presents with chronic low back pain that has been ongoing for 6 to 8 years. The back pain is worse with prolonged rest, and it improves with exercises, as well as activities. Sometimes 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 examination, as well as systemic examination, is normal. Blood tests show normal sed rate and normal CRP, but she’s positive HLA-B27 gene.

A Closer Look at Strategies to Improve the Timely Recognition of Axial Spondyloarthritis

Sacroiliitis Grade 0 (Normal)a

a Image courtesy of Dr. Abhijeet Danve.

An x-ray of the pelvis was performed that did not show sacroiliitis.

Patient Casea (Cont’d)

Patient referred to a rheumatologist

who had high suspicion of spondyloarthritisb

a Image courtesy of Dr. Abhijeet Danve. 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 see, it showed inflammatory changes on both sides of the bilateral SIJs. Here you can see the bone marrow edema in the subchondral aspect of the right, as well as the left, SIJ on the T2-weighted STIR image.

So what can we call patients who do not have definitive sacroiliitis but have other features

suggestive of spondyloarthritis?

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



Spectrum of Spondyloarthritis1

1. Raychaudhuri SP, Deodhar A. J Autoimmun. 2014;48-49:128-133.

Undifferentiated peripheral

spondyloarthritis

Axial spondyloarthritis

Peripheral spondyloarthritis

PsA

ReA

Arthritis of IBD

Nonradiographic axial spondyloarthritis

AS

The term spondyloarthritis is used for a group of interrelated conditions that share similar genetic, pathophysiologic, and clinical features. Largely, the spondyloarthritis would be axial or peripheral. The axial disease affects the spine, hips, and the SIJs. Peripheral spondyloarthritis mainly affects the peripheral joints in the extremities. However, this classification is not absolute, and significant overlap is seen among patients with axial spondyloarthritis and peripheral spondyloarthritis.

Main types of axial spondyloarthritis are nonradiographic axial spondyloarthritis and ankylosing spondylitis. Prominent diseases that come under the peripheral spondyloarthritis umbrella are psoriatic arthritis, reactive arthritis, and arthritis of inflammatory bowel disease.

Axial spondyloarthritis is an expanded concept of ankylosing spondylitis. In the past we used to wait until patients developed structural changes in the spine and SIJs on x-ray to formally diagnose them with ankylosing spondylitis and start treatment. But now we realize that ankylosing spondylitis is an advanced stage, and patients have been suffering with back pain and other symptoms for many years before the radiographic changes occur. To include the earlier stages of the disease, the term axial spondyloarthritis was introduced.

• axSpA became the standard nomenclature in 2009 based on a multinational study by ASAS1,2

• ASAS divided axSpA into 2 main subtypes

– AS (r-axSpA)

– nr-axSpA

• ASAS classification is also validated for patients with peripheral, rather than axial, SpA3

– Patients whose symptoms are not predominantly back pain but PsA, reactive arthritis, and arthritis-associated IBD

Nomenclature1

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.

Axial spondyloarthritis became the standard nomenclature in 2009 based on a multinational study done by The Assessment of a Spondyloarthritis International Society called ASAS. ASAS

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

Defining AS and nr-axSpA1,2

1. van der Heijde et al. Ann Rheum Dis. 2017;76:978-991. 2. Sieper J et al. Arthritis Rheum. 2013;65:534-551.

AS (r-axSpA) nr-axSpA

• Clear evidence of sacroiliitis on plain radiographs (x-rays)

• Spinal involvement is more extensive • Structural abnormalities of vertebrae

often present

• No radiographic evidence of sacroiliitis • Inflammation of sacroiliac joints may be

detected by MRI • Severity of symptoms usually similar

• Emerging thinking is that axSpA is a single disease continuum with radiographic severity increasing over time

• Sacroiliitis is now considered a late or alternative finding in the disease course; inflammation precedes structural spinal damage

• Of patients with nr-axSpA, 5%-10% develop radiographic evidence of AS within 2 years and 20% after 5 years

In patients who have ankylosing spondylitis, there is clear evidence of sacroiliitis on plain x-rays. The spinal involvement is more extensive. The structural abnormalities of vertebrae often present on x-rays, whereas in nonradiographic axial spondyloarthritis by definition, the x-ray does not show definite radiographic sacroiliitis. The inflammation in the SI joints may be detected by MRI. The severity of symptoms is similar between nonradiographic axial disease and ankylosing spondylitis. The emerging thinking is that axial spondyloarthritis is a single disease continuum with radiographic severity increasing over the time. Therefore, radiographic sacroiliitis is now considered a late finding in the disease course, because inflammation precedes structural damage in the SIJs and the spine, too.

• Immune-mediated chronic inflammatory disease affecting the axial and peripheral skeleton, as well as extra-articular organs such as skin, gut, and eyes

• Mainly affects young individuals in their third or fourth decade

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

• Heterogeneous presentation and progression

What is axSpA?1

1. Danve A, Deodhar A. Curr Rheumatol Rep. 2017;19:22.

Overall, axSpA, or axial spondyloarthritis, is an immune-mediated chronic inflammatory disease affecting the axial, as well as peripheral, skeleton, and extra-articular organs such as skin, intestines, and eyes. It mainly affects young individuals in their third or fourth decade and frequently leads to significant pain, loss of function, work disability, and impaired quality of life. Patients with this condition have a heterogeneous presentation, as well as progression.



Why Care About axSpA?

Not every patient’s

back pain is mechanical

Much more common than

we think

Frequently missed by internists

axSpA has great treatment options, and if treated early future progression may be prevented

Associated with comorbidities such as HTN, CAD, and CVA

Why should internal medicine doctors care about axial spondyloarthritis? Because not every patient’s back pain is mechanical. Axial spondyloarthritis is much more common than we think. It is frequently missed in internists’ offices. Now axial spondyloarthritis has a great treatment options, and if treated early it may prevent future progression, as well as the complications. For internal medicine in particular, axial spondyloarthritis being an inflammatory disease can be associated with comorbidities such as hypertension, coronary artery disease, sleep apnea, and an increased risk of stroke.

How Common Is axSpA in Clinical Practice?

This begs the next question, how common is axial spondyloarthritis in clinical practice? We think that this is one of the commonly underdiagnosed and misdiagnosed disorders for various reasons.

• NHANES 2009-2010 of 5,103 participants in the United States showed

– CLBP in 19.4%

– Inflammatory back pain (IBP) in 7%

– HLA-B27 prevalence of 6%

Non-Hispanic whites (Caucasians): 7.5%

Mexican Americans: 4.6%

– axSpA in 1% (0.9%-1.4%)

– AS in 0.5%

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

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

The National Health and Nutrition Examination Survey, which was performed in 2009 with 5,103 participants in the United States, showed that the prevalence of axial spondyloarthritis was about 1% and ankylosing spondylitis was 0.5%. This survey also showed that chronic back pain is reported by almost 20% of the population, out of which 7% of them can have features of inflammatory back pain. Overall, the prevalence of HLA-B27 in United States is 6%. In non-Hispanic whites, it’s about 7.5%, and in Mexican Americans, it’s about 4.6%. In African Americans, it ranges 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 the prevalence of axial spondyloarthritis.

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

0.15 0.31 0.31

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AS SpA RA

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1. Saraux A et al. Ann Rheum Dis. 2005;64:1431-1435. 2. Guillemin F et al. Ann Rheum Dis. 2005;64:1427-1430. 3. Adomaviciute D et al. Scand J Rheumatol. 2008;37:113-119. 4. Helmick CG et al. Arthritis Rheum. 2008;58:15-25.

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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.



• Patients with axSpA are seen by other clinicians before rheumatologists

– Family practice, internal medicine, chiropractors, osteopaths, physical therapists, orthopedic surgeons, spine surgeons, neurosurgeons, physiatrists, dermatologists, ophthalmologists, gastroenterologists

• X-rays take 8 to 10 years to show radiographic sacroiliitis

• Most common MRI scan ordered is L Spine, so SIJs are missed

• Lack of reliable biomarkers other than HLA-B27

Reasons for Missed and Delayed Diagnosis

There are several reasons for missed and delayed diagnosis of this condition. The patients with axial spondyloarthritis are seen by nonrheumatology doctors, like family practice, internal medicine, chiropractors, osteopaths, physical therapists, spine surgeons, and orthopedic surgeons. These patients may not be referred to rheumatologists, because we do not think about this condition when we are assessing patients with back pain.

Another limitation is physical examination findings. There’s a lack of specific physical examination findings in patients with axial spondyloarthritis. There are no reliable markers available for diagnosis of axial spondyloarthritis other than HLA-B27, which is a sensitive test but not as specific for the diagnosis of axial spondyloarthritis. The x-rays take 8 to 10 years to show radiographic sacroiliitis, and during this time, the disease may be missed. Also commonly, a lumbar spine MRI is ordered for patients with chronic back pain, and this does not include the sacroiliac joint cuts, so the sacroiliac joint findings are missed on MRI.

Diagnostic Challenges

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.

• Interval between onset of symptoms and diagnosis is 4 to 9 years on average1

– Multiple nuanced presentations mean diagnosis is never straightforward

– axSpA is rarely diagnosed early

– Majority of affected people are not yet diagnosed

• Some studies indicate as many as 25% of patients who present to primary care offices with CLBP may have axSpA2

~9 mo

~7.4 y

RA

axSpA

Average Time to Diagnosis3,4

The average delay between symptom onset and diagnosis of axial spondyloarthritis ranges from 4 to 9 years, depending on different studies. Some studies indicate that as many as 25% of patients who present to primary care offices with chronic low back pain may indeed have axial spondyloarthritis. Axial spondyloarthritis can be missed in rheumatology offices as well. Overall, a high 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

of rheumatoid arthritis and examination findings make the diagnosis quite obvious. Moreover, we all are more familiar with its symptoms, examination findings, and the ways of diagnosis of rheumatoid arthritis.

We just saw that the population prevalence of axial spondyloarthritis is 1.4%, and that of ankylosing spondylitis is 0.5%. But in actual clinical practice, the diagnostic prevalence of axial spondyloarthritis is very low, as compared with that of population prevalence.

Insufficient Awareness of AS in the Primary Care Setting1

When patients with a diagnosis of AS are referred to a rheumatologist, the diagnosis is confirmed in only 42% of cases

Truven Healthcare Database: 127 million patients

63% of AS diagnoses made by nonrheumatologists

1. Deodhar A et al. Clin Rheumatol. 2016;35:1769-1776.

In this study, done using the Truven Healthcare Database that has 127 million patients, about 63% of the time an ankylosing spondylitis diagnosis was made by nonrheumatologists. When these patients were referred to rheumatologists, the diagnosis was confirmed only in 40% of the patients.

1. Curtis JR et al. Perm J. 2016;20:15-151.

Kaiser Permanente Northern California: Underrecognition and Lack of Referral of Patients With AS by PCPs1

Less than 50% of patients diagnosed were referred to rheumatology

Kaiser Permanente Northern California Database

Point prevalence of “any” spondyloarthritis was 0.2%, AS was 0.1% that is one-tenth of real prevalence

A large study performed in the Kaiser Permanente Northern California Database found the point prevalence of ankylosing spondylitis was 0.1%, as compared with the population prevalence of 0.5%. The point prevalence of any spondyloarthritis was 0.2%, as compared with 1%, which may explain how this diagnosis is not picked up in the regular clinical practice. Also in this study, less than 50% of the patients who were diagnosed to have ankylosing spondylitis were indeed referred to rheumatology.



Frequency of axSpA Diagnosis in Patients Seen by Rheumatologists for Evaluation of Chronic Back Pain1

There is a 14-year delay in the diagnosis of axSpA in the United States

Referral strategy: If patients with CBP starting before aged 45 years with either IBP, HLB-B27 positivity, or sacroiliitis

Prevalence of axSpA was 46%

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

The PROSpA was performed in the United States to evaluate the frequency of axial spondyloarthritis diagnoses among patients seen by rheumatologists, and it showed that about 40% of patients in rheumatology practices did have axial spondyloarthritis that was not identified in the past.

This study used a referral strategy of referring the patients or evaluating the patients with chronic back pain starting before age of 45 who had either inflammatory back pain, positive for HLA-B27, or had imaging evidence of sacroiliitis. Among subsequently referred patients using this strategy, the prevalence of axial spondyloarthritis was 46%. This study also reported that the delay in an axial spondyloarthritis diagnosis in the United States is 14 years, which is unacceptable.

• 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

• Diagnostic prevalence of axSpA is one-tenth of population prevalence, indicating that axSpA (diluted amongst mechanical back pain [MBP]) is underrecognized

• Delay in diagnosis from onset of symptoms is 14 years

• 63% of patients with AS are diagnosed by nonrheumatologists; when re-examined by rheumatologists, only 40% of diagnoses are confirmed

• axSpA diagnosis is also missed by rheumatologists

– 47% of patients were existing patients of rheumatologists who remained undiagnosed for a long time

Combined Conclusions of Epidemiologic Studies on axSpA in the United States1-3

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.

Overall, we saw that population prevalence of axial spondyloarthritis is about 1%, and that of ankylosing spondylitis is 0.5%. However, diagnostic prevalence is one-tenth of the population prevalence. This confirms our suspicion that axial spondyloarthritis is a widely underdiagnosed condition. And this underscores the importance of having a high suspicion when you see patients with chronic low back pain, especially young adults who also have some other features that would suggest axial spondyloarthritis.

Typical Clinical Features of axSpA

Musculoskeletal Nonmusculoskeletal • IBP • Peripheral arthritis • Dactylitis • Enthesitis • Anterior chest wall pain

• Uveitis • IBD • PsO

Other features specific to spondyloarthritis • Strong association with HLA-B27 • Familial aggregation • Osteoproliferation • Negative RF

The typical clinical features of axial spondyloarthritis could be divided as musculoskeletal and nonmusculoskeletal. The musculoskeletal symptoms include inflammatory back pain, peripheral arthritis, dactylitis, enthesitis, and anterior chest wall pain. The nonmusculoskeletal symptoms, also called extra-articular symptoms, include uveitis, inflammatory bowel disease, and psoriasis. Some features that are specific to spondyloarthritis in general are strongly associated with HLA-B27, familial aggregation, presence of new bone formation or osteoproliferation, and negative rheumatoid factor. That’s why this disease used to be called seronegative spondyloarthropathy.

Cohort Studies: Key Differences Between AS and nr-axSpA1-6

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;60:717-727. 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.

Variable AS vs nr-axSpA

Age at onset Similar

Sex AS: men more frequently afflicted (up to 3:1 vs women) nr-axSpA: similar rates, but may be slightly more likely in women

HLA-B27 positive Similar

CRP Higher for patients with AS

Pain scores Similar

BASDAI Similar

BASFI Higher for patients with AS

BASMI Higher for patients with AS

TNFi response Similara

There are some key differences between ankylosing spondylitis and nonradiographic axial spondyloarthritis. Ankylosing spondylitis is seen more frequently in men, whereas nonradiographic axial spondyloarthritis tends to be [seen in similar numbers] among men and women. The CRP is more frequently elevated in patients with ankylosing spondylitis. The functional impairment, as well as the limited range of movement, tends to occur more frequently with ankylosing spondylitis as compared with nonradiographic axial spondyloarthritis. However, the pain scores and the disease activity as measured with different indices, such as Bath Ankylosing Spondylitis Disease Activity Index, are 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.



• Cardinal symptom particularly in patients with axSpA

• Usually starts before aged 45 years and lasts >3 months

• Prevalence of low back pain in general population is ~20%

– Only 5% of these patients have axSpA

• Sensitivity of IBP for diagnosis of axSpA is 70%-80%, and specificity variable is 20%

• In large cohorts of patients with back pain, up to 30% patients without axSpA may have IBP

Inflammatory Back Pain (IBP)1-3

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 spondyloarthritis. More than 85% of patients with axSpA have chronic inflammatory back pain. Of the patients who have chronic back pain in general population, only 5% have axial spondyloarthritis. The inflammatory back pain is sensitive but not a specific feature of axial spondyloarthritis. Sensitivity of inflammatory back pain is 70% to 80%, and specificity varies between 30% to 50%. In large cohorts of patients with back pain, up to 30% of patients without axial spondyloarthritis may fulfill the inflammatory back pain criteria. So, in short, inflammatory back pain is sensitive, but it is not a specific feature.

Age at onset <45 y

Duration >3 mo

Insidious onset

Morning stiffness >30 min

Improvement with exercise (OR = 23)

No improvement with rest

Awakening from pain, especially during second half of night, with improvement on arising (OR = 20)

Alternating buttock pain

1. Taurog JD et al. N Engl J Med. 2016;374:2563-2574.

Characteristics of IBP1

IBP if 4 or more are positive

Characteristics of inflammatory back pain include age of onset before aged 45 years, duration more than 3 months, usually insidious onset, morning stiffness lasting more than 30 minutes, pain improving with exercise but not with the rest, and the back pain waking the patient up during the second half of the night with improvement on arising. Also, alternating buttock pain is one of the specific features of inflammatory back pain. The diagnosis of inflammatory back pain is usually clinical and depends on obtaining the right information when assessing patients.

IBP vs MBP

IBP MBP

Onset Insidious Variable

Morning stiffness Usually >30 min Usually minor

Maximum pain/stiffness Early morning and second half of night (OR = 20) Late in day

Exercise/activity Improves symptoms (OR = 23) Worsens symptoms

Duration Chronic Acute or chronic

Age at onset Before aged 45 y Variable

Response to NSAIDs Significant Variable

Overall, inflammatory back pain is insidious as opposed to mechanical back pain where the onset is variable. Morning stiffness is prolonged in patients with inflammatory back pain, whereas it’s minor in patients who have mechanical back pain. The pain is also worse in the morning and second half of night in patients with inflammatory back pain, whereas in those with mechanical back pain, it’s worse late in the day.

Exercises or activities improve the inflammatory back pain but may make the mechanical back pain worse. The age of onset for 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 to those with mechanical back pain.

Extra-Articular Manifestations1,2

• Major musculoskeletal manifestations include pain and inflammation in

– SIJs and spine – Low back and neck; pain may improve with exercise

but not with rest – Shoulders – Hips and buttocks – Fingers and toes

• Disease can result in – Impaired mobility – Postural abnormalities

Hyperkyphosis can appear within the first 10 years

– Extra-articular manifestations in organs outside the spine

Uveitisa

PsO

IBD Subclinical IBDb

Dactylitis

Peripheral arthritis

Enthesitis

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. 1. Rudwaleit M et al. Arthritis Rheum. 2009;60:717-727. 2. Kopylov U et al. J Rheumatol. 2018;45:498-505.

Coming to the peripheral arthritis, it’s usually acute in onset, intermittent. It is asymmetrical and oligoarthritis, meaning it involves four or less joints.

Peripheral arthritis usually favors joints of the lower extremities, 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



insertion, plantar fascia insertion, iliac crest, and lateral epicondyle. In the clinical research studies, various enthesitis indices are used. Dactylitis is a characteristic feature of spondyloarthritis, especially psoriatic arthritis and reactive arthritis. It occurs because of diffuse swelling of flexor tendon sheath and adjacent soft tissue. It may also involve the joints.

Among the extra-articular manifestations, uveitis is the most common, and it affects about 25% of patients with axial spondyloarthritis. Uveitis in axial spondyloarthritis is usually acute anterior uveitis. Of the patients who present to their eye doctor 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 self-limiting. Only less than 5% of patients develop chronic visual impairment. Psoriasis is seen in about 10% of patients with axial spondyloarthritis.

Burden of Disease in AS and nr-axSpA Is Similar1

3.9

5.1

3.1

2

4

4.8

3.1

2

3.9

4.8

2.5

1.1

0

1

2

3

4

5

6

BASDAI Pain BASFI BASMI

AS 5-10 y (n = 117)

AS <5 y (n = 119)

nr-axSpA <5 y (n = 226)

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

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.

• Prevalence of HLA-B27 in Caucasians is 6%-9%

• 90%-95% of patients with AS 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 of spondyloarthritis

• HLA-B27 forms about 40% of the overall risk for spondyloarthritis

• MZ twin concordance rate for AS is 63% compared with DZ concordance rate of 12.5%

Genetics of AS1

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

Spondyloarthritis is strongly associated with the HLA-B27 gene. Prevalence of HLA-B27 in Caucasians ranges between 6% to 9%. About 90% to 95% of patients with ankylosing spondylitis are HLA-B27 positive. However, if you look at 100 patients with a HLA-B27-positive status, only about 5 patients will go on to develop ankylosing spondylitis. That means over 90 people with a positive HLA-B27 status will never develop ankylosing spondylitis. In summary, HLA-B27 forms about 40% of the overall risk for spondyloarthritis.

Population AS Prevalence, % HLA-B27 Prevalence, %

United States1,2 0.52 6

The Netherlands3 0.1 8

Germany4 0.55 9

Norway5 1.1-1.4 14

Haida Indians6 6.1 50

Prevalence of AS

1. Helmick CG et al. Arthritis Rheum. 2008;58:15-25. 2. Reveille JD et al. Arthritis Rheum. 2012; 64:1407-1411. 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.

The prevalence of ankylosing spondylitis mirrors the prevalence of HLA-B27 in a particular geographic area. For example, among Haida Indians, the HLA-B27 prevalence is 50% and prevalence of ankylosing spondylitis is 6%. Whereas in United States, the prevalence of HLA-B27 is 6%, and that of ankylosing spondylitis is 0.5%.

Prevalence of AS and axSpA1-6

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. 5. Adomaviciute D et al. Scand J Rheumatol. 2008;37:113-119. 6. Helmick CG et al. Arthritis Rheum. 2008;58:15-25.

AS in HLA-B27+

AS in the population

SpA in the population

In summary, only about 5% to 8% patients who are HLA-B27 positive will develop axial spondyloarthritis. This underlines the fact that we should not be sending HLA-B27 gene tests for all patients with chronic back pain. We should have a high suspicion of the patient having axial spondyloarthritis before ordering the HLA-B27 test.



Frequency of HLA-B27 in Patients With SpA

Disorder Frequency, % AS 80-90 Reactive arthritis 30-50 Psoriatic arthritis 25 Psoriatic spondylitis 60 Enteropathic arthritis 7 Enteropathic spondylitis 70 General US population 6.1

HLA-B27 tends to be positive whenever a patient with spondyloarthritis has spinal involvement or axial involvement as compared with peripheral involvement.

Pathogenesis of axSpA1

1. Watad A et al. Front Immunol. 2018;9:2668.

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 positivity, there is inflammation brought on by innate immune mechanisms with subsequent involvement of adaptive immunity, leading to inflammation, bone marrow edema, causing osteitis and new bone formation, and subsequently leading to the fusion.

Natural History of axSpA: Previous Concept1

Risk factors for progression: high CRP, extensive MRI changes, male sex, smoking

Back pain Sacroiliitis

on MRI

Back pain Radiographic

sacroiliitis

Back pain Syndesmophytes

Nonradiographic stage Radiographic stage 6-10 years

modified New York Criteria (1984)

Time, y

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

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 or ankylosing spondylitis in 6 to 10 years. The risk factors for progression include high CRP, extensive MRI changes, male sex, and smoking.

Natural History of axSpA: Newer Trends1

• IBP occurs in 6% of the US population, but only a small percentage develop nr-axSpA

• Up to 12% of patients with nr-axSpA will develop AS within 2 years

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.

Estimated that 10%-40% of patients with nr-axSpA progress to radiographic axSpA (AS) over a period of 2-10 years

Patients with nr-axSpA who do not progress to AS do not necessarily remit—they just do not develop radiographic changes

despite persistence of the IBP

Radiographic Progression in nr-axSpA

The longitudinal studies in patients with nonradiographic disease show that 10% to 40% of patients progress to the radiographic stage over a period of 2 to 10 years.

The patients at the nonradiographic stage who do not progress to ankylosing spondylitis do not necessarily remit. Rather, they do not develop the radiographic changes despite the persistence of the inflammatory back pain, as well as other symptoms.



Risk Factors Associated With Progression to AS

Consistent Risk Factors

•Baseline low-grade x-ray sacroiliitis1,2

•Baseline MRI inflammation3

•Elevated CRP2

Inconsistent Risk Factors

• HLA-B27 positivity inconsistent between studies2,3

• Male sex predictive for nr-axSpA but protective for AS2

• Buttock pain4

• Smoking5,6

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. 5. Machado P et al. Arthritis Rheum. 2011;63(suppl 10):1650. 6. Poddubnyy D et al. Arthritis Rheum. 2012;64:1388-1398.

The risk factors associated with progression to ankylosing spondylitis can be classified into consistent risk factors and inconsistent risk factors. The consistent risk factors include baseline mild x-ray changes, baseline MRI inflammation, and elevated CRP. The inconsistent risk factors include positive HLA-B27, male sex, buttock pain, and smoking.

1. Little H et al. Am J Med. 1976;60:279-285.

Natural History and Disease Progression1

As you can see, if left untreated, patients with nonradiographic disease may develop ankylosing spondylitis, which leads to structural changes in the spine and joints and causes deformities.

Late Complications of axSpA1

1. Ewerton Maia Rodrigues C et al. Rev Bras Rheumatol. 2012;52:375-383.

Extra-Articular Manifestations Clinical Manifestations

Cardiac Aortitis; aortic insufficiency; conduction disorders; bundle-branch and atrioventricular blocks

Renal Secondary amyloidosis; IgA nephropathy

Pulmonary Fibrosis of the upper lobe and pleural thickening

Neurologic Cauda equina syndrome

Late complications of axial spondyloarthritis include osteoporosis, aortic valve incompetence, apical fibrosis in the lungs, IgA nephropathy, amyloidosis, and rarely cauda equina syndrome.

Cardiovascular Comorbidities in Patients With AS: Integrated US Health Plan Data1

a P < .01. b P < .005. 1. Han C et al. J Rheumatol. 2006;33:2167-2172.

Athero

Prev

alen

ce, %

CHF PVD CVD IHD T2DM HTN Hyperlipid

0.7 1.0 1.2 2.2

a

b

1.8 2.8 2.3

3.9 5.3

6.6 7.1 8.3

22

25.4

21.7

27.1 Controls (n = 7,372) AS (n = 1,843) 30

25

20

15

10

5

0

Cardiovascular Comorbidities

a a

a

a

Patients with ankylosing spondylitis are at a higher risk of cardiovascular comorbidities, including hypertension, coronary artery disease, and stroke as compared with those without ankylosing spondylitis.

How Do We Make the Diagnosis of axSpA?

Gold standard for diagnosis of axSpA is clinician’s judgement

No specific biomarker yet

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

So how do we make the diagnosis of axial spondyloarthritis? The gold standard for diagnosis of axial spondyloarthritis is clinician’s judgment. There is no specific biomarker yet, but we take help from C-reactive protein, HLA-B27, x-ray, and an MRI of the sacroiliac joint.

How Do Rheumatologists Diagnose axSpA in Practice?1

CBP for >3 months, onset <45 years

SIJs x-ray AS

<4 SpA features

Presence of SpA features

nr-axSpA

≥4 SpA features

Confirmatory tests • HLA-B27 • MRI

Consider another

diagnosis

SpA features • IBP • Inflammatory arthritis • IBD, PsO, uveitis • Enthesitis • F/H of IBD and PsO

1. van den Berg R et al. Ann Rheum Dis. 2013;72:646-653.

Not explained by other causes, such as MBP

or fibromyalgia

Among the patients with chronic back pain that started before aged 45 years that is not explained by other causes, such as mechanical back pain or fibromyalgia, we prefer to get a plain



film of the pelvis. If there is sacroiliitis, that patient has ankylosing spondylitis. If there is no sacroiliitis, we look into specific spondyloarthritis features. These spondyloarthritis features include inflammatory back pain, inflammatory peripheral arthritis, uveitis, psoriasis, inflammatory bowel disease, enthesitis, and family history. If they have less than four spondyloarthritis features, we proceed to get the HLA-B27 status, as well as an MRI to further evaluate for the presence of axial spondyloarthritis.

Modified New York Criteria (1984) for AS1

Clinical Criteria 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

frontal planes c. Limitation of chest expansion relative to normal values correlated

for age and sex

Radiologic Criterion a. Sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally

Definition of AS 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 diagnosis.

To fulfill the Modified New York Criteria, a patient must have radiographic sacroiliitis with at least one additional clinical criterion, which includes inflammatory back pain, limitation of motion at lumbar spine, and limitation of chest expansion.

ASAS Classification Criteria for axSpA1

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

Sacroiliitis on imaging plus ≥1 SpA feature

HLA-B27 plus ≥2 other SpA features

In patients with ≥3 mo back pain and age at onset <45 y

or

• 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

• Active (acute) inflammation on MRI highly suggestive of sacroliitis associated with SpA

• Definite radiographic sacroliitis according to modified New York criteria

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.

Diagnostic vs Classification Criteria1

Diagnostic Criteria

Used by a physician to make a diagnosis

When making the diagnosis, the value of diagnostic tests/parameters depends on the prevalence

of the disease (pretest probability)

The purpose of diagnostic criteria/algorithms is to help diagnose individual patients

Criteria for diagnosis should have a high sensitivity in order to identify as many patients with the disease as possible

Should allow for flexibility in diagnostic confidence (definite, probable, possible)

Applies to the individual patient

Classification Criteria

Applied to patients in whom the diagnosis has already been made

Prevalence of the disease is not important, since all patients should have the disease (have been previously diagnosed)

Purpose of classification criteria is to provide a unique language for researchers to evaluate homogenous groups of patients,

which facilitates comparisons of clinical or experimental studies

Criteria for classification should have a high specificity (close to 100%) in order to avoid misclassification (inclusion of patients who do not have the disease)

Gives a yes or no answer (criteria fulfilled or not fulfilled)

Applies to groups of patients

1. Deodhar A. Clin Rheumatol. 2014;33:741-747.

As I said, the classification criteria are not supposed to be used for diagnostic criteria; it is mainly for clinical research studies.

Imaging in Spondyloarthritis1

Grade II

Grade III

Grade IV

Grade I

1. Sudoł-Szopinska I, Urbanik A. Pol J Radiol. 2013;78:43-49.

Imaging has particular importance in evaluation of patients with suspected spondyloarthritis, mainly because of a lack of specific 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 the joint. On spinal films, we look for syndesmophytes. Sometimes it can be difficult to distinguish between syndesmophytes in ankylosing spondylitis from osteophytes from degenerative disease. Syndesmophytes tend to have vertical orientation, whereas osteophytes have a horizontal orientation.

Bamboo Spine1

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.



Imaging in Spondyloarthritis1

T2W

T1W

T2W T1W

1. Baraliakos X et al. Best Pract Res Clin Rheumatol. 2016;30:608-623.

The use of MRI has revolutionized the assessment and evaluation of patients with spondyloarthritis. With the help of MRI, we can diagnose the axial spondyloarthritis much earlier. The specific findings on MRI include bone marrow edema on the T2-weighted image and erosion and sclerosis on T1-weighted 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 patients with suspected axial spondyloarthritis.

Differential Diagnoses

AS and nr-axSpA are commonly misdiagnosed as

• Acute or chronic MBP or strain • Fibromyalgia • Diffuse idiopathic skeletal hyperostosis • Vertebral compression facture • SIJ infection • Osteitis condensans ilii • Erosive osteochondrosis • Familial Mediterranean fever

Differential diagnosis for patients with axial spondyloarthritis include mechanical back pain; fibromyalgia; diffuse idiopathic skeletal hyperostosis; vertebral compression fracture; infections, especially when there is unilateral sacroiliitis; osteitis condensans ilii; and rarely familial Mediterranean fever.

Sensitivity, % Specificity, % +LR IBP (updated information) 80 72 2.9 Enthesitis (heel pain) 37 89 3.4 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

Clinical Utility of the Clinical Parameters of Spondyloarthritis1


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

Probability of axSpA Diagnosis Based on Clinical Features and Imaging1


Insidious onset, chronicity (>3 mo),

association with morning stiffness, improvement with

exercise but not rest, and alternating

buttock pain

Among patients with CBP in GP/PCP office

Presence of IBP

Presence of 1 or 2 additional SpA features: enthesitis, dactylitis, uveitis, positive family

history, Crohn’s disease, alternating buttock pain, PsO, asymmetrical arthritis, positive

response to NSAIDs, acute phase reactants (raised ESR/CRP)

HLA-B27+ (59%-90%)

X-ray SIJ+ = AS X-ray SIJ- and MRI SIJ+ = nr-axSpA

Imaging

5%

15%

30%-70%

>90% Probability of axSpA

Among the patients with chronic back pain presenting to 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 spondyloarthritis features, the likelihood goes up to 30% to 70%. If they have a positive HLA-B27 status, there is more than a 90% probability that they have axial spondyloarthritis.

• IBP—an integral part of all the strategies

• Evidence of sacroiliitis on available imaging (x-ray or MRI)

• Presence of HLA-B27

• Family history of AS or axSpA

• Good response to NSAIDs

• Extra-articular manifestations of spondyloarthritis (PsO, IBD, and uveitis)

• Family history of AS, IBD, and PsO

Candidate Parameters Used in the Referral Strategies

In general, in primary care doctors’ offices, the evaluation should start with focusing on identification of inflammatory back pain. The candidate parameters used in referral strategies include inflammatory back pain, evidence of sacroiliitis on available imaging, presence of HLA-B27, family history of spondyloarthritis, good response to NSAIDs, and extra-articular manifestations.



Author and Year Referring Physicians Strategy N Male, % axSpA, % AS, % nr-axSpA, %

Brandt 2007 Ortho primary care • LBP >3 mo, onset at <45 y ≥1 of IBP, + HLA-B27, sacroiliitis on available imaging 350 48.6 45.4 50.3 49.7

Hermann 2009 GP • Calin criteria (4/5) 92 41 33 53.3 46.7

Braun 2011 Ortho • LBP >2 mo < 10 y, onset at <45 y, ≥1 of AM stiffness,

improvement with exercise, not rest, waking at night, improvement with NSAID

322 50 35 41.6 58.4

Poddubnyy 2011 (MASTER study) GP and ortho

• LBP >3 mo, onset <45 y • Strategy 1: ≥1 of IBP, + HLA-B27, sacroiliitis on available

imaging • Strategy 2: 2 of 5 IBP, + HLA-B27, sacroiliitis on available

imaging, positive family history for AS, good response to NSAID

318 242

53 55

41.8 36.8

61.6 61.8

38.4 38.2

Sieper 2012 (RADAR study)

Primary care Other (GP,

neuro, ortho)

• LBP >3 mo, onset <45 y • Strategy 1: ≥1 of IBP, + HLA-B27, sacroliitis on available

imaging • Strategy 2: 2 of 6 IBP, + HLA-B27, sacroliitis on available

imaging, positive family history for AS, good response to NSAID, EAM

504 568

47 55

35.6 39.8

77 78

23 22

van den Berg 2013 GP, eye, gastroenterology • LBP >3 mo but <2 y, onset <45 y 157 33 41.4 18 82

Deodhar 2014 (ProSpA study)

Self rheumatology Other physicians

• LBP >3 mo, onset <45 y, ≥1 of IBP, + HLA-B27, sacroliitis on available imaging 751 50 46 31 69

Single Center, Multicenter, and International Studies Evaluating Strategies for the Screening and Referral of axSpA1

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 axial spondyloarthritis.

Possible Screening Approach for axSpA in Patients With Chronic Low Back Pain1

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.

Refer to a rheumatologist

CBP (>3 mo) first symptoms in patients aged <45 years

IBP

• Sensitivity: 75% • Specificity: 75% • ~1 in 5 patients has

axSpA, if positive • Simple to apply: yes • Costs: low

Sacroiliitis on any imaging

• Only if available • Not recommended

for screening

HLA-B27+ • Sensitivity: 80%-90% • Specificity: 90% • If positive, 1 in 3 patients

has axSpA • Simple to apply: yes • Costs: moderate (only

once)

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.

• 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.

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

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,

extra-articular manifestations, positive family history, good response to NSAIDs, or elevated acute phase reactants.

Disease Activity1,2

BASDAI 1. Fatigue 2. Axial pain 3. Peripheral joint pain/swelling 4. Entheses 5. AM stiffness intensity 6. AM stiffness duration

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.

ASDAS 1. Total back pain 2. Patient global 3. BASDAI q3 4. BASDAI q6 5. CRP or ESR

Among patients with axial spondyloarthritis, we use composite indices to monitor the disease activity. The prominent disease activity indices include the Bath Ankylosing Spondylitis Disease Activity Index and Ankylosing Spondylitis Disease Activity Score.



Goals of axSpA Management

Reduce symptoms

Maintain spinal flexibility and posture

Reduce functional limitations

Maintain ability to work

Decrease complications

Dr. Danve: The goals of management in axial spondyloarthritis include reducing the patient’s symptoms, maintaining spinal flexibility and posture, reducing functional limitations, maintaining the ability to work, and decreasing long-term complications.

Primary Goals of Management for Patients With axSpA1

Optimize short- and long-term HRQOL through the following:

Relief of symptoms

To eliminate symptoms

such as pain, stiffness, and fatigue or to reduce them

to the minimal possible level

Maintenance of function

To maintain the best possible

functional capacity

Prevention of complications

of spinal disease

To prevent flexion

contractures, especially

dorsal kyphosis

Minimization of extraspinal

and extra-articular manifestations

and comorbidities

To reduce the impact of axSpA-associated disorders such as

uveitis and aortic valve insufficiency

Maintenance of effective

psychosocial functioning

To preserve social

participation, prevent job loss,

and improve health status and function

1. van der Heidje D et al. Ann Rheum Dis. 2017;76:978.

Overall, we would like to preserve social participation, prevent job loss, improve health-related quality of life, and function of the patients.

Expert Insight on the Treatment of Axial Spondyloarthritis

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

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 • Importance of regular follow-up and management of comorbidities • 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

and training • 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

According to these recommendations, the management of patients with axial spondyloarthritis includes nonpharmacological interventions and pharmacotherapy. The nonpharmacological interventions are of particular importance in patients with axial 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 training program. The importance of regular follow-ups and management of comorbidities should be explained. Patients should be educated about medication compliance, monitoring of their disease activity, and the potential adverse events of the therapies.

Smoking cession is strongly recommended. As with other chronic diseases, patients should be screened for depression, and psychosocial support should be provided. Patients with newly diagnosed axial spondyloarthritis should be referred to physical therapists for initial evaluation and training of exercises, which include postural training and range-of-motion exercises. Spinal manipulation should be avoided in patients with spinal fusion or advanced spinal osteoporosis because of the risk of fracture.

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



better than no exercise. Supervised group physical therapy was better than home exercises, and combined inpatient exercises followed by group physical therapy were better than group physical therapy alone. The ACR guidelines strongly recommend physical therapy in patients with both active and stable ankylosing spondylitis. The recommendations include supervised physical therapy and unsupervised back exercises. The recommendations state that both land-based, as well as aquatic physical therapy, are effective for patients with ankylosing spondylitis.

Pharmacological Treatment Options

NSAIDs csDMARDS

JAK inhibitors and IL-23 inhibitors are in development

TNF inhibitors

IL-17 inhibitors

These are exciting times in regard to the pharmacotherapy for axial spondyloarthritis; treatment options include NSAIDs, conventional DMARDs—mainly sulfasalazine and methotrexate—TNF inhibitors, and IL-17 inhibitors. In development, there are JAK inhibitors and IL-23 inhibitors.

Of the TNF inhibitors, certolizumab has been approved by the FDA for use in nonradiographic disease. Recently, the IL-17 inhibitors secukinumab and ixekizumab have been approved by FDA for nonradiographic disease.

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

First-Line Treatment of Active AS: 2019 ACR/SAA/SPARTAN Recommendations1

Determine additional disease

manifestations

Isolated Sacroiliitis or Enthesitis

NSAIDs

Isolated Sacroiliitis or Enthesitis Despite

NSAIDs Local GC Avoid Achilles, patellar, and quadriceps entheses GC injections

Peripheral Arthritis Despite NSAIDs

Local GC if ≤2 joints SSX • SSZ over MTX Against LEF, APR, THL, and PAM

Active AS and nr-axSpA (Axial Disease)

NSAIDs • Continuous • No preferred NSAID Physical therapy • Active over passive • Land-based over aquatic Against systemic GCs

Patients with active ankylosing spondylitis should be started on NSAIDs and sent for physical therapy. Continuous NSAIDs are preferred. The guidelines recommend against using systemic 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.

In patients with axial spondyloarthritis, sulfasalazine works better than methotrexate for peripheral arthritis. If the patient has isolated sacroiliitis or enthesitis despite NSAIDs, you could consider local glucocorticoid injections. The steroid injections should be avoided at sites like Achilles tendon, patellar tendon, and quadriceps enthesis because of the risk of tendon rupture.

• NSAIDs as first-line therapy in axSpA/AS – Various NSAIDs are equally effective

– 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

Multiple RCTs Support Efficacy of NSAIDs in axSpA1,2

1. Ward MM et al. Arthritis Rheumatol. 2016;68:282-298. 2. Kroon FP et al. Cochrane Database Syst Rev. 2015;7:CD010952.

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 in patients with axial spondyloarthritis.

• 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 • Most patients with AS commonly used diclofenac, naproxen, and

indomethacin • Response rates

– 20% had complete pain response – 35% had a 50% response – 25% had a 25% response – 20% had minimal response

How Effective Are NSAIDs?1

1. Zochling J et al. Clin Rheumatol. 2006;25:794-800.

In a cross-sectional study from Germany of 1,080 patients with ankylosing spondylitis, 20% of patients had complete response to NSAIDs, 20% of patients had no response to NSAIDs, and the remaining had variable response.


ACR/SAA/SRTN Treatment Recommendations 2019: NSAIDs1

Recommendation Level of Evidence In adults with active AS, NSAIDs are strongly recommended over no treatment with NSAIDs Low

Continuous treatment with NSAIDs over on-demand treatment with NSAIDs is conditionally recommended Low to moderate

No particular NSAID is recommended as the preferred choice for treatment Low to moderate



Overall, the guidelines strongly recommend using NSAIDs for initial therapy in patients with ankylosing spondylitis. Continuous treatment with NSAIDs is preferred over on-demand treatment. The guidelines do not recommend any particular NSAID as the preferred choice.


ACR/SAA/SRTN Treatment Recommendations 2019: DMARDs1

Recommendation Level of Evidence

In patients with active AS despite NSAIDs, sulfasalazine, methotrexate, or tofacitinib are conditionally recommended over no treatment with these medications—sulfasalazine or methotrexate should be considered only in patients with prominent peripheral arthritis when TNFis are not available

Very low to moderate

The role of conventional DMARDs in axial spondyloarthritis is mainly limited to patients with peripheral arthritis, because these DMARDs usually are not effective for axial disease.


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

Active AS despite NSAIDs TNFi • Over TOF, SEC/IXE

No preferred TNFi, except for AS + IBD or uveitis AS + recurrent uveitis

or AS + IBD

TNFi monoclonal antibodies over other biologics

Active AS despite TNFi (1° nonresponder)

SEC/IXE (over TOF)

TOF Against biosimilar of 1st TNFi

Against non-TNFi/non-SEC/ IXE or adding SSZ, MTX

Active AS despite TNFi (2° nonresponder)

Alternative TNFi

Against biosimilar of 1st TNFi Against non-TNFi/non-SEC/ IXE or adding SSZ, MTX

AS with unclear activity while on biologic

Spinal or pelvis MRI

2L Therapy

3L Therapy Active AS on TNFi Against co-treatment with low-dose MTX

For patients who active ankylosing spondylitis despite NSAIDs, we use TNF inhibitors. Depending on the patient preferences and comorbidities, the choice of TNF inhibitor is decided. For those who have active ankylosing spondylitis on TNF inhibitors, we see if they had primary nonresponse or secondary nonresponse. If they had primary nonresponse to the TNF inhibitor, we switch them to IL-17 inhibitor, either secukinumab or the ixekizumab. Those who had secondary nonresponse to the TNF inhibitor—meaning they initially responded but over the period they stopped responding—for those patients, we use an alternative TNF inhibitor before switching them to IL-17 inhibitors.

TNFi Therapy

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.

ASAS20 response rates at week 24 for infliximab, week 14 for golimumab, and week 12 for adalimumab, certolizumab pegol, and etanercept

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. Deodhar A et al. Arthritis Rheumatol. 2019;71:1101-1111.

Certolizumab Pegol in nr-axSpA: Phase 3 C-axSpAnd Study1

Proportion of Patients Achieving Major Improvement in ASDAS-MI

Proportion of Patients Achieving ASAS40 by Week 52

Recently, certolizumab has been approved for use in non-radiographic disease, based on the data from C-axSpAnd study.

• Objective: Evaluate spinal radiographic progression in a large cohort of patients with AS (n = 210) who are on TNFis; 8-year follow-up

– GLAS cohort starting a TNFi 2004-2012 – X-rays at baseline and every 2 years scored by mSASSS – Baseline mean mSASSS was 10

• During first 4 years, x-ray progressed linearly (estimated mean progression rate 1.7 for 0-2 and 2-4 years)

• However after 2 years, estimated mean progression rate was reduced from 2.3 to 0.8 in patients who completed 8 years of treatment

• Conclusions: Patients with AS on long-term TNFi showed reduction in spinal radiographic progression after >4 years of follow-up

Prolonged Treatment With TNFis Reduces Spinal Radiographic Progression in AS1

1. Maas F et al. Arthritis Care Res (Hoboken). 2017;69:1011-1019.

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.



The researchers found that during the first 4 years, the x-ray 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 been on long-term TNF inhibitors showed a reduction in the spinal radiographic progression after more than 4 years of follow-up. 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.

TNFis: Contraindications and Adverse Events

• Active infection • Latent TB • Demyelinating disease • Heart failure • Malignancy

Contraindications

• Injection-site reactions • Infusion reactions • Neutropenia • Infections • Demyelinating disease

AEs

• HF • Cutaneous reactions • Malignancy • Induction of autoimmunity

The contraindications for TNF inhibitors include active infection, 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.


ACR/SAA/SRTN Treatment Recommendations 2019: TNFis1

Recommendation Level of Evidence In adults with active AS despite treatment with NSAIDs, a TNFi is strongly recommended over no treatment with a TNFi High

No particular TNFi is considered the preferred choice of treatment Moderate

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

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

The ACR guidelines recommend TNF inhibitors as the next option for patients whose disease is not adequately controlled with NSAIDs. No particular TNF inhibitor is preferred as such.

1. Sieper J et al. Lancet. 2017;390:73-84.

TNFi: axSpA1

Variables associated with TNFi response

Elevated CRP/ESR

Short duration of symptoms

Inflammation noted by MRI

30%-40% of patients with AS continue with active disease despite NSAIDs/TNFi therapy

Overall, 30% to 40% of patients with ankylosing spondylitis continued to have active disease despite treatment with NSAIDs or TNF inhibitors and need something else.

IL-17 Inhibitors for axSpA

Secukinumab (approved)

Ixekizumab (approved)

Bimekizumab (in development)

Netakimab (in development)

And that something else now is IL-17 inhibitors. Of the IL-17 inhibitors, secukinumab and ixekizumab have been approved for use in AS, as well as nonradiographic disease. The other IL-17 inhibitors in development include bimekizumab and netakimab.

1. McGonagle et al. Ann Rheum Dis. 2019;78:1167-1178.

Role of IL-17A in Bone Erosion and Bone Formation in Spondyloarthritis1

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.



A Closer Look at the Approved IL-17 Inhibitors for axSpA

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.

Indication Dosage and Administration Adverse Reactions

Secukinumab1

• Adults with active AS

• Adults with active nr-axSpA with objective signs of inflammation

• AS recommended dosages, ± loading dosage – With a loading dosage: 150 mg at weeks 0, 1, 2, 3,

and 4, and every 4 weeks thereafter – Without a loading dosage: 150 mg every 4 weeks – If a patient continues to have active AS, consider a

dosage of 300 mg every 4 weeks • nr-axSpA recommended dosages, ± loading dosage

– With a loading dosage: 150 mg at weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter

– Without a loading dosage: 150 mg every 4 weeks

Most common adverse reactions (>1%) are nasopharyngitis, diarrhea, and upper respiratory tract infection

Ixekizumab2

• Adults with active AS

• Adults with active nr-axSpA with objective signs of inflammation

• AS recommended dose – 160 mg by subcutaneous injection (two 80 mg

injections) at week 0, followed by 80 mg every 4 weeks

• nr-axSpA recommended dose – 80 mg by subcutaneous injection every 4 weeks

Most common (≥1%) adverse reactions are injection-site reactions, upper respiratory tract infections, nausea, and tinea infections.

Based on several randomized controlled studies, now we know that IL-17 inhibitors, including secukinumab and ixekizumab, improve the disease activity in patients with axial spondyloarthritis, including ankylosing spondylitis, as well as nonradiographic disease. These two medications now have been approved by FDA for use in nonradiographic disease, as well as ankylosing spondylitis.

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

Forest Plot of the Efficacy of IL-17 Inhibitors in the Treatment of AS: ASAS201

In a recent systematic review and meta-analysis to assess the efficacy and safety of IL-17 inhibitors in active ankylosing spondylitis, the researchers included data from six studies including 1,733 patients of which 1,153 patients received IL-17 inhibitors, whereas 580 patients who received placebo were included. At week 16, the IL-17 inhibitor regimen produced significant increase in ASAS20 response rate and ASAS40 response rate. With respect to the safety profile, patients treated with IL-17 inhibitors are at increased risk of infections, including reactivation of latent tuberculosis.


ACR/SAA/SPARTAN Treatment Recommendations 2019: IL-17 Inhibitors1

Recommendation Level of Evidence

• In patients with AS despite treatment with NSAIDs, secukinumab or ixekizumab is strongly recommended over no treatment with secukinumab or ixekizumab

High

• In patients with active AS despite treatment with TNFi, secukinumab or ixekizumab is conditionally recommended over treatment with a different TNFi in patients with a primary nonresponse to TNFi

Very low

• In adults with active AS despite treatment with NSAIDs who have contraindications to TNFis, secukinumab or ixekizumab are conditionally recommended over treatment with methotrexate, sulfasalazine, or tofacitinib

Low

The ACR guidelines recommend using secukinumab or ixekizumab in patients who had primary nonresponse to TNF inhibitors. Some patients with axial spondyloarthritis may respond well to TNF inhibitors for initial months or years, and then they lose the response. In such patients, we use alternative TNF inhibitor before switching them to IL-17 inhibitors. Patients who had contraindications to TNF inhibitors are candidates for IL-17 inhibitor therapy.

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.

JAK Inhibitors for axSpA1-3

.

Tofacitinib Filgotinib Upadacitinib

Clinical trials are underway for JAK inhibitors in axial spondyloarthritis. These include tofacitinib, upadacitinib and filgotinib.


Treatment of Stable AS: 2019 ACR/SAA/SPARTAN Recommendations1

Stable AS (axial disease)

NSAIDs • On-demands

Physical Therapy

Spinal fusion or advanced osteoporosis

Avoid spinal manipulation

Advanced hip arthritis Total hip arthroplasty

Stable AS on TNFi

If on originator TNFi, do not switch to biosimilar TNFi as a standard approach

Against cotreatment with low-dose MTX

Severe kyphosis Avoid spinal osteotomy

Stable AS on TNFi + NSAID

Continue TNFi alone; stop NSAID

Stable AS on biologic

• Against discontinuation of biologic

• Against biologic tapering as a standard approach

Stable AS on TNFi + oral small molecule Continue TNFi alone;

stop csARD

Determine additional disease manifestation

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



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.

• 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

Summary1,2

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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