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November 2012
PRINTER-FRIENDLY VERSION AT RHEUMATOLOGYPRACTICENEWS.COM
Rheumatology Practice News SPECIAL EDITION SOUMYA D. CHAKRAVARTY, MD, PHD
Fellow in Rheumatology, Hospital for Special Surgery; Clinical Fellow in Medicine, Weill Cornell Medical College, New York, New York All rights r
STEPHEN A. PAGET, MD, FACP, FACR
Copyright 2012 McMahon Publishing Gr
Physician-in-Chief Emeritus, Department of Medicine, Division of Rheumatology, Hospital for Special Surgery; Professor of Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York eserved. Repr
Dr. Paget has served as an advisor or consultant for Crescendo Bioscience, Inc., and Medscape. Dr. Chakravarty reported no relevant financial conflicts. Ankylosing spondylitis (AS) is a term derived oduction in whole or in part without permission is pr
from the Greek roots ankylos or “bent” (modern implications being fusion or adhesions), and spondylos or “vertebral disk.” A chronic inflammatory disease, AS predominantly affects the axial skeleton, specifically the spine and sacroiliac joints. It is the classic prototypical member of a large and broader oup unless otherwise noted.
family of disease states termed spondyloarthritides (SpA), which include psoriatic arthritis, reactive arthritis, spondylitis and arthritis associated with inflammatory bowel disease, and undifferentiated SpA. eral clinical and genetic features, sive cumulative joint damage, defor- among them being axial skeletal mity, extraarticular manifestations, cess driven by the activity of T or B ric oligoarthritis with dactylitis and cause. ohibited. xamining disease concor-
ifestations, such as anterior uveitis; Pathogenesis of AS
AS is known to be a chronic immunologic disorders, in which genetic association with AS is that of HLA-B27. In particular, AS is gen- immune-mediated inflammatory a hereditary component (such as of HLA-B27, with its association first young adulthood between ages 20 gin remains to be fully elucidated. matory response appear to propel overall contribution to the herita-and 30 years, with men being slightly Initially, the identification of HLA- B27 as a factor in the development and 10 years.2 Understanding the dominance, or an association with geting T-cell co-stimulation using role for autoreactive CD8-positive underlying pathogenesis of AS, iden- disease-specific autoantibodies. abatacept (Orencia, Bristol-Myers T cells. In this model, an “arthrito- tifying its clinical features early in the ing early, aggressive therapy may be driven primarily by an innate Genentech), an anti-CD20 monoclo- immune response triggered by nal antibody used in the treatment November 2012
Rheumatology Practice News SPECIAL EDITION Table 1. ASAS
HLA-B27), roles played by other pro- Classification Criteria
teins such as E-cadherin and α E/β7 having demonstrated sacroiliitis on For Axial SpA
Sacroiliitis on imaging plus 1 or
more SpA feature
OR
Classification of Disease
HLA-B27-positive plus 2 or
more SpA features
AS typically are used for research SpA.26 SpA features:
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become incorporated into clinical cohort of patients (where the pre- practice. The modified New York test probability of having axial SpA Copyright 2012 McMahon Publishing Gr
are the most widespread. Under a sensitivity of 82.9% and specific- eserved. Repr
HLA-B27 with AS, less than 1 in 20 HLA-B27-positive individuals will met.24 The clinical criteria include purposes in clinical practice, in the nal mobility, and restricted chest they may help physicians make an oduction in whole or in part without permission is pr
likelihood of a HLA-B27-positive car- Unfortunately, the mNY criteria festations of SpA only (but that later tions. One of these, ERAP1 (endoplas- ASAS, Assessment of SpondyloArthritis
international Society; CRP, C-reactive
protein; NSAID, nonsteroidal anti-inflam-
matory drug; SpA, spondyloarthritides
endoplasmic reticulum. ERAP1 serves clinically relevant features, and an dactylitis plus (a) 1 or more of the emphasis on restrictions in spine following—psoriasis, IBD, anteced- mobility and chest expansion that ent inf oup unless otherwise noted. ection, HLA-B27, uveitis, sac-
Clinical Features and Diagnosis
suggests that dysfunctional antigen has considerable heterogeneity but following: inflammatory back pain, graphic disease often lags behind SpA.27 Another contributor appears oligoarthritis of the lower extrem- to be the interleukin (IL)-17–IL-23 ities predominantly, dactylitis, by as much as 10 years.25 There- Imaging in AS
extraarticular manifestations such classifying definite cases of AS but receptor (IL-23R) gene associated as apical pulmonary fibrosis, aor- tic insufficiency, heart block, uveitis, sis and IBD.16-18 IL12B, which encodes To better enable clinicians in with AS. Indeed, the presence of component of the IL-12 and IL-23 to a well-established paradigm of identifying those patients with early ohibited.
receptors, also has been linked to the “joint-gut axis,” with prevalence It should be noted that more ranging from 16% to 33% and involve- express HLA-B27.20 These patients a feature of SpA in about 70% of oped classification criteria for axial generally have clinical symptoms patients (7% to 12% of patients with SpA—which encompasses patients the annulus fibrosus (the Sharpey’s similar to those who are positive SpA develop overt IBD over the long with chronic back pain who have fibers), also can be seen on spine for HLA-B27, except for a later age tion with any HLA gene has been IBD, with a much larger number of history, and responsiveness to non- steroidal anti-inflammatory drugs sions and sclerosis. Coupled with patients with AS, although IL-23R and IL-12B have been found to be copy or by histologic findings.23 A The criteria can be fulfilled damage before detection of disease, shared etiology between IBD and through 1 of 2 pathways: by imag- tive of a patient’s HLA-B27 status, SpA (including idiopathic AS) is ing or clinical, although both require thought to exist and includes the the presence of chronic back pain iac joints and spine increasingly has presence of the HLA-B27 gene (25% (≥3 months) and onset of symptoms been adopted to evaluate patients November 2012
Rheumatology Practice News SPECIAL EDITION Table 2. BASDAI
Each of the following rated by
the patient on a scale of 0 to 10:
Treatment of AS
over the years, beginning with a trial of 2 or more NSAIDs over All rights r
sists despite NSAID therapy—as measured by an elevated Copyright 2012 McMahon Publishing Gr
scores from 1 to 4) + (Sum of scores from 5 to 6)/2 Figure 1. Pelvic radiographs demonstrating varying stages of sacroiliitis. A. Mild
BASDAI, Bath Ankylosing Spondylitis
eserved. Repr
irregularity in both sacroiliac joints with minimal subcortical sclerosis and slight subligamentous erosive change on the right. B. Fusion of the sacroiliac joints, as well as bridging syndesmophytes in the lower lumbar spine. apy.34,35 Of note, nonbiologic disease-modifying antirheu- who are thought to have clinically Accurate quantification also empow- matic drugs (DMARDs), such been extended to establishing effi- ers the clinician to assess response as methotrexate, sulfasalazine, and cacy in nonradiographic axial SpA oduction in whole or in part without permission is pr
radiographs would otherwise be to current therapy and determine leflunomide, have not proven effica- patients. In the first such clinical trial, axial inflammation compared with used, the most common being the infliximab (Remicade, Centocor), for 12 weeks, followed by an open- MRI sequences, the fluid-sensitive ease Activity Index (BASDAI). This etanercept (Enbrel, Amgen/Pfizer), label extension that continued up to short-tau inversion recovery (STIR) straightforward scoring system is adalimumab (Humira, Abbott Labo- patient-driven and consists of 6 ratories), and golimumab (Simponi, oup unless otherwise noted.
TNF agents in axial SpA first was (P=0.004). After switching to adali- demonstrated in studies enrolling mumab, a similar degree of efficacy ered the most significant finding score has a range of 0 to 10, with a of active inflammation in AS, and score of 4 or greater indicating high ohibited.
treated patients (P=0.033).37 Signif-icantly more lesions resolved in the Assessment of Disease
infliximab group (P<0.001), whereas Activity in AS
Figure 2. MRI (T2-weighted imaging) showing osseous fusion of the
imaged portions of the sacroiliac joints bilaterally, reflecting bony ankylo- sis. Black arrows indicate bone marrow edema, reflecting ongoing active November 2012
Rheumatology Practice News SPECIAL EDITION Table 3. Current Therapeutic Recommendations in AS
(with fulfillment of the ASAS criteria for axial SpA)
kopf-1 (DKK-1), an inhibitor of the Wnt DKK-1 has been associated with higher with osteopenia.48 DKK-1 has been All rights r
Copyright 2012 McMahon Publishing Gr
AS, ankylosing spondylitis; ASAS, Assessment of SpondyloArthritis international Society;
BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; COX, cyclooxygenase;
DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor
eserved. Repr
48 was significantly larger (P=0.02) Predicting Response
oduction in whole or in part without permission is pr
some specific positive predictors of after 3 months of therapy.50 Serum response to treatment. The first is short levels of DKK-1 were significantly between baseline and 48 weeks, years for all treatment groups.39 controls (P<0.0001), whereas lev- 10 years have had better responses els of osteocalcin and osteopro- in the sulfasalazine group (P=0.04), reduced spinal inflammation of AS more than 10 years.42 Second, young (P<0.0001).50 However, serum lev- and 50% of patients treated with detected on MRI. Improvements were tor of good response—the highest after 3 months of anti-TNF therapy, oup unless otherwise noted. eas osteocalcin significantly
increased (P<0.0001) and osteopro- Recently published results from lowed by those in the 30- to 39-year- graphic and nonradiographic) are treatment of nonradiographic axial levels of DKK-1 in AS patients con- under way. Recently published SpA.41 The study included patients umab—A Randomized Study in teria for axial SpA, had a BASDAI of Ankylosing Spondylitis Subjects at least 4, a total back pain score of Another active area of current undergoing longer durations of anti- cacy and safety of golimumab in meeting mNY criteria for AS were spe- damage in patients with AS, with a explanation for the inability of anti- ohibited.
Patients were randomized to as spinal ankylosis has the highest of new bone despite tangible symp- with active AS were randomly either adalimumab 40 mg every effect on long-term spinal immobility and disability. It has been previously with AS.
tions of placebo, golimumab 50 cantly more patients in the adalim- weeks.39 After 16 weeks, patients weeks than those receiving placebo desmophytes, as measured by a scor- (36% vs 15%; P<0.001) and signifi- ing system termed the modified Stoke Ankylosing Spondylitis Spinal Score (if originally on placebo) or 100 mg (if ent protective effects of NSAIDs is appears to have no meaningful effi- sacroiliac joints on MRI significantly thought to be due not to their anti- concluded that adalimumab has a ity through the downregulation of imab and abatacept in AS also has progression in patients with AS has cacy of rituximab in patients with November 2012
Rheumatology Practice News SPECIAL EDITION NSAID-refractory AS who either 3. Burn GL, Svensson L, Sanchez-Blanco spondyloarthritis. Ann Rheum Dis. early sacroiliitis. Arthritis Rheum. 2009;60(4):946-954.
Dekker-Saeys AJ, Keat AC. Follow-up study for autoimmune disease? FEBS Lett. of ankylosing spondylitis over a period of 12 38. Song IH, Hermann K, Haibel H, et al. years (1977-1989). Scand J Rheumol Suppl. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active classifi cation of the immunological diseases. 22. Brakenhoff LK, van der Heijde DM, Hommes DW, Huizinga TW, Fidder HH. The joint-gut randomised controlled trial. Ann Rheum Dis. Song IH, Heldmann F, Rudwaleit M, et al. Treatment of active ankylosing spondylitis J Crohns Colitis. 2010;4(3):257-268.
with abatacept: an open-label, 24-week pilot 39. Braun J, Deodhar A, Inman RD, et al. study. Ann Rheum Dis. 2011;70(6):1108-1110.
spondylitis and bowel disease. Best Pract every 4 weeks in ankylosing spondylitis: Song IH, Heldmann F, Rudwaleit M, et al. Res Clin Rheumatol. 2006;20(3):451-471.
Different response to rituximab in tumor 24. van der Linden S, Valkenburg HA, Cats Ann Rheum Dis. 2012;71(5):661-667.
necrosis factor blocker-naive patients with A. Evaluation of diagnostic criteria for 40. Braun J, Baraliakos X, Hermann KG, et al. All rights r
active ankylosing spondylitis and in patients modifi cation of the New York criteria. Golimumab reduces spinal infl ammation in have failed: a twenty-four-week clinical trial. Arthritis Rheum. 1984;27(4):361-368.
ankylosing spondylitis: MRI results of the Copyright 2012 McMahon Publishing Gr
Arthritis Rheum. 2010;62(5):1290-1297.
25. Mau W, Zeidler H, Mau R, et al. Clinical study. Ann Rheum Dis. 2012;71(6):878-884.
possible ankylosing spondylitis. Results spondylitis in twins: the role of genes, HLA, of a 10-year followup. J Rheumatol. et al. Effi cacy and safety of adalimumab eserved. Repr
and the environment. Arthritis Rheum. spondyloarthritis: results of a randomised 26. Rudwaleit M, van der Heijde D, Landewe placebo-controlled trial (ABILITY-1). Ann Rheum Dis. 2012 Jul 7 [Epub ahead of print].
Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Society classifi cation criteria for axial 42. Rudwaleit M, Listing J, Brandt J, Braun Rheum Dis. 2000;59(11):883-886.
J, Sieper J. Prediction of a major clinical and fi nal selection. Ann Rheum Dis. of ankylosing spondylitis. Brief Funct oduction in whole or in part without permission is pr
ankylosing spondylitis. Ann Rheum Dis. Genomics. 2011;10(5):249-257.
27. Rudwaleit M, van der Heijde D, Landewe R, et al. The Assessment of SpondyloArthritis Hermann E, Yu DT, Meyer zum Buschenfelde 43. Wanders A, Heijde D, Landewe R, et al. KH, Fleischer B. HLA-B27-restricted CD8 T International Society classifi cation criteria Nonsteroidal antiinfl ammatory drugs reduce cells derived from synovial fl uids of patients for peripheral spondyloarthritis and for radiographic progression in patients with spondyloarthritis in general. Ann Rheum Dis. 2011;70(1):25-31.
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May E, Dorris ML, Satumtira N, et al. CD8 Maksymowych WP. The impact of MRI on the Prostaglandins in bone: bad cop, good cop? the pathogenesis of arthritis or colitis clinical management of infl ammatory arthritides. Skeletal Radiol. 2011;40(9):1153- Trends Endocrinol Metab. 2010;21(5):294- in HLA-B27 transgenic rats. J Immunol. 45. van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic fi ndings following two utility of MRI in early spondyloarthritis. Curr oup unless otherwise noted.
Rheumatol Rep. 2011;13(5):402-408.
years of infl iximab therapy in patients with beta2-microglobulin-transgenic rats is not ankylosing spondylitis. Arthritis Rheum. prevented by lack of CD8. Arthritis Rheum. Sieper J, Schöntube M, Braun J. Very early 46. van der Heijde D, Landewe R, Einstein S, et spondyloarthritis: where the infl ammation in Conclusion
al. Radiographic progression of ankylosing the sacroiliac joints starts. Arthritis Rheum. treatment with etanercept. Arthritis Rheum. response augment interleukin-23 production in transgenic rats. Arthritis Rheum. 47. van der Heijde D, Salonen D, Weissman in sacroiliac joints enhances diagnostic utility of magnetic resonance imaging in with ankylosing spondylitis treated with Jongh BM, Cats A. The risk of developing early spondylarthritis. Arthritis Care Res. 2010;62(12):1763-1771.
adalimumab for up to 2 years. Arthritis Res ankylosing spondylitis in HLA-B27 positive Ther. 2009;11(4):R127.
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is it the main switch controlling bone and joint remodeling? Semin Arthritis Rheum. Yan J, Parekh VV, Mendez-Fernandez Y, et ohibited.
al. In vivo role of ER-associated peptidase approach to defi ning disease status in 49. Uderhardt S, Diarra D, Katzenbeisser J, et activity in tailoring peptides for presentation ankylosing spondylitis: the Bath Ankylosing by MHC class Ia and class Ib molecules. J al. Blockade of Dickkopf (DKK)-1 induces Exp Med. 2006;203(3):647-659.
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fusion of sacroiliac joints. Ann Rheum Dis. 34. Braun J, van den Berg R, Baraliakos X, 50. Kwon SR, Lim MJ, Suh CH, et al. Dickkopf-1 level is lower in patients with ankylosing identifi es autoimmunity variants. Nat Genet. of ankylosing spondylitis. Ann Rheum Dis. spondylitis than in healthy people and is not infl uenced by anti-tumor necrosis factor therapy. Rheumatol Int. 2012;32(8):2523- 35. van der Heijde D, Sieper J, Maksymowych WP, et al. 2010 Update of the international Haibel H, Rudwaleit M, Listing J, Sieper identifi cation of IL23R as psoriasis-risk J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann spondyloarthritis. Ann Rheum Dis. Rheum Dis. 2005;64(2):296-298.
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