Axial Spondyloarthritis: Issues & Controversies

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1 Axial Spondyloarthritis: Issues & Controversies Atul Deodhar, MD Professor of Medicine Oregon Health & Science University Portland, OR WRA 2018 Annual Meeting, Leavenworth, WA. 16 th September, 2018

2 Disclosures: ACCME- defined commercial relationships Consulting fees for serving on advisory boards for Abbvie, BMS, Eli Lilly, Janssen, Novartis, Pfizer and UCB I have been the principal investigator for research studies which received grants (paid to OHSU) from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer and UCB My presentations will be evidence based and free of bias

3 Axial Spondyloarthritis: Agenda The terminology: AS vs axspa vs nr- axspa Issues with the term nr- axspa Issues with the current classification criteria The appropriate role of MRI in the diagnosis of axspa Prevalence of axspa: latest data from the US Is disease modification possible?

$30-40% Characterized by inflammatory back pain, loss of spinal mobility In severe cases, extensive fusion (ankylosis) of vertebrae can increase the risk of spinal deformity, fracture, &$

4 Ankylosing Spondylitis: Definition A chronic, systemic, inflammatory disorder involving the SI joints, spine & often hips Axial joints are always involved, peripheral joints are affected in 30-40% Characterized by inflammatory back pain, loss of spinal mobility In severe cases, extensive fusion (ankylosis) of vertebrae can increase the risk of spinal deformity, fracture, & disability

5 Modified New York classification Criteria for Ankylosing Spondylitis 1. Low back pain >3 months Improved with exercise Not relieved by rest 2. Limited lumbar motion 3. Reduced chest expansion Definite AS equals: at least 1 criteria PLUS 4. Bilateral grade >2 sacroiliitis on x- ray 5. Unilateral grade 3 or 4 sacroiliitis on x- ray Either 4 or 5 In the absence of diagnostic criteria for AS, classification criteria are used for diagnosis van der Linden S et al Arthritis Rheum1984;;27:

6 Sacroiliitis on X- Ray is Essential for the Diagnosis of AS Sacroiliitis may take up to 10 years to appear on x-ray 1 Thus, AS can not be diagnosed by NY criteria for several years after onset 1 Mau W., et al., J Rheum 1988;; 15:

7 ASAS Classification Criteria for Axial SpA In patients with chronic (>3 months) back pain, age at onset <45 years Sacroiliitis** plus 1 clinical parameter* or HLA- B27 plus 2 other clinical parameters* **Sacroiliitis (x- rays or MRI): Definite radiographic sacroiliitis (grade 2 bilat or grade 3-4 unilat; according to modified NYcriteria 1984) or Active (acute) inflammation of sacroiliac joints on MRI, highly suggestive of sacroiliitis associated with SpA *Clinical parameters: - Inflammatory back pain - Arthritis - Enthesitis (heel) - Uveitis - Dactylitis - Psoriasis - Crohn s disease / ulcerative colitis - Good response to NSAIDs - Family history for SpA - Elevated CRP - HLA-B*27 Rudwaleit M, et al. Ann Rheum Dis. 2009; 68(6):

8 ACR Annual Meeting 2016: Query from a senior rheumatologist from a very prestigious institute Atul, I have received different answers for this question, and I thought I will ask you for the final confirmation. If someone has normal SI Joint x- ray, but positive MRI of the SI joints, that can not be called non- radiographic axial SpA, right? For non- radiographic axial SpA, they should have normal x- ray and normal MRI, right? Confusion between nr- axspa and the Clinical Arm of the ASAS criteria

9 ASAS Classification Criteria for Axial SpA In patients with chronic (>3 months) back pain, age at onset <45 years Imaging Arm Sacroiliitis** plus 1 clinical parameter* or Clinical Arm HLA- B27 plus 2 other clinical parameters* **Sacroiliitis (x- rays or MRI): Definite radiographic sacroiliitis (grade 2 bilat or AS grade 3-4 unilat; according to modified NYcriteria 1984) or Active (acute) inflammation of sacroiliac joints on MRI, highly suggestive of sacroiliitis associated with SpA *Clinical parameters: - Inflammatory back pain - Arthritis - Enthesitis (heel) - Uveitis - Dactylitis - Psoriasis Nr- axspa - Crohn s disease / ulcerative colitis - Good response to NSAIDs - Family history for SpA - Elevated CRP - HLA-B*27 Rudwaleit M, et al. Ann Rheum Dis. 2009; 68(6):

10 Problems with the Terminology Non- radiographic axial SpA The word Non- radiographic is a misnomer It doesn t clarify which radiographs we are talking about Someone with normal SIJ x- rays but syndesmophytes is still non- radiographic Someone with bilateral grade 1 or unilateral grade 2 sacroiliitis is still non- radiographic FDA doesn t like nr- axspa : hasn t approved any drugs Should it matter in daily practice if someone is non- radiographic or radiographic we treat them the same way Whether someone is non- radiographic axspa or radiographic axspa is completely arbitrary - depends on your opinion against someone else's

11 Radiographic Sacroiliitis Grading van der Linden, et al. Arthritis Rheum 1984; 27:361-8 Grade 0 Grade I Grade II Grade III Grade IV Normal Suspicious changes Minimum abnormality small localized areas with erosion or sclerosis without alteration in joint width Unequivocal abnormality moderate or advanced sacroiliitis with erosions, sclerosis, widening, narrowing or partial ankylosis Severe abnormality total ankylosis

13 13

15 Does this person have MRI SI joints. STIR technique sacroiliitis? R Grade 1 L Grade 0 o Survey sent to 5229 ACR members in o 225 responded (4%) o 46% said that they assess sacroiliitis themselves *Garg et al. PANLAR 2018

16 Taken from Slide Presentation by Sarah Yim, MD (FDA)

patients over long- term? Do they spontaneously remit?

17 Implications of the New Concept of Axial Spondyloarthritis Pre-AS? May never progress to AS AS Non-radiographic axspa What happens to these patients over long- term? Do they spontaneously remit? If someone has not developed any features of SpA after years, should we reconsider the diagnosis?

18 Is nr- axspa & AS differentiation useful? To classify someone as AS we require sacroiliitis at least Grade 2 bilateral, or higher & there is a poor agreement between readers (even experts) regarding grade of sacroiliitis The distinction between AS and nr- axspa is therefore completely arbitrary In daily practice we should use the term axial SpA, and leave the term nr- axspa for classification purposes only 1 With MRI, we can identify people with true inflammatory disease of the axial skeleton, even before SIJ x- rays show Grade 2 or higher sacroiliitis If nr- axspa & AS are two different diseases, then non- erosive RA and erosive RA are two different diseases too 1 Deodhar A. et al. Ann Rheum Dis May;75(5):791-4

Clinical Conceptualization of the Natural History of axspa Subclinical process in genetically predisposed patients a b Inflammatory back pain d Spontaneous remission c Non- radiographic axspa

19 Clinical Conceptualization of the Natural History of axspa Subclinical process in genetically predisposed patients a b Inflammatory back pain d Spontaneous remission c Non- radiographic axspa Quiescent disease activity e Non- radiographic axspa g Ankylosing spondylitis (AS) f Non- progressing AS i h AS late complications Garg N, van den Bosch F, Deodhar A. Best Pract Res Clin Rheumatol Oct;28(5):

20 ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 10, October 2014, pp DOI /art , American College of Rheumatology SPECIAL ARTICLE The Concept of Axial Spondyloarthritis Joint Statement of the Spondyloarthritis Research and Treatment Network and the Assessment of SpondyloArthritis international Society in Response to the US Food and Drug Administration s Comments and Concerns Atul Deodhar, 1 John D. Reveille, 2 Filip van den Bosch, 3 Jürgen Braun, 4 Ruben Burgos-Vargas, 5 Liron Caplan, 6 Daniel O. Clegg, 7 Robert A. Colbert, 8 Lianne S. Gensler, 9 Désirée van der Heijde, 10 Irene E. van der Horst-Bruinsma, 11 Robert D. Inman, 12 Walter P. Maksymowych, 13 Philip J. Mease, 14 Siba Raychaudhuri, 15 Andreas Reimold, 16 Martin Rudwaleit, 17 Joachim Sieper, 17 Michael H. Weisman, 18 and Robert B. M. Landewé 19

21 Deodhar A. et al. Ann Rheum Dis May;75(5):791-4

22 Other Issues with ASAS axspa Classification Criteria

ASAS Classification Criteria for Axial SpA: (to be applied in patients with chronic back pain and age at onset <45 yrs) 1 SpA feature* plus sacroiliitis** *SpA features: IBP arthritis enthesitis

23 ASAS Classification Criteria for Axial SpA: (to be applied in patients with chronic back pain and age at onset <45 yrs) 1 SpA feature* plus sacroiliitis** *SpA features: IBP arthritis enthesitis uveitis dactylitis psoriasis Crohn s/colitis Good response to NSAIDs Family history for SpA HLA-B27 or HLA-B27 plus 2 other SpA features n = 649 back pain patients **Inflammation is highly compatible with sacroiliitis on MRI or definite radiographic sacroiliitis, according to modified NY criteria. Rudwaleit M, et al. Ann Rheum Dis. 2009; 68(6):

24 CLASSIC Study: A Combined SPARTAN & ASAS Research Study CLASSIC: Classification of Axial Spondyloarthritis Inception Cohort 1000 patient study of suspected axspa patients referred to rheumatologists 500 in North America, 500 in the rest of the world Study to validate ASAS axspa classification criteria If the sensitivity & specificity is not found to be >75% & >90% respectively, the criteria would be modified

25 Appropriate Use of SIJ MRI

27 Frequency of bone marrow edema in pre-radiographic SpA and controls What is the diagnostic utility of SIJ MRI to differentiate axspa from nonspecific back pain & healthy volunteers? N=187: 75 with AS, 27 with nr- axspa, 26 with nonspecific back pain, 59 controls; all < 45 years 5 trained readers 12% of normal healthy controls have MRI changes of bone marrow edema in SI joints fulfilling the ASAS definition of inflammatory sacroiliitis Any 2 readers IBP (n = 27) No (%) Affecting 1 SIJ quadrant Affecting 2 SIJ quadrants Meets ASAS definition of positive MRI Affecting 3 SIJ quadrants Controls (n = 85) No (%) 21 (77.8) 20 (23.5) 18 (66.7) 13 (15.3) 18 (66.7) 10 (11.8) 16 (59.3) 10 (11.8) Weber U et al. Arthritis Rheum 2010;;62:

28 The Dangers of Relying on SIJ MRI to Diagnose axspa Quoted high specificity has led rheumatologists to use SIJ MRI changes for diagnostic purposes (ASAS definition: 1 BME lesion on 2 consecutive slices, or >2 BME lesion on single slice) CLBP pts (n=1020, ages 18-40) referred to LBP clinic underwent detailed assessment: clinical features, HLA- B27, CRP, very careful MRI assessments of spine & SI joints 1 10% of patients were HLA B27+, 21% had MRI sacroiliitis, according to ASAS definition, and of those, 42% had BME at the minimum requirement according to ASAS definition ( two white spots ) The two white spots on MRI is not specific, and is seen in healthy volunteers plus degenerative disease of SIJ & spine 2 1 Arnbak B. et al. Arthritis Rheumatol Apr;68(4): 2 Deodhar A. Arthritis Rheumatol Apr;68(4):775-8

30 Does this patient have axspa? A 35- yr old female with H/O fibromyalgia for 8 years is referred for suspected axial spondyloarthritis She is HLA B27 positive, has F/H of SpA (she claims her 70 year- old uncle has ReA) No H/O uveitis, psoriasis, IBD, inflammatory back pain On enquiry, she says that NSAIDs used to work for her pain, but now she only gets relief from Oxycodone O/E no evidence of inflammatory arthritis, Schober s test to 3.5 CM, normal lab tests (CRP), negative SI joint x- ray and her insurance did not allow an MRI scan of the SI joints She decides to pay for an MRI of the SI joint out- of- pocket and that shows two small areas of bone marrow edema Does she have axspa?

31 SI Joints MRI has the danger of becoming the ANA of backache If the pre- test probability is low, applying a specific test will still have a low post- test probability of the disease

32 If the pre- test probability is low, do not order a test: e.g. do not order an ANA in someone with generalized aches and pains, similarly do not order MRI of SI joints in someone with a clinical diagnosis of FM Do not apply classification criteria just to see if they fit if pre- test probability is low Classification Criteria Should Only be Applied to Patients Already Diagnosed

33 Diagnostic vs. Classification Criteria 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) The purpose of the 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 Deodhar A. Clin Rheumatol Jun;33(6):741-7.

How Should We Diagnose axial SpA in Practice?

Not explained by other causes such as mechanical back pain

SpA features Confirmatory tests HLA- B27 MRI nr- axspa

34 How Should We Diagnose axial SpA in Practice? AS Chronic back pain >3 months, onset <45 years SIJ X- ray Not explained by other causes such as mechanical back pain or fibromyalgia Presence of SpA features 4 SpA features <4 SpA features Confirmatory tests HLA- B27 MRI nr- axspa Consider other diagnosis van den Berg R, et al. Ann Rheum Dis 2013;72:

35 Appropriate use of SI Joint MRI Order SI joint MRI only if you have high pre- test probability of patient having axspa Order T1, T2 and STIR images, no contrast required Please do not order SIJ MRI scan to well, I am unsure about his diagnosis let me see if the MRI can give me the diagnosis Only depending upon bone marrow edema can lead to over- diagnosis normal volunteers, degenerative pathology, athletes can have BME Discuss with your radiologist does the T1 weighted image also suggest sacroiliitis? Are there any erosions? Any other structural changes? Fatty changes to suggest old inflammation?

36 Epidemiology of axspa in the US

Epidemiology of axspa in the US National Health & Nutrition Examination Survey 2009-10 NHANES: To monitor the health & nutritional status of the

37 Epidemiology of axspa in the US National Health & Nutrition Examination Survey NHANES: To monitor the health & nutritional status of the civilian, non- institutionalized population of the US Mobile Examination Centers Centers for Disease Control and Prevention National Center for Health Statistics

38 Important Findings of NHANES Study Prevalence of chronic low back pain in US adults (age 20 to 69) is 19.4% Prevalence of inflammatory back pain in US adults is 6.9% Prevalence of HLA B- 27 Overall in the US adults (age 20-69): 6.1% In non- Hispanic whites: 7.5% In Mexican- Americans: 4.6% Prevalence of ankylosing spondylitis (self- reported by participants that they were diagnosed with): 0.55% Prevalence of axial spondyloarthritis by ESSG criteria 1.4% and by Amor criteria 0.9% Reveille JD et al. Arthritis Rheum May;64(5):

39 Axial SpA may be More Common than RA in US Estimated Prevalence, % France US Lithuania AS SpA RA France: Saraux A et al. Ann Rheum Dis 2005;64:431-5; Guillemin F et al. Ann Rheum Dis 2005;64: Lithuania: Adomaviciute D et al. Scand J Rheumatol. 2008;37: USA: Helmick CG et al. Arthritis Rheum. 2008;58: Reveille JD et al. Arthritis Rheum May;64(5):

41 Combined conclusions of US epidemiologic studies on axspa Population- based studies show that the prevalence of axspa is 1%, and prevalence of AS is 0.5% (RA is 0.6%) Rheumatologists are not interested in back pain, hence back pain patients (including undiagnosed axspa) see other providers. there, axspa diagnosis is not suspected, hence patients are missed, not referred, and not seen in rheumatology practices 63% AS patients are diagnosed by non- rheumatologists, and minority of them really have AS axspa diagnosis is missed by rheumatologists too, and there is a 14 year delay in diagnosing axspa in the US

42 Strategies for Disease Modification in axspa

43 Oh, But That s The NEXT Talk! (Watch this space!)

44 So, what have we learnt? Classification criteria should not be used for making a diagnosis, and SIJ MRI scan may not necessarily be diagnostic if it only shows bone marrow edema In daily practice, axial SpA is an appropriate diagnosis, nr- axspa should be used only for classification purposes AxSpA is more common than RA, but rheumatologists don t want to see back pain patients, and hence don t believe this statistics! AxSpA diagnosis is unfortunately missed by generalists and specialists alike and this leads to severe delay in making the diagnosis

45 Thank you!

Spondyloarthritis: Practice. New Concepts in. Epidemiology and Clinical

Spondyloarthritis: Practice. New Concepts in. Epidemiology and Clinical New Concepts in Spondyloarthritis: Epidemiology and Clinical Practice Atul Deodhar MD Professor of Medicine Oregon Health & Science University Portland, OR Northwest Rheumatism Society, Seattle, April