Concept of Spondyloarthritis (SpA)

Spondyloarthritis: Characteristic Parameters Used for Diagnosis I Symptoms Inflammatory back pain Imaging Lab ESR/CRP Patient s history Good response to NSAIDs

Spondyloarthritis-Characteristic Spondyloarthritis: Characteristic Parameters Parameters Used for Used Diagnosis for Diagnosis II II Genetics HLA-B27 positive family history Predisposing/ concomitant diseases Infection* psoriasis Crohn s *positive staining for Chlamydia in synovial membrane 1 1. Schumacher HR et al. Arthritis Rheum 1988; 31:937-46

Axial Spondyloarthritis according to ASAS criteria AS according to mod. NY criteria

Spondyloarthritis: Common Features Familial aggregation and genetic predisposition Enthesopathy is hallmark Absence of rheumatoid factor Inflammatory arthritis of the spine Radiological evidence of sacroiliitis Peripheral arthritis

Environmental triggers Biomechanical Microbial Entheseal insertion Microtrauma Deposition, persistence TNF-α blockade Genes: HLA- B27 and others Enthesitis Entheseal ossification: new bone formation/syndesmophyte Ankylosis

ENTHESITIS Inflammation primarily affects the sacroiliac joints & axial skeleton (red) in AS, but extra-articular or juxta-articular bony tenderness occurs from enthesitis at many other sites (e.g. costosternal junctions, spinous processes, greater femoral trochanters, iliac crests, ischial tuberosities, tibial tubercles, or heels (blue), etc.) Enthesitis can be an early or prominent feature of AS & related SpA. Khan MA; Rheumatology. Eds. Hochberg M. London, Mosby. 3rd ed. 2003

AS and Non-radiographic Axial SpA Same Disease Duration <5 years AS (n=119) Non-radiographic Axial SpA (n=226) HLA-B27+ 73% 75% IBP 82% 87% Positive family history Data from the German Spondyloarthritis Inception Cohort = GESPIC. Rudwaleit et al, Arthritis Rheum.2009, 60: 717-727 39% 35% Peripheral arthritis 40% 41% Enthesitis 38% 44% Uveitis 19.3% 12.4% IBD 2.5% 1.8%

Burden of Disease in AS and Non- Radiographic Axial SpA Is Similar 6 5 4 AS 5-10 yr (n=117) AS <5 yr (n=119) Axial non-radiogr. SpA <5 yr (n=226) 3 2 1 0 BASDAI Pain BASFI BASMI Data from the German Spondyloarthritis Inception Cohort = GESPIC. Rudwaleit et al, Arthritis Rheum.2009, 60: 717-727

Prevalence of AS/Axial SpA among patients with chronic LBP in General Practice 313 back pain sufferers filled questionnaire 46/313 (15%) had LBP (mean age 38.6 yrs) 33 were examined & 27 had x-ray of SI joints 2 had definite AS, and 18 had other features of SpA (ESSG) 5% of back pain sufferers may have a mild form of AS that may never progress to definite ankylosis, but for whom treatment as if they had AS may be of benefit. Underwood & Dawson. Brit J Rheumatol 1995; 35: 1074-7

AXIAL SPONDYLOARTHRITIS ASAS criteria for classification In patients with 3 months back pain and age at onset <45 years!!! HLA-B27 OR Sacroiliitis on imaging + 2x + 1x SpA features Inflammatory back pain Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn s/colitis Good response to NSAIDs Family history for SpA HLA-B27 Elevated CRP 28 Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with axial spondyloarthritis Definite radiographic sacroiliitis DougadosaMcc, oetrdali.nagrtthoritmisordhiefiuemd.n19y91croitcet;r3ia4(10):1218-1227. + elevated CRP or current evidence for sacroiliitis in MRI

Chronic low back pain Axial SpA LR= likelihood ratio Rudwaleit M et at. Arthritis Rheum 2005;52:1000-8 (with permission)

the Sacroiliac Joints in Spondyloarthritis Areas of bone marrow edema: hypointense signal periarticular fat deposition ASAS handbook, Ann Rheum Dis 2009;68 (Suppl II) (with permission) Areas of bone marrow edema: hyperintense

Definition of Positive MRI-SI Joint subchondral bone marrow edema acute (bilateral) sacroiliitis STIR Rudwaleit et al; Ann Rheum Dis 2009;68:1520-7.

Sacroiliitis Grade 2 Right, Grade 3 Left

in Ankylosing Spondylitis-Patients Age at first symptoms, es 476 females Age in years Average delay in diagnosis: 5 7years Feldtkeller E et at. Curr Opin Rheumatol 2000;12:239-247 (with permission)

Rheumatoid arthritis Osteoclast Osteoclast progenitor Osteoclast Synovitis Bone erosion and bone loss Bone destruction Ankylosing spondylitis Osteoblast Osteoblast Ligament Enthesitis Bony fusion and new bone formation (syndesmophyte) New bone formation

PHYSIOTHERAPY Use it or lose it. Classic arthritis therapy,- stretching, ROM exercises for both peripheral arthritis and complete spinal ROM, including deep breathing exercises. Avoid overuse. Energy conservation. Not a muscle strengthening program.

NSAID THERAPY Can be very helpful in acute or active disease patients, should be taken consistently. In some patients, can give as much as 20-30 percent improvement. Pts. have to be advised of and monitored for Side effects ie: upper GI, Renal function, increased BP. Marked individual variation in patient s response to specific NSAIDS.

ONLY GOLIMUMAB HAS BEEN APPROVED IN CANADA AND EUROPE FOR Rx of SPONDYLOARTHROPATHY. NONE IN US AS OF YET. TNF S FOR SPNDYLOARTHROPATHY

Select genetic factors that confer susceptibility to ankylosing spondylitis 1 Functional Pathway Intracellular antigen processing Th17 pathway NFκB pathway Immune response Genes of unclear immune relevance Genetic Factor HLA-B27, ERAP1 IL23R, IL12B, STAT3, PTGER4 CARD9 IL1R2, ORMDL3 CDKAL1, KIF21B HLA-B27, Human Leukocyte Antigen B27 1. Reveille JD. Nat Rev Rheumatol. 2012;8:296 304; 2. Burton PR, et al. Nat Genet. 2007;39:1329 37; 3. Bowness P, et al. J Immunol. 2011;186:2672 80

Number of IL-17+ Cells Number of IL-17+ Cells/ HPF 60 50 40 30 20 10 0 CD3+ T cells AA-1+ mast cells AS MPO+ cells CD15+ neutrophils Mononuclear cells 60 50 40 30 20 10 0 CD3+ T cells Osteoarthritis AA-1+ MPO+ mast cells cells Mononuclear cells CD15+ neutrophils Cells with polysegmental nuclei AS, ankylosing spondylitis; HPF, high-power field 1. Appel H, et al. Arthritis Res Ther. 2011;13:R95

Secukinumab is a fully human IgG1k monoclonal antibody selectively targeting IL-17A IL-17A Delayed-type hypersensitivity and cellular immunity IFN-γ IL-2 Th1 IL-12 TNF Secukinumab (bound to IL-17A) Tissue inflammation and pathogen defense Tissue inflammation and pathogen defense Secukinumab is a Fully Human Monoclonal Antibody that Selectively Binds to and Prevents IL-17A Binding to its Receptor Inhibiting Production of Pro-inflammatory Mediators Target tissue cell membrane IL-17A receptor Neutralization of IL-17A rapidly inhibits downstream inflammatory cytokine and chemokine networks and thus may be useful for the treatment of several immune-mediated diseases IL-17A neutralized by secukinumab IL-17F IL-21 IL-22 IL-17A Th17 IL-23 Mast cells Other leukocytes Selective inhibition of IL-17A may be associated with preservation of normal components of the host immune response Dendritic cells

CONCLUSIONS: IL-17A IS A KEY CYTOKINE IN THE PATHOGENESIS OF SPA IL-17A is the main proinflammatory cytokine expressed by Th17 cells Evidence for the role of IL-17A in SpA comes from genetic, pathophysiologic, human expression, and animal studies IL-17A has been implicated in chronic inflammation, psoriasis, bone erosion, bone proliferation, and enthesitis IL-17A offers a rational target for treatment of SpA at the point of maximal specificity for inhibition of the IL-17 pathway