Ankylosing Spondylitis. DR. Milt Baker SEA Courses 2017

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1 Ankylosing Spondylitis DR. Milt Baker SEA Courses 2017

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Antiquity

4 Inflammatory Back Pain 1. AM stiffness > 30 min. 2. Night pain- tossing and turning. 3. Can t sit long. Has to get up and move around. Better to move than sit still.

5 Modified New York Criteria for Ankylosing Spondylitis Limitation of motion in the lumbar spine in both the sagittal and frontal planes Limitation of chest expansion relative to normal values corrected to age and sex Low back pain and stiffness greater than three months duration and not relieved by rest

6 Two Radiographic Criteria for Ankylosing Spondylitis Sacroilitis with more than minimal abnormality bilaterally Sacroilitis of unequivocal abnormality unilaterally

7 Definite, as is considered to be present with one radiological criteria associated with one clinical criteria. Probable, as if three clinical criteria are present or if one of the radiographic criteria is present without signs or symptoms satisfying clinical criteria.

9 Sacroiliitis Grade 2 Right, Grade 3 Left

13 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: (with permission)

15 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

16 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

22 Extra-articular Manifesations (EAMS) Enthesitis- ie.achilles tendonitis, Plantar fasciitis. Dactylitis- fingers, toes. Inflammatory bowel disease- up to 60% of AS. patients may have pos. biopsy evidence or positive fecal calprotectins.

23 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.

24 Physical activity, Exercise Fundamental requirement for AS Patients. Range of Motion exercises for entire spine, large joints, and then small joints done once or twice daily. Yoga or swimming, or Tai Chi. No impact loading. Can provide up to half the improvement. Wt. loss, stop smoking. Observe for Cardiovascular health

25 NSAIDS Fallen out of favor? Safety concerns. Still very effective if tolerated. Continous use vs. intermittent use. Double-Blind study proved Celebrex effective in slowing progression in AS. Ensure G-I tolerability and safety. Ensure normal renal function and no appreciable change in BP. Heterogeneity of response to different Nsaids.

26 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.

27 Sulfasalazine - 3 doubleblind placebo-controlled trials with 36 month follow-up period Was effective in reactive arthritis and psoriatic arthritis but less so in A.S. axial arthritis. Pts. had long term disease, >18 yrs. 2000mg/day well tolerated, effective. Have been 2 trials in recent years, primarily biologic trials, that used Sulfasalazine as one of the controls, unexpectantly showed significant improvement. Methotrexate no double-blind controlled trials. Open label mg/week. 17 pts., all had prompt response to axial symptoms

AS -DMARDS Methotrexate is felt to be effective to some degree for the peripheral joint disease of AS, although there are no studies that confirm this.

28 AS -DMARDS Methotrexate is felt to be effective to some degree for the peripheral joint disease of AS, although there are no studies that confirm this. Clinical experience tells us this. It is not felt that Methotrexate has much effect on axial disease. A few studies have shown no significant effect.

29 Sulfasalazine Start with low dose, slowly escalating from 500 mg,/day up to 3-4 Gm. S/E- G-I upset, headaches, rash. Monitor Hg & LFts only q 3 months. Improvement over 1-3 months.

30 Methotrexate Oral or sub-cut. Doses up to 25 mg./wk. Parenteral form is 20-30% more effective and comparably less S/E. Studies show benefit in peripheral involvement only, but not yet done in undifferentiated spondyloarthropathy. LFTs and CBC done monthly.

31 Biologic Therapy Infliximab, Entanercept, adalimumab- All have been shown to be approx. equally effective in AS. 80% respond. 50 % get 50% improvement. As measured by pain and Functional ability scores. Effective even in patients of 10 or 20 years duration of disease.

32 TNF Inhibitors Infliximab- chimeric mouse-human monoclonal anti- TNF. Etanercept- soluble TNF receptor blocker. Adalimumab- humanized anti-tnf therapy All of the above agents have extensive studies confirming efficacy in AS. Golimimab- high affinity human anti-tnf. Certiluzimab- PEGylated Fab of a humanized anti-tnf alpha Mab.

33 Anti-TNF Agents All 5 Anti-TNF agents have extensive doubleblind control Studies that show marked efficacy in PSA and AS. Pharmacare has approved all these agents Humira, Remicade, and Enbrel, Simponi, and Cimzia, now for AS, and Psoriatic arthritis. BASDAI is the important evaluation of patients functional ability.

34 Susceptibility to Ankylosing Spondylitis is Associated with Polymorphisms in Genetic Loci Involved in IL-17A Signaling 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 Polymorphisms in IL-23R confers protection from ankylosing spondylitis through impairment of IL-17A production 2 Misfolding or aberrant homodimerization of HLA-B27 results in increased production of cytokines in the IL-17 pathway 3 HLA-B27, Human Leukocyte Antigen B27 1. Reveille JD. Nat Rev Rheumatol. 2012;8: ; 2. Burton PR, et al. Nat Genet. 2007;39: ; 3. Bowness P, et al. J Immunol. 2011;186:

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 Higher Levels of IL 17-Producing Cells in Facet Joints of Patients

35 Number of IL-17+ Cells Number of IL-17+ Cells/ HPF CD3+ T cells AA-1+ mast cells AS MPO+ cells CD15+ neutrophils Higher Levels of IL 17-Producing Cells in Facet Joints of Patients with AS Than Those With 60 Osteoarthritis CD3+ T cells Mononuclear 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 is a Fully Human

36 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 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 ovartis Pharma, AG; n A. Trends Pharmacol Sci. 2009;30: Secukinumab (bound to IL-17A) 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 Tissue inflammation and pathogen defense Tissue inflammation and pathogen defense 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

JAK Inhibitors Studies are now underway with at least 2 new JAK inhibitors in both Psoriatic arthritis and Ankylosing Spondylitis. These block predominately JAK1 and JAK 2.

37 JAK Inhibitors Studies are now underway with at least 2 new JAK inhibitors in both Psoriatic arthritis and Ankylosing Spondylitis. These block predominately JAK1 and JAK 2. ABT-494, Upadalumab- is now being studied in phase 3 studies. Tofacitinib- has been found to be effective in one phase 3 study in ankylosing Spondylitis, however Pfizer has dropped that program.

Concept of Spondyloarthritis (SpA)

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